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{ "abstract": "The authors report about a patient who was admitted after developing nausea, vomiting, change in vision and lethargy. She was on digoxin 250 mcg once daily among all her other medications in the wake of a recent stroke that was accompanied by atrial fibrillation (AF). Her digitalis levels shortly before and on admission were 3.4 and 2.9 ng/ml, respectively. Her admission rhythm was slowly conducted AF at an average of 35 bpm. After a careful assessment by the cardiology consultant in charge, she received Digibind infusion for a chronic digitalis toxicity with the digoxin immune Fab dose based on the formula recommended in the product literature.(3) A few days observation on the ward ensured that her resting heart rate rose to 65 bpm and that she did not need a pacemaker for a slow AF. Her functional status remained reasonably good as she enjoyed a satisfactory recovery postthrombolysis for her recent stroke.", "affiliations": "Cardiology Department, Broomfield Hospital, Chelmsford, Essex, UK. kkk181172@yahoo.com", "authors": "Kolev|Kolyu Kirov|KK|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D004071:Digitalis Glycosides; D007140:Immunoglobulin Fab Fragments; C050199:digoxin antibodies Fab fragments; D004077:Digoxin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2012()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000889:Anti-Arrhythmia Agents; D001281:Atrial Fibrillation; D002316:Cardiotonic Agents; D004071:Digitalis Glycosides; D004077:Digoxin; D005260:Female; D006339:Heart Rate; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D020521:Stroke", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "23008361", "pubdate": "2012-09-24", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "1997020;3800074;4715199", "title": "Digoxin--'a friend or foe'.", "title_normalized": "digoxin a friend or foe" }

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"activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BISOPROLOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BISOPROLOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ERYTHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERYTHROMYCIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020405", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACENOCOUMAROL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACENOCUMEROL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "INDAPAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDAPAMIDE SR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LISINOPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypersensitivity", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KOLEV K. DIGOXIN - ^A FRIEND OR FOE^. BMJ CASE REPORTS 2012 2012 SEP 24;.", "literaturereference_normalized": "digoxin a friend or foe", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20171120", "receivedate": "20171116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14193293, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "A 60-year-old woman was referred to our hospital because of gross hematuria, right lumbar pain and lower abdominal pain. Computed tomography (CT) scan revealed hydronephrosis of the right kidney, irregular bladder wall thickening at the right lateral and posterior portion and external iliac lymph node swelling of the right side. Laboratory data revealed disseminated intravascular coagulation syndrome (DIC) and eosinophilia. Because she developed a high fever that was caused by acute obstructive pyelonephritis of the right kidney, percutaneous nephrostomy was placed and the therapy for DIC was initiated. Pathological examination of transurethral resection of bladder tumor performed twice showed no malignancy but inflammatory infiltration of many eosinocytes, leading to the diagnosis of eosinophilic cystitis (EC). We considered the possibility of allergic reaction to the drugs she was taking as the etiology of EC and discontinued all drugs. Although eosinophilia was resolved afterward, she then developed brain infarction, followed by cerebral hemorrhage. She was transferred to a rehabilitation hospital for long-term care. CT scan that was performed 4 months after the initial presentation showed the resolution of hydronephrosis of the right kidney and external iliac lymph node swelling and the improvement of bladder wall thickness. Hydronephrosis of the right kidney has not recurred after removing the nephrostomy catheter. EC is a rare condition that could mimic an invasive bladder cancer. EC should be considered if bladder tumor is associated with eosinophilia. Therapeutic consideration for thromboembolic events should be made in patients with EC.", "affiliations": "The Department of Renal and Urologic Surgery, Asahikawa Medical University.;The Department of Renal and Urologic Surgery, Asahikawa Medical University.;The Department of Renal and Urologic Surgery, Asahikawa Medical University.;The Department of Urology, Kitasaito Hospital.;The Department of Urology, Asahikawa Rehabilitation Hospital.;The Department of Renal and Urologic Surgery, Asahikawa Medical University.", "authors": "Okazaki|Satoshi|S|;Hori|Jun-Ichi|J|;Kita|Masafumi|M|;Yamaguchi|Satoshi|S|;Kawakami|Norihiro|N|;Kakizaki|Hidehiro|H|", "chemical_list": null, "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0018-1994", "issue": "60(12)", "journal": "Hinyokika kiyo. Acta urologica Japonica", "keywords": null, "medline_ta": "Hinyokika Kiyo", "mesh_terms": "D003556:Cystitis; D003937:Diagnosis, Differential; D004211:Disseminated Intravascular Coagulation; D004802:Eosinophilia; D005260:Female; D006801:Humans; D008875:Middle Aged; D014057:Tomography, X-Ray Computed; D001749:Urinary Bladder Neoplasms", "nlm_unique_id": "0421145", "other_id": null, "pages": "635-9", "pmc": null, "pmid": "25602481", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A case of eosinophilic cystitis mimicking an invasive bladder cancer.", "title_normalized": "a case of eosinophilic cystitis mimicking an invasive bladder cancer" }

[ { "companynumb": "JP-TAKEDA-2015TJP001312", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TIQUIZIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THIATON" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LORATADINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SYRUP", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORATADINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLENBUTEROL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SPIROPENT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LANSOPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAKEPRON" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOXOPROFEN SODIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LOXONIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREGABALIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE, HARD", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LYRICA" } ], "patientagegroup": null, "patientonsetage": "60", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "50", "reaction": [ { "reactionmeddrapt": "Hydronephrosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral infarction", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Eosinophilic cystitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hydroureter", "reactionmeddraversionpt": "18.0", "reactionoutcome": null }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "18.0", "reactionoutcome": null } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201303" } }, "primarysource": { "literaturereference": "OKAZAKI S, HORI J, KITA M, YAMAGUCHI S, YAMAGAMI N, KAKISAKI H. A CASE OF EOSINOPHILIC CYSTITIS MIMICKING AN INVASIVE BLADDER CANCER. HINYOKI KIYO. 2014;60(12):635-639", "literaturereference_normalized": "a case of eosinophilic cystitis mimicking an invasive bladder cancer", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150326", "receivedate": "20150130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10750566, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" }, { "companynumb": "JP-PFIZER INC-2015025930", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLENBUTEROL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": 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{ "abstract": "Hemorrhagic rupture is a very rare and life-threatening hepatic cyst complication. Several treatment methods have been used for hepatic cyst hemorrhage and/or rupture; however, transcatheter arterial embolization for hepatic cyst hemorrhage has been poorly documented. An 80-year-old man receiving dual antiplatelet therapy was diagnosed with hemorrhagic rupture of a hepatic cyst. Transcatheter arterial embolization using a coil was performed for A6 branch confirmed active extravasation. His condition improved promptly after treatment, and the hepatic cyst gradually became smaller as compared to the size before hemorrhage. Transcatheter arterial embolization is suitable for hepatic cyst hemorrhage and might be a minimally invasive treatment option for a symptomatic hepatic cyst.", "affiliations": "Department of surgery, Nagoya Tokushukai General Hospital, Kasugai City, Japan.;Department of surgery, Nagoya Tokushukai General Hospital, Kasugai City, Japan.;Department of surgery, Nagoya Tokushukai General Hospital, Kasugai City, Japan.;Department of surgery, Nagoya Tokushukai General Hospital, Kasugai City, Japan.;Department of surgery, Nagoya Tokushukai General Hospital, Kasugai City, Japan.", "authors": "Imagami|Toru|T|;Takayama|Satoru|S|;Maeda|Yohei|Y|;Sakamoto|Masaki|M|;Kani|Hisanori|H|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.radcr.2021.04.066", "fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433\nElsevier\n\nS1930-0433(21)00274-0\n10.1016/j.radcr.2021.04.066\nCase Report\nTranscatheter arterial embolization for hemorrhagic rupture of a simple hepatic cyst: A case report\nImagami Toru MD gamiyan49812@yahoo.co.jp\n⁎\nTakayama Satoru MD, PhD\nMaeda Yohei MD\nSakamoto Masaki MD, PhD\nKani Hisanori MD, PhD\nDepartment of surgery, Nagoya Tokushukai General Hospital, Kasugai City, Japan\n⁎ Corresponding author. gamiyan49812@yahoo.co.jp\n08 6 2021\n8 2021\n08 6 2021\n16 8 19561960\n15 4 2021\n26 4 2021\n27 4 2021\n© 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHemorrhagic rupture is a very rare and life-threatening hepatic cyst complication. Several treatment methods have been used for hepatic cyst hemorrhage and/or rupture; however, transcatheter arterial embolization for hepatic cyst hemorrhage has been poorly documented. An 80-year-old man receiving dual antiplatelet therapy was diagnosed with hemorrhagic rupture of a hepatic cyst. Transcatheter arterial embolization using a coil was performed for A6 branch confirmed active extravasation. His condition improved promptly after treatment, and the hepatic cyst gradually became smaller as compared to the size before hemorrhage. Transcatheter arterial embolization is suitable for hepatic cyst hemorrhage and might be a minimally invasive treatment option for a symptomatic hepatic cyst.\n\nKeywords\n\nHepatic cyst hemorrhage\nHemorrhagic rupture of hepatic cyst\nSymptomatic hepatic cyst\nTranscatheter arterial embolization\nInterventional radiology\n==== Body\nIntroduction\n\nA hepatic cyst is typically asymptomatic liver tumor; however, it can sometimes cause various complications such as intracystic hemorrhage (2%-5% of cases), infection (1% of cases), and rupture (very rare) [1]. Hemorrhagic rupture is a very rare and life-threatening hepatic cyst complication [2]. Currently, no definitive etiology has been confirmed for hepatic cyst hemorrhage [3]. Hepatic cyst rupture is generally associated with a large volume increase [1]. Several treatment methods have been used for hepatic cyst hemorrhage and/or rupture; however, there is no consensus on the optimal management strategy for a hepatic cyst hemorrhage [3]. Additionally, interventional radiology (IVR) for hepatic cyst hemorrhage has been poorly documented.\n\nHere, we performed IVR for hemorrhagic rupture of a hepatic cyst and successfully treated the condition with transcatheter arterial embolization (TAE). TAE for hemorrhagic rupture of a hepatic cyst is extremely rare; to the best our knowledge, this is the first report describing the clinical course of a simple hepatic cyst after TAE. In this report, we present our clinical experience and new findings with a review of the literature.\n\nCase report\n\nAn 80-year-old man was referred to the emergency department because of shivering and fever. His surgical history included coronary artery bypass grafting, aortic valve replacement, and femoral-popliteal artery bypass. He received dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Additionally, he received regular rehabilitation therapy for heart disease in our hospital's outpatient department.\n\nOn laboratory assessment, his hemoglobin level was low (7.5 g/dL). Abdominal computed tomography (CT) showed an enlarged, heterogeneous hepatic cyst (Fig. 1A). Two hours later, contrast-enhanced CT revealed active extravasation in the hepatic cyst (Fig. 1B and C). Ascites was found throughout the peritoneal cavity on contrast-enhanced CT (Fig. 2); however, it was not found on the initial abdominal CT. Based on these findings, he was diagnosed with hemorrhagic rupture of hepatic cyst with active bleeding.Fig. 1 The CT findings at the emergency department.\n\n(A) Abdominal CT showed an enlarged, heterogeneous hepatic cyst (88 × 63 mm in size).\n\n(B) Extravasation in the hepatic cyst was shown on contrast-enhanced CT in early phase.\n\n(C) Extravasation was found throughout the cyst on contrast-enhanced CT in late phase.\n\nFig1 –\n\nFig. 2 Contrast-enhanced CT revealed ascites in the entire abdominal cavity.\n\nFig 2 –\n\nThe patient was hemodynamically stable; therefore, we decided to perform IVR. The patient agreed with our decision to treatment. Under local anesthesia, the right femoral artery was cannulated using a 4-Fr long-sheath catheter. Hepatic arteriography was performed using a 4-Fr RH catheter, and selective angiography of the A6 branch confirmed active extravasation. TAE was performed using a coil (Azur 2 mm/2 cm, TERUMO). The findings of IVR are shown in Fig. 3. After TAE, the arterial flow in the A6 branch disappeared. The patient received 4 units of erythrocytes after IVR.Fig. 3 The findings of IVR.\n\n(A) Angiography from common hepatic artery showed slight extravasation (black arrow).\n\n(B) Selective angiography of the A6 branch confirmed active bleeding (black arrow).\n\n(C) Contrast agent spread in the hepatic cyst (black arrow). TAE was performed using coil.\n\nFig 3 –\n\nThe laboratory data showed an increased hemoglobin level 1 day after surgery, which indicated hemostasis. On contrast-enhanced CT, performed 5 day’s after surgery, extravasation in the hepatic cyst was not noted. On ultrasonography (US), the hemorrhagic hepatic cyst was recognized as a cyst with a distinct border and heterogeneous contents, similar to the CT findings. The patient's postoperative course was uneventful, and he was discharged 7 day’s after TAE.\n\nIn the outpatient department, we assessed the CT, and US findings for a hepatic cyst after TAE. On contrast-enhanced CT, the hepatic cyst gradually became smaller and homogeneous. Additionally, the hepatic cyst shrank 1 year after TAE when compared to the size before hemorrhage (Fig. 4). The patient is being followed through our hospital's outpatient department.Fig. 4 The clinical course of the hepatic cyst on contrast-enhanced CT findings.\n\n(A) A simple hepatic cyst (43 × 35 mm in size) was found 1.5 years before hemorrhage.\n\n(B) No active bleeding was shown 5 day's after TAE. The cyst (84 × 59 mm in size) was heterogeneous.\n\n(C) The hepatic cyst (50 × 43 mm in size) became homogeneous 3 months’ after TAE.\n\n(D) The hepatic cyst shrank 1 year after TAE when compared to the size before hemorrhage (27 × 21 mm in size).\n\nFig 4 –\n\nDiscussion\n\nHepatic cysts can be divided into the following 2 general categories: Congenital and acquired [4]. Congenital hepatic cysts include simple hepatic cysts and polycystic liver disease (PCLD) [5]. Regarding simple hepatic cysts hemorrhage etiology, it has been hypothesized that, under high intracystic pressure, the cyst's epithelial lining undergoes necrosis and sloughing, injuring fragile blood vessels in the cystic wall and leading to intracystic hemorrhage [3,6,7]. Intracystic bleeding increases the tension inside the cyst and causes rupture with shock [8].\n\nFor a symptomatic simple hepatic cyst, conservative management, percutaneous drainage, sclerotherapy, surgical fenestration, and liver resection are common treatment options. More recently, minimally invasive therapeutic approaches have played increasing roles in managing cystic diseases of the liver [9]. In most centers, sclerotherapy is attempted first as a noninvasive option, and laparoscopic fenestration is usually indicated in refractory cases [10]. Currently, TAE is not performed for a symptomatic simple hepatic cyst. This is the first report of successful TAE for simple hepatic cyst hemorrhage rupture.\n\nAccording to a review article on managing a bleeding liver tumor, when active bleeding is visualized, TAE is recommended over surgery unless there is severe hemodynamic instability [11]. In trauma practice guidelines, TAE is recommended for hemodynamically stable patients with evidence of active extravasation on imaging [12]. From these findings in other fields, the management strategy in our case is considered optimal. Our patient received DAPT, leading to a high risk of surgical complications such as intraoperative bleeding. Thus, TAE appears to have advantages over emergency surgery.\n\nHemorrhagic rupture of a hepatic cyst is a fatal condition. Imaoka et al. reported that 6 of 7 hepatic cyst rupture cases with intracystic bleeding required emergency surgery [8]. Marion et al. reported that 6 patients with hemorrhagic rupture of a hepatic cyst presented with hemodynamic decompensation, causing death in 3 patients [1]. In this case, hemorrhagic rupture of a hepatic cyst was successfully treated by TAE without hemodynamic failure. On the other hand, if there is no active extravasation on angiography, it may be difficult to select the treatment method. Ishikawa et al. reported on hepatic cyst hemorrhage with no active extravasation at the time of angiography [13]. They performed TAE for the peripheral vessels of a huge hepatic cyst suspected to be associated with bleeding; however, surgery was required later. The applicable circumstances may be limited, and TAE for hepatic cyst hemorrhage requires more cases and further discussion.\n\nThe incidence rate of a hepatic cyst increases with age. Tenja reported that the overall prevalence rate was 5.81% and that the rates were 20.30% at the age of 50 years, 28.39% at the age of 60 years, and 38.46% at the age of more than 70 years [14]. It has been reported that anticoagulant or antiplatelet therapy does not appear to increase the risk of bleeding from liver tumors [11]. In contrast, there are some cases of hemorrhagic rupture of hepatic cysts with anticoagulation therapy, including our case [2,15,16]. Hepatic cyst hemorrhage may become severe in patients who receive anticoagulant or antiplatelet therapy. Given the future aging society, the number of elderly people with hepatic cysts and antithrombotic agent therapy is expected to increase [3,17], which may lead to more occurrences of hepatic cyst hemorrhage.\n\nThe distinction between hemorrhagic simple hepatic cysts and hepatobiliary cystic neoplasms can be difficult because both lesions have intracystic structures [5,6,13]. In hepatic cyst hemorrhage, US clearly shows intracystic blood clots as papillary, nodular tumorous or irregular septal images, whereas CT cannot demonstrate intracystic blood clots [18]. Discordance between US and CT findings has been proposed as an important element for diagnosing hepatic cyst hemorrhage vs hepatobiliary cystic neoplasm [3,18]. In the present case, identifying active extravasation on contrast-enhanced CT resulted in the diagnosis of hepatic cyst hemorrhage. On contrast-enhanced CT performed 5 day’s after TAE, the contrast effect of the hepatic cyst was not recognized. According to the experience of this case, if improvement is not obtained promptly, the image diagnosis must be reevaluated for the possibility of a cystic tumor. Magnetic resonance imaging (MRI) may help differentiate intracystic hemorrhage from other cystic lesions [19,20], because MRI images clearly show the morphologic features of blood clots in the cyst [18]. Repeated observation with CT or US is recommended as the most reliable method for distinguishing intracystic hemorrhage from a cystic neoplasm [19].\n\nOur patient underwent repeated observation with CT and US as an outpatient. During outpatient follow-up after TAE, the hepatic cyst gradually reduced in size. To our knowledge, no report has described the course of a simple hepatic cyst following TAE. In limited facilities, TAE has become an accepted treatment option for patients with symptomatic PCLD [21]. In cystic lesions, almost all hepatic arterial branches are well developed, and they predominate over portal vein branches [22]. Therefore, TAE of hepatic artery branches that supply major hepatic cysts causes the cysts to shrink [23]. We hypothesized that a simple hepatic cyst is also artery dominant and that TAE shrinks the cyst by the same mechanism as in PCLD cases.\n\nBasil et al. reported that radiologic drainage is reserved for a hepatic cyst in the posterior segment, where access with laparoscopy may be limited [9]. On the other hand, TAE is not restricted in any segment. Therefore, TAE might be an option for cases that surgical approach is difficult.\n\nIn summary, hemorrhagic rupture of a simple hepatic cyst was treated successfully with TAE. The hepatic cyst size reduced after TAE. In a future aging society, the incidence of hepatic cyst hemorrhage may increase, and various treatment options will be required. TAE might be a versatile and minimally invasive treatment option for hemorrhagic rupture of a hepatic cyst. Further discussion of appropriate TAE for a symptomatic simple hepatic cyst is necessary while referring to PCLD cases.\n\nPatient consent\n\nThe written informed consent was obtained for publication.\n\nCompeting Interests: The authors have no conflict of interest to declare.\n==== Refs\nReference\n\n1 Marion Y. Brevartt C. Plard L. Chiche L Hemorrhagic liver cyst rupture: an unusual life-threatening complication of hepatic cyst and literature review Ann Hepatol. 12 2 2013 336 339 23396748\n2 Simon T. Bakker I.S. Penninga L. Nellensteijin D.R. Haemorrhagic rupture of hepatic simple cysts BMJ Case Rep. 2015 2015 10.1136/bcr-2014-208676\n3 Fong Z.V. Wolf A.M. Doria C. Berger A.C. Rosato E.L. Falazzo F. Hemorrhagic hepatic cyst: report of a case and review of the literature with emphasis on clinical approach and management J Gastrointest Surg. 16 9 2012 1782 1789 22688416\n4 Cowles R.A. Mulholland M.W Solitary hepatic cysts J Am Coll Surg. 191 3 2000 311 321 10989905\n5 Zhang Y.L. Yuan L. Shen F. Wang Y Hemorrhagic hepatic cysts mimicking biliary cystadenoma World J Gastroenterol. 15 36 2009 4601 4603 19777623\n6 Takahashi G. Yoshida H. Mamada Y. Taniai N. Bando K. Tajiri T. Intracystic hemorrhage of a large simple hepatic cyst J Nippon Med Sch. 75 5 2008 302 305 19023172\n7 GAVISER D Solitary nonparasitic cysts of the liver Minn Med. 36 8 1953 831 836 13086878\n8 Imaoka Y. Ohira M. Kobayashi T. Shimizu S. Tahara H. Kuroda S. Elective laparoscopic deroofing to treat the spontaneous rupture of a large simple liver cyst: a case report Surg Case Rep. 2 1 2016 148 27928780\n9 Ammori B.J. Jenkins B.L. Lim P.C. Prasad K.P. Pollad S.G. Lodge J.Peter A Surgical strategy for cystic diseases of the liver in a western hepatobiliary center World J Surg. 26 4 2002 462 469 11910481\n10 Macedo F.I Current management of noninfectious hepatic cystic lesions: A review of the literature World J Hepatol. 5 9 2013 462 469 24073297\n11 Darnis B. Rode A. Mohkam K. Ducerf C. Mabrut J.Y. Management of bleeding liver tumors J Visc Surg. 151 5 2014 365 375 24950941\n12 Stassen N.A. Bhullar I. Cheng J.D. Crandall M. Friese R. Guillamondegui O Nonoperative management of blunt hepatic injury: an Eastern association for the surgery of trauma practice management guideline J Trauma Acute Care Surg. 73 5 Suppl 4 2012; S288 S293 23114483\n13 Ishikawa H. Uchida S. Yokokura Y. Iwasaki Y. Horiuchi H. Hiraki M. Nonparasitic solitary huge liver cysts causing intracystic hemorrhage or obstructive jaundice J Hepatobiliary Pancreat Surg. 9 6 2002 764 768 12658414\n14 Kaltenbach T.E. Engler P. Kratzer W. Oeztuerk S. Seufferlein T. Haenle M.M. Prevalence of benign focal liver lesions: ultrasound investigation of 45,319 hospital patients Abdom Radiol (NY) 41 1 2016 25 32 26830608\n15 Wang S.H. Liu C.H. Lin Y.P. Chang W.K. Hypovolemic shock caused by a ruptured hemorrhagic hepatic cyst J Emerg Med. 49 3 2015 e93 e94 25934380\n16 Carels R.A. van Bommel E.F Ruptured giant liver cyst: a rare cause of acute abdomen in a haemodialysis patient with autosomal dominant polycystic kidney disease Neth J Med. 60 9 2002 363 365 12572709\n17 Bhatt D.L. Scheiman J. Abraham N.S. Antman F.M Chan Francis.K.L Furberg C.D ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents J Am Coll Cardiol. 52 18 2008 1502 1517 19017521\n18 Kitajima Y. Okayama Y. Hirai M. Hayashi H Imai H Okamoto T Intracystic hemorrhage of a simple liver cyst mimicking a biliary cystadenocarcinoma J Gastroenterol. 38 2 2003 190 193 12640536\n19 Yamaguchi M. Kuzume M. Matsumoto T. Matsumiya A. Nakano H. Kumada K. Spontaneous rupture of a nonparasitic liver cyst complicated by intracystic hemorrhage J Gastroenterol. 34 5 1999 645 648 10535497\n20 Vilgrain V. Silbermann O. Benhamou J.P. Nahum H. MR imaging in intracystic hemorrhage of simple hepatic cysts Abdom Imaging 18 2 1993 164 167 8439758\n21 Zhang J.L. Yuan K. Wang M.Q. Yan J.Y Xin H.N. Wang Y. Transarterial Embolization for Treatment of Symptomatic Polycystic Liver Disease: More than 2-year Follow-up Chin Med J (Engl) 130 16 2017 1938 1944 28776546\n22 Takei R. Ubara Y. Hoshino J. Higa Y. Sawabe T. Sogawa Y. Percutaneous transcatheter hepatic artery embolization for liver cysts in autosomal dominant polycystic kidney disease Am J Kidney Dis. 49 6 2007 744 752 17533017\n23 Park H.C. Kim C.W. Ro H. Moon J.M Oh K.H. Kim Y. Transcatheter arterial embolization therapy for a massive polycystic liver in autosomal dominant polycystic kidney disease patients J Korean Med Sci. 24 1 2009 57 61 19270814\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1930-0433", "issue": "16(8)", "journal": "Radiology case reports", "keywords": "Hemorrhagic rupture of hepatic cyst; Hepatic cyst hemorrhage; Interventional radiology; Symptomatic hepatic cyst; Transcatheter arterial embolization", "medline_ta": "Radiol Case Rep", "mesh_terms": null, "nlm_unique_id": "101467888", "other_id": null, "pages": "1956-1960", "pmc": null, "pmid": "34149982", "pubdate": "2021-08", "publication_types": "D002363:Case Reports", "references": "26830608;12640536;25934380;13086878;24950941;10535497;28776546;19777623;24073297;12658414;17533017;22688416;19023172;11910481;8439758;10989905;23114483;19270814;27928780;12572709;25697302;19017521;23396748", "title": "Transcatheter arterial embolization for hemorrhagic rupture of a simple hepatic cyst: A case report.", "title_normalized": "transcatheter arterial embolization for hemorrhagic rupture of a simple hepatic cyst a case report" }

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Transcatheter arterial embolization for hemorrhagic rupture of a simple hepatic cyst: A case report. Radiol-Case-Rep 2021;16(8):1956-1960.", "literaturereference_normalized": "transcatheter arterial embolization for hemorrhagic rupture of a simple hepatic cyst a case report", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220630", "receivedate": "20220614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20959087, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20220721" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-339755", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90494", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antiplatelet therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antiplatelet therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic cyst ruptured", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "Imagami T, Takayama S, Maeda Y, Sakamoto M, Kani H. Transcatheter arterial embolization for hemorrhagic rupture of a simple hepatic cyst: A case report. Radiol Case Rep. 2021;16(8):1956-1960", "literaturereference_normalized": "transcatheter arterial embolization for hemorrhagic rupture of a simple hepatic cyst a case report", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220609", "receivedate": "20220609", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20935373, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]

{ "abstract": "We report a 42-year-old female who presented with retrosternal pain, dyspnoea and nausea. Electrocardiography suggested a recent anterior myocardial infarction. However, emergency coronary angiography showed normal blood flow through all the coronary arteries. Paroxysmal hypertension raised the suspicion of a pheochromocytoma. Indeed, abdominal ultrasonography and computed tomography revealed a mass in the left adrenal gland. Elevated levels of plasma and urine catecholamines supported the diagnosis of pheochromocytoma. Left adrenalectomy was performed without complications and pathological examination revealed a 5.5 cm pheochromocytoma. After surgery, all antihypertensive medication was discontinued and the blood pressure returned to normal within several days. Currently, the patient is asymptomatic, has normal catecholamine levels and the electrocardiographic signs of ischaemia have resolved entirely. This case illustrates that a rare clinical entity such as pheochromocytoma should be considered in the differential diagnosis of acute coronary syndrome. (Neth Heart J 2007;15:248-51.).", "affiliations": "Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.", "authors": "Menke-van der Houven van Oordt|C W|CW|;Twickler|Th B|TB|;van Asperdt|F G M H|FG|;Ackermans|P|P|;Timmers|H J L M|HJ|;Hermus|A R R M|AR|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1007/BF03085991", "fulltext": null, "fulltext_license": null, "issn_linking": "1568-5888", "issue": "15(7-8)", "journal": "Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation", "keywords": "Q wave; myocardial infarction; pheochromocytoma", "medline_ta": "Neth Heart J", "mesh_terms": null, "nlm_unique_id": "101095458", "other_id": null, "pages": "248-51", "pmc": null, "pmid": "17923879", "pubdate": "2007", "publication_types": "D016428:Journal Article", "references": "16855135;16492700;12074275;9088853;16112304;9623219;11882600;11381579;6136843;14686578;17923879;15517048;15583228;10918553;15042254;15558925", "title": "Pheochromocytoma mimicking an acute myocardial infarction.", "title_normalized": "pheochromocytoma mimicking an acute myocardial infarction" }

[ { "companynumb": "NL-PFIZER INC-IDA-00102", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "016418", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "40 MG, 3X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TACHYCARDIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INDERAL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENOXYBENZAMINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOXYBENZAMINE" } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MENKE?VAN DER HOUVEN VAN OORDT, C.. PHEOCHROMOCYTOMA MIMICKING AN ACUTE MYOCARDIAL INFARCTION. NETHERLANDS HEART JOURNAL. 2007?15 (7):248?251", "literaturereference_normalized": "pheochromocytoma mimicking an acute myocardial infarction", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20210526", "receivedate": "20210526", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19309372, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis.", "affiliations": "Department of Neurology, Friedrich Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.;Neuroradiology Section, Friedrich Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.;Department of Nephrology, Friedrich Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.;Department of Neurology, Friedrich Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.;Department of Neurology, Friedrich Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.;Department of Neurology, Friedrich Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. Electronic address: de-hyung.lee@uk-erlangen.de.", "authors": "Sauer|Roland|R|;Gölitz|Philipp|P|;Jacobi|Johannes|J|;Schwab|Stefan|S|;Linker|Ralf A|RA|;Lee|De-Hyung|DH|", "chemical_list": "D000904:Antibiotics, Antitubercular; D007166:Immunosuppressive Agents; D004247:DNA; D009173:Mycophenolic Acid; D016559:Tacrolimus", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jns.2017.01.046", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-510X", "issue": "375()", "journal": "Journal of the neurological sciences", "keywords": "Immunosuppression; Mycophenolate mofetil; Outcome; Polyoma virus; Progressive multifocal leukoencephalopathy; Renal transplantation; Tacrolimus", "medline_ta": "J Neurol Sci", "mesh_terms": "D000328:Adult; D000904:Antibiotics, Antitubercular; D001933:Brain Stem; D004247:DNA; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007577:JC Virus; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D009173:Mycophenolic Acid; D016559:Tacrolimus", "nlm_unique_id": "0375403", "other_id": null, "pages": "76-79", "pmc": null, "pmid": "28320193", "pubdate": "2017-04-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient: Importance of early detection and rapid immune reconstitution.", "title_normalized": "good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient importance of early detection and rapid immune reconstitution" }

[ { "companynumb": "DE-STRIDES ARCOLAB LIMITED-2017SP003147", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, LOW DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "720 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "720", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "9 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dysphagia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nystagmus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dysarthria", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "JC virus infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pleocytosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningism", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SAUER R, GOLITZ P, JACOBI J, SCHWAB S, LINKER RA, LEE D-H. GOOD OUTCOME OF BRAIN STEM PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY IN AN IMMUNOSUPPRESSED RENAL TRANSPLANT PATIENT:IMPORTANCE OF EARLY DETECTION AND RAPID IMMUNE RECONSTITUTION. J-NEUROL-SCI. 2017;37576-37579", "literaturereference_normalized": "good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient importance of early detection and rapid immune reconstitution", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20170227", "receivedate": "20170227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13272236, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-ROCHE-1893609", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050722", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SAUER R, GOLITZ P, JACOBI J, SCHWAB S, LINKER R AND LEE D-H. GOOD OUTCOME OF BRAIN STEM PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY IN AN IMMUNOSUPPRESSED RENAL TRANSPLANT PATIENT: IMPORTANCE OF EARLY DETECTION AND RAPID IMMUNE RECONSTITUTION.. JOURNAL OF THE NEUROLOGICAL SCIENCES 2017;375:76-79.", "literaturereference_normalized": "good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient importance of early detection and rapid immune reconstitution", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170216", "receivedate": "20170216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13237736, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "DE-MYLANLABS-2017M1010339", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", 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"drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090596", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIAL TARGET LEVEL 10-12 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "720", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SAUER R, GOLITZ P, JACOBI J, SCHWAB S, LINKER RA, LEE D-H. GOOD OUTCOME OF BRAIN STEM PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY IN AN IMMUNOSUPPRESSED RENAL TRANSPLANT PATIENT: IMPORTANCE OF EARLY DETECTION AND RAPID IMMUNE RECONSTITUTION. J-NEUROL-SCI 2017;375:76-79.", "literaturereference_normalized": "good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient importance of early detection and rapid immune reconstitution", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20170223", "receivedate": "20170223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13266019, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "DE-TEVA-743423GER", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2000 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090402", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "18 MILLIGRAM DAILY; INITIAL TARGET LEVEL 10-12 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "9", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1440 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "720", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090402", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Immune reconstitution inflammatory syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SAUER R, GOLITZ P, JACOBI J, SCHWAB S, LINKER RA, LEE D-H. GOOD OUTCOME OF BRAIN STEM PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY IN AN IMMUNOSUPPRESSED RENAL TRANSPLANT PATIENT: IMPORTANCE OF EARLY DETECTION AND RAPID IMMUNE RECONSTITUTION. J-NEUROL-SCI 2017;375:76-79.", "literaturereference_normalized": "good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient importance of early detection and rapid immune reconstitution", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20170303", "receivedate": "20170303", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13292062, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "TR-ROCHE-1893609", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050722", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "SAUER R, GOLITZ P, JACOBI J, SCHWAB S, LINKER R AND LEE D-H. GOOD OUTCOME OF BRAIN STEM PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY IN AN IMMUNOSUPPRESSED RENAL TRANSPLANT PATIENT: IMPORTANCE OF EARLY DETECTION AND RAPID IMMUNE RECONSTITUTION.. JOURNAL OF THE NEUROLOGICAL SCIENCES 2017;375:76-79.", "literaturereference_normalized": "good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient importance of early detection and rapid immune reconstitution", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20170516", "receivedate": "20170516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13549241, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" } ]

{ "abstract": "A 67-year-old male patient presents to the hospital complaining of severe nausea and vomiting failing oral antiemetics. He carries the history of initial diagnosis of stage III prostate cancer. He underwent radical prostatectomy followed by external beam radiation. After 5 years of initial excellent control with androgen deprivation therapy (ADT), imaging study showed retroperitoneal adenopathy denoting ADT failure. His prostate-specific antigen continued to rise while on enzalutamide and then abiraterone reflecting disease progression. He maintained excellent functional capacity through 23 cycles of docetaxel however he started developing hip pain after the last cycle with imaging studies suggesting new hip metastatic disease. Following the first cycle of radium-223, the patient presented with intractable nausea and vomiting. MRI showed a high suspicion of leptomeningeal spread which was confirmed through a meningeal biopsy after lumbar puncture showed negative results. The patient had excellent symptomatic response to high-dose dexamethasone. After receiving whole-brain radiation, the patient opted to be on best supportive care and succumbed to his illness 3 months later.", "affiliations": "Division of Oncology/Hematology, Department of Internal Medicine, East Tennessee State University, Johnson City, Tennessee, USA.;Division of Oncology/Hematology, Department of Internal Medicine, East Tennessee State University, Johnson City, Tennessee, USA.;Department of Pathology, East Tennessee State University James H Quillen College of Medicine, Johnson City, Tennessee, USA.;Division of Oncology/Hematology, Department of Internal Medicine, East Tennessee State University, Johnson City, Tennessee, USA.", "authors": "Tawadros|Fady|F|;Manthri|Sukesh|S|;Zayko|Maria|M|;Chakraborty|Kanishka|K|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/bcr-2019-230922", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(9)", "journal": "BMJ case reports", "keywords": "oncology; urology", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms; D009325:Nausea; D010384:Pelvic Bones; D064129:Prostatic Neoplasms, Castration-Resistant; D018714:Radiotherapy, Adjuvant; D014839:Vomiting", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "31527212", "pubdate": "2019-09-16", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25601341;18830829;29949494;8137217;21989810;20888992;3765236;21424585;24132735;18182665;29436722;23863050;12711638;23292836;18591564;29313949;17857618;6895713;29420164;18811763;20818862;31123457;20473531;30763142", "title": "Leptomeningeal involvement by prostate carcinoma an ominous head of a well-known Hydra.", "title_normalized": "leptomeningeal involvement by prostate carcinoma an ominous head of a well known hydra" }

[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-227066", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "22534", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (75MG/M2) EVERY 3 WEEKS (23 CYCLES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hormone-refractory prostate cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hormone-refractory prostate cancer", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastatic neoplasm", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Prostatic specific antigen increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Tawadros F, Manthri S, Zayko M, Chakraborty K. Leptomeningeal involvement by prostate carcinoma an ominous head of a well-known Hydra. BMJ Case Rep. 2019;12(9):e230922 (1-5)", "literaturereference_normalized": "leptomeningeal involvement by prostate carcinoma an ominous head of a well known hydra", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211231", "receivedate": "20191115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17035877, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "BACKGROUND\nRadiation recall pneumonitis (RRP) is a special form of radiation pneumonitis precipitated by certain pharmacological agents. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is an effective treatment for advanced nonsmall-cell lung cancer (NSCLC) and has been reported as a potent radiation sensitizer. The incidence and general characteristics of EGFR-TKI-related RRP in patients with NSCLC remain unclear.\n\n\nMETHODS\nClinical records and serial chest images of consecutive patients with advanced NSCLC who had received thoracic radiotherapy (TRT) and EGFR-TKI treatment were retrospectively reviewed. EGFR-TKI-related RRP was diagnosed according to history, clinical manifestations, and radiographic characteristics. Potential risk factors were analyzed.\n\n\nRESULTS\nIn total, 160 patients with NSCLC who received EGFR-TKI after TRT were identified. Of these patients, seven (4.4%) developed EGFR-TKI-related RRP. The median time interval between the end of radiotherapy and RRP was 124 days (range, 80-635 days) and that between the initiation of EGFR-TKI and RRP was 43 days (range, 18-65 days). No risk factor for the development of RRP was identified except that patients in whom EGFR-TKI was initiated within 90 days after the completion of radiotherapy had significantly higher rates of RRP than those of patients who began receiving EGFR-TKI treatment after 90 days (21% vs. 2.1%, p = 0.005).\n\n\nCONCLUSIONS\nIn patients with NSCLC who have a history of TRT, treatment with EGFR-TKI may induce not only interstitial lung disease but also RRP. Physicians should be aware of both unexpected adverse events when using EGFR-TKI.", "affiliations": "Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.;Division of Radiotherapy, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.;Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.;Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.;Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.;Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. Electronic address: jhchiou@vghtpe.gov.tw.", "authors": "Chiang|Chi-Lu|CL|;Chen|Yi-Wei|YW|;Wu|Mei-Han|MH|;Huang|Hsu-Ching|HC|;Tsai|Chun-Ming|CM|;Chiu|Chao-Hua|CH|", "chemical_list": "D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1726-4901", "issue": "79(5)", "journal": "Journal of the Chinese Medical Association : JCMA", "keywords": "epidermal growth factor receptor; nonsmall-cell lung cancer; radiation recall pneumonitis; radiotherapy; tyrosine kinase inhibitor", "medline_ta": "J Chin Med Assoc", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D017564:Radiation Pneumonitis; D012189:Retrospective Studies; D013909:Thorax; D013997:Time Factors", "nlm_unique_id": "101174817", "other_id": null, "pages": "248-55", "pmc": null, "pmid": "27036494", "pubdate": "2016-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Radiation recall pneumonitis induced by epidermal growth factor receptor-tyrosine kinase inhibitor in patients with advanced nonsmall-cell lung cancer.", "title_normalized": "radiation recall pneumonitis induced by epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced nonsmall cell lung cancer" }

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RADIATION RECALL PNEUMONITIS INDUCED BY EPIDERMAL GROWTH FACTOR RECEPTOR-TYROSINE KINASE INHIBITOR IN PATIENTS WITH ADVANCED NONSMALL-CELL LUNG CANCER. J-CHIN-MED-ASSOC 2016;79(5):248-55.", "literaturereference_normalized": "radiation recall pneumonitis induced by epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced nonsmall cell lung cancer", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20171108", "receivedate": "20171108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14171956, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "TW-MYLANLABS-2017M1069659", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091002", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ADENOCARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERLOTINIB" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Radiation pneumonitis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHIANG CL, CHEN YW, WU MH, HUANG HC, TSAI CM, CHIU CH. RADIATION RECALL PNEUMONITIS INDUCED BY EPIDERMAL GROWTH FACTOR RECEPTOR-TYROSINE KINASE INHIBITOR IN PATIENTS WITH ADVANCED NONSMALL-CELL LUNG CANCER. J-CHIN-MED-ASSOC 2016;79(5):248-55.", "literaturereference_normalized": "radiation recall pneumonitis induced by epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced nonsmall cell lung cancer", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20171108", "receivedate": "20171108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14171952, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "TW-MYLANLABS-2017M1069668", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "091002", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SQUAMOUS CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERLOTINIB" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Radiation pneumonitis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHIANG CL, CHEN YW, WU MH, HUANG HC, TSAI CM, CHIU CH. RADIATION RECALL PNEUMONITIS INDUCED BY EPIDERMAL GROWTH FACTOR RECEPTOR-TYROSINE KINASE INHIBITOR IN PATIENTS WITH ADVANCED NONSMALL-CELL LUNG CANCER. J-CHIN-MED-ASSOC 2016;79(5):248-55.", "literaturereference_normalized": "radiation recall pneumonitis induced by epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced nonsmall cell lung cancer", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20171108", "receivedate": "20171108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14171955, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]

{ "abstract": "BACKGROUND\nPlatelet aggregation may predict the bleeding outcomes after percutaneous coronary intervention (PCI).\n\n\nMETHODS\nConsecutive patients with non-high risk acute coronary syndrome and indication for PCI were enrolled. Maximum adenosine diphosphate-induced platelet aggregation (ADP-PGmax) was assessed by light transmission aggregometry. Study endpoints were the incidence of haemorrhage, categorised by Thrombolysis in Myocardial Infarction criteria, and significant entry-site complications during hospitalisation and six-month follow-up period. Platelet aggregation test was organised at 24h after PCI and 1 month after discharge respectively. The optimal platelet aggregation was detected defining enhanced clopidogrel response, and associations of measurements with endpoints were assessed.\n\n\nRESULTS\nA total of 278 patients were included in analyses. Study endpoints were observed in 24 (8.6%) patients [major bleeding, n=4 (1.4%); minor bleeding, n=11 (4.0%); significant entry-site complication, n=9 (3.2%)]. In multivariate analysis, follow-up ADP-PGmax[odds ratio (OR)=0.96;95% confidence interval (CI),0.93-0.99;p=0.008) and renal insufficiency (OR=3.29; 95%CI, 1.23-8.85; p=0.018) were predictors of bleeding events. The optimal cutoff value for follow-up ADP-PGmax was 24.5% (area under the curve=0.72; 95% CI, 0.59-0.85; p<0.001). Bleeding occurred in 26.2% (16/61) of patients with enhanced clopidogrel response and 3.7% (8/217) of other patients (OR=9.26; p<0.001).\n\n\nCONCLUSIONS\nEnhanced clopidogrel responsiveness was associated with an increased risk of bleeding and entry-site complication. Platelet function testing at an appropriate time after clopidogrel administration helps to identify patients at high risk of bleeding.", "affiliations": "Department of Cardiology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangdong Cardiovascular Institute, 510080, Guangzhou, China. Electronic address: lijun_jin2000@126.com.;Department of Cardiology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangdong Cardiovascular Institute, 510080, Guangzhou, China.;Department of Cardiology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangdong Cardiovascular Institute, 510080, Guangzhou, China.;Department of Cardiology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangdong Cardiovascular Institute, 510080, Guangzhou, China.;Department of Cardiology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangdong Cardiovascular Institute, 510080, Guangzhou, China.;Department of Cardiology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangdong Cardiovascular Institute, 510080, Guangzhou, China.;Department of Medical Statistical Record, Guangzhou Oncology Hospital, Guangzhou Medical College, Guangzhou, 510095, China.", "authors": "Jin|Lijun|L|;Yu|Huimin|H|;Dong|Taiming|T|;Zhang|Bin|B|;Yan|Hong|H|;Liao|Hongtao|H|;Zou|Xia|X|", "chemical_list": "D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine", "country": "Australia", "delete": false, "doi": "10.1016/j.hlc.2016.05.113", "fulltext": null, "fulltext_license": null, "issn_linking": "1443-9506", "issue": "26(1)", "journal": "Heart, lung & circulation", "keywords": "Clopidogrel; Haemorrhage; Percutaneous Coronary Intervention; Platelet aggregation", "medline_ta": "Heart Lung Circ", "mesh_terms": "D054058:Acute Coronary Syndrome; D000244:Adenosine Diphosphate; D000368:Aged; D000077144:Clopidogrel; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010974:Platelet Aggregation; D011379:Prognosis; D012307:Risk Factors; D013988:Ticlopidine", "nlm_unique_id": "100963739", "other_id": null, "pages": "49-57", "pmc": null, "pmid": "27451349", "pubdate": "2017-01", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "The Prognostic Value of ADP-Induced Platelet Aggregation for Bleeding Complications in Low - Intermediate Risk Patients with Acute Coronary Syndrome Taking Clopidogrel After Percutaneous Coronary Intervention.", "title_normalized": "the prognostic value of adp induced platelet aggregation for bleeding complications in low intermediate risk patients with acute coronary syndrome taking clopidogrel after percutaneous coronary intervention" }

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"activesubstancename": "TIROFIBAN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIROFIBAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESOMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESOMEPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE CORONARY SYNDROME", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TIROFIBAN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIROFIBAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70 IU/KG, ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "028", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG, ONCE (LOADING DOSE 300MG DURING PCI PROCEDURAL)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug administration error", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Labelled drug-drug interaction medication error", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haemoglobin abnormal", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20101217" } }, "primarysource": { "literaturereference": "JIN L; YU H; DONG T; ZHANG B; YAN H; LIAO H; ZOU X. THE PROGNOSTIC VALUE OF ADP-INDUCED PLATELET AGGREGATION FOR BLEEDING COMPLICATIONS IN LOW - INTERMEDIATE RISK PATIENTS WITH ACUTE CORONARY SYNDROME TAKING CLOPIDOGREL AFTER PERCUTANEOUS CORONARY INTERVENTION. HEART LUNG AND CIRCULATION. 2016;XX:1-9", "literaturereference_normalized": "the prognostic value of adp induced platelet aggregation for bleeding complications in low intermediate risk patients with acute coronary syndrome taking clopidogrel after percutaneous coronary intervention", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20160909", "receivedate": "20160909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12728138, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" } ]

{ "abstract": "The objective of this study was to evaluate antimicrobial therapy outcomes of bone and joint infections (BJI) caused by Clostridium perfringens. We investigated remission of symptoms and the absence of relapse or reinfection during follow-up. Among the 8 patients with C. perfringens BJI, the type of infection was early prosthesis infection (n = 2), osteosynthetic device infection (n = 4), and chronic osteomyeletis (n = 2). Clindamycin-rifampicin combination was given in 4 cases and metronidazole in 4 cases. The overall success rate was 87.5%. Among the 7 patients who completed antibiotic treatment, the success rate was 100%. The clindamycin-rifampicin combination appeared to be effective in patients with C. perfringens BJI.", "affiliations": "Department of Internal Medicine and Infectious Diseases, Reims Teaching Hospitals, Avenue du Général Koenig, 51092, Reims, France.;Department of Bacteriology, Reims Teaching Hospitals, Reims, France.;Department of Hygiene, Reims Teaching Hospitals, Reims, France.;Department of Internal Medicine and Infectious Diseases, Manchester Hospital, Charleville-Mezieres, France.;Department of Pharmacy, Reims Teaching Hospitals, Reims, France.;Department of Internal Medicine and Infectious Diseases, Reims Teaching Hospitals, Avenue du Général Koenig, 51092, Reims, France.;Department of Orthopedic Surgery, Reims Teaching Hospitals, Reims, France.;Department of Orthopedic Surgery, Reims Teaching Hospitals, Reims, France.;Department of Internal Medicine and Infectious Diseases, Reims Teaching Hospitals, Avenue du Général Koenig, 51092, Reims, France. fbanisadr@chu-reims.fr.", "authors": "Visse|Margaux|M|;Vernet-Garnier|Véronique|V|;Bajolet|Odile|O|;Lebrun|Delphine|D|;Bonnet|Morgane|M|;Hentzien|Maxime|M|;Ohl|Xavier|X|;Diallo|Saidou|S|;Bani-Sadr|Firouzé|F|http://orcid.org/0000-0001-8268-866X", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1007/s10096-021-04225-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0934-9723", "issue": "40(10)", "journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology", "keywords": "Bone infection; Clindamycin-rifampicin; Clostridium perfringens; Metronidazole", "medline_ta": "Eur J Clin Microbiol Infect Dis", "mesh_terms": null, "nlm_unique_id": "8804297", "other_id": null, "pages": "2221-2225", "pmc": null, "pmid": "33723737", "pubdate": "2021-10", "publication_types": "D016428:Journal Article", "references": "30657582", "title": "Bone and joint infections caused by Clostridium perfringens: a case series.", "title_normalized": "bone and joint infections caused by clostridium perfringens a case series" }

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Bone and joint infections caused by Clostridium perfringens: A case series. Journal of Clinical Microbiology and Infectious Diseases. 2021;40:2221-2225", "literaturereference_normalized": "bone and joint infections caused by clostridium perfringens a case series", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220613", "receivedate": "20220613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20953515, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2022-08461", "fulfillexpeditecriteria": "2", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, 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Bone and joint infections caused by Clostridium perfringens: a case series. European Journal of Clinical Microbiology + Infectious Diseases. 2021;40:2221-2225", "literaturereference_normalized": "bone and joint infections caused by clostridium perfringens a case series", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220611", "receivedate": "20220611", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20948191, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]

{ "abstract": "BACKGROUND\nIntranasal corticosteroids are widely used for management of many upper airway diseases because of their ability to effectively deliver local relief of inflammation.\n\n\nMETHODS\nThis paper presents the case of a 51-year-old man with human immunodeficiency virus treated with ritonavir who was started on fluticasone intranasal spray for presumed chronic rhinosinusitis. Months after starting this therapy, he developed symptoms of Cushing's syndrome and avascular necrosis of the shoulder due to the pharmacological interactions between fluticasone and ritonavir.\n\n\nCONCLUSIONS\nAlthough intranasal corticosteroids are deemed a low-risk route of drug administration, clinicians need to be vigilant in appropriately prescribing corticosteroids in the setting of drug potentiators, particularly in these high-risk patients. Alternative corticosteroids such as beclomethasone dipropionate should be considered in such cases.", "affiliations": "City University of New York School of Medicine, USA.;Department of Otolaryngology - Head and Neck Surgery, University of Ottawa, Ottawa Hospital, Canada.;ENT Department, Guy's Hospital, London, UK.;ENT Department, Guy's Hospital, London, UK.", "authors": "James|J|J|;Caulley|L|L|;Collins|J|J|;Hopkins|C|C|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1017/S0022215121002516", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-2151", "issue": null, "journal": "The Journal of laryngology and otology", "keywords": "Cushing Syndrome; Drug Interactions; Fluticasone; HIV; Osteonecrosis; Ritonavir; Sinusitis", "medline_ta": "J Laryngol Otol", "mesh_terms": null, "nlm_unique_id": "8706896", "other_id": null, "pages": "1-4", "pmc": null, "pmid": "34579804", "pubdate": "2021-09-28", "publication_types": "D016428:Journal Article", "references": null, "title": "Complications of combination intranasal corticosteroids and anti-retroviral therapy.", "title_normalized": "complications of combination intranasal corticosteroids and anti retroviral therapy" }

[ { "companynumb": "US-CIPLA LTD.-2021US07047", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203759", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUTICASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Nasal spray", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Sinusitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUTICASONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteonecrosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Labelled drug-drug interaction issue", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "James J, Caulley L, Collins J, Hopkins C. Complications of combination intranasal corticosteroids and anti-retroviral therapy. The Journal of Laryngology + Otology. 2021;1 to 4", "literaturereference_normalized": "complications of combination intranasal corticosteroids and anti retroviral therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211027", "receivedate": "20211027", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19999784, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220304" }, { "companynumb": "US-WOCKHARDT BIO AG-2021WBA000029", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUTICASONE" }, "drugadditional": "1", "drugadministrationroute": "045", "drugauthorizationnumb": "078492", "drugbatchnumb": "unk", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Spray", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic rhinosinusitis without nasal polyps", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUTICASONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "unk", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITONAVIR" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteonecrosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Potentiating drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "James J, Caulley L, Collins J, Hopkins C.. Complications of combination intranasal corticosteroids and anti-retroviral therapy.. J Laryngol Otol. 2021;135:1119-1122", "literaturereference_normalized": "complications of combination intranasal corticosteroids and anti retroviral therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220110", "receivedate": "20220110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20316677, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "GB-OPTINOSE US, INC-2021OPT000257", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUTICASONE PROPIONATE" }, "drugadditional": "1", "drugadministrationroute": "045", "drugauthorizationnumb": "209022", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Nasal spray", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Sinusitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "XHANCE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITONAVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unknown", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITONAVIR" } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteonecrosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "James J, Caulley L, Collins J, Hopkins C. Complications of combination intranasal corticosteroids and anti-retroviral therapy. The Journal of Laryngology and Otology. 2021 SEP 28;1-4. doi:https:// doi.org/10.1017/S0022215121002516", "literaturereference_normalized": "complications of combination intranasal corticosteroids and anti retroviral therapy", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20211028", "receivedate": "20211028", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20008328, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2022GMK069711", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUTICASONE PROPIONATE" }, "drugadditional": "3", "drugadministrationroute": "045", "drugauthorizationnumb": "090759", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, FORMULATION: INTRANASAL SPRAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Sinusitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUTICASONE PROPIONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITONAVIR" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteonecrosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "James J., Caulley L., Collins J., Hopkins C. Complications of combination intranasal corticosteroids and anti-retroviral therapy.. Journal of Laryngology and Otology. 2021;135(12):1119-1122", "literaturereference_normalized": "complications of combination intranasal corticosteroids and anti retroviral therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220113", "receivedate": "20220113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20332596, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-APOTEX-2021AP045173", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUTICASONE PROPIONATE" }, "drugadditional": "3", "drugadministrationroute": "045", "drugauthorizationnumb": "077538", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Nasal spray, suspension", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Sinusitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUTICASONE PROPIONATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITONAVIR" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteonecrosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "James J, Caulley L, Collins J, Hopkins C. Complications of combination intranasal corticosteroids and anti-retroviral therapy.. Journal of Laryngology and Otology. 2021;1-4", "literaturereference_normalized": "complications of combination intranasal corticosteroids and anti retroviral therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211111", "receivedate": "20211108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20042376, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "US-AUROBINDO-AUR-APL-2021-047321", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "206614", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUTICASONE PROPIONATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Spray", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Allergic sinusitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUTICASONE PROPIONATE" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Osteonecrosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "James J, Caulley L, Collins J, Hopkins C.. Complications of combination intranasal corticosteroids and anti-retroviral therapy.. J-Laryngol-Otol. 2021;1-4", "literaturereference_normalized": "complications of combination intranasal corticosteroids and anti retroviral therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211126", "receivedate": "20211120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20093059, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "GB-AMNEAL PHARMACEUTICALS-2021-AMRX-05159", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "208890", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITONAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUTICASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUTICASONE" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteonecrosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "James J, Caulley L, Collins J, Hopkins C. Complications of combination intranasal corticosteroids and anti-retroviral therapy. J. Laryngol. Otol.. 2021;135 (12):1119-22", "literaturereference_normalized": "complications of combination intranasal corticosteroids and anti retroviral therapy", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20220105", "receivedate": "20220105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20299242, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]

{ "abstract": "This case demonstrates the effective and sustainable use of intermittent fasting (IF) and ketogenic diet (KD) in a normal weight patient with type 2 diabetes, who did not attain glycaemic control with a standard care approach. A 57-year-old woman with type 2 diabetes treated with metformin and strict adherence to a standard diabetic diet presented with a haemoglobin A1c (HbA1c) of 9.3%. Within 4 months of transitioning to KD, combined with IF, she achieved glycaemic control off pharmacotherapy, with HbA1c of 6.4. IF regimens started as 24 hours three times per week, followed by 42 hours three times per week, then 42 hours two times per week and 16 hours once per week. A maintenance phase was then begun at 8 months; IF was reduced to 16 hours per day, with 24 hours three times per month, and metformin was restarted. At 14 months, HbA1c reached 5.8%, and body mass index was minimally changed.", "affiliations": "Department of Medicine, Cedars-Sinai Medical Center, Beverly Hills, California, USA charlene.lichtash@gmail.com.;Department of Medicine, Scarborough Health Network, Scarborough, Ontario, Canada.;National University of Ireland Galway, Galway, Ireland.;Institute of Kidney Life Science Technologies, Scarborough, Ontario, Canada.", "authors": "Lichtash|Charlene|C|http://orcid.org/0000-0003-3166-1373;Fung|Jason|J|;Ostoich|Katherine Connor|KC|;Ramos|Megan|M|", "chemical_list": "D001786:Blood Glucose; D006442:Glycated Hemoglobin A", "country": "England", "delete": false, "doi": "10.1136/bcr-2019-234223", "fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2019-234223\n10.1136/bcr-2019-234223\nInnovations in Treatment\n1506\n1325\n77\n157\n1331\n258\n1560\n1310\nCase reportTherapeutic use of intermittent fasting and ketogenic diet as an alternative treatment for type 2 diabetes in a normal weight woman: a 14-month case study\nhttp://orcid.org/0000-0003-3166-1373Lichtash Charlene 1 Fung Jason 2 Ostoich Katherine Connor 3 Ramos Megan 4 1 Department of Medicine, Cedars-Sinai Medical Center, Beverly Hills, California, USA\n2 Department of Medicine, Scarborough Health Network, Scarborough, Ontario, Canada\n3 National University of Ireland Galway, Galway, Ireland\n4 Institute of Kidney Life Science Technologies, Scarborough, Ontario, Canada\nCorrespondence to Dr. Charlene Lichtash; charlene.lichtash@gmail.com\n2020 \n7 7 2020 \n7 7 2020 \n13 7 e23422312 6 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.This case demonstrates the effective and sustainable use of intermittent fasting (IF) and ketogenic diet (KD) in a normal weight patient with type 2 diabetes, who did not attain glycaemic control with a standard care approach. A 57-year-old woman with type 2 diabetes treated with metformin and strict adherence to a standard diabetic diet presented with a haemoglobin A1c (HbA1c) of 9.3%. Within 4 months of transitioning to KD, combined with IF, she achieved glycaemic control off pharmacotherapy, with HbA1c of 6.4. IF regimens started as 24 hours three times per week, followed by 42 hours three times per week, then 42 hours two times per week and 16 hours once per week. A maintenance phase was then begun at 8 months; IF was reduced to 16 hours per day, with 24 hours three times per month, and metformin was restarted. At 14 months, HbA1c reached 5.8%, and body mass index was minimally changed.\n\ndiabetesgeneral practice / family medicinedietendocrine systemspecial-featureunlocked\n==== Body\nBackground\nDiabetes mellitus type 2 is a disease characterised by hyperglycaemia, varying levels of insulin resistance and impaired pancreatic beta-cell function. Both genetic and environmental factors contribute to the pathogenesis of type 2 diabetes.1 The growing epidemic of type 2 diabetes worldwide highlights the need for accessible preventative and therapeutic strategies. According to a global estimate by the WHO in 2014, an estimated 422 million adults were living with diabetes, with the prevalence of diabetes having doubled since 1980.2 In 2012, diabetes was the eighth leading cause of death among both sexes and the fifth leading cause of death in women.2\n\nStandard approaches to the treatment of type 2 diabetes incorporate lifestyle management, pharmacotherapy and occasionally bariatric surgery.3–5 The goal of treatment is euglycaemia and a reduction of the incidence of microvascular and macrovascular complications of type 2 diabetes. Medical nutrition therapy (MNT) is widely accepted as part of the standard of care in a diabetic patient.4 Guidelines cite several diets, including the Mediterranean diet, the Dietary Approaches to Stop Hypertension diet, vegetarian diet and low-carbohydrate diet, as effective in lowering haemoglobin A1c (HbA1c).4 However, there is no consensus on the ideal macronutrient composition of diet to achieve control or remission of type 2 diabetes.4 Ketogenic diets (KDs), which induce a state of nutritional ketosis (defined in the medical literature as a blood beta-hydroxybutyrate level of 0.5–3.0 mmol/L), have demonstrated effective reduction in HbA1c and metabolic parameters in patients with type 2 diabetes; however, studies are limited in size and number.6–8\n\nRemission in type 2 diabetes has been demonstrated in large trials studying caloric restriction, as well as bariatric surgery.9–11 While effective, bariatric surgery is limited by its accessibility, potential for complications and invasive nature. Caloric restriction is limited by long-term patient adherence.12 Caloric restriction results in compensatory changes in the hormonal regulators of body weight, effectively reducing energy expenditure and increasing hunger.12 These changes have been shown to persist for at least 12 months after implementing a calorie-restricted diet, explaining the challenge in applying this approach to the treatment of type 2 diabetes.12\n\nBy contrast, intermittent fasting (IF) is emerging as a potentially sustainable strategy to achieve control or remission of type 2 diabetes. Fasting is the voluntary abstinence from food, and IF is an eating regimen by which all meals are consumed within a strictly defined window of time, followed by fasting.13 Some available studies on IF use variations of fasting that allow for the ingestion of fewer calories during this window, while others abstain from caloric intake altogether.13 Patterns and lengths of fasting also vary among studies. Studies on the therapeutic use of IF in type 2 diabetes are very limited. Herein, we present a case of woman with type 2 diabetes who successfully used a combination of IF and a low-carbohydrate KD to achieve glycaemic control.\n\nWhile reduction of body weight is typically the goal of IF regimens, not all patients who suffer from type 2 diabetes are overweight. Many cases of type 2 diabetes improve or remit with weight loss, but the two goals are not the same. In this case, a change in dietary pattern effectively controlled type 2 diabetes, although the patient was not overweight and overall weight change was minimal.\n\nCase presentation\nA 57-year-old woman with a 15-year history of type 2 diabetes had been managed for the majority of her illness with metformin and a standard diabetic diet. She had a remote history of gestational diabetes at age 20 and 34 years. At the time of her diagnosis with type 2 diabetes mellitus at age 42 years, her HbA1c was 7.1% and body mass index (BMI) was 21.9 kg/m2, classified as normal weight. During the course of her illness, she had strictly adhered to a diet prescribed to her by a registered dietician and based on prior American Diabetes Association (ADA) guidelines.14 It had consisted of carbohydrates from fruits, vegetables, whole grains, legumes and low-fat dairy, as well as poultry, fish and nuts. She had strictly limited her intake of saturated fat, red meats, sweets, sugar-sweetened beverages and sodium. She had regularly eaten three meals per day with two snacks.\n\nIn June 2016, at age 54 years, her HbA1c had risen to 8.7% and BMI to 23.2 kg/m², while on metformin and her diabetic diet; glipizide was then added to her regimen. By February 2017, her HbA1c had only marginally improved to 8.3%, but she experienced weight gain with a rise in her BMI to 24%, a common side effect of sulfonylurea drugs. Pioglitazone was subsequently added to her regimen of metformin and glipizide, but she reported not taking it consistently due to episodes of hypoglycaemia and dizziness. In June 2017, her HbA1c was 7.8%, and she was told to lower her dose of glipizide, continue metformin and to resume pioglitazone. In October 2017, her HbA1c had improved to 6.5%; however, she reported frequent hypoglycaemia, dizziness and feeling unwell, and she discontinued her pioglitazone and glipizide on her own. In July 2018, her HbA1c had risen to 9.3% on a regimen of metformin and her diabetic diet.\n\nTreatment\nIn July 2018, she began strictly following a KD, followed by the initiation of an IF regimen 2 weeks later. The KD, a low-carbohydrate high-fat (LCHF) diet, consisted of the following macronutrient composition: 80% fat, 15% protein and 5% carbohydrates. The diet focused on eating natural, unprocessed fats containing a variety of monounsaturated and polyunsaturated sources. Protein was predominantly from pasture-raised chicken and eggs, grass-fed beef and wild-caught fish. Grains, starches, legumes and the majority of fruits were eliminated, with most of the carbohydrates in the diet consisting of leafy greens and raw or fermented vegetables. Total daily consumption was estimated to be 20–30 g of carbohydrates and 1500 calories. She reported eating to satiety, without strictly measuring calories.\n\nIF was started at 24 hours three times per week on Monday, Wednesday and Friday. After 2 weeks, she increased the duration of fasting to 42 hours three times per week, which she continued for 4 months. Because of the significant improvement in blood glucose, and the lack of available data to guide the choice of a follow-up regimen, she then reduced her fasting to 42 hours on Mondays and Wednesdays, and 16 hours on Fridays for 4 months. In an effort to test the need for continued 42 hours fasts, a maintenance phase was then started, during which fasting was reduced to 16 hours per day and 24 hours three times per month for 6 months. Metformin 1000 mg two times per day was reinitiated at the start of the maintenance phase. When not fasting, she ate two meals per day with no additional snacks between meals. On days she fasted 24 hours, she ate one meal per day. During fasts she drank water, plain tea or coffee and occasionally homemade bone broth.\n\nOutcome and follow-up\nFour weeks after initiating her dietary changes, the patient discontinued all medications, including metformin, an antihypertensive and a statin, while at the same time significantly improving glycaemic control. A timeline and summary of the patient’s diabetic medications with health parameters recorded at each visit are displayed in table 1. HbA1c dropped by 2.9%, from 9.3% to 6.4% during the first 4 months of dietary treatment, as depicted in figure 1. A few hypoglycemic episodes were noted only when initiating the IF regimen, but none subsequently. Her HbA1c at 8 months was 6.4%, at which time, fasting insulin, postprandial insulin rise and C peptide were all at the lower end of normal range. At this point, when glycaemic control had been achieved, metformin was added. At 14 months, HbA1c was reduced to 5.8. The patient’s weight and BMI were mildly reduced, as demonstrated in figure 2, with her most recent weight and BMI being 53.5 kg and 21.6 kg/m2, respectively. When fasting, she recorded ketone levels at 0.5–1 mmol/L using a commercial blood ketone monitor, confirming nutritional ketosis. During the first 8 days after initiating KD, the patient reported mild fatigue and headache. These self-limited symptoms are common when starting a KD and are often referred to colloquially as keto flu. Thereafter, she reported no difficulties in maintaining the diet and fasting regimen, and she noted an improvement in her energy level, exercise tolerance and quality of life. Despite tolerating the 42 hours fasting periods without difficulty, she reported greater satisfaction with her fasting regimen in the maintenance phase, citing a greater sense of normalcy when able to engage in daily meals. The patient currently continues with her KD and IF, which she plans to maintain indefinitely.\n\nTable 1 Timeline of patient treatment modality for type 2 diabetes and measured health parameters\n\nDate of visit\tTreatment at time of visit\tHbA1C (%)\tWeight (kg)\tBMI (kg/m2)\t\nJune 2016\tMetformin 1000 mg two times per day\t8.7\t57.8\t23.2\t\nFebruary 2017\tMetformin 1000 mg two times per day\nGlipizide 10 mg two times per day\t8.3\t59.6\t24.0\t\nJune 2017\tMetformin 1000 mg two times per day\nGlipizide 10 mg two times per day\nPioglitazone 15 mg/day (not taken consistently due to side effects)\t7.8\t58.2\t23.5\t\nOctober 2017\tMetformin 1000 mg two times per day\nGlipizide 10 mg/day, 5 mg nightly\nPioglitazone 30 mg/day\t6.5\t60.0\t24.2\t\nJuly 2018\tMetformin 1000 mg two times per day\t9.3\t55.3\t22.3\t\nNovember 2018\tKetogenic diet\nIntermittent fasting\t6.4\t51.7\t20.9\t\nDecember 2018\tKetogenic diet\nIntermittent fasting\t6.1\t52.6\t21.2\t\nJanuary 2019\tKetogenic diet\nIntermittent fasting\t6.5\t53.0\t21.4\t\nFebruary 2019\tKetogenic diet\nIntermittent fasting\t6.1\t52.1\t21.0\t\nMarch 2019\tKetogenic diet\nIntermittent fasting\t6.4\t54.9\t22.1\t\nSeptember 2019\tKetogenic diet\nIntermittent fasting\nMetformin 1000 mg two times per day\t5.8\t53.5\t21.6\t\nBMI, body mass index; HbA1c, haemoglobin A1c.\n\nFigure 1 Glycosylated haemoglobin prior to and during treatment with intermittent fasting and ketogenic diet. HbA1c, haemoglobin A1c.\n\nFigure 2 Weight and body mass index during treatment with intermittent fasting and ketogenic diet. BMI, body mass index.\n\nWe present a case of a normal weight patient with uncontrolled type 2 diabetes despite adherence to oral hypoglycemic medications and standard dietary advice, who successfully managed her condition using a relatively novel lifestyle approach, combining IF with a KD. The therapeutic benefits of IF and KD in the management of type 2 diabetes are reported in the medical literature, but they have not been studied in large scale. Their use is guided predominately by an understanding of their proposed pathophysiologic mechanisms reported in animal data, and by outcomes reported in limited human data.\n\nStudies on IF generally demonstrate its effectiveness in improving glycaemic control and other metabolic parameters, including reduction in visceral fat, blood pressure and markers of oxidative stress and inflammation.13 15–20 The available human data for IF show marked benefit in pre-diabetes and type 2 diabetes. In a case report of three patients with long-standing type 2 diabetes each requiring at least 70 units of insulin per day, the implementation of 24 hours fasts either three times per week or on alternate days, combined with a recommended low-carbohydrate diet resulted in the complete discontinuation of insulin in all three patients; reductions in HbA1c, BMI and waist circumference were also demonstrated.17 Moreover, the benefits of IF on insulin sensitivity extend beyond its influence on weight loss. A recent trial in men with pre-diabetes and overweight or obesity showed that 5 weeks of an IF regimen improved insulin sensitivity and pancreatic beta-cell responsiveness, independent of weight loss.20 Another study comparing caloric restriction to an IF regimen for weight loss showed a greater increase in insulin sensitivity when using an IF strategy.21 The findings in our case mirror those in the literature; IF was an effective and sustainable tool for achieving glycaemic control and reducing the need for pharmacotherapy in our patient, independent of weight loss.\n\nAnimal data propose a mechanistic understanding of the effects of IF on glycaemic control, providing hope that this treatment modality may slow or reverse the progression of type 2 diabetes. Mice fed a fasting-mimicking diet showed an increase in the proliferation and number of insulin-generating pancreatic beta cells in late-stage type 2 diabetes.22 Differentiated cells in the pancreas first decreased in number in the fasted state, and then pancreatic transitional cells and beta cells proliferated in the refed state.22 This study suggests that the therapeutic benefit of IF lies in the combined physiologic effects caused by both the fasted state, and by the recovery period during the feeding phase, to promote beta-cell repair. Another study in mice showed increased pancreatic beta-cell mass using IF.23 Glucose stimulated insulin secretion increased and beta-cell apoptosis decreased.23 Additionally, weight loss was not required for the benefits of IF on pancreatic beta-cell survival and function.23 The possibility that IF can promote pancreatic beta cells to regenerate and has the potential to revolutionise our treatment of type 2 diabetes, currently viewed as a chronic progressive disease. Further human studies are needed to help illuminate the potential role IF may have in slowing or reversing this disease.\n\nThe processes linking IF and benefits in insulin sensitivity are currently being studied to help with targeted pharmacologic therapy that can mimic effects of IF. One such area of ongoing research is in the sirtuin proteins, a family of enzymes with regulatory effects on glucose homeostasis, fat metabolism and life span regulated by both nutrient levels and calorie restriction.18 19 In particular, sirtuin-6 (SIRT6) is currently being studied as a potential therapeutic target for treating insulin resistance.24 SIRT6 in animal studies enhances insulin sensitivity and thereby decreases fasting blood glucose levels.24–26 Both short-term fasting and long-term calorie restriction increase SIRT6 levels in animal data further highlighting the role IF may play in disease modification19\n\nCarbohydrate restriction is considered an effective treatment of type 2 diabetes in standard MNT, as defined by the ADA and the European Association for the Study of Diabetes.4 This approach even predates the development of exogenous insulin treatment in 1921, and is based on the fact that carbohydrates are the macronutrient with the highest glycaemic and insulin indices.27 An increased carbohydrate intake worsens markers of insulin resistance, such as postprandial glucose and insulin levels.28 Several trials have demonstrated improvements in HbA1c and insulin sensitivity when implementing a low-carbohydrate diet.29 The benefits of dietary carbohydrate restriction on control of blood glucose do not necessarily require weight loss, and low-carbohydrate diets have been shown to be generally well tolerated.30 31\n\nWhile the benefits of low-carbohydrate diets in type 2 diabetes are well accepted, the role of KD in the management of type 2 diabetes is not widely accepted at the present time, partly due to limited long-term safety data. A KD is typically defined as a LCHF diet that induces a shift in energy source from glucose to fatty acids and fatty-acid-derived ketones. Achieving nutritional ketosis has been shown to result in diabetes remission and reversal in some cases.8 A non-randomised long-term study implementing KD found significant improvements in biomarkers, including HbA1c, weight, fasting glucose, fasting insulin, blood pressure, cholesterol profile, high sensitivity C-reactive protein and a reduced need for type 2 diabetic medication.6 By contrast, the control arm consisting of patients with type 2 diabetes receiving ‘usual care’ with counselling on lifestyle interventions by a registered dietitian showed no significant change in any of the biomarkers measured.6\n\nHowever, in other disease states, both KDs and IF have a long history of safety. KD was first used in the 1920s in the treatment of epilepsy.32 During nearly a century of clinical use, there have been remarkably few health concerns. IF has been used even longer in the treatment of epilepsy, having been described by the ancient Greek physician Hippocrates more than 2400 years ago.33 Further, IF has been a traditional part of virtually every major religion in the world.\n\nOur patient tolerated the KD well, with her only reported difficulty being the week-long initial period of adjustment, termed in popular media as keto flu and in the medical literature as keto induction.34 Common symptoms of keto flu include influenza-like symptoms, headache, fatigue, nausea, dizziness, gastrointestinal discomfort and decreased energy.34 The symptoms tend to peak within the first 7 days of initiating a KD and resolve within the first month.34 While data show that IF and the production of ketone bodies result in adaptive responses that influence health and longevity, further research on KDs is needed to help support their widespread use in the treatment of diabetes mellitus.\n\nIF and a low-carbohydrate diet, such as a KD, appear to be particularly effective when used in combination. These two dietary interventions address different but complementary parts of the total diet. A KD specifies which foods should or should not be eaten (what to eat), but does not give guidance on the timing of meals (when to eat). IF provides guidance on the meal timing but not meal composition. Together they provide a complete dietary solution that each lacks on its own.\n\nThe time to achieving glycaemic control in type 2 diabetes with this combined approach varies, and further studies are needed to define the determining factors, such as degree of insulin resistance and pancreatic beta-cell reserve. Our patient achieved glycaemic control within 4 months of combining KD and IF. Another study found that in three patients with insulin-dependent diabetes, implementation of IF and a low-carbohydrate diet resulted in discontinuation of insulin between 5 and 18 days of initiating treatment.17 For maintenance of glycaemic control, the duration and degree of IF and carbohydrate restriction must also be tailored to the individual patient. As demonstrated in our case, once glycaemic control was achieved the lengths of fasts were able to be reduced, without compromising glycaemic control. Further studies should help identify patient characteristics that predict ideal fasting lengths and carbohydrate limits in the management of type 2 diabetes.\n\nThe available data on KD and IF is encouraging, and our case report and review of the literature highlights the need for more extensive research on these two treatment modalities in the treatment of type 2 diabetes. With the alarming rise in incidence of type 2 diabetes worldwide, the need for cost-effective and widely available strategies to manage this disease is growing. The need for pharmacotherapy and invasive bariatric surgery can be effectively lowered through the use of our approach. Further, as shown in animal and preliminary human data, the strategies we discussed in our study have the potential to modify the course of type 2 diabetes, which has long been understood as a chronic progressive disease. If validated in large-scale randomised studies, the current data on both IF and KD have the potential to revolutionise our understanding of the pathophysiology of type 2 diabetes and profoundly impact the standard approach to treatment of this disease.\n\nLearning points\nThe use of intermittent fasting (IF) and a ketogenic diet (KD) is an effective and sustainable alternative to a standard care approach in the treatment of type 2 diabetes.\n\nIF and a KD can be used in a patient with type 2 diabetes who is normal weight. Glycaemic control can be achieved without resulting in significant weight loss.\n\nThe use of this dietary strategy minimises or eliminates the need for pharmacotherapy, and it may be superior to a standard care approach to type 2 diabetes.\n\nWe demonstrate good adherence to a strategy of IF and a KD in a patient who could not tolerate the adverse effects of additional oral hypoglycemic medications when under a standard care approach.\n\nTwitter: @drjasonfung\n\nContributors: CL compiled patient history, medical records and data, performed literature review and developed introduction and discussion and finalised the remaining sections of the report. KCO synthesised data and drafted the case history, treatment and results section of the case report. JF and MR edited the case report through several revisions.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Schulz LO , Bennett PH , Ravussin E , et al \nEffects of traditional and Western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S\n. Diabetes Care \n2006 ;29 :1866 –71\n. 10.2337/dc06-0138 16873794 \n2 Roglic G \nGlobal report on diabetes . Geneva, Switzerland : World Health Organization , 2016 : 86 .\n3 Qaseem A , Barry MJ , Humphrey LL , et al \nOral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of physicians\n. 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FEBS Lett \n2008 ;582 :543 –8\n. 10.1016/j.febslet.2008.01.019 18242175 \n20 Sutton EF , Beyl R , Early KS , et al \nEarly Time-Restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes\n. Cell Metab \n2018 ;27 :1212 –21\n. 10.1016/j.cmet.2018.04.010 29754952 \n21 Harvie MN , Pegington M , Mattson MP , et al \nThe effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women\n. Int J Obes \n2011 ;35 :714 –27\n. 10.1038/ijo.2010.171 \n22 Cheng C-W , Villani V , Buono R , et al \nFasting-Mimicking diet promotes Ngn3-Driven β-cell regeneration to reverse diabetes\n. Cell \n2017 ;168 :775 –88\n. 10.1016/j.cell.2017.01.040 28235195 \n23 Liu H , Javaheri A , Godar RJ , et al \nIntermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway\n. 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Perspect Biol Med \n2006 ;49 :77 –83\n. 10.1353/pbm.2006.0017 16489278 \n28 Kodama S , Saito K , Tanaka S , et al \nInfluence of fat and carbohydrate proportions on the metabolic profile in patients with type 2 diabetes: a meta-analysis\n. Diabetes Care \n2009 ;32 :959 –65\n. 10.2337/dc08-1716 19407076 \n29 Wheeler ML , Dunbar SA , Jaacks LM , et al \nMacronutrients, food groups, and eating patterns in the management of diabetes: a systematic review of the literature, 2010\n. Diabetes Care \n2012 ;35 :434 –45\n. 10.2337/dc11-2216 22275443 \n30 Nickols-Richardson SM , Coleman MD , Volpe JJ , et al \nPerceived hunger is lower and weight loss is greater in overweight premenopausal women consuming a low-carbohydrate/high-protein vs high-carbohydrate/low-fat diet\n. J Am Diet Assoc \n2005 ;105 :1433 –7\n. 10.1016/j.jada.2005.06.025 16129086 \n31 Gannon MC , Nuttall FQ \nControl of blood glucose in type 2 diabetes without weight loss by modification of diet composition\n. Nutr Metab \n2006 ;3 :16 . 10.1186/1743-7075-3-16 \n32 D'Andrea Meira I , Romão TT , Pires do Prado HJ , et al \nKetogenic diet and epilepsy: what we know so far\n. Front Neurosci \n2019 ;13 :5. 10.3389/fnins.2019.00005 30760973 \n33 Hippocrates \nOn the sacred disease 400 BCE\n. Available: http://classics.mit.edu/Hippocrates/sacred.html\n34 Bostock ECS , Kirkby KC , Taylor BV , et al \nConsumer Reports of \"Keto Flu\" Associated With the Ketogenic Diet\n. Front Nutr \n2020 ;7 :20 . 10.3389/fnut.2020.00020 32232045\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1757-790X", "issue": "13(7)", "journal": "BMJ case reports", "keywords": "diabetes; diet; endocrine system; general practice / family medicine", "medline_ta": "BMJ Case Rep", "mesh_terms": "D001786:Blood Glucose; D015992:Body Mass Index; D031204:Caloric Restriction; D003924:Diabetes Mellitus, Type 2; D055423:Diet, Ketogenic; D005215:Fasting; D005260:Female; D006442:Glycated Hemoglobin A; D006801:Humans; D008875:Middle Aged; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32641437", "pubdate": "2020-07-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "30559235;24915261;30291106;29221645;16489278;31231311;18544345;18165339;22275443;20047575;16556307;20921964;31194993;22449317;22029981;28055075;18242175;29322219;30301822;27240637;28235195;16873794;16129086;31881139;19641727;30760973;29754952;29417495;28853981;30683819;19407076;32232045", "title": "Therapeutic use of intermittent fasting and ketogenic diet as an alternative treatment for type 2 diabetes in a normal weight woman: a 14-month case study.", "title_normalized": "therapeutic use of intermittent fasting and ketogenic diet as an alternative treatment for type 2 diabetes in a normal weight woman a 14 month case study" }

[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-257859", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201606", "drugstartdateformat": "610", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIOGLITAZONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201706", "drugstartdateformat": "610", "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIOGLITAZONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIOGLITAZONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201710", "drugstartdateformat": "610", "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIOGLITAZONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GLIPIZIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "77820", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201702", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLIPIZIDE." } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "LICHTASH C, FUNG J, OSTOICH KC, RAMOS M. THERAPEUTIC USE OF INTERMITTENT FASTING AND KETOGENIC DIET AS AN ALTERNATIVE TREATMENT FOR TYPE 2 DIABETES IN A NORMAL WEIGHT WOMAN: A 14?MONTH CASE STUDY. BMJ CASE REP. 2020?13(7):E234223", "literaturereference_normalized": "therapeutic use of intermittent fasting and ketogenic diet as an alternative treatment for type 2 diabetes in a normal weight woman a 14 month case study", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200821", "receivedate": "20200821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18177730, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "US-APOTEX-2020AP016427", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GLIPIZIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "075795", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, Q.H.S.", "drugenddate": "201710", "drugenddateformat": "610", "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLIPIZIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIOGLITAZONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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"610", "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLIPIZIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PIOGLITAZONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIOGLITAZONE." } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201702" } }, "primarysource": { "literaturereference": "LICHTASH C, FUNG J, OSTOICH KC, RAMOS M. THERAPEUTIC USE OF INTERMITTENT FASTING AND KETOGENIC DIET AS AN ALTERNATIVE TREATMENT FOR TYPE 2 DIABETES IN A NORMAL WEIGHT WOMAN: A 14?MONTH CASE STUDY. BMJ CASE REPORTS. 2020?13: 7 (E234223):1?5", "literaturereference_normalized": "therapeutic use of intermittent fasting and ketogenic diet as an alternative treatment for type 2 diabetes in a normal weight woman a 14 month case study", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210728", "receivedate": "20210728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19620613, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" } ]

{ "abstract": "OBJECTIVE\nHospital admissions associated with an adverse drug reaction are often coded to the International Classification of Diseases external cause Y-codes, denoting the medicine class deemed to cause the adverse drug reaction. Matching hospital data with outpatient dispensing data has the potential to identify the specific causative medicines but the ability to identify the causative medicines in this way has not been previously assessed. This study aimed to determine the proportion of Y-coded hospitalizations for drug-induced hepatotoxicity that could be matched with a potential causative medicine from outpatient dispensing data.\n\n\nMETHODS\nA retrospective cohort study was undertaken from 1 Jan 2005 to 30 June 2012 using data from the Australian Government Department of Veterans' Affairs of all admissions coded to drug-induced hepatotoxicity. Medicine use in the 6 months prior to hospitalization was examined to identify the probable causative medicines.\n\n\nCONCLUSIONS\nThirty five admissions were identified for 31 patients. All admissions were preceded by use of medicines known to cause hepatotoxicity. Twenty four admissions had a Y-code recorded, of which 19 admissions had at least one Y-code specifying the causative medicine class (22 Y-codes). Of the 22 Y-codes, 95% could be successfully matched with a medicine from the same class that had been dispensed in the 6 months prior to admission. Further, 92% were preceded by use of multiple hepatotoxic medicines.\n\n\nCONCLUSIONS\nResults of our study demonstrate that hospital administrative data can be linked to prescription dispensing data to identify specific medicines suspected of causing the adverse drug reaction.", "affiliations": "Quality Use of Medicines and Pharmacy Research Centre, School of Pharmacy and Medical Sciences, Sansom Institute, University of South Australia, Adelaide, SA, Australia.", "authors": "Nguyen|T A|TA|;Caughey|G|G|;Pratt|N|N|;Shakib|S|S|;Kemp|A|A|;Roughead|E|E|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/jcpt.12249", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-4727", "issue": "40(2)", "journal": "Journal of clinical pharmacy and therapeutics", "keywords": "adverse event; drug-related; hepatitis; medicine use", "medline_ta": "J Clin Pharm Ther", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006760:Hospitalization; D006801:Humans; D007345:Insurance Claim Review; D038801:International Classification of Diseases; D008297:Male; D012189:Retrospective Studies", "nlm_unique_id": "8704308", "other_id": null, "pages": "213-9", "pmc": null, "pmid": "25682802", "pubdate": "2015-04", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Hospitalization for drug-induced hepatotoxicity: linking Y-codes with pharmaceutical claims data to identify implicated medicines.", "title_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines" }

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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. J CLIN PHARM THER 2015 APR;40(2):213-9.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20161007", "receivedate": "20161007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12825064, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "AU-TEVA-697370ISR", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS. 2015 JAN 01;40:213-219.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20161006", "receivedate": "20161006", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12823864, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "AU-APOTEX-2016AP012189", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. J-CLIN-PHARM-THER. 2015;40(2):213-219.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160926", "receivedate": "20160926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12778397, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-MYLANLABS-2016M1040309", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRBESARTAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRBESARTAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUCLOXACILLIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCLOXACILLIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATORVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATORVASTATIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E. 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"drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GLICLAZIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLICLAZIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN T.A.. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS. 2015?40 (2):213-219", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20180409", "receivedate": "20150327", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10960627, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "AU-IPCA LABORATORIES LIMITED-IPC201609-000837", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALLOPURINOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ROXITHROMYCIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLAVULANIC ACID" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN T,CAUGHEY G,PRATT N,SHAKIB S,KEMP A,ROUGHEAD E. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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"patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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E. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. J-CLIN-PHARM-THER 2015;40(2):213-219.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160922", "receivedate": "20160922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12772636, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-APOTEX-2016AP012193", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RAMIPRIL" }, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN T. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. JOURNAL OF CLINICAL PHARMACY THERAPEUTICS 2015;40(2):213-219.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20170803", "receivedate": "20150415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11032146, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "AU-MYLANLABS-2016M1040279", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESOMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "078936", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESOMEPRAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULPHAMETHOXAZOLE/TRIMETHOPRIM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, 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"drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LANSOPRAZOLE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ATENOLOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATENOLOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." }, { "actiondrug": "5", 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SERTRALINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. J-CLIN-PHARM-THER 2015;40(2):213-219.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160922", "receivedate": "20160922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12772659, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-APOTEX-2016AP012183", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRBESARTAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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"reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E.. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. J-CLIN-PHARM-THER. 2015;40(2):213-219", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160923", "receivedate": "20160923", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12774082, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-DRREDDYS-USA/AUS/16/0083547", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYPROTERONE" }, 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. J CLIN PHARM THER. 2015;40(2):213-9.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "AU", "receiptdate": "20160929", "receivedate": "20160929", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12791372, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-PFIZER INC-2015103065", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS. 2015?40 (2):213-219", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20180517", "receivedate": "20150326", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10956932, "safetyreportversion": 8, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "AU-APOTEX-2016AP012179", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FELODIPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E.. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. J-CLIN-PHARM-THER. 2015;40(2):213-219", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160926", "receivedate": "20160926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12778832, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-DRREDDYS-USA/AUS/16/0083536", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DICLOXACILLIN" }, 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CODEINE/PARACETAMOL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN T, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. J CLIN PHARM THER. 2015;40(2):213-9.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "AU", "receiptdate": "20160929", "receivedate": "20160929", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12791192, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-APOTEX-2016AP012174", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076048", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ROXITHROMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROXITHROMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN, CLAVULANATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E.. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. J-CLIN-PHARM-THER. 2015;40(2):213-219", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160926", "receivedate": "20160926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12779302, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-VALIDUS PHARMACEUTICALS LLC-AU-2016VAL002715", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL TARTRATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "017963", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL TARTRATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E.. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. JOURNAL OF CLINICAL PHARMACY + THERAPEUTICS. 2015;40(2):213-9", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20161017", "receivedate": "20160927", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12784992, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "AU-MYLANLABS-2016M1040234", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRBESARTAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRBESARTAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\CODEINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CODEINE PHOSPHATE/PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. J-CLIN-PHARM-THER 2015;40(2):213-219.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160921", "receivedate": "20160921", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12767812, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-APOTEX-2016AP012184", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\CODEINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "APO-PARACETAMOL CODINE 500/30" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRBESARTAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200832", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRBESARTAN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E.. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. J-CLIN-PHARM-THER. 2015;40(2):213-19", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160926", "receivedate": "20160926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12778592, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-ALVOGEN-2015-ALVOGEN-016159", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESOMEPRAZOLE" }, 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. J-CLIN-PHARM-THER. 2015;40(2):213-219", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160926", "receivedate": "20160926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12779450, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-PFIZER INC-2015103063", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RAMIPRIL" }, 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS. 2015;40 (2):213-219", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20150331", "receivedate": "20150327", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10962235, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" }, { "companynumb": "AU-MYLANLABS-2016M1040307", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RAMIPRIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "090650", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RAMIPRIL MYLAN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN T, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. J-CLIN-PHARM-THER. 2015;40(2):213-219", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160926", "receivedate": "20160926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12779081, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "AU-MYLANLABS-2016M1040238", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INDOMETHACIN" }, 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. 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HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES.. 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"reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN TA, CAUGHEY G, PRATT N, SHAKIB S, KEMP A, ROUGHEAD E. HOSPITALIZATION FOR DRUG-INDUCED HEPATOTOXICITY: LINKING Y-CODES WITH PHARMACEUTICAL CLAIMS DATA TO IDENTIFY IMPLICATED MEDICINES. J-CLIN-PHARM-THER 2015;40(2):213-219.", "literaturereference_normalized": "hospitalization for drug induced hepatotoxicity linking y codes with pharmaceutical claims data to identify implicated medicines", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160921", "receivedate": "20160921", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12767813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "BACKGROUND\nCryptococcosis is a potentially severe infection that usually occurs in a setting of immunosuppression. Its occurrence outside of this context is rare. We report a case of disseminated cryptococcosis revealed by a spectacular skin disease in an immunocompetent patient.\n\n\nMETHODS\nA 40-year-old male patient had been presenting multiple nodules and tumors on his face for one month in a context of asthenia and intermittent fever. Histological examination of a skin biopsy revealed encapsulated yeasts strongly suggestive of Cryptococcus neoformans. Mycological examination of the skin biopsy and cerebrospinal fluid isolated Cryptococcus gattii. The blood cultures were positive. Brain MRI demonstrated cryptococcal parenchymal involvement. Screening for primary or secondary immunodeficiency was negative. The patient received amphotericin B 1mg/kg/day and fluconazole 600mg/day but died 2months after diagnosis.\n\n\nCONCLUSIONS\nCryptococcosis is a potentially severe infection caused by C. neoformans. This rare condition occurs most commonly in patients with profound deficiency in terms of cellular immunity. Although rare, the occurrence of cryptococcosis in immunocompetent patients is possible, and in this event the signs are highly polymorphic, which usually makes it very difficult to diagnose. The diagnosis of cryptococcosis is based on the identification by direct examination and after staining with India ink of encapsulated yeasts of the Cryptococcus genus. Culture on Sabouraud medium is essential for identification of the species. Treatment for disseminated cryptococcosis involves amphotericin B, often associated with flucytosine IV. In the event of meningitis infection in non-HIV patients, mortality continues to be around 15%, despite adequate medical treatment.\n\n\nCONCLUSIONS\nAlthough rare, cryptococcosis can occur in immunocompetent subjects. The prognosis is severe even after treatment.", "affiliations": "Service de dermatologie-vénéréologie, CHU Ibn Sina, rue Famfdal Cherkaoui Rabat-Instituts, BP 6527, 10170 Rabat, Maroc. Electronic address: hananerachadi@gmail.com.;Service de dermatologie-vénéréologie, CHU Ibn Sina, rue Famfdal Cherkaoui Rabat-Instituts, BP 6527, 10170 Rabat, Maroc.;Service de parasitologie, CHU Ibn Sina, rue Famfdal Cherkaoui Rabat-Instituts, BP 6527, 10170 Rabat, Maroc.;Centre d'anatomie pathologique nations unies, 1, angle avenue des Nations Unies et rue Ibn Hanbal Agdal, 1090 Rabat, Maroc.;Service de dermatologie-vénéréologie, CHU Ibn Sina, rue Famfdal Cherkaoui Rabat-Instituts, BP 6527, 10170 Rabat, Maroc.;Service de dermatologie-vénéréologie, CHU Ibn Sina, rue Famfdal Cherkaoui Rabat-Instituts, BP 6527, 10170 Rabat, Maroc.;Service de dermatologie-vénéréologie, CHU Ibn Sina, rue Famfdal Cherkaoui Rabat-Instituts, BP 6527, 10170 Rabat, Maroc.;Service de dermatologie-vénéréologie, CHU Ibn Sina, rue Famfdal Cherkaoui Rabat-Instituts, BP 6527, 10170 Rabat, Maroc.;Service de dermatologie-vénéréologie, CHU Ibn Sina, rue Famfdal Cherkaoui Rabat-Instituts, BP 6527, 10170 Rabat, Maroc.", "authors": "Rachadi|H|H|;Senouci|K|K|;Lyagoubi|M|M|;Benzekri|A|A|;Mansouri|S|S|;Ramli|I|I|;Ismaili|N|N|;Hassam|B|B|;Benzekri|L|L|", "chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole", "country": "France", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0151-9638", "issue": "143(4)", "journal": "Annales de dermatologie et de venereologie", "keywords": "Amphotericin B; Amphotéricine B; Cryptococcose disséminée; Cryptococcus neoformans; Disseminated cryptococcosis; Facial nodules; Immunocompetent; Immunocompétent; Nodules du visage", "medline_ta": "Ann Dermatol Venereol", "mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D003453:Cryptococcosis; D056285:Cryptococcus gattii; D005148:Facial Dermatoses; D017809:Fatal Outcome; D015725:Fluconazole; D016469:Fungemia; D006801:Humans; D007121:Immunocompetence; D008297:Male; D016919:Meningitis, Cryptococcal", "nlm_unique_id": "7702013", "other_id": null, "pages": "289-94", "pmc": null, "pmid": "26971369", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Multiple facial nodules revealing disseminated cryptococcosis in an immunocompetent patient.", "title_normalized": "multiple facial nodules revealing disseminated cryptococcosis in an immunocompetent patient" }

[ { "companynumb": "MA-PFIZER INC-2016272645", "fulfillexpeditecriteria": "1", "occurcountry": "MA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/KG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CRYPTOCOCCOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPHOTERICIN B." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUCONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CRYPTOCOCCOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCONAZOLE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "RACHADI, H.. MULTIPLE FACIAL NODULES REVEALING DISSEMINATED CRYPTOCOCCOSIS IN AN IMMUNOCOMPETENT PATIENT. ANNALES DE DERMATOLOGIE ET DE VENEREOLOGIE. 2016;143 (4):289-294", "literaturereference_normalized": "multiple facial nodules revealing disseminated cryptococcosis in an immunocompetent patient", "qualification": "3", "reportercountry": "MA" }, "primarysourcecountry": "MA", "receiptdate": "20160527", "receivedate": "20160527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12412850, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" } ]

{ "abstract": "Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a multisystemic disease. Despite the improvement in mortality rate since the introduction of immunosuppression, long-term prognosis is still uncertain not only because of the disease activity but also due to treatment associated adverse effects. The neutrophil-to-lymphocyte ratio (NLR) has been demonstrated as an inflammatory marker in multiple settings. In this study, we aimed to investigate the prognostic ability of the NLR in AAV patients.\n\n\n\nWe conducted a retrospective analysis of the clinical records of all adult patients with AVV admitted to the Nephrology and Renal Transplantation Department of Centro Hospitalar Universitário Lisboa Norte from January 2006 to December 2019. NLR was calculated at admission. The outcomes measured were severe infection at 3 months and one-year mortality. The prognostic ability of the NLR was determined using the receiver operating characteristic (ROC) curve. A cut-off value was defined as that with the highest validity. All variables underwent univariate analysis to determine statistically significant factors that may have outcomes. Only variables which significantly differed were used in the multivariate analysis using the logistic regression method.\n\n\n\nWe registered 45 cases of AVV. The mean age at diagnosis was 67.5±12.1 years and 23 patients were male. The mean Birmingham Vasculitis Activity Score (BVAS) at presentation was 26.0±10.4. Twenty-nine patients were ANCA-MPO positive, 7 ANCA-PR3 positive and 9 were considered negative ANCA vasculitis. At admission, mean serum creatinine (SCr) was 4.9±2.5mg/dL, erythrocyte sedimentation rate (ESR) was 76.9±33.8mm/h, hemoglobin was 9.5±1.7g/dL, C-reactive protein was 13.2±5.8mg/dL and NLR was 8.5±6.8. Thirty-five patients were treated with cyclophosphamide, eight patients with rituximab for induction therapy. Twenty patients developed severe infection within the first three months after starting induction immunosuppression. In a multivariate analysis, older age (73.6±10.5 vs. 62.6±11.3, p=0.002, adjusted OR 1.08 [95% CI 1.01-1.16], p=0.035) and higher NLR (11.9±7.4 vs. 5.9±5.0, p=0.002, adjusted OR 1.14 [95% CI 1.01-1.29], p=0.035) were predictors of severe infection at 3 months. NLR ≥4.04 predicted severe infection at 3 months with a sensitivity of 95% and specificity of 52% and the AUROC curve was 0.0794 (95% CI 0.647-0.900). Nine patients died within the first year. Severe infection at 3 months was independently associated with mortality within the first year (OR 6.19 [95% CI 1.12-34.32], p=0.037).\n\n\n\nNLR at diagnosis was an independent predictor of severe infection within the first 3 months after immunosuppression start, and severe infection within the first three months was consequently correlated with one-year mortality. NLR is an easily calculated and low-cost laboratory inflammation biomarker and can prove useful in identifying AAV patients at risk of infection and poorer prognosis.", "affiliations": "Division of Nephrology and Renal Transplantation, Department of Medicine. Centro Hospitalar Universitário Lisboa Norte, EPE. Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal. Electronic address: joana.estrelagameiro@gmail.com.;Division of Nephrology and Renal Transplantation, Department of Medicine. Centro Hospitalar Universitário Lisboa Norte, EPE. Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.;Division of Nephrology and Renal Transplantation, Department of Medicine. Centro Hospitalar Universitário Lisboa Norte, EPE. Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.;Division of Nephrology and Renal Transplantation, Department of Medicine. Centro Hospitalar Universitário Lisboa Norte, EPE. Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.;Division of Nephrology and Renal Transplantation, Department of Medicine. Centro Hospitalar Universitário Lisboa Norte, EPE. Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.", "authors": "Fonseca|José Agapito|JA|;Gameiro|Joana|J|;Duarte|Inês|I|;Jorge|Sofia|S|;Lopes|José António|JA|", "chemical_list": null, "country": "Spain", "delete": false, "doi": "10.1016/j.nefro.2020.07.013", "fulltext": null, "fulltext_license": null, "issn_linking": "2013-2514", "issue": "41(3)", "journal": "Nefrologia", "keywords": "ANCA; Anca; Glomerulonefritis; Glomerulonephritis; Linfocitos; Lymphocytes; Neutrophils; Neutrófilos; Prognosis; Pronóstico; Vasculitis; Vasculitis asociada a ANCA; Vasculitis associated with ANCA", "medline_ta": "Nefrologia (Engl Ed)", "mesh_terms": null, "nlm_unique_id": "101778581", "other_id": null, "pages": "321-328", "pmc": null, "pmid": "33309337", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": null, "title": "The neutrophil-to-lymphocyte ratio as a marker of vasculitis activity, severe infection and mortality in anca-associated vasculitis: A retrospective study.", "title_normalized": "the neutrophil to lymphocyte ratio as a marker of vasculitis activity severe infection and mortality in anca associated vasculitis a retrospective study" }

[ { "companynumb": "PT-CELLTRION HEALTHCARE HUNGARY KFT-2021PT013365", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION THERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anti-neutrophil cytoplasmic antibody positive vasculitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Anti-neutrophil cytoplasmic antibody positive vasculitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukopenia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Fonseca J, Gameiro J, Duarte I, Jorge S, Lopes JA. The neutrophil-to-lymphocyte ratio as a marker of vasculitis activity, severe infection and mortality in anca-associated vasculitis: A retrospective study. Nefrologia 2021 May 01;41 (3):321-8.", "literaturereference_normalized": "the neutrophil to lymphocyte ratio as a marker of vasculitis activity severe infection and mortality in anca associated vasculitis a retrospective study", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20220207", "receivedate": "20211019", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19966721, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "PT-CELLTRION INC.-2021PT013365", "fulfillexpeditecriteria": "1", "occurcountry": "PT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "761088", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Concentrate for solution for infusion", "drugdosagetext": "INDUCTION THERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anti-neutrophil cytoplasmic antibody positive vasculitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Fonseca JA, Gameiro J, Duarte I, Jorge S, Lopes JA. The neutrophil-to-lymphocyte ratio as a marker of vasculitis activity, severe infection and mortality in anca-associated vasculitis: A retrospective study. Nefrologia. 2021;41 (3):321-328", "literaturereference_normalized": "the neutrophil to lymphocyte ratio as a marker of vasculitis activity severe infection and mortality in anca associated vasculitis a retrospective study", "qualification": "3", "reportercountry": "PT" }, "primarysourcecountry": "PT", "receiptdate": "20211006", "receivedate": "20211006", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19921253, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "BACKGROUND\nThe safety and efficacy of second-line chemotherapy for treating patients with small cell lung cancer (SCLC) and interstitial lung disease (ILD) have not been elucidated to date.\n\n\nMETHODS\nBetween January 2005 and September 2013, we analyzed 23 patients with SCLC and ILD who received second-line chemotherapy. Pre-existing ILD was diagnosed according to clinical features and pretreatment chest high-resolution computed tomography results.\n\n\nRESULTS\nThe overall objective response rates and disease control rates were 22% and 52%, respectively. The median respective durations of progression-free survival and overall survival were 2.1 months (95% confidence interval (CI)=2.0-3.0 months) and 7.1 months (95% CI=3.6-11.3 months), respectively. Three patients with unusual interstitial pneumonia pattern (13%) developed chemotherapy-related pneumonitis.\n\n\nCONCLUSIONS\nSecond-line treatment may be an effective and safe option for SCLC patients with ILD after sufficient evaluation of risks and benefits.", "affiliations": "Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan daichianzen@yahoo.co.jp.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.", "authors": "Fujimoto|Daichi|D|;Shimizu|Ryoko|R|;Kato|Ryoji|R|;Sato|Yuki|Y|;Kogo|Mariko|M|;Ito|Jiro|J|;Teraoka|Shunsuke|S|;Otoshi|Takehiro|T|;Nagata|Kazuma|K|;Nakagawa|Atsushi|A|;Otsuka|Kojiro|K|;Katakami|Nobuyuki|N|;Tomii|Keisuke|K|", "chemical_list": "D019772:Topotecan; D016190:Carboplatin; D017239:Paclitaxel", "country": "Greece", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0250-7005", "issue": "35(11)", "journal": "Anticancer research", "keywords": "Chemotherapy-related exacerbation; interstitial lung disease; small cell lung cancer; usual interstitial pneumonia", "medline_ta": "Anticancer Res", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel; D011379:Prognosis; D012189:Retrospective Studies; D016879:Salvage Therapy; D055752:Small Cell Lung Carcinoma; D015996:Survival Rate; D019772:Topotecan", "nlm_unique_id": "8102988", "other_id": null, "pages": "6261-6", "pmc": null, "pmid": "26504060", "pubdate": "2015-11", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Second-line Chemotherapy for Patients with Small Cell Lung Cancer and Interstitial Lung Disease.", "title_normalized": "second line chemotherapy for patients with small cell lung cancer and interstitial lung disease" }

[ { "companynumb": "JP-HQ SPECIALTY-JP-2015INT000714", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020262", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70-100 MG/M2, EVERY 4 WEEKS ON DAYS 1, 8, AND 15", "drugenddate": null, "drugenddateformat": null, "drugindication": "SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "FUJIMOTO D, SHIMIZU R, KATO R, SATO Y, KOGO M, ITO J, ET AL.. SECOND-LINE CHEMOTHERAPY FOR PATIENTS WITH SMALL CELL LUNG CANCER AND INTERSTITIAL LUNG DISEASE.. ANTICANCER RESEARCH. 2015?35 (11):6261-6266", "literaturereference_normalized": "second line chemotherapy for patients with small cell lung cancer and interstitial lung disease", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151229", "receivedate": "20151229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11876524, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" }, { "companynumb": "JP-HQ SPECIALTY-JP-2015INT000724", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020262", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70-100 MG/M2, EVERY 4 WEEKS ON DAYS 1, 8, AND 15", "drugenddate": null, "drugenddateformat": null, "drugindication": "SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FUJIMOTO D, SHIMIZU R, KATO R, SATO Y, KOGO M, ITO J, ET AL.. SECOND-LINE CHEMOTHERAPY FOR PATIENTS WITH SMALL CELL LUNG CANCER AND INTERSTITIAL LUNG DISEASE.. ANTICANCER RESEARCH. 2015?35 (11):6261-6266", "literaturereference_normalized": "second line chemotherapy for patients with small cell lung cancer and interstitial lung disease", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151231", "receivedate": "20151231", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11883428, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]

{ "abstract": "Pythium insidiosum causes a rare sight-threatening keratitis and is a devastating ocular pathology with a high morbidity. It is frequently mistaken as fungal keratitis. Here we highlight a rare case of pediatric Pythium insidiosum keratitis which was successfully managed using an antibiotic combination of linezolid and azithromycin with cyanoacrylate glue.\nA 9-year-old young male child presented to our clinic with defective vision, pain, redness in the right eye for 5 days post stick injury. In the right eye, Snellen's best-corrected visual acuity (BCVA) was 6/12 which deteriorated to hand movements within 5 days of treatment. Ocular examination revealed 6 × 5 mm dry-looking mid stromal corneal infiltrate with feathery margin involving the visual axis. The clinical picture was suggestive of fungal keratitis. Corneal scraping and smear examination with 10% KOH and Gram stain revealed long slender hyaline hyphae with sparse septations. Before the culture result, the patient was started on 5% Natamycin and 1% Itraconazole hourly, but still, the infiltrate progressed. Further, P. Insidiosum keratitis was considered as the differential, which was confirmed on blood agar culture. After receiving culture results, the patient was managed with 0.2% Linezolid and 1% Azithromycin hourly. Due to the rapid progression of infiltrate, corneal melt, and younger age, cyanoacrylate glue, and bandage contact lens were used. On the last follow-up, the BCVA recovered to 6/12.\nPrompt diagnosis, clinical awareness, and a specific treatment regime is needed for managing this devastating corneal entity. Cyanoacrylate glue due to its antibacterial properties can be a potential rescuer and can be considered for managing these cases.", "affiliations": "Cornea and Refractive Surgery Services, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Pondicherry, Tamil Nadu, India.;Cornea and Refractive Surgery Services, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Pondicherry, Tamil Nadu, India.;Cornea and Refractive Surgery Services, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Pondicherry, Tamil Nadu, India.;Cornea and Refractive Surgery Services, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Pondicherry, Tamil Nadu, India.;Pediatric Ophthalmology and Squint Fellow, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Pondicherry, Tamil Nadu, India.;Department of Microbiology, Aravind Eye Hospital and Post Graduate Institute of Ophthalmology, Pondicherry, Tamil Nadu, India.", "authors": "Gurnani|Bharat|B|https://orcid.org/0000-0003-0848-5172;Narayana|Shivananda|S|;Christy|Josephine|J|;Rajkumar|Purushothama|P|;Kaur|Kirandeep|K|https://orcid.org/0000-0002-0951-7415;Gubert|Joseph|J|https://orcid.org/0000-0002-6053-7120", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/11206721211006564", "fulltext": null, "fulltext_license": null, "issn_linking": "1120-6721", "issue": null, "journal": "European journal of ophthalmology", "keywords": "Pythium insidiosum keratitis; azithromycin; cyanoacrylate glue; linezolid; pediatric", "medline_ta": "Eur J Ophthalmol", "mesh_terms": null, "nlm_unique_id": "9110772", "other_id": null, "pages": "11206721211006564", "pmc": null, "pmid": "33779337", "pubdate": "2021-03-28", "publication_types": "D016428:Journal Article", "references": null, "title": "Successful management of pediatric pythium insidiosum keratitis with cyanoacrylate glue, linezolid, and azithromycin: Rare case report.", "title_normalized": "successful management of pediatric pythium insidiosum keratitis with cyanoacrylate glue linezolid and azithromycin rare case report" }

[ { "companynumb": "IN-ALKEM-IN-ALKEM-2021-01914", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DICLOFENAC SODIUM" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIINFLAMMATORY THERAPY", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DICLOFENAC SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HOMATROPINE HYDROBROMIDE" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 PERCENT, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL TREATMENT", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HOMATROPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ITRACONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": "208591", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 PERCENT, HOURLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITRACONAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.2 PERCENT, HOURLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".2", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 PERCENT, HOURLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NATAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 PERCENT, HOURLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NATAMYCIN" } ], "patientagegroup": null, "patientonsetage": "9", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GURNANI B, NARAYANA S, CHRISTY J, RAJKUMAR P, ET AL.. SUCCESSFUL MANAGEMENT OF PEDIATRIC PYTHIUM INSIDIOSUM KERATITIS WITH CYANOACRYLATE GLUE, LINEZOLID, AND AZITHROMYCIN: RARE CASE REPORT. EUROPEAN JOURNAL OF OPHTHALMOLOGY. 2021?00:1?5", "literaturereference_normalized": "successful management of pediatric pythium insidiosum keratitis with cyanoacrylate glue linezolid and azithromycin rare case report", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20210809", "receivedate": "20210809", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19674481, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" } ]

{ "abstract": "Ketamine's rapid antisuicidal action has gathered significant clinical interest in treatment of depression though concerns exist that its actions occur through the Opioid pathway. A recent study additionally reported that Naltrexone blocks antisuicidal effects of Ketamine suggesting that its antisuicidal effects are also due to opioid mechanisms. We present a case of treatment refractory depression with recent suicide attempt and active suicidal ideations who was on an Opioid partial agonist, Buprenorphine, for management of pain. Patient responded to a trial of IV ketamine treatment with rapid improvement in suicidal thoughts. Patient's suicidal ideations decreased after first Ketamine treatment and resolved after second treatment while maintained on Buprenorphine. Our finding shows that Buprenorphine does not block Ketamine's effects on suicidal ideations and therefore Ketamine treatment could be provided safely in controlled environment to those with substance use disorders or with chronic pain while being maintained on Buprenorphine. Additionally, our case suggests that non-Opioid mechanisms may be involved in Ketamine's antidepressant effects and its response to suicidal ideations in those on Opioid partial agonists.", "affiliations": "University of Michigan, Department of Psychiatry, Ann Arbor, Michigan, United States; Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, United States. Electronic address: avinashh@med.umich.edu.;University of Michigan, Department of Psychiatry, Ann Arbor, Michigan, United States.;University of Michigan, Department of Psychiatry, Ann Arbor, Michigan, United States; Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, United States.", "authors": "Hosanagar|Avinash|A|;Schmale|Andrew|A|;LeBlanc|Andrew|A|", "chemical_list": "D000928:Antidepressive Agents; D002047:Buprenorphine; D007649:Ketamine", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jad.2020.12.120", "fulltext": null, "fulltext_license": null, "issn_linking": "0165-0327", "issue": "282()", "journal": "Journal of affective disorders", "keywords": "Antidepressant; Antisuicidal; Buprenorphine; Ketamine; Suicide; TRD", "medline_ta": "J Affect Disord", "mesh_terms": "D000928:Antidepressive Agents; D002047:Buprenorphine; D061218:Depressive Disorder, Treatment-Resistant; D006801:Humans; D007649:Ketamine; D059020:Suicidal Ideation", "nlm_unique_id": "7906073", "other_id": null, "pages": "252-254", "pmc": null, "pmid": "33418374", "pubdate": "2021-03-01", "publication_types": "D002363:Case Reports; D016422:Letter", "references": null, "title": "Ketamine's rapid antisuicidal effects are not attenuated by Buprenorphine.", "title_normalized": "ketamine s rapid antisuicidal effects are not attenuated by buprenorphine" }

[ { "companynumb": "US-INDIVIOR US-INDV-128032-2021", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022410", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUBOXONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MELATONIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM, QHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELATONIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DULOXETINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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INDICATION", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Suicidal ideation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Inappropriate schedule of product administration", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, 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KETAMINE^S RAPID ANTISUICIDAL EFFECTS ARE NOT ATTENUATED BY BUPRENORPHINE. JOURNAL OF AFFECTIVE DISORDERS. 2020?282:252?254", "literaturereference_normalized": "ketamine s rapid antisuicidal effects are not attenuated by buprenorphine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210217", "receivedate": "20210125", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18785250, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" } ]

{ "abstract": "A 63-year-old female patient who had undergone cholecystectomy for inflammatory myofibroblastic tumor (IMT) in the gallbladder was referred to our hospital. The patient's disease relapsed, involving the pancreas, and was diagnosed as inoperable IMT 13 months after the cholecystectomy. The patient failed to respond to steroid and non-steroidal anti-inflammatory drug therapy, but subsequently exhibited a good response to vinorelbine and methotrexate combination chemotherapy. Little information is currently available on the efficacy of chemotherapy for adult-onset IMT. The present case suggests that chemotherapy with vinorelbine and methotrexate is a viable therapeutic option for adult patients with unresectable IMT.", "affiliations": "Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.", "authors": "Maruyama|Yasuhiro|Y|;Fukushima|Toshirou|T|;Gomi|Daisuke|D|;Kobayashi|Takashi|T|;Sekiguchi|Nodoka|N|;Sakamoto|Akiyuki|A|;Sasaki|Shigeru|S|;Mamiya|Keiko|K|;Koizumi|Tomonobu|T|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3892/mco.2017.1383", "fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2017.1383MCO-0-0-1383ArticlesRelapsed and unresectable inflammatory myofibroblastic tumor responded to chemotherapy: A case report and review of the literature Maruyama Yasuhiro 12Fukushima Toshirou 1Gomi Daisuke 1Kobayashi Takashi 1Sekiguchi Nodoka 1Sakamoto Akiyuki 1Sasaki Shigeru 1Mamiya Keiko 1Koizumi Tomonobu 11 Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan2 Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, JapanCorrespondence to: Dr Tomonobu Koizumi, Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan, E-mail: tomonobu@shinshu-u.ac.jp10 2017 18 8 2017 18 8 2017 7 4 521 524 13 6 2016 23 9 2016 Copyright: © Maruyama et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.A 63-year-old female patient who had undergone cholecystectomy for inflammatory myofibroblastic tumor (IMT) in the gallbladder was referred to our hospital. The patient's disease relapsed, involving the pancreas, and was diagnosed as inoperable IMT 13 months after the cholecystectomy. The patient failed to respond to steroid and non-steroidal anti-inflammatory drug therapy, but subsequently exhibited a good response to vinorelbine and methotrexate combination chemotherapy. Little information is currently available on the efficacy of chemotherapy for adult-onset IMT. The present case suggests that chemotherapy with vinorelbine and methotrexate is a viable therapeutic option for adult patients with unresectable IMT.\n\nvinorelbinemethotrexatemetastatic pancreatic tumorunresectable inflammatory myofibroblastic tumor\n==== Body\nIntroduction\nInflammatory myofibroblastic tumor (IMT) is a rare disease of unknown etiology (1–3). This tumor was previously described as an inflammatory pseudotumor, inflammatory myofibroblastoma, lymphoplasmacytic histiocytoma and fibrous pseudotumor until 1994, when myofibroblastic tumor was established as a distinct low-grade malignancy by the World Health Organization (1–3). IMT is considered to be a neoplasm of intermediate biological potential, which may recur and metastasizes infrequently (1–4). Histologically, IMT is characterized by myofibroblastic spindle cells mixed with a hyalinized stroma and various degrees of inflammatory infiltrates (1–3). IMT occurs principally in children and young adults (4–10) and may affect any site in the body, although it is most commonly found in the lungs (4–6).\n\nIt is well established that total surgical excision is the most effective therapeutic option for surgically accessible IMT (2). However, the treatment options for relapsed and/or inoperable IMT are extremely limited due to the lack of reports regarding effective treatments. In particular, little evidence has been reported in the literature regarding the efficacy of chemotherapy for IMT (7–14). We encountered a case of inoperable IMT with pancreatic involvement following cholecystectomy for IMT originating from the gallblabber. The patient failed to respond to non-steroidal anti-inflammatory drugs (NSAIDs) and steroid therapy, but subsequently showed a good response to vinorelbine (VNB) and methotrexate (MTX) combination chemotherapy. We herein describe the clinical course and present a review of the literature on the effectiveness of chemotherapy for advanced and unresectable IMT.\n\nCase report\nA 63-year-old woman with no significant past medical history was admitted to a local hospital with the complaint of abdominal fullness and pain. A tumor was detected in the gallbladder, and the patient underwent surgical resection. Distant metastasis or invasion into adjacent organs were not observed based on radiographic findings prior to the operation and intraoperative inspection. The pathological diagnosis was IMT (Fig. 1). Thirteen months following resection, tumors in the pancreatic head and tail (Fig. 2A) were identified on whole-body computed tomography (CT) during postoperative follow-up. The patient was subsequently referred to the Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine (Matsumoto, Japan) for further examination. Positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) revealed abnormal uptake by both tumors. Endoscopic examination revealed a submucosal tumor in the duodenum (Fig. 2B). Endoscopic ultrasound-guided fine-needle aspiration in the pancreatic head tumor was performed and the histological diagnosis was recurrence of IMT (Fig. 3). The histological findings and molecular analysis of specimens collected from the pancreas and gallbladder revealed no pathological evidence of malignancy. In addition, there was no presence of anaplastic lymphoma kinase (ALK) protein by immunohistochemical staining or gene rearrangement by fluorescence in situ hybridization. Treatment with NSAIDs and methylprednisolone (500 mg/dayx3 day, intravenously) followed by 1 mg/kg of prednisolone for 1 month was continued, but the tumors were not reduced in size. Subsequently, treatment with methotrexate (MTX; 30 mg/m2 on day 1) plus vinorelbine (VNB; 20 mg/m2 on days 1 and 7) per 3 weeks chemotherapy was administered. The chemotherapy was continued without any severe toxicities. The dosage was repeated six times and partial response was achieved as determined by CT and endoscopic examination (Fig. 2C and D).\n\nDiscussion\nWe herein describe a case of abdominal IMT that developed in an elderly female and responded well to VNB and MTX chemotherapy. IMT is usually encountered in children and adolescents, mostly occurring between 2 and 16 years of age and mainly involving the lungs (1–3). Kovach et al (4) summarized 44 cases of IMT in their institutes and reported a mean age of 44 years, ranging from 9 to 88 years. In addition, the tumor location included several extrapulmonary lesions in addition to the lung (4). The patient reported herein had abdominal IMT and was aged 63 years. The association between age of onset and the involved location of IMT remains unclear. However, it has been suggested that recurrence was more common if the lesions were extrapulmonary (4).\n\nAlthough our patient had an ALK-negative tumor, it has been demonstrated that ~50% of IMTs harbor ALK gene rearrangement (2,15). Coffin et al (2) analyzed 59 IMTs and reported that ALK-negative IMTs had a more aggressive clinical course with a high risk of distant metastasis. In addition, the absence of ALK expression was associated with older age (2). Thus, clinical manifestations, including age, location and ALK negativity in the present case were consistent with those reported in the literature.\n\nSurgical resection has been considered the preferred treatment for IMT, and may also be used to confirm this diagnosis (2,16). However, IMT is considered to be a neoplasm of intermediate biological potential, which may recur and metastasize, although infrequently (1–4). In unresectable cases, radiotherapy and chemotherapy, including steroids and NSAIDs, were applied (7–14,17,18). Indeed, several clinical reports indicated the usefulness of steroids and NSAIDs (11,13,17,18), although both failed to shrink the tumor in the present case. Various cytotoxic agents or regimens, including MTX, VNB, vincristine, cyclophosphamide, doxorubicin, 5-fluorouracil, cisplatin, carboplatin, paclitaxel, ifosfamide and etoposide, have been used. However, due to the rarity of IMT, the availability of data regarding the efficacy of cytotoxic chemotherapeutic agents is limited. Previously reported treatment regimens, consisting of cytotoxic chemotherapy alone or in combination with NSAIDs, that were found to be effective for IMT are summarized in Table I. However, none of the chemotherapeutic regimens had been evaluated in a case series. In addition, the majority of data were obtained from pediatric populations. Thus, there is still a lack of definitive clinical evidence, particularly for adults. As Favini et al (10) reported a case of IMT that responded to VNB plus MTX, this chemotherapy regimen was used in the present case. Chemotherapy was performed without any severe toxicities and the patient responded well. Although the efficacy of this chemotherapy was evaluated in aggressive fibromatosis in cases series (19,20), our experience, including the case reported by Favini et al (10), may provide a treatment choice for patients with unresectable IMT. With regard to other optimal regimens, Kubo et al (12) described the case of an adult IMT patient (aged 26 years) who responded to carboplatin+paclitaxel chemotherapy. As this combination is the most commonly used chemotherapy regimen in various malignancies, carboplatin+paclitaxel may be an optimal choice for adult and inoperable IMT. An optimal agent or combination chemotherapy has not yet been determined for unresectable IMT. Further clinical experience and studies are required to determine the usefulness of chemotherapy for inoperable IMT.\n\nIn summary, our observations in the present case suggest that intermediate-dose chemotherapy using vinorelbine and methotrexate is a feasible therapeutic option in adult patients with unresectable IMT.\n\nFigure 1. (A) Abdominal computed tomography findings at initial presentation in the present case. A gallbladder tumor was detected prior to the operation. (B) Macroscopically, the resected tumor was a multinodular tan mass with a fleshy surface on cross-section. (C) The histological findings on hematoxylin and eosin staining showed proliferation of myofibroblastic spindle cells with lymphoplasmacytic inflammatory infiltrates. These findings were consistent with the diagnosis of inflammatory myofibroblastic tumor.\n\nFigure 2. (A) Abdominal computed tomography (CT) showed pancreatic head and tail tumors and (B) endoscopic examination revealed a submucosal tumor in the duodenum prior to chemotherapy. The (C) abdominal CT and (D) endoscopic findings after 6 cycles of chemotherapy revealed that the pancreatic tumors in the head and tail of the pancreas had shrunk following vinorelbine and methotrexate chemotherapy.\n\nFigure 3. (A and B) The histological findings of specimens collected from the pancreatic tumor revealed a relapsed inflammatory myofibroblastic tumor [hematoxylin and eosin (H&E) staining]. Immunohistochemical examination showed (C) positive staining for α-smooth muscle actin (SMA) and (D) negative staining for anaplastic lymphoma kinase (ALK).\n\nTable I. Previous case reports successfully treated with cytotoxic chemotherapy.\n\nCase\tAge, years\tLocation\tAgent/regimen\tResponse\tNSAIDs\tSurgery\t(Refs.)\t\n1\t  7\tAbdomen\tVincristine+etoposide→cisplatin, adriamycin, methotrexate\tPR\t+\t+\t(8)\t\n2\t10\tAbdomen\tMethotrexate+vinblastine, adriamycin, ifosfamide\tPR\t\t+\t(9)\t\n3\t12\tConjuctiva\tMethotrexate+vinorelbine\tPR\t\t\t(10)\t\n4\t14\tPeritoneum\tCisplatin+methotrexate\tCR\t+\t+\t(11)\t\n5\t26\tMediastinum\tCarboplatin+paclitaxel\tCR\t\t\t(12)\t\n6\t64\tFrontal bone\tMethotrexate\tPR\t+\t\t(13)\t\n7\t64\tAbdomen\tDoxorubicin+ifosfamide\tPR\t\t\t(14)\t\nPR, partial response; CR, complete response; NSAIDs, non-steroidal anti-inflammatory drugs.\n==== Refs\nReferences\n1 Fletcher CDM Unni KK Mertens F Inflammatory myofibroblastic tumor. In: World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Soft Tissue and Bone IARC Press Lyon 91 93 2002 \n2 Coffin CM Hornick JL Fletcher CD Inflammatory myofibroblastic tumor: Comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases Am J Surg Pathol 31 509 520 2007 10.1097/01.pas.0000213393.57322.c7 17414097 \n3 Mergan F Jaubert F Sauvat F Hartmann O Lortat-Jacob S Révillon Y Nihoul-Fékété C Sarnacki S Inflammatory myofibroblastic tumor in children: Clinical review with anaplastic lymphoma kinase, Epstein-Barr virus, and human herpesvirus 8 detection analysis J Pediatr Surg 40 1581 1586 2005 10.1016/j.jpedsurg.2005.06.021 16226988 \n4 Kovach SJ Fischer AC Katzman PJ Salloum RM Ettinghausen SE Madeb R Koniaris LG Inflammatory myofibroblastic tumors J Surg Oncol 94 385 391 2006 10.1002/jso.20516 16967468 \n5 Coffin CM Watterson J Priest JR Dehner LP Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases Am J Surg Pathol 19 859 872 1995 10.1097/00000478-199508000-00001 7611533 \n6 Tunçözgür B Ustünsoy H Bakir K Uçak R Elbeyli L Inflammatory pseudotumor of the lung Thorac Cardiovasc Surg 48 112 113 2000 10.1055/s-2000-9865 11028717 \n7 Sanders BM West KW Gingalewski C Engum S Davis M Grosfeld JL Inflammatory pseudotumor of the alimentary tract: Clinical and surgical experience J Pediatr Surg 36 169 173 2001 10.1053/jpsu.2001.20045 11150459 \n8 Dishop MK Warner BW Dehner LP Kriss VM Greenwood MF Geil JD Moscow JA Successful treatment of inflammatory myofibroblastic tumor with malignant transformation by surgical resection and chemotherapy J Pediatr Hematol Oncol 25 153 158 2003 10.1097/00043426-200302000-00014 12571469 \n9 Bertocchini A Lo Zupone C Callea F Gennari F Serra A Monti L de Ville de Goyet J Unresectable multifocal omental and peritoneal inflammatory myofibroblastic tumor in a child: Revisiting the role of adjuvant therapy J Pediatr Surg 46 e17 e21 2011 10.1016/j.jpedsurg.2011.01.007 21496520 \n10 Favini F Resti AG Collini P Casanova M Meazza C Trecate G Ferrari A Inflammatory myofibroblastic tumor of the conjunctiva: Response to chemotherapy with low-dose methotrexate and vinorelbine Pediatr Blood Cancer 54 483 485 2010 10.1002/pbc.22342 19890966 \n11 Tao YL Wang ZJ Han JG Wei P Inflammatory myofibroblastic tumor successfully treated with chemotherapy and nonsteroidals: A case report World J Gastroenterol 18 7100 7103 2012 10.3748/wjg.v18.i47.7100 23323014 \n12 Kubo N Harada T Anai S Otsubo K Yoneshima Y Ijichi K Koga T Takayama K Nakanishi Y Carboplatin plus paclitaxel in the successful treatment of advanced inflammatory myofibroblastic tumor Intern Med 51 2399 2401 2012 10.2169/internalmedicine.51.7599 22975556 \n13 Kusunoki-Nakamoto F Matsukawa T Tanaka M Miyagawa T Yamamoto T Shimizu J Ikemura M Shibahara J Tsuji S Successful treatment of an unresectable inflammatory myofibroblastic tumor of the frontal bone using a cyclooxygenase-2 inhibitor and methotrexate Intern Med 52 623 628 2013 10.2169/internalmedicine.52.8785 23448776 \n14 Inadomi K Kumagai H Takayoshi K Ariyama H Kusaba H Nishie A Yamamoto H Takase K Tanaka M Sagara K Successful combination chemotherapy for metastatic inflammatory myofibroblastic tumor: A case report Oncol Lett 10 2981 2985 2015 26722275 \n15 Butrynski JE D'Adamo DR Hornick JL Dal Cin P Antonescu CR Jhanwar SC Ladanyi M Capelletti M Rodig SJ Ramaiya N Crizotinib in ALK rearranged inflammatory myofibroblastic tumor N Engl J Med 363 1727 1733 2010 10.1056/NEJMoa1007056 20979472 \n16 Janik JS Janik JP Lovell MA Hendrickson RJ Bensard DD Greffe BS Recurrent inflammatory pseudotumors in children J Pediatr Surg 38 1491 1495 2003 10.1016/S0022-3468(03)00501-3 14577073 \n17 Berger A Kim C Hagstrom N Ferrer F Successful preoperative treatment of pediatric bladder inflammatory myofibroblastic tumor with anti-inflammatory therapy Urology 70 372 e13 e15 2007 \n18 Chan PW Omar KZ Ramanujam TM Successful treatment of unresectable inflammatory pseudotumor of the lung with COX-2 inhibitor Pediatr Pulmonol 36 167 169 2003 10.1002/ppul.10308 12833497 \n19 Azzarelli A Gronchi A Bertulli R Tesoro JD Baratti D Pennacchioli E Dileo P Rasponi A Ferrari A Pilotti S Casali PG Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis Cancer 92 1259 1264 2001 10.1002/1097-0142(20010901)92:5<1259::AID-CNCR1446>3.0.CO;2-Y 11571741 \n20 Meazza C Bisogno G Gronchi A Fiore M Cecchetto G Alaggio R Milano GM Casanova M Carli M Ferrari A Aggressive fibromatosis in children and adolescents: The Italian experience Cancer 116 233 240 2010 19950127\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2049-9450", "issue": "7(4)", "journal": "Molecular and clinical oncology", "keywords": "metastatic pancreatic tumor; methotrexate; unresectable inflammatory myofibroblastic tumor; vinorelbine", "medline_ta": "Mol Clin Oncol", "mesh_terms": null, "nlm_unique_id": "101613422", "other_id": null, "pages": "521-524", "pmc": null, "pmid": "29046787", "pubdate": "2017-10", "publication_types": "D016428:Journal Article", "references": "19890966;11571741;23323014;26722275;23448776;11028717;17414097;17826515;22975556;12833497;11150459;16226988;12571469;16967468;19950127;20979472;21496520;7611533;14577073", "title": "Relapsed and unresectable inflammatory myofibroblastic tumor responded to chemotherapy: A case report and review of the literature.", "title_normalized": "relapsed and unresectable inflammatory myofibroblastic tumor responded to chemotherapy a case report and review of the literature" }

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{ "abstract": "Pediatric glioblastoma multiforme is an uncommon and highly mortal brain cancer. New therapeutic treatments are being intensively investigated by researchers in order to extend the survival of patients. The immune checkpoint inhibitor nivolumab in the treatment of pediatric glioblastoma multiforme is currently under review; it is a human immunoglobulin G4 monoclonal antibody that works against the programmed cell death protein 1 receptor, designed to enhance an immunologic reaction against cancer cells. Herein, we describe the first report of a bilateral optic neuritis induced by nivolumab in a grade 4 glioblastoma multiforme patient.", "affiliations": "Division of Pediatric Hematology and Oncology, Gülhane Training and Research Hospital, 06300 Ankara, Turkey. dr.omerkartal@hotmail.com.;Division of Pediatric Oncology, Gülhane Training and Research Hospital, 06300 Ankara, Turkey. eatasdr@gmail.com.", "authors": "Kartal|Ömer|Ö|;Ataş|Erman|E|", "chemical_list": "D000305:Adrenal Cortex Hormones; D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab", "country": "Switzerland", "delete": false, "doi": "10.3390/medicina54050082", "fulltext": "\n==== Front\nMedicina (Kaunas)medicinaMedicina1010-660X1648-9144MDPI 10.3390/medicina54050082medicina-54-00082Case ReportBilateral Optic Neuritis Secondary to Nivolumab Therapy: A Case Report Kartal Ömer 1*Ataş Erman 21 Division of Pediatric Hematology and Oncology, Gülhane Training and Research Hospital, 06300 Ankara, Turkey2 Division of Pediatric Oncology, Gülhane Training and Research Hospital, 06300 Ankara, Turkey; eatasdr@gmail.com* Correspondence: dr.omerkartal@hotmail.com; Tel.: +90-0312-304-200006 11 2018 11 2018 54 5 8231 8 2018 31 10 2018 © 2018 by the authors.2018Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Pediatric glioblastoma multiforme is an uncommon and highly mortal brain cancer. New therapeutic treatments are being intensively investigated by researchers in order to extend the survival of patients. The immune checkpoint inhibitor nivolumab in the treatment of pediatric glioblastoma multiforme is currently under review; it is a human immunoglobulin G4 monoclonal antibody that works against the programmed cell death protein 1 receptor, designed to enhance an immunologic reaction against cancer cells. Herein, we describe the first report of a bilateral optic neuritis induced by nivolumab in a grade 4 glioblastoma multiforme patient.\n\nglioblastoma multiformenivolumaboptic neuritis\n==== Body\n1. Introduction\nThe current standard treatment for the newly diagnosed pediatric glioblastoma multiforme (GBM) is surgical debulking followed by radiation therapy and chemotherapy. However, a 5-year survival rate is less than 10%, and the median survival is 1–2 years [1]. Therefore, there is an urgent need to develop new therapeutics that can improve survival in GBM.\n\nThe immune checkpoint inhibitor nivolumab has been shown to improve antitumour response in a number of different advanced malignancies in different studies. The treatment of pediatric GBM is currently under review. It is a human immunoglobulin G4 monoclonal antibody that works against the programmed cell death protein 1 receptor, and is designed to enhance an immunologic reaction against cancer cells. On the other hand, using immune checkpoint inhibitors may cause an autoimmune phenomenon, including pneumonitis, hepatitis, vitiligo, colitis, hypophysitis, pruritis, arthritis, nephritis, neurologic syndromes (e.g., aseptic meningitis, Guillain-Barre’ syndrome), and autoimmune hemolytic anemia [2]. Herein, we describe the first report of a bilateral optic neuritis induced by nivolumab in an advanced GBM patient. \n\n2. Case Presentation\nThe patient was a 9 year old male with a 10-day history of severe headache, vomiting, and numbness in the right arm and foot. Bilateral papilledema was found at the ophthalmic examination. Magnetic resonance imaging (MRI) displayed a mass with homogenous contrast enhancement in the left brain hemisphere and brainstem (Figure 1). On the operation, a subtotal excision was performed. Histopathological examination of the excisional piece revealed a malignant tumor that had anaplasia, marked cellularity, necrotic areas, and a remarkable neoangiogenesis with proliferation of endothelium of the capillaries. The tumor was histopathologically diagnosed as a glioblastoma multiforme. The subtotal excisional surgery was followed by cranial radiotherapy with a total dose of 60 Gy. Then we applied temozolomide (200 mg/m2/day peroral for 5 days; every 4 weeks for 10 cycles) and bevacizumab (10 mg/kg IV; every 2 weeks for 6 cycles) plus irinotecan (125 mg/m2 IV; every 2 weeks for 6 cycles) as first and second-line treatments. However, in the control magnetic resonance imaging, the tumor showed progression despite these treatments. Therefore, we began to use nivolumab as a third-line treatment.\n\nNivolumab therapy was started at a dose of 3 mg/kg intravenously every two weeks. Two days after the second dose, the patient was admitted to the hospital with a rapidly progressive decline in visual acuity of the eyes. On ophthalmic examination, the visual acuity of the right eye was counting fingers at 1 m and was very low on his left eye (limited to light perception). At the posterior segment examination, there was an optic disc swelling bilaterally. Other vital findings, such as blood electrolyte levels and neurological examination, were normal. An urgent MRI showed bilateral thickening of the optic nerves suggestive of optic neuritis, with normal intracranial pressure (Figure 1). Bilateral optic neuritis was diagnosed with the combination of clinical features, ophthalmic examination and radiological findings. Bilateral optic neuritis was diagnosed four days after the progressive decline in visual acuity of the eyes and, first we stopped nivolumab therapy and then the patient began pulse dose steroids; he received intravenous corticosteroids (1 g/day) for 5 days, which resulted in a progressive improvement in visual acuity. After a week, the vision improved to 20/20 in both eyes and he did not need any additional treatment at the next follow-up.\n\n3. Discussion\nAs a treatment option, nivolumab and other immune checkpoint inhibitors are beginning to be preferred in daily clinical practice by researchers. Therefore, immune-related adverse events have significantly increased, however, the adverse events are reported to be less undoubtedly in clinical studies. For example, pneumonitis, type I diabetes mellitus, pruritis, encephalitis, myasthenia gravis, hepatitis, thyroiditis, colitis and other autoimmune diseases can emerge in any part of the body [2,3]. To the best of the authors’ knowledge, this is the first case of nivolumab-associated optic neuritis confirmed by the combination of clinical features, ophthalmic examination, and radiological findings.\n\nIn one case reported by de Velasco and colleagues, nivolumab was associated with uveitis after cycle 28 (10 mg/kg, every 3 weeks) and in another case reported by Karlin and colleagues, the patient developed bilateral uveitis after cycle 10 (3 mg/kg, every 2 weeks) [4,5]. In contrast to these cases, the uveitis was not seen in our patient, however, we encountered bilateral optic neuritis after cycle 2 (3 mg/kg, every 2 weeks). These cases show that, immun ophthalmic disorders could be seen at a considerably lower cumulative dose of the drug.\n\nAccording to some clinical studies, a pulse dose of steroids can be used for optic neuritis [6]. In the study that was made by Beck and colleagues, the response to the IV steroid administration was more rapid than after placebo or oral steroids on the 15th day [7]. The rate of return of visual acuity to normal was higher in the IV steroid group than in the placebo group at six months; however, there are not any significant differences between the oral steroid group and the placebo group [7]. Additionally, the benefit of long-term use of steroids is unknown. Jayakody and colleagues found that, there are no differences in outcome between a shorter (two weeks) and longer (more than two weeks) course of steroids in children with optic neuritis [8]. In our case, immediately after the diagnosis, we started treatment by giving of 30 mg/kg per day IV methylprednisolone, maximum 1 g daily, for 5 days. Because of the patient’s good response to the therapy, we did not prolong the steroid treatment. \n\nIn the pediatric period, bilateral optic neuritis is more common in the younger age-group (<10) as compared to the older age-group (≥10). Waldman and colleagues found that optic neuritis is correlated with age [9]. For every 1-year increase in age, the rate of unilateral optic neuritis (compared with bilateral involvement) is increased by 25% [9]. In accordance with this study, our case is also 9 years old and optic neuritis developed bilaterally.\n\nClinical presentation of optic neuritis may be dramatic, however, the visual outcome of optic neuritis in children, especially in younger children, is fairly good. Wilejto and colleagues evaluated 36 cases with optic neuritis in Canada and found that the visual acuity of 39 of 47 eyes (83%) recovered to ≥20/40 after 2.4 years [10]. Mizota and colleagues evaluated 41 cases and 54 of 61 eyes (95%) recovered to 20/20 or better after a mean follow-up of 10.7 years [11]. In our case, after a week, the vision improved to 20/20 in both eyes. Most likely, this rapid improvement is associated with beginning the pulse steroid treatment immediately.\n\nProbably, nivolumab is responsible for the optic neuritis seen in this patient because of the short duration of time between nivolumab initiation and decrease in visual acuity in this case. Nivolumab, a human immunoglobulin G4 monoclonal antibody against programmed cell death protein 1 receptor, blocks T cell inhibition and stimulates the immunologic response towards cancer cells, however, it may also reduce the self-tolerance of the immune system and may cause an autoimmune phenomenon. Presumably, because of this mechanism the optic neuritis developed bilaterally in our case [12,13].\n\n4. Conclusions\nBilateral optic neuritis as an adverse event of nivolumab therapy has not been reported yet. It is the first known report of bilateral optic neuritis associated with nivolumab in childhood. Nivolumab may stimulate many unknown autoimmune disorders and these may become possible limiting factors in the clinical usage of the drug. Further work is also needed to determine the association between nivolumab and optic neuritis.\n\nAuthor Contributions\nÖ.K.: Concept, study design, data analysis, searching for literature. E.A.: Study design, data analysis.\n\nFunding\nThis article received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 (A) Magnetic resonance image (MRI) of the patient’s brain demonstrating a left brain hemisphere and brainstem glioblastoma; (B) On T1-weighted sequence, after contrast injection, an enhancement of the bilateral optic nerve compatible with optic neuritis.\n==== Refs\nReferences\n1. Yi Y. Hsieh I. Huang X. Li J. Zhao W. Glioblastoma Stem-Like Cells: Characteristics Microenviron. Ther. Front. Pharmacol. 2016 7 477 \n2. Tanaka R. Maruyama H. Tomidokoro Y. Yanagiha K. Hirabayashi T. Ishii A. Okune M. Inoue S. Sekine I. Tamaoka A. Nivolumab-induced chronic inflammatory demyelinating polyradiculoneuropathy mimicking rapid-onset Guillain-Barré syndrome: A case report Jpn. J. Clin. Oncol. 2016 46 875 878 10.1093/jjco/hyw090 27380808 \n3. Abe J. Sato T. Tanaka R. Okazaki T. Takahashi S. Nivolumab-Induced Severe Akathisia in an Advanced Lung Cancer Patient Am. J. Case Rep. 2016 17 880 882 10.12659/AJCR.900941 27893699 \n4. De Velasco G. Bermas B. Choueiri T. Autoimmune Arthropathy and Uveitis as Complications of Programmed Death 1 Inhibitor Treatment Arthritis Rheumatol. 2016 68 556 557 10.1002/art.39406 26314277 \n5. Karlin J. Gentzler R. Golen J. Bilateral Anterior Uveitis Associated with Nivolumab Therapy Ocul. Immunol. Inflamm. 2016 26 283 285 10.1080/09273948.2016.1215473 27599197 \n6. Yeh E. Graves J. Benson L. Wassmer E. Waldman A. Pediatric optic neuritis Neurology 2016 87 53 58 10.1212/WNL.0000000000002822 27572862 \n7. Beck R. Cleary P. Anderson M.M. Jr. Keltner J. Shults W. Kaufman D. Buckley E.G. Corbett M.J. Kupersmith M.J. Miller N.R. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis: The Optic Neuritis Study Group N. Engl. J. Med. 1992 326 581 588 10.1056/NEJM199202273260901 1734247 \n8. Jayakody H. Bonthius D. Longmuir R. Joshi C. Pediatric optic neuritis: Does a prolonged course of steroids reduce relapses? A preliminary study Pediatr. Neurol. 2014 51 721 725 10.1016/j.pediatrneurol.2014.07.020 25152962 \n9. Waldman A. Stull L. Galetta S. Balcer L. Liu G. Pediatric optic neuritis and risk of multiple sclerasis: Meta-analysis of observational studies J. AAPOS 2011 15 441 446 10.1016/j.jaapos.2011.05.020 22108356 \n10. Wilejto M. Shroff M. Buncic J. Kennedy J. Goia C. Banwell B. The clinical features, MRI findings, and outcome of optic neuritis in children Neurology 2006 67 258 262 10.1212/01.wnl.0000224757.69746.fb 16864818 \n11. Mizota A. Niimura M. Adachi-Usami E. Clinical characteristics of Japanese children with optic neuritis Pediatr. Neurol. 2004 31 42 45 10.1016/j.pediatrneurol.2003.11.011 15246491 \n12. Jung K. Zeng X. Bilusic M. Nivolumab-associated acute glomerulonephritis: A case report and literature review BMC Nephrol. 2016 17 188 10.1186/s12882-016-0408-2 27876011 \n13. Edmondson L.A. Smith L.V. Mallik A. Nivolumab-induced vitiligo in a metastatic melanoma patient: A case report J. Oncol. Pharm. Pract. 2017 23 629 634 10.1177/1078155216667636 27609337\n\n", "fulltext_license": "CC BY", "issn_linking": "1010-660X", "issue": "54(5)", "journal": "Medicina (Kaunas, Lithuania)", "keywords": "glioblastoma multiforme; nivolumab; optic neuritis", "medline_ta": "Medicina (Kaunas)", "mesh_terms": "D000305:Adrenal Cortex Hormones; D000074322:Antineoplastic Agents, Immunological; D001327:Autoimmune Diseases; D001932:Brain Neoplasms; D002648:Child; D018450:Disease Progression; D005909:Glioblastoma; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D000077594:Nivolumab; D009902:Optic Neuritis", "nlm_unique_id": "9425208", "other_id": null, "pages": null, "pmc": null, "pmid": "30404191", "pubdate": "2018-11-06", "publication_types": "D002363:Case Reports", "references": "22108356;25152962;27599197;1734247;27609337;27572862;28003805;15246491;26314277;27876011;27380808;16864818;27893699", "title": "Bilateral Optic Neuritis Secondary to Nivolumab Therapy: A Case Report.", "title_normalized": "bilateral optic neuritis secondary to nivolumab therapy a case report" }

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{ "abstract": "OBJECTIVE\nTo evaluate platinum rechallenge efficacy and tolerance in patients presenting recurrent head and neck squamous cell carcinoma (HNSCC) after platinum-based chemoradiation.\n\n\nMETHODS\nWe retrospectively included all patients treated from 2007 to 2016 by platinum-based polychemotherapy for recurrence of HNSCC previously treated by primary or postsurgical platinum-based chemoradiation. The primary end-point was disease control rate (DCR) on platinum rechallenge.\n\n\nRESULTS\nForty-five patients were included. Median disease-free interval (DFI) after chemoradiation was 5.7 months. DCR on platinum rechallenge was 40%. Progression-free survival at recurrence was 3.7 months and overall survival 5.0 months. DCR in patients with recurrence within 6 months of chemoradiotherapy was 47.8%. DFI>4.5 months was associated with better DCR: 28.5% versus 54.8%; P=0.0311.\n\n\nCONCLUSIONS\nPlatinum rechallenge provided good DCR in recurrent HNSCC after chemoradiation.", "affiliations": "Head and Neck Oncology, Centre François Baclesse, Avenue du Général Harris, 14000 Caen, France; Medical Oncology Department, Centre François Baclesse, Caen, France. Electronic address: audrey.rambeau@gmail.com.;Clinical Research Department, Centre François Baclesse, Caen, France.;Head and Neck Oncology, Centre François Baclesse, Avenue du Général Harris, 14000 Caen, France; Radiotherapy Department, Centre Francois Baclesse, Caen, France.;Head and Neck Oncology, Centre François Baclesse, Avenue du Général Harris, 14000 Caen, France; Medical Oncology Department, Centre François Baclesse, Caen, France.;Head and Neck Oncology, Centre François Baclesse, Avenue du Général Harris, 14000 Caen, France; Radiotherapy Department, Centre Francois Baclesse, Caen, France.;Head and Neck Surgery Department, University Hospital, Caen, France.;Head and Neck Oncology, Centre François Baclesse, Avenue du Général Harris, 14000 Caen, France; Head and Neck Surgery Department, Centre François Baclesse, Caen, France.;Head and Neck Oncology, Centre François Baclesse, Avenue du Général Harris, 14000 Caen, France; Medical Oncology Department, Centre François Baclesse, Caen, France.;Head and Neck Oncology, Centre François Baclesse, Avenue du Général Harris, 14000 Caen, France; Radiotherapy Department, Centre Francois Baclesse, Caen, France.", "authors": "Rambeau|A|A|;Licaj|I|I|;Gery|B|B|;Gervais|R|R|;Florescu|C|C|;Babin|E|E|;De Raucourt|D|D|;Johnson|A|A|;Thariat|J|J|", "chemical_list": "D016190:Carboplatin; D000068818:Cetuximab; D002945:Cisplatin", "country": "France", "delete": false, "doi": "10.1016/j.anorl.2019.04.007", "fulltext": null, "fulltext_license": null, "issn_linking": "1879-7296", "issue": "136(4)", "journal": "European annals of otorhinolaryngology, head and neck diseases", "keywords": "Carboplatin; Cisplatin; Head and neck cancer; Recurrence", "medline_ta": "Eur Ann Otorhinolaryngol Head Neck Dis", "mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D000068818:Cetuximab; D059248:Chemoradiotherapy; D002945:Cisplatin; D018572:Disease-Free Survival; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck; D055815:Young Adult", "nlm_unique_id": "101531465", "other_id": null, "pages": "257-261", "pmc": null, "pmid": "31003864", "pubdate": "2019-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Platinum rechallenge in recurrent head and neck squamous cell carcinoma after primary chemoradiation.", "title_normalized": "platinum rechallenge in recurrent head and neck squamous cell carcinoma after primary chemoradiation" }

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{ "abstract": "BACKGROUND\nAnti-tumour necrosis factor [anti-TNF] treatment was demonstrated to have disease-modifying abilities in inflammatory bowel disease [IBD]. In this study, we aimed to determine the effect of anti-TNF treatment timing on IBD disease complications and mucosal healing [MH].\n\n\nMETHODS\nThe following IBD-related complications were tested in relation to timing of anti-TNF therapy start in newly diagnosed IBD patients [n = 413]: fistula formation, abscess formation, extra-intestinal manifestations [EIM], surgery, referral to academic centre, and MH.\n\n\nRESULTS\nA total of 85 patients [21%] received anti-TNF (66 Crohn's disease [CD], 16 ulcerative colitis [UC], 3 inflammatory bowel disease unclassified [IBDU]) of whom 57% [48 patients] were treated < 16 months after diagnosis. Patients receiving anti-TNF early [< 16 months] did not differ from patients receiving anti-TNF late [> 16 months] regarding gender, age, smoking status, and familial IBD. More importantly, patients receiving anti-TNF early did not suffer less IBD-related complications during follow-up as compared with patients started on anti-TNF late, nor was more MH observed. Similar results were obtained when anti-TNF treated patient were stratified more stringently, ie < 12 months [40 patients] vs >2 4 months [24 patients]. Cox regression analysis showed no beneficial correlations between anti-TNF timing and IBD-related complications. Anti-TNF treated patients achieving MH were 11 times less likely to develop EIMs compared with patients who did not achieved MH while on anti-TNF.\n\n\nCONCLUSIONS\nThis study was unable to confirm a benefit of earlier anti-TNF treatment on IBD disease complications. This could be explained by more aggressive treatment earlier in disease, resulting in fewer IBD complications. However, it seems more likely that inappropriate selection of patients for therapy leads to suboptimal treatment and subsequently suboptimal outcome.", "affiliations": "Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands v.nuij@erasmusmc.nl.;Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.;Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.;Department of Gastroenterology and Hepatology, Ikazia Hospital, Rotterdam, The Netherlands.;Department of Gastroenterology and Hepatology, Amphia Hospital, Breda, The Netherlands.;Department of Gastroenterology and Hepatology, Albert Schweitzer Hospital, Dordrecht, The Netherlands.;Department of Gastroenterology and Hepatology, Reinier de Graaf Gasthuis, Delft, The Netherlands.;Department of Gastroenterology and Hepatology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands.;Department of Gastroenterology and Hepatology, IJsselland Hospital, Capelle aan den IJssel, The Netherlands.;Department of Internal Medicine, Lievensberg Hospital, Bergen op Zoom, The Netherlands.;Department of Gastroenterology and Hepatology, Tweesteden Hospital, Tilburg, The Netherlands.;Department of Gastroenterology and Hepatology, Franciscus Hospital, Roosendaal, The Netherlands.;Department of Gastroenterology and Hepatology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-les-Nancy, France.;Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.", "authors": "Nuij|Veerle|V|;Fuhler|Gwenny M|GM|;Edel|Annemarie J|AJ|;Ouwendijk|Rob J T|RJ|;Rijk|Marno C M|MC|;Beukers|Ruud|R|;Quispel|Rutger|R|;van Tilburg|Antonie J P|AJ|;Tang|Thjon J|TJ|;Smalbraak|Hermen|H|;Bruin|Karlien F|KF|;Lindenburg|Flordeliz|F|;Peyrin-Biroulet|Laurent|L|;van der Woude|C Janneke|CJ|;|||", "chemical_list": "D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D000069285:Infliximab; D000068879:Adalimumab", "country": "England", "delete": false, "doi": "10.1093/ecco-jcc/jjv130", "fulltext": null, "fulltext_license": null, "issn_linking": "1873-9946", "issue": "9(11)", "journal": "Journal of Crohn's & colitis", "keywords": "Inflammatory bowel disease; anti-TNF; disease complications", "medline_ta": "J Crohns Colitis", "mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D007413:Intestinal Mucosa; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D016016:Proportional Hazards Models; D012017:Referral and Consultation; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult", "nlm_unique_id": "101318676", "other_id": null, "pages": "997-1003", "pmc": null, "pmid": "26223842", "pubdate": "2015-11", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Benefit of Earlier Anti-TNF Treatment on IBD Disease Complications?", "title_normalized": "benefit of earlier anti tnf treatment on ibd disease complications" }

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{ "abstract": "BACKGROUND\nUlcerative colitis (UC) is one of the major types of inflammatory bowel diseases and is associated with a significantly increased risk of not only lymphoproliferative disorders but also lymphomas, of which most cases are related to the long-term usage of immunosuppressants. Here, we demonstrate a very rare case of other iatrogenic immunodeficiency-associated colonic diffuse large B-cell lymphoma (Oii-DLBCL) complicating UC and rectal perforation. In addition, we reviewed the clinicopathological features of previous cases of DLBCL related to UC.\n\n\nMETHODS\nA 68-year-old man was diagnosed with left-sided UC 26 months prior. Although he was followed by immunosuppressive therapy with azathioprine and infliximab, an emergency total proctocolectomy was performed due to rectal perforation. The resected specimen exhibited irregular wall thickening and elevated multinodular lesions extending from the mid-transverse colon to the rectum, measuring up to 52 cm in length. Histologically, the lesion was diagnosed as Oii-DLBCL and crypt abscess surrounded by mixed inflammatory cell was remained.\n\n\nCONCLUSIONS\nOii-DLBCL complicating UC with rectal perforation is extremely rare. Macro- and microscopic findings are important for early diagnosis of the lesion.", "affiliations": "Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.;Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan. r-ooe@med.id.yamagata-u.ac.jp.;Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.;Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.;Department of Gastroenterological, General, Breast and Thyroid Surgery (First Department of Surgery), Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Gastroenterology, Sanyudo Hospital, Yonezawa, Japan.;Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan.;Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.", "authors": "Suzuki|Kazushi|K|;Ohe|Rintaro|R|https://orcid.org/0000-0002-8035-791X;Kabasawa|Takanobu|T|https://orcid.org/0000-0001-7349-3748;Aung|Naing Ye|NY|https://orcid.org/0000-0001-5309-781X;Yano|Mitsuhiro|M|;Katsumi|Shuichiro|S|;Yanagiya|Ryo|R|;Yamamoto|Masakazu|M|;Toubai|Tomomi|T|;Ishizawa|Kenichi|K|;Yamakawa|Mitsunori|M|", "chemical_list": "D007166:Immunosuppressive Agents; D000069285:Infliximab; D001379:Azathioprine", "country": "England", "delete": false, "doi": "10.1186/s13000-020-00954-8", "fulltext": "\n==== Front\nDiagn Pathol\nDiagn Pathol\nDiagnostic Pathology\n1746-1596 BioMed Central London \n\n954\n10.1186/s13000-020-00954-8\nCase Report\nA case of iatrogenic immunodeficiency-associated colonic lymphoma complicating ulcerative colitis\nSuzuki Kazushi 1 https://orcid.org/0000-0002-8035-791XOhe Rintaro r-ooe@med.id.yamagata-u.ac.jp 1 https://orcid.org/0000-0001-7349-3748Kabasawa Takanobu 1 https://orcid.org/0000-0001-5309-781XAung Naing Ye 1 Yano Mitsuhiro 2 Katsumi Shuichiro 3 Yanagiya Ryo 4 Yamamoto Masakazu 4 Toubai Tomomi 4 Ishizawa Kenichi 4 Yamakawa Mitsunori 1 1 grid.268394.20000 0001 0674 7277Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585 Japan \n2 grid.268394.20000 0001 0674 7277Department of Gastroenterological, General, Breast and Thyroid Surgery (First Department of Surgery), Yamagata University Faculty of Medicine, Yamagata, Japan \n3 Department of Gastroenterology, Sanyudo Hospital, Yonezawa, Japan \n4 grid.268394.20000 0001 0674 7277Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan \n7 4 2020 \n7 4 2020 \n2020 \n15 343 3 2020 30 3 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nUlcerative colitis (UC) is one of the major types of inflammatory bowel diseases and is associated with a significantly increased risk of not only lymphoproliferative disorders but also lymphomas, of which most cases are related to the long-term usage of immunosuppressants. Here, we demonstrate a very rare case of other iatrogenic immunodeficiency-associated colonic diffuse large B-cell lymphoma (Oii-DLBCL) complicating UC and rectal perforation. In addition, we reviewed the clinicopathological features of previous cases of DLBCL related to UC.\n\nCase presentation\nA 68-year-old man was diagnosed with left-sided UC 26 months prior. Although he was followed by immunosuppressive therapy with azathioprine and infliximab, an emergency total proctocolectomy was performed due to rectal perforation. The resected specimen exhibited irregular wall thickening and elevated multinodular lesions extending from the mid-transverse colon to the rectum, measuring up to 52 cm in length. Histologically, the lesion was diagnosed as Oii-DLBCL and crypt abscess surrounded by mixed inflammatory cell was remained.\n\nConclusion\nOii-DLBCL complicating UC with rectal perforation is extremely rare. Macro- and microscopic findings are important for early diagnosis of the lesion.\n\nJapan Society for the Promotion of ScienceJP17K08736JP19K16577Ohe Rintaro Yamakawa Mitsunori issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nIt is generally accepted that inflammatory bowel disease (IBD) itself is not a risk factor for lymphomas [1]. Lymphomas complicating ulcerative colitis (UC), which are known as other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPDs), are caused by immunosuppressants such as azathioprine, 6-mercaptopurine, and infliximab [2, 3].\n\nAccording to data found in PubMed between 2001 and 2019, only ten cases of diffuse large B-cell lymphoma (DLBCL) complicating UC, including one case of large B-cell lymphoma with unknown details, have been reported [1, 3–11]. Approximately half of these cases are closely related to the long-term usage of immunosuppressants (70%, 7/10 cases) and a very high rate of Epstein-Barr virus (EBV) infection (80%, 4/5 cases) and are classified as Oii-LPD. In Oii-LPD, an EBV-positive mucocutaneous ulcer (EBVMCU) is a specific type of immunosuppression-associated LPD due to the long-term usage of iatrogenic immunosuppressants or age-related immunosenescence [2, 12].\n\nHere, we report a very rare case of Oii-LPD complicating UC and rectal perforation. At first, the histological findings were similar to those of DLBCL or EBVMCU. Then, the macroscopic and histological findings with the aid of immunophenotypic analysis suggested that the lesion was of the Oii-LPD, DLBCL phenotype.\n\nCase presentation\nClinical presentation\nA 68-year-old man was diagnosed with left-sided UC 26 months prior and was followed up without any treatment. He was first treated with 5-aminosalicylate because of worsening of diarrhea. A dose of 30–50 mg/day of prednisolone was also administered for the control of diarrhea and bloody stools. However, his symptoms repeatedly recurred with the sequentially decreasing usage of prednisolone. He was treated with an initial dose of 25 mg/day of azathioprine and a dose of 5 mg/kg twice daily of infliximab 8 months prior, but he could not obtain a satisfactory improvement in symptoms. Ultimately, he was diagnosed with pancolitic UC by colonoscopy. Ganciclovir was administered 1 month prior due to cytomegalovirus (CMV) antigenemia. Though the serum CMV antigen disappeared, the patient was transferred to our hospital with a complaint of a persistent fever and a perianal fistula. Immediately, abdominal computed tomography showed circumferential thickening of the rectal wall and a discontinuity in contrast enhancement of the posterior rectal wall. Because of suspicion of rectal perforation, an emergency total proctocolectomy was performed. After the total proctocolectomy, the patient achieved clinical remission without any additional treatment. There was no recurrence for 40 months after the operation, as shown by computed tomography. The resected specimen was fixed in 10% buffered formalin, and paraffin-embedded tissue sections were used for histological examination.\n\nPathological findings\nThe resected specimen exhibited irregular wall thickening and elevated multinodular lesions extending from the mid-transverse colon to the rectum, measuring up to 52 cm in length (Fig. 1). Multiple sharply circumscribed ulcers and geographic necrosis were present. A rectal perforation, approximately 2 cm in diameter, was also noted. No abnormal mesenteric lymphadenopathy was noted.\nFig. 1 Total proctocolectomy specimen: Diffuse, irregular thickening of the colorectal wall extends from the middle of the transverse colon (red broken lines) to the rectum with a rectal perforation (yellow circular broken line). The image of perforation department is shown (Inset)\n\n\n\nMicroscopically, the resected lesion exhibited the diffuse transmural proliferation of lymphocytes and immunoblasts (Fig. 2a). Many polymorphic, large, atypical lymphocytes and scattered Hodgkin-like cells were present intermingled with scattered plasma cells, histiocytes and eosinophils in the background (Fig. 2b & c). Apoptotic bodies with plasmacytoid features were absent. Additionally, around the lymphoma, more remarkably in the distal colon than in the proximal colon remote to the lymphoma, admixed inflammatory cells composed of reactive lymphocytes with occasional lymphoid follicles, plasma cells including basal plasmacytosis, histiocytes, neutrophils often with cryptitis and crypt abscesses, and eosinophils infiltrated in the lamina propria mucosae with or without erosion or ulcers, indicating histological features compatible with UC, grade 5 in the maximal degree (Fig. 2d). Pleomorphic, large, atypical lymphocytes were immunohistochemically positive for CD20 (Fig. 3a), CD79a, MUM-1, and κ-light chain and negative for CD3, CD5, BCL-2, BCL-6, c-Myc, GCET1, Foxp1, and λ-light chain. The cells were also positive for κ-light chain but not λ-light chain according to in situ hybridization (ISH) (Fig. 3b & c). Scattered Hodgkin-like cells were immunohistochemically positive for CD20, CD30 (Fig. 3d), CD79a, PAX5, and LMP-1 (partially) but not CD10, CD15, BOB1, OCT2, BCL-6, or MUM-1. In both atypical lymphocytes and Hodgkin-like cells, Epstein-Barr encoding region (EBER)-1 positivity was detected by ISH (Fig. 3e). The base of the ulcer was rimmed by numerous medium-sized T-cells positive for CD3. Polymerase chain reaction (PCR) revealed a gene rearrangement of the immunoglobulin heavy chain but not the γ-chain of the T-cell receptor. Based on these clinical, histological and immunohistochemical findings, this lesion was diagnosed as Oii-LPD, DLBCL phenotype, polymorphous subtype. Large, atypical cells with a viral inclusion body were absent and immunohistochemically negative for CMV.\nFig. 2 Histological findings of the resected colon: a The resected colon is transmurally infiltrated by lymphoid cells, and the existing structure is indistinct. b Atypical polymorphous cells diffusely proliferate. c A few Hodgkin-like cells with an eosinophilic nucleolus in the center of a large nucleus are present. d A crypt abscess surrounded by mixed inflammatory cell infiltrates is present in the lamina propria mucosae remote from the lymphoma, compatible with the findings of UC\n\nFig. 3 Immunophenotypic findings of the resected colon: Large, atypical polymorphous lymphoid cells are positive for CD20 by immunohistochemistry (a), positive for the κ-light chain (b) and negative for λ-light chain (c) by in situ hybridization (ISH). Hodgkin-like cells are positive for CD30 by immunohistochemistry (d) and Epstein-Barr encoding region (EBER)-1 (e, Arrowhead) by ISH. Some large, atypical lymphoid cells also are positive for EBER-1 (e) by ISH. In a retrospective analysis, EBER-1-positive large atypical cells are present on the 9-day and 3-week colorectal tissue sections (f & g)\n\n\n\nAs a retrospective analysis, immunohistochemistry for CMV and ISH for EBER-1, κ-light chain, and λ-light chain were performed on paraffin-embedded tissue sections obtained from the colorectal biopsies of our patient at 9 days, 3 weeks, 6 months, 8 months, and 10 months before admission to our hospital. CMV-positive cells were present on the 3-week and 6-month tissue sections. EBER-1-positive large, atypical cells were present on the 9-day and 3-week tissue sections (Fig. 3f & g). There was no restriction of the κ-light chain or λ-light chain by ISH on any biopsied specimen.\n\nDiscussion and conclusion\nWe reviewed the clinicopathological data of 11 cases of DLBCL complicating UC published in the English literature, including our case, as shown in Table 1 [1, 3–11]. The age at diagnosis ranged from 20 to 73 (median, 55) years. Surprisingly, this disease occurs more frequently in males than in females (male to female ratio = 10:1). The UC lesion was confined to the left side of the colon in 4 cases and extended to the whole colon in 5 cases. The duration of disease ranged from 26 to 300 (median, 84) months, and the duration of treatment with immunosuppressants ranged from 6 to 60 (median, 32) months. Both durations in our case were the shortest among all cases. Among these 6 available cases, 3 achieved remission and 3 died. Infliximab was used in 4 cases. However, it is difficult to conclude that treatment with infliximab is related to the increased risk of lymphoma because there are few cases of patients treated by infliximab monotherapy, and the influence of the azathioprine combination is unclear [1]. Conversely, there were 3 cases with DLBCL complicating UC without immunosuppressant treatment, although IBD itself is not a risk factor of lymphoma [1]. Surprisingly, colorectal perforation occurred in 4 cases, including ours. Our patient unavoidably underwent a proctocolectomy because of rectal perforation. The choice of surgical resection may not necessarily be better when the lesion is diagnosed as Oii-DLBCL. Therefore, a careful follow-up with recognition of the possibility of Oii-DLBCL complicating UC and early detection of the disease confirmed by an appropriate pathological diagnosis may be crucial to obtain a good prognosis.\nTable 1 Clinicopathological data of diffuse large B-cell lymphoma (DLBCL) complicating ulcerative colitis published in English literature from 2001 to 2019\n\nAuthors, year\tAge/Sex\tUlcerative colitis\tImmunosuppressant treatment\tIatrogenic immunodeficiency-associated lymphoproliferative disorders\tOutcome\t\nSite\tDuration (month)\tImmuno-suppressant\tDuration (month)\tType\tSite\tMass\tEBV\tperforation\t\nTan, et al., 2001 [4]\t36/M\tLeft-side\t84\tAZA\t32\tDLBCL\tRectum\t+\tN/A\tN/A\tDead (due to renal insufficiency by the disease progression)\t\nKhan, et al., 2001 [5]\t55/M\tPancolic\t300\tNone\tNone\tLCL, B-cell lineage\tRectum\tN/A\tN/A\tN/A\tRemission\t\nWatanabe, et al., 2003 [6]\t42/F\tLeft-side\t120\tNone\tNone\tDLBCL\tColon\t+\tN/A\tN/A\tDead (due to MRSA pneumonia after the transplant)\t\nSchwartz, et al., 2006 [7]\t29/M\tPancolic\t48\t6MP, IFX, CYA\t24\tDLBCL\tIleal pouch\t+\t+\tN/A\tRemission\t\nShibahara, et al., 2006 [8]\t33/M\tPancolic\t108\tAZA, CYA\t48\tDLBCL\tRectum\t+\tN/A\tN/A\tRemission\t\nVan Hauwaert, et al., 2010 [9]\t20/M\tN/A\tN/A\tAZA, IFX\t60\tDLBCL\tRectum\t+\t–\tN/A\tN/A\t\nKhan, et al., 2012 [10]\t59/M\tN/A\t132\tNone\tNone\tDLBCL\tRectum\t+\tN/A\t+\tN/A\t\nAllen, et al., 2013 [1]\t65/M\tLeft-side\t60\tAZA, 6MP, IFX\t60\tDLBCL\tColon\t+\t+\t+\tN/A\t\nHiyama, et al., 2014 [11]\t69/M\tLeft-side\t42\tAZA\t24\tDLBCL\tRectum\t-;\n\nUlcer\n\n\t+\t+\tDead (due to DIC secondary to sepsis)\t\nChang, et al. 2016 [3]\t73/M\tPancolic\tN/A\tMTX\tSeveral years\tDLBCL\tColon\t+\t+\tN/A\tN/A\t\nOur case\t68/M\tPancolic\t26\tAZA, IFX\t6\tDLBCL\tColon\t+\t+\t+\tRemission\t\nM male, F female, AZA azathioprine, 6MP 6-mercaptopurine, IFX infliximab, CYA cyclosporine A, MTX methotrexate, LCL large cell lymphoma, LN lymph node, EBV Epstein-Barr virus, N/A not available, MRSA methicillin-resistant Staphylococcus aureus, DIC disseminated intravascular coagulation syndrome\n\n\n\nEBVMCU is recognized by characteristic histological features, such as well-circumscribed ulcers and the infiltration of polymorphous cells (e.g., Hodgkin/Reed-Sternberg-like cells, numerous medium-sized T-cells, and apoptotic bodies with plasmacytoid features) in the background of lymphoma [13]. Natkunam et al. proposed additional findings, including ulcerative lesions without a mass, the rimming of small T-cells at the ulcer base, and detection of the clonal immunoglobulin or T-cell receptor gene rearrangement [14]. The lesions described in the present case were grossly composed of mostly circumscribed ulcers and multiple nodules without apparent voluminous mass lesions, measuring 52 cm in length. Histologically, large B-cells diffusely proliferated intermingled with scattered CD30-positive Hodgkin/Reed-Sternberg-like cells and numerous medium-sized CD3-positive T-cells rimming the base of the ulcer. However, plasmacytoid apoptotic bodies were absent. Clonal immunoglobulin κ-light chain was detected by immunohistochemistry and ISH. PCR also revealed a gene rearrangement of the immunoglobulin heavy chain but not the γ-chain of the T-cell receptor. Although these findings suggested EBVMCU, this patient was diagnosed with Oii-LPD, DLBCL phenotype.\n\nSatou A et al. speculated that defective immune surveillance may be caused by a strong suppression of EBV-specific cytotoxic T-cell function, leading to CMV colitis [15], which is a candidate parameter of immunosuppression but not a causative event of the evolution of Oii-LPD. In our case, CMV infection was treated with ganciclovir, and CMV-positive cells were not detected immunohistochemically on either the surgical specimen or the colorectal biopsy specimen 9 days before admission or 3 days before admission to our hospital.\n\nIn conclusion, Oii-DLBCL complicating UC with rectal perforation is extremely rare and poorly understood. Macro- and microscopic findings suggested EBVMCU; these findings included well-circumscribed ulcers without an evident voluminous mass lesion, polymorphous infiltration, the absence of plasmacytoid apoptotic bodies, and the rimming of small T-cells at the ulcer base, as well as detection of the clonal immunoglobulin or T-cell receptor gene rearrangement, which are important for early diagnosis of the lesion. Furthermore, it should be emphasized that colonic perforation frequently occurs in cases of Oii-DLBCL.\n\nAbbreviations\nIBDInflammatory bowel disease\n\nUCUlcerative colitis\n\nOii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorder\n\nDLBCLDiffuse large B-cell lymphoma\n\nEBVMCUEBV-positive mucocutaneous ulcer\n\nCMVCytomegalovirus\n\nISHIn situ hybridization\n\nEBEREpstein-Barr encoding region\n\nPCRPolymerase chain reaction\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThis work was supported by a Grant-in-Aid for Scientific Research (C) (JP17K08736) and a Grant-in-Aid for Young Scientists (JP19K16577) of Japan Society for the Promotion of Science. The author is grateful to Hiromi Murata, Junko Takeda, Takumi Kitaoka, Nobuyuki Tamazawa, Yuka Tamura, and Aya Utsunomiya (Department of Pathological Diagnostics, Yamagata University Faculty of Medicine, Yamagata, Japan), and Yumi Eguchi and Hiromi Takahashi (Division of Clinical Laboratory, Sanyudo Hospital, Yonezawa, Japan) for their valuable assistance during this study.\n\nAuthors’ contributions\nData preparation, SK, OR, KT, AN, Yano M, KS, YR, Yamamoto M, TT, IK, Yamakawa M; Original draft preparation and writing, SK, OR; Draft review and editing OR, Yamakawa M; All authors read and approved the final manuscript.\n\nFunding\nJapan Society for the Promotion of Science, Grant/Award Number: JP17K08736 & JP19K16577.\n\nAvailability of data and materials\nIs available upon request from the corresponding author.\n\nEthics approval and consent to participate\nThis study was approved by the Research Ethics Committee of Yamagata University Faculty of Medicine (2019-S-84) and was performed in accordance with the Declaration of Helsinki.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. 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Van Hauwaert V Meers S Verhoef G Rectal non-Hodgkin's lymphoma in an infliximab treated patient with ulcerative colitis and primary sclerosing cholangitis J Crohns Colitis 2010 4 683 686 10.1016/j.crohns.2010.06.006 21122582 \n10. Khan A Lloyd GM Ihedioha U Hemingway D Rectovesical fistula secondary to B-cell lymphoma of the rectum: a unique presentation of a rare disease Color Dis 2012 14 e358 e359 10.1111/j.1463-1318.2011.02868.x \n11. Hiyama K Terashima H Nakano Y Primary rectal diffuse large B-cell lymphoma associated with ulcerative colitis: a case report Clin Case Rep 2015 3 150 155 10.1002/ccr3.185 25838903 \n12. Gaulard P Swerdlow SH Harris NL C. S Jaffe ES Swerdlow SH Campo E Harris NL EBV-positive mucocutaneous ulcer WHO classification of tumors of hematopoietic and lymphoid tissues. Revised 4th ed 2017 Lyon IARC 307 308 \n13. Dojcinov SD Venkataraman G Raffeld M Pittaluga S Jaffe ES EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression Am J Surg Pathol 2010 34 405 417 10.1097/PAS.0b013e3181cf8622 20154586 \n14. Natkunam Y Goodlad JR Chadburn A EBV-positive B-cell proliferations of varied malignant potential: 2015 SH/EAHP workshop report-part 1 Am J Clin Pathol 2017 147 129 152 10.1093/ajcp/aqw214 28395107 \n15. Satou A Kohno A Fukuyama R Elsayed AA Nakamura S Epstein-Barr virus-positive mucocutaneous ulcer arising in a post-hematopoietic cell transplant patient followed by polymorphic posttransplant lymphoproliferative disorder and cytomegalovirus colitis Hum Pathol 2017 59 147 151 10.1016/j.humpath.2016.08.001 27569297\n\n", "fulltext_license": "CC BY", "issn_linking": "1746-1596", "issue": "15(1)", "journal": "Diagnostic pathology", "keywords": null, "medline_ta": "Diagn Pathol", "mesh_terms": "D000368:Aged; D001379:Azathioprine; D003093:Colitis, Ulcerative; D015179:Colorectal Neoplasms; D006801:Humans; D007049:Iatrogenic Disease; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D000069285:Infliximab; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male", "nlm_unique_id": "101251558", "other_id": null, "pages": "34", "pmc": null, "pmid": "32264892", "pubdate": "2020-04-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11450782;24081592;11507370;14714955;28395107;16854631;16460502;27785332;27569297;21122582;22022922;25838903;20154586", "title": "A case of iatrogenic immunodeficiency-associated colonic lymphoma complicating ulcerative colitis.", "title_normalized": "a case of iatrogenic immunodeficiency associated colonic lymphoma complicating ulcerative colitis" }

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A CASE OF IATROGENIC IMMUNODEFICIENCY?ASSOCIATED COLONIC LYMPHOMA COMPLICATING ULCERATIVE COLITIS. DIAGN?PATHOL 2020?:.", "literaturereference_normalized": "a case of iatrogenic immunodeficiency associated colonic lymphoma complicating ulcerative colitis", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210506", "receivedate": "20210506", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19220413, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" } ]

{ "abstract": "The combination of rituximab, cyclophosphamide, and dexamethasone (RCD) is highly effective in the treatment of warm autoimmune hemolytic anemia (WAIHA) associated with chronic lymphocytic leukemia (CLL). We treated a cohort of patients with relapsed/refractory WAIHA, without CLL, with RCD. The primary objective was to evaluate the overall response (OR) of RCD therapy. Complete response (CR) was defined as a hemoglobin (Hgb) ≥12 g/dL. Partial response (PR) was defined as Hgb 10-11.9 g/dL or ≥2 g/dL increase in Hgb. Sustained response was defined as Hgb ≥10 g/dL with no treatment changes. A total of 16 patients with relapsed/refractory WAIHA received RCD (7 primary WAIHA, 9 secondary WAIHA) for a median of 4 cycles (range: 2-6). The median pretreatment Hgb was 10.0 g/dL (range: 4.3-12.2). The median best Hgb achieved was 12.5 g/dL (range: 10.6-15.1) with a median of 2 cycles until best Hgb response. The OR was 94% (11 CR, 4 PR). Two immunocompromised patients were admitted for infections during RCD treatment. There were no deaths during the treatment or follow-up period. Following a response to RCD, 4 patients received noncorticosteroid immune modulation therapy and 4 patients continued on corticosteroid therapy. Seven patients received no additional treatment.", "affiliations": "Jane Anne Nohl Division of Hematology, Department of Medicine, University of Southern California - Keck School of Medicine, Los Angeles, California, USA, caroline.piatek@med.usc.edu.;Department of Medicine, University of Southern California - Keck School of Medicine, Los Angeles, California, USA.;Jane Anne Nohl Division of Hematology, Department of Medicine, University of Southern California - Keck School of Medicine, Los Angeles, California, USA.;Jane Anne Nohl Division of Hematology, Department of Medicine, University of Southern California - Keck School of Medicine, Los Angeles, California, USA.;Jane Anne Nohl Division of Hematology, Department of Medicine, University of Southern California - Keck School of Medicine, Los Angeles, California, USA.;Jane Anne Nohl Division of Hematology, Department of Medicine, University of Southern California - Keck School of Medicine, Los Angeles, California, USA.", "authors": "Piatek|Caroline I|CI|;Bocian|Hillel|H|;Algaze|Sandra|S|;Weitz|Ilene C|IC|;O'Connell|Casey|C|;Liebman|Howard A|HA|", "chemical_list": "D000305:Adrenal Cortex Hormones; D006454:Hemoglobins; D007155:Immunologic Factors; D000069283:Rituximab; D003907:Dexamethasone; D003520:Cyclophosphamide", "country": "Switzerland", "delete": false, "doi": "10.1159/000501538", "fulltext": null, "fulltext_license": null, "issn_linking": "0001-5792", "issue": "143(3)", "journal": "Acta haematologica", "keywords": "Autoimmune hemolytic anemia; Hemolytic anemia; Immune cytopenias", "medline_ta": "Acta Haematol", "mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D003907:Dexamethasone; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006454:Hemoglobins; D006801:Humans; D007155:Immunologic Factors; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D013156:Splenectomy; D016896:Treatment Outcome", "nlm_unique_id": "0141053", "other_id": null, "pages": "244-249", "pmc": null, "pmid": "31665725", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": null, "title": "A Retrospective Study of the Combination of Rituximab, Cyclophosphamide and Dexamethasone for the Treatment of Relapsed/Refractory Warm Antibody Autoimmune Hemolytic Anemia.", "title_normalized": "a retrospective study of the combination of rituximab cyclophosphamide and dexamethasone for the treatment of relapsed refractory warm antibody autoimmune hemolytic anemia" }

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A RETROSPECTIVE STUDY OF THE COMBINATION OF RITUXIMAB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE FOR THE TREATMENT OF RELAPSED/ REFRACTORY WARM ANTIBODY AUTOIMMUNE HEMOLYTIC ANEMIA. ACTA HAEMATOL. 2019?1-6. 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A RETROSPECTIVE STUDY OF THE COMBINATION OF RITUXIMAB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE FOR THE TREATMENT OF RELAPSED/ REFRACTORY WARM ANTIBODY AUTOIMMUNE HEMOLYTIC ANEMIA. ACTA HAEMATOL. 2019?1-6. DOI:10.1159/000501538", "literaturereference_normalized": "a retrospective study of the combination of rituximab cyclophosphamide and dexamethasone for the treatment of relapsed refractory warm antibody autoimmune hemolytic anemia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": null, "receiptdate": "20191126", "receivedate": "20191126", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17077013, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]

{ "abstract": ": Anticoagulation in a neonate is a challenge and the availability of anticoagulant options is extremely limited. Here we describe the use of a direct thrombin inhibitor, bivalirudin, in a full-term neonate with symptomatic cerebral sinovenous thrombosis complicated by bilateral thalamic hemorrhagic stroke and intraventricular hemorrhage, who could not be effectively treated with sodium heparin due to heparin resistance (HR) and showed thrombosis regression after start of bivalirudin treatment, without worsening of the hemorrhage. While the use of bivalirudin in neonates has been previously described, the indication of cerebral sinovenous thrombosis and the setting of HR are unique.", "affiliations": "Rehabilitation and Physical Medicine Unit, Giannina Gaslini Institute.;Neuroradiology Unit, Giannina Gaslini Institute.;Neonatal Intensive Care Unit, Giannina Gaslini Institute.;DINOGMI Department, University of Genoa.;Neonatal Intensive Care Unit, Giannina Gaslini Institute.;Thrombosis and Hemostasis Unit, Giannina Gaslini Institute, Genoa, Italy.;Neuroradiology Unit, Giannina Gaslini Institute.;Rehabilitation and Physical Medicine Unit, Giannina Gaslini Institute.;Thrombosis and Hemostasis Unit, Giannina Gaslini Institute, Genoa, Italy.;DINOGMI Department, University of Genoa.", "authors": "Bertamino|Marta|M|;Severino|Mariasavina|M|;Parodi|Alessandro|A|;Andreato|Chiara|C|;Malova|Mariya|M|;Svahn|Johanna|J|;Tortora|Domenico|D|;Moretti|Paolo|P|;Molinari|Angelo C|AC|;Ramenghi|Luca A|LA|", "chemical_list": "D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C074619:bivalirudin", "country": "England", "delete": false, "doi": "10.1097/MBC.0000000000000879", "fulltext": null, "fulltext_license": null, "issn_linking": "0957-5235", "issue": "31(1)", "journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis", "keywords": null, "medline_ta": "Blood Coagul Fibrinolysis", "mesh_terms": "D000991:Antithrombins; D006629:Hirudins; D006801:Humans; D007231:Infant, Newborn; D020767:Intracranial Thrombosis; D008297:Male; D010446:Peptide Fragments; D011994:Recombinant Proteins", "nlm_unique_id": "9102551", "other_id": null, "pages": "97-100", "pmc": null, "pmid": "31833869", "pubdate": "2020-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Bivalirudin anticoagulation to overcome heparin resistance in a neonate with cerebral sinovenus thrombosis.", "title_normalized": "bivalirudin anticoagulation to overcome heparin resistance in a neonate with cerebral sinovenus thrombosis" }

[ { "companynumb": "IT-PFIZER INC-2019554327", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "004570", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 IU/KG/H, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CEREBRAL VENOUS SINUS THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "004570", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "33 IU/KG/H, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug clearance increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERTAMINO, M.. BIVALIRUDIN ANTICOAGULATION TO OVERCOME HEPARIN RESISTANCE IN A NEONATE WITH CEREBRAL SINOVENUS THROMBOSIS. BLOOD COAGULATION AND FIBRINOLYSIS. 2019?30:10.1097/MBC.0000000000000879", "literaturereference_normalized": "bivalirudin anticoagulation to overcome heparin resistance in a neonate with cerebral sinovenus thrombosis", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20191230", "receivedate": "20191230", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17214634, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]

{ "abstract": "Oxygen toxicity seizures are a well-known complication of hyperbaric oxygen treatment (HBOT). Until now, there have not been any reported cases of an acute ischaemic event (stroke) as the result of a HBOT-associated oxygen toxicity seizure. We report an event in which a seizure and stroke occurred together and consider that the stroke may have been caused by seizure-induced demand ischaemia. This challenges the generally held view that oxygen toxicity seizures in the clinical hyperbaric setting are benign. A discussion of the literature on the subject of seizure-induced brain injury is included. Risk factors for cerebrovascular disease should be taken into consideration in determining treatment pressures for HBOT, as reducing pressure reduces seizure risk.", "affiliations": "Department of Emergency Medicine, 981150 NMC, University of Nebraska Medical Centre, Omaha, NE 68198-1150, USA, jeffrey.cooper@unmc.edu.;Department of Emergency Medicine, University of Nebraska Medical Centre, Omaha, Nebraska, USA.;Department of Neurology, University of Nebraska Medical Centre, Omaha.", "authors": "Warchol|Jordan M|JM|;Cooper|Jeffrey S|JS|;Diesing|Thomas S|TS|", "chemical_list": null, "country": "Australia", "delete": false, "doi": "10.28920/dhm47.4.260-262", "fulltext": null, "fulltext_license": null, "issn_linking": "1833-3516", "issue": "47(4)", "journal": "Diving and hyperbaric medicine", "keywords": "Case reports; Central nervous system; Hyperoxia; Toxicity", "medline_ta": "Diving Hyperb Med", "mesh_terms": "D000369:Aged, 80 and over; D006801:Humans; D006931:Hyperbaric Oxygenation; D007871:Leg Ulcer; D008297:Male; D009460:Neurologic Examination; D012307:Risk Factors; D012640:Seizures; D020521:Stroke", "nlm_unique_id": "101282742", "other_id": null, "pages": "260-262", "pmc": null, "pmid": "29241238", "pubdate": "2017-12", "publication_types": "D002363:Case Reports", "references": "11139368;11906510;15281962;15857444;21192190;22293507;23357721;25558546;6834064;8743983", "title": "Hyperbaric oxygen-associated seizure leading to stroke.", "title_normalized": "hyperbaric oxygen associated seizure leading to stroke" }

[ { "companynumb": "US-ALSI-201700469", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXYGEN" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SKIN ULCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "100% OXYGEN" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cerebrovascular accident", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "WARCHOL JM, COOPER JS, DIESING TS. HYPERBARIC OXYGEN-ASSOCIATED SEIZURE?LEADING TO STROKE. DIVING HYPERB MED. D?C 2017;47(4):260-2.", "literaturereference_normalized": "hyperbaric oxygen associated seizure leading to stroke", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171227", "receivedate": "20171227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 14328048, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "The decreased affinity to β-lactams in Haemophilus influenzae is usually caused by specific alterations in penicillin-binding protein 3 due to varieties of substitutions in ftsI gene. This study aimed to characterize the polymorphism of ftsI gene in 19 H. influenzae strains, isolated between 2014 and 2016 (different resistance phenotypes to β-lactams (n = 9) and susceptible strains (n = 10) used for comparative purposes). All strains were characterized for capsular type by PCR and agglutination tests and for β-lactam resistance by amplification and sequencing of ftsI. Biotyping and clonality were performed by API-NH and pulsed-field gel electrophoresis, respectively. Four strains were β-lactamase-negative ampicillin-resistant and five were β-lactamase-positive clavulanic-acid-resistant. One strain from each group was resistant to cefotaxime. Our isolates belonged mainly to biotype IV and I and were non-typeable and genetically unrelated. According to mutation profiles of their ftsI, strains were classified as group I (n = 3), group II (n = 4), group-III-like (n = 1) and group III (n = 1). All group II strains were further classified as subgroup IIb, except for one strain, which harboured a new mutation (N422I). Ampicillin MICs of β-lactamase-negative ampicillin-resistant strains were 6 to 12 times the MICs of susceptible strains. Only bla TEM-1 was detected in β-lactamase-positive clavulanic-acid-resistant strains, and was responsible for high MICs for ampicillin (>256 mg/L), whatever the ftsI mutational resistance group. The emergence of cefotaxime-resistant isolates in our country is a matter of concern and requires strict surveillance and rationalization of antibiotic use to preserve these molecules.", "affiliations": "University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research 'Resistance to Antimicrobial Agents, Tunis, Tunisia.;Charles Nicolle Hospital, Laboratory of Microbiology, Tunis, Tunisia.;University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research 'Resistance to Antimicrobial Agents, Tunis, Tunisia.;Abderrahmen Mami Hospital, Laboratory of Microbiology, Ariana, Tunisia.;Abderrahmen Mami Hospital, Laboratory of Microbiology, Ariana, Tunisia.;University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research 'Resistance to Antimicrobial Agents, Tunis, Tunisia.;Abderrahmen Mami Hospital, Laboratory of Microbiology, Ariana, Tunisia.;University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research 'Resistance to Antimicrobial Agents, Tunis, Tunisia.", "authors": "Ferjani|S|S|;Sassi|I|I|;Saidani|M|M|;Mhiri|E|E|;Ghariani|A|A|;Boutiba Ben Boubaker|I|I|;Slim|L|L|;Amine|S|S|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.nmni.2020.100690", "fulltext": "\n==== Front\nNew Microbes New Infect\nNew Microbes New Infect\nNew Microbes and New Infections\n2052-2975 Elsevier \n\nS2052-2975(20)30042-1\n10.1016/j.nmni.2020.100690\n100690\nOriginal Article\nPolymorphism of ftsI gene in Haemophilus influenzae and emergence of cefotaxime resistance in two Tunisian hospitals\nFerjani S. ferjsana@yahoo.fr1∗ Sassi I. 2 Saidani M. 12 Mhiri E. 3 Ghariani A. 3 Boutiba Ben Boubaker I. 12 Slim L. 3 Amine S. 12 1) University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research ‘Resistance to Antimicrobial Agents, Tunis, Tunisia\n2) Charles Nicolle Hospital, Laboratory of Microbiology, Tunis, Tunisia\n3) Abderrahmen Mami Hospital, Laboratory of Microbiology, Ariana, Tunisia\n∗ Corresponding author. F. Sana, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research ‘Resistance to Antimicrobial Agents’, 1007, Tunis. Tunisia. ferjsana@yahoo.fr\n05 5 2020 \n7 2020 \n05 5 2020 \n36 10069023 4 2019 19 3 2020 27 4 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).The decreased affinity to β-lactams in Haemophilus influenzae is usually caused by specific alterations in penicillin-binding protein 3 due to varieties of substitutions in ftsI gene. This study aimed to characterize the polymorphism of ftsI gene in 19 H. influenzae strains, isolated between 2014 and 2016 (different resistance phenotypes to β-lactams (n = 9) and susceptible strains (n = 10) used for comparative purposes).\n\nAll strains were characterized for capsular type by PCR and agglutination tests and for β-lactam resistance by amplification and sequencing of ftsI. Biotyping and clonality were performed by API-NH and pulsed-field gel electrophoresis, respectively.\n\nFour strains were β-lactamase-negative ampicillin-resistant and five were β-lactamase-positive clavulanic-acid-resistant. One strain from each group was resistant to cefotaxime. Our isolates belonged mainly to biotype IV and I and were non-typeable and genetically unrelated. According to mutation profiles of their ftsI, strains were classified as group I (n = 3), group II (n = 4), group–III–like (n = 1) and group III (n = 1). All group II strains were further classified as subgroup IIb, except for one strain, which harboured a new mutation (N422I). Ampicillin MICs of β-lactamase-negative ampicillin-resistant strains were 6 to 12 times the MICs of susceptible strains. Only blaTEM-1 was detected in β-lactamase-positive clavulanic-acid-resistant strains, and was responsible for high MICs for ampicillin (>256 mg/L), whatever the ftsI mutational resistance group.\n\nThe emergence of cefotaxime-resistant isolates in our country is a matter of concern and requires strict surveillance and rationalization of antibiotic use to preserve these molecules.\n\nKeywords\nβ-lactamases genesCefotaxime resistanceftsI geneHaemophilus influenzaePenicillin-binding protein 3\n==== Body\nIntroduction\nHaemophilus influenzae is a commensal bacterium of the human upper respiratory tract, oropharynx and nasopharynx. It is one of the most frequent pathogens responsible for bronchopulmonary, ear, nose and throat infections [1]. Also, it represents the principal aetiology of invasive infections such as purulent meningitis, bacteraemia and epiglottitis mainly in infants [1]. β-Lactams, mainly third-generation cephalosporins, are active against H. influenzae. However, the emergence and spread of resistant strains worldwide can severely affect their efficacy [2]. Resistance to β-lactams in H. influenzae is predominantly mediated by TEM-1 or ROB-1 β-lactamase production and is associated with resistance to aminopenicillins, of which the activity spectrum is limited to penicillins. Strains producing β-lactamases are termed β-lactamase-positive ampicillin-resistant. The second mechanism of resistance is non-enzymatic, due to decreased affinity of β-lactams for the altered transpeptidase domain of penicillin-binding protein 3 (PBP3), involved in septal peptidoglycan synthesis and encoded by the ftsI gene [1]. Strains expressing this mechanism are termed β-lactamase-negative ampicillin-resistant (BLNAR). Resistance by the latter mechanism can affect penicillins, penicillin and penicillinase inhibitor associations, cephalosporins and carbapenems, depending on the number and the type of mutations in the ftsI gene [1]. Strains that accumulate the two mechanisms are termed β-lactamase-positive clavulanic-acid-resistant (BLPCAR) [1]. In BLNAR strains, amino acid substitutions are usually surrounding the conserved motifs Lys512-Thr-Gly (KTG) and Ser379-Ser-Asn (SSN) of the PBP3 transpeptidase domain. More than 40 substitutions have been described in the literature and it has been found that a single BLNAR isolate could accumulate from one to 11 substitutions [1]. According to specific substitutions, BLNAR isolates have been classified into four major mutational groups (I, II, III and III-like). In group I, His-517 was substituted by Arg and in group II Lys-526 was substituted by Asn. Ampicillin MICs of these groups varied between 0.5 and 8 mg/L and they are considered low BLNAR. Group III and group III-like were defined by the second substitution S385T in addition to the first one N526K or R517H, respectively. They present full resistance to ampicillin (MIC range 1–32 mg/L) and cephalosporins (MIC range 0.12–2 mg/L) and considered high BLNAR [3,4]. Furthermore, isolates from group III and group–III–like with the additional substitution L389F showed generally higher MICs to extended-spectrum cephalosporins and meropenem. Hence, two new groups—III+ and group–III–like+—have been proposed by Skaare et al. for these strains [2]. In H. influenzae enzymatic resistance has historically predominated, with a prevalence >20% in many European countries, Australia and Canada. Recent studies showed that the prevalence of β-lactamase-positive ampicillin-resistant strains is stabilizing or decreasing. By contrast, a significant increase of BLNAR phenotype was observed in these same countries [1]. The situation in Japan is different and usually marked by high prevalence of BLNAR strains. In addition, high BLNAR strains have been rarely reported outside Asian countries, particularly Japan and Korea [5].\n\nIn Tunisia, multicentric studies on antimicrobial resistance of H. influenzae showed that β-lactamase production was the most common mechanism of resistance to β-lactams during all years of surveillance (1999–2017). The prevalence of β-lactamase-positive ampicillin-resistant strains varied from 17.3% in 1999 to 36.6% in 2017. BLNAR isolates emerged in 2006 at low frequencies with significant increase from 2.9% in 2007 to 8.2% in 2017 (www.infectiologie.org.tn). In Tunisia, BLNAR strains are routinely detected by phenotypic methods and few data are available on the genetic classification of their ftsI gene. Accordingly, we aimed to characterize the polymorphism of ftsI gene in a Tunisian collection of 19 H. influenzae strains, isolated between 2014 and 2016, and to assess the clonality among them.\n\nMaterials and methods\nStrain collection\nHaemophilus influenzae isolates included in the study were distributed as follows:• Seven strains recovered from the microbial Laboratory of Charles Nicolle Hospital, including three low BLNAR isolates (β-lactamase-negative, ampicillin MIC >1 mg/L) and four BLPCAR isolates (ampicillin/clavulanic acid MIC >2 mg/L).\n\n• Two cefotaxime-resistant H. influenzae strains (Hi16 and Hi19) isolated at the microbiology laboratories of the Charles Nicolle (Tunis city) and Abderrahman Mami (Ariana city) hospitals, respectively.\n\n• Ten control isolates, fully susceptible to β-lactams: β-lactamase-negative ampicillin-susceptible strains, randomly selected, used for comparative purposes.\n\n\n\nStrain identification\nIsolates were identified through Gram-staining that usually showed a pleomorphic Gram-negative bacilli, their requirements for β-NAD+ (V factor) and haemin (X factor) for growth and by API NH (bioMérieux, Marcy-l’Étoile, France). Chocolate agar plates (bioMérieux) were routinely used for subcultures of H. influenzae. Biotypes were determined using indole, urease and ornithine decarboxylase reactions revealed by API NH [6].\n\nAntimicrobial susceptibility testing\nAntimicrobial susceptibility was determined by disc diffusion method, according to the European Committee on Antimicrobial Susceptibility Testing recommendations (CA-SFM/EUCAST) [7]. The antibiotics tested were penicillin G (1 μg), ampicillin (2 μg), amoxicillin/clavulanic acid (2 μg/1 μg), cefotaxime (5 μg), nalidixic acid (30 μg), ciprofloxacin (5 μg), tetracycline (30 μg), chloramphenicol (30 μg), rifampicin (5 μg) and trimethoprim-sulfamethoxazole (1.25–23.75 μg). β-Lactamase production was determined by the chromogenic cephalosporin test (cefinase test) with nitrocefin as the substrate (bioMérieux). MICs of ampicillin, amoxicillin/clavulanic acid and cefotaxime were determined by E-test strips (bioMérieux) and were interpreted according to the EUCAST breakpoints.\n\nAmplification and sequencing of ftsI gene\nMutations in ftsI gene encoding PBP3 were identified by PCR and sequencing as previously described [8].\n\nβ-lactamases gene detection\nHaemophilus influenzae strains with BLPCAR phenotype were screened for blaTEM and blaROB genes using multiplex PCR as previously described [9].\n\nCapsular typing and genetic relationship\nCapsular type was identified by slide agglutination using specific anti-sera (Difco, BD, Le Pont de Claix, France) and was confirmed by PCR [10]. The H. influenzae ATCC 10211 (strain with capsular type b was used as a positive control.\n\nThe genetic relationship between isolates was analysed by pulsed-field gel electrophoresis (PFGE). The PFGE Pulse Net protocol of Escherichia coli was adapted to H. influenzae strains using SmaI restriction enzyme (New England BioLabs, Ipswich, MA, USA; https://www.cdc.gov/pulsenet/pathogens/pfge.html). DNA profiles were examined with FP-Quest software (BioRad, Marnes la Coquette, France) and using the Dice coefficient and UPGMA (unweighted pair group method with arithmetic mean). Clusters were defined as DNA patterns sharing ≥70% similarity, which corresponds to the possibly related criteria of Tenover et al. [11].\n\nResults\nClinical data\nDemographic and clinical data of patients are summarized in Table 1. Most H. influenzae strains were isolated from sputum (n = 15). They were mainly recovered from pneumology (n = 5), otorhinolaryngology (n = 3) and paediatrics (n = 3) wards. Fifteen (78.9%) infections were classified as community-acquired (Table 1).Table 1 Clinical characteristics and biotype of Haemophilus influenzae strains (n = 19)\n\nTable 1\tReference strains\tDate of isolation\tPatient age/Gender\tSpecimens\tWards\tInfection origin\tBiotype\t\nβ-lactam-susceptible strains (Control group)\tHi 2\t18/07/2014\t79 years/F\tBronchial secretion\tIntensive care unit\tCA\tI\t\nHi 3\t11/03/2015\t–/F\tSputum\tExternal consultation\tCA\tIV\t\nHi 5\t12/05/2015\t–/M\tSputum\tPneumology\tCA\tIV\t\nHi 6\t01/06/2015\t81 years/M\tBronchial secretion\tIntensive care unit\tHA\tIV\t\nHi 7\t10/07/2015\t–/F\tSputum\tPneumology\tCA\tI\t\nHi 8\t28/07/2015\t–/M\tBronchial secretion\tPneumology\tCA\tI\t\nHi 9\t12/08/2015\t75 years/M\tBronchial secretion\tSurgery\tHA\tIV\t\nHi 11\t12/09/2015\t14 years/M\tSputum\tPaediatrics\tCA\tI\t\nHi 12\t30/10/2015\t–/F\tSputum\tPaediatrics\tCA\tI\t\nHi 13\t11/11/2015\t14 years/F\tPus\tOtorhinolaryngology\tCA\tI\t\nβ-lactam-resistant strains\tHi 1\t17/07/2014\t55 years/F\tSputum\tOtorhinolaryngology\tCA\tI\t\nHi 4\t10/04/2015\t–/F\tSputum\tPneumology\tCA\tII\t\nHi 10\t23/09/2015\t9 years/F\tSputum\tPaediatrics\tCA\tVIII\t\nHi 14\t30/10/2015\t–/F\tSputum\tPneumology\tCA\tI\t\nHi 15\t30/12/2015\t1 year/M\tPus\tForensicMedicine\tCA\tIV\t\nHi 16\t20/01/2016\t62 years/M\tSputum\tGastroenterology\tHA\tIV\t\nHi 17\t05/03/2016\t–/M\tPus\tOtorhinolaryngology\tCA\tIV\t\nHi 18\t11/03/2016\t–/F\tSputum\tPaediatrics\tCA\tIV\t\nHi 19a\t30/08/2016\t72 years/M\tSputum\tThoracic surgery\tHA\tIV\t\nCA, community-acquired infections were defined as infections in which the onset of patient symptoms occurred before admission or within 48 h of admission to the hospital; HA, hospital-acquired infections were defined as infections in which the onset of symptoms occurred more than 48 h after admission.\n\na Isolate from Abdurrahman Mami hospital.\n\n\n\nFor the two H. influenzae strains resistant to cefotaxime (Hi16 and Hi19) and given the importance of this novel resistance, detailed clinical histories of patients are given below.\n\nClinical observation no. 1\nHi16 was recovered from a 61-year-old man hospitalized in the gastroenterology ward for decompensated cirrhosis post-viral hepatitis C. Two weeks previously, he was treated with cefotaxime (4 g/day for 15 days) for bacteraemia caused by E. coli. Four days after having completed his course of antimicrobial therapy, his clinical state deteriorated and he developed stage II encephalopathy, with dyspnoea and recurrence of fever. An infectious investigation was conducted including chest X-ray, which revealed diffuse alveolar images. Sputum and urine cultures were positive for H. influenzae resistant to cefotaxime and Enterococcus faecium resistant to glycopeptides, respectively. The patient was treated with ofloxacin (800 mg/day) for 10 days, with clinical and biological improvement.\n\nClinical observation no. 2\nHi19 was isolated from a 72-year-old man hospitalized in thoracic surgery for acute coronary syndrome. He was a former smoker and was previously hospitalized for acute exacerbation of his chronic obstructive pulmonary disease in 2006 and in 2015. The patient did not receive antibiotics in the previous 6 months. For the current episode, an infectious investigation, including sputum and urine cultures was carried out. The two specimens were positive for H. influenzae resistant to cefotaxime and E. coli, respectively. The patient was treated with a high dose of cefotaxime (6 g/day) for 10 days and with ciprofloxacin (1500 mg/day) on discharge.\n\nStrain characterization\nThe H. influenzae strains were classified into four biotypes. Biotypes IV and I were identified in nine and eight strains, respectively. Susceptible isolates belonged mainly to biotype I (60%), whereas 55.5% of resistant isolates belonged to biotype IV. Biotypes II and VIII were identified in two strains each (Table 1).\n\nAll strains were non-typeable by slide agglutination as well as by PCR amplification. PFGE analysis of H. influenzae isolates showed 19 unrelated pulsotypes (Fig. 1). They were susceptible to nalidixic acid, chloramphenicol and rifampicin, Eight and three strains were resistant to tetracycline and cotrimoxazole, respectively. All four β-lactamase-producing isolates harboured blaTEM-1 gene (Table 2).Fig. 1 Dendrogram of pulsed-field gel electrophoresis DNA patterns of Haemophilus influenzae strains obtained after the UPGMA analysis of the Dice's coefficient. BLNAS, β-lactamase-negative ampicillin-susceptible; BLNAR, β-lactamase-negative ampicillin-resistant; BLPCAR, β-lactamase-positive clavulanic-acid-resistant).\n\nFig. 1Table 2 Antimicrobial resistance profiles and deduced amino acid substitution patterns in the transpeptidase region of penicillin-binding protein 3 (PBP3) of Haemophilus influenzae strains\n\nTable 2Reference Strains\tResistance profile\tCefinase/bla genes\tMICs\tftsI groupa\tMutations in ftsI gene\t\nAMP\tAMC\tCTX\t\tD350\tS357\tM377\tS385\tL389\tP392\tN422\tG490\tA502\tV511\tR517\tN526\tS532\tF535\tV547\tI549\tY557\tN569\t\nHi 3\t—\t—\t0.25\t0.25\t0.012\tNA\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nHi 7\t—\t—\t0.25\t0.38\t0.016\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nHi 9\tTET\t—\t0.38\t0.25\t0.012\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nHi 12\tTET\t—\t0.19\t0.125\t0.023\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nHi 13\t—\t—\t0.25\t0.125\t0.016\t\t\t\t\t\tP\t\t\t\t\t\t\t\t\t\t\t\t\t\nHi 11\tTET\t—\t0.125\t0.125\t0.016\t\t\t\t\t\t\t\t\t\t\t\t\t\tI\t\t\t\t\t\nHi 8\tSXT\t—\t0.25\t0.25\t0.012\t\t\t\t\t\t\t\t\t\t\t\t\t\tI\t\t\t\t\t\nHi 6\t—\t—\t0.75\t0.25\t0.047\t\t\t\t\t\t\t\t\t\t\t\t\t\t\tI\t\t\t\t\nHi 5\tTET\t—\t0.5\t0.38\t0.08\t\t\ts\t\t\t\t\t\t\t\t\t\t\t\tI\t\t\t\t\nHi 2\t—\t—\t0.25\t0.25\t0.016\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\tF\t\t\t\nHi 14\tAMX-TET\t—\t2\t0.125\t0.064\tGroup I\t\t\t\t\t\t\t\t\t\t\tH\t\t\t\t\t\t\t\t\nHi 1\tAMX\t—\t4\t0.125\t0.023\t\t\t\t\t\t\t\t\t\tA\tH\t\t\t\t\t\t\t\t\nHi 10\tAMX-TET\t—\t4\t0.38\t0.023\t\t\t\t\t\t\t\t\t\tA\tH\t\t\t\t\t\t\t\t\nHi 17a\tAMX-AMC-SXT\t+/blaTEM-1\t>256\t2\t0.064\tGroup IIb\tN\t\tI\t\t\t\t\t\tV\t\t\tK\t\tI\t\t\t\t\t\nHi 18 a\tAMX-AMC\t+/blaTEM-1\t>256\t4\t0.047\tGroup Iib\tN\t\tI\t\t\t\t\tE\tV\t\t\tK\t\t\t\t\t\t\t\nHi 4 a\tAMX-AMC-TET-SXT\t+/blaTEM-1\t>256\t2\t0.047\tGroup Iib\tN\t\tI\t\t\t\t\tE\tV\t\t\tK\t\t\tI\t\t\t\t\nHi 15b\tAMX-AMC\t+/blaTEM-1\t>256\t2\t0.032\tGroup II\tN\t\tI\t\t\t\tI∗\t\tV\t\t\tK\t\t\t\t\t\t\t\nHi 19\tAMX-AMC-CTX\t+/blaTEM-1\t>256\t>256\t1\tGroup–III–like+\tN\tN\tI\tT\tF\t\t\t\t\t\tH\t\tT\t\tI\t\tH\tS\t\nHi 16\tAMX-AMC-CTX-TET\t—\t24\t4\t0.5\tGroup III+\tN\tN\tI\tT\tF\t\t\t\tT\t\t\tK\t\t\t\t\t\t\t\nAMC, ampicillin/clavulanic acid; AMP, ampicillin, CTX, cefotaxime.\n\na Classification according to Ubukata et al. [30] (Group I, II and III), Dabernat et al. [3] (Subgroup II: IIa, IIb, IIc and IId), García-Cobos et al. [4] (Group–III–like), Skaare et al. [23] (Group III+ and Group–III–like+): –, negative; NA, non-assigned resistance group, ∗, new mutation.\n\n\n\nftsI genotypes and correlation with β-lactam MICs\nSequence analysis of the transpeptidase region of PBP3 showed a total of 19 substitutions in 18 positions. The most frequent mutations were (D350N), (S357I), (R517H) and (N526K). In the Hi15 BLPCAR isolate, a new mutation was observed at position 422 (N422I). For this strain, MICs of ampicillin, amoxicillin/clavulanic acid and cefotaxime were >256, 2 and 0.032 mg/L, respectively.\n\nAmong strains with a β-lactamase-negative ampicillin-susceptible phenotype (control group), four did not harbour mutations in the ftsI gene and six displayed different point mutations (Table 2). Ampicillin MICs varied from 0.19 to 0.75 mg/L (MIC50 0.25 mg/L).\n\nAccording to the mutation profile of their ftsI gene, strains with BLNAR phenotype (n = 4) were classified as group I (n = 3) and group III+ (n = 1) and those with BLPCAR phenotype (n = 5) were classified as group II (n = 4) and group–III–like (n = 1) (Table 2). Three strains (Hi4, Hi17 and Hi18) from group II were further assigned to subgroup II-b, and were also TEM-1 β-lactamase producers. The remaining strain (Hi15) that had a new mutation (N422I) could not be assigned to any of the previously described group II subgroups. Ampicillin MICs varied between 2 and 4 mg/L in group I and was >256 mg/L in group II.\n\nResistance to cefotaxime in strains Hi16 and Hi19 was associated with S385T and L389F mutations, respectively. Strain Hi19 was also a TEM-1 producer. Cefotaxime MICs were 0.5 mg/L and 1 mg/L for Hi16strain (group III+) and Hi19 strain (group III like+), respectively.\n\nHigh resistance level of ampicillin (>256 mg/L) was associated with TEM-1 production whatever the ftsI mutational resistance group. ROB enzyme has not been found in our collection.\n\nDiscussion\nIn this study, molecular mechanisms of resistance to β-lactams in clinical H. influenzae isolates showing different β-lactam resistance phenotypes were investigated. All strains were non-typeable by slide agglutination as well as by PCR amplification. The predominance of non-typeable strains was also reported in other Tunisian studies, and in Korea, Spain and France [12,13]. However, previous reports demonstrated the limitation of slide agglutination for H. influenzae serotyping in comparison with the results provided by PCR [14,15]. This may be related to the individual characteristics of expression of capsule and/or other antigens on the bacterial surface [16,17].\n\nIn Tunisia, until 2002, all invasive infections in young children were caused by H. influenzae b strains [18], justifying the introduction of the anti-Hib conjugate vaccine. However, given its high cost, it was abandoned at the beginning of 2006. Then, based on extensive evidence demonstrating the economic impact of the anti-Hib conjugate vaccine through direct and indirect cost savings, as well as through contributions to the Tunisian economy in general, this vaccine was reintroduced into the vaccination schedule in 2011 [19].\n\nIn the present study, PFGE analysis of the H. influenzae isolates showed diverse pulsotypes, which is in agreement with the genetic heterogeneity of non-capsulated H. influenzae previously reported [1]. Also, according to resistance phenotype, many studies have shown that BLNAR and BLPCAR strains of H. influenzae are genetically diverse with a general absence of related PFGE DNA profiles [1]. Otherwise, clonal spread of BLNAR strains of serotype b was reported by a limited number of studies in Japan [20,21]. In comparison, some local outbreaks caused by BLNAR H. influenzae strains have been reported, in Norway, Spain and Canada. of BLNAR H. influenzae strains that were caused by closely related clones [4,8,22].\n\nAmong the β-lactamase-negative ampicillin-susceptible phenotypes (n = 10), four strains of our collection had the prototype amino acid sequence of the transpeptidase region of PBP3. In the remaining six strains, different point mutations were found. These observations were previously reported [2,8,23]. Many silent mutations have been reported in the DNA region encoding the transpeptidase domain of PBP3 in susceptible strains [23]. The results of García-Cobos et al. showed that β-lactams susceptible H. parainfluenzae strains presented various substitutions not previously assigned to any ftsI-resistant groups [4].\n\nAccording to mutational profiles of ftsI genes, BLNAR and BLPCAR isolates of our collection were classified as group I, II, IIb, III-like+ and III+. Strain Hi15 belonging to group II, but not assigned to any group II subgroups, showed a new mutation (N422I) in its ftsI gene, suggesting a novel subgroup II. The β-lactam resistance in H. influenzae due to ftsI mutations is increasing worldwide [22]. Low-level resistance isolates, mainly with the N526K substitutions, predominated in most geographical regions, whereas high-level resistance isolates with additional L389F substitution (ampicillin MIC50: 128 mg/L and cephalosporins MIC50: 1 mg/L) are common in Japan and South Korea. Epidemiological data from European countries and Canada showed a gradual increase in resistant isolates from group II with sporadic cases of cefotaxime-resistant strains [1,13,22,24,25].\n\nIn Tunisia, resistance to cefotaxime has been recently reported among six H. influenzae isolates from Habib Bourguiba hospital. These strains belonged to group IIa, group IIb, group III and group–III–like [26]. The two cefotaxime-resistant strains described in our study belonged to group III+ and group–III–like+. According to clinical data, H. influenzae-resistant strains were isolated from two elderly individuals with severe underlying diseases, chronic cirrhosis in one and chronic obstructive pulmonary disease in the other. It has been demonstrated that people suffering from chronic obstructive pulmonary disease are frequently colonized by H. influenzae in their respiratory tract [12,27]. In addition, previous antimicrobial treatment by cefotaxime and iterative hospitalizations are contributing factors for selection of such resistant strains. According to Dabernat et al., the inappropriate use of oral antibiotics for the treatment of community-acquired bronchopulmonary and upper respiratory tract infections seems to be responsible for the selection of BLNAR strains [3].\n\nIn our series, the five BLPCAR isolates harboured the blaTEM-1 gene. This finding is in agreement with previous Tunisian studies [28,29]. Although the predominance of TEM-1 β-lactamase was largely reported worldwide, ROB-1 is rarely found outside North America [1].\n\nOur study presents two major limitations. First, clinical data were collected retrospectively and detailed information for all patients, such as age, co-morbidities, severity of diseases, antimicrobial treatment history and clinical outcomes could not be obtained. Second, our results gave limited data on the distribution of the ftsI group in our country because of the low number of studied strains. Further large studies including other hospital centres will be necessary to assess the real clinical impact of this emerging resistance and to identify additional risk factors for selection of resistant strains.\n\nIn conclusion, this study revealed the diversity of mutation profiles in ftsI gene among BLNAR and BLPCAR H. influenzae strains. Our results further indicate that these strains were non-capsulated and were genetically unrelated. The emergence of strains resistant to extended spectrum β-lactams is alarming and requires strict epidemiological surveillance. Furthermore, rationalization and strict control of antibiotic use, mainly in the community, is needed to preserve the activity of these molecules.\n\nConflict of interest\nThe authors have no conflicts of interest to declare. No funding was received for the study.\n\nAuthors' contributions\nFS and SM were responsible for the conception or design of the work; SI, ME and SL performed the data collection; and FS performed the data analysis and interpretation. FS drafter the article; BBBI critically revised the article and the final approval for publication was given by FS, SI, SM, ME, GA, SL, SA and BBBI.\n\nAcknowledgements\nThis work was supported by the 10.13039/100012964Ministry of Higher Education and Scientific Research of Tunisia.\n==== Refs\nReferences\n1 Tristram S. Jacobs M.R. Appelbaum P.C. Antimicrobial resistance in Haemophilus influenzae Clin Microbiol Rev 20 2007 368 389 17428889 \n2 Skaare D. Anthonisen I.L. Kahlmeter G. Matuschek E. Natås O.B. Steinbakk M Emergence of clonally related multidrug resistant Haemophilus influenzae with penicillin-binding protein 3-mediated resistance to extended-spectrum cephalosporins, Norway, 2006 to 2013 Eurosurveillance 19 2014 1 13 \n3 Dabernat H. Delmas C. 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Phenotypic and molecular characterization of β-lactams resistance and capsular typing of colonizing Haemophilus influenzae strains isolated from neutropenic patients in Tunisia Path Biol 57 2009 353 357 18178031 \n30 Ubukata K. Shibasaki Y. Yamamoto K. Chiba N. Hasegawa K. Takeuchi Y. Association of amino acid substitutions in penicillin-binding protein 3 with β-lactam resistance in β-lactamase-negative ampicillin-resistant Haemophilus influenzae Antimicrob Agents Chemother 45 2001 1693 1699 11353613\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2052-2975", "issue": "36()", "journal": "New microbes and new infections", "keywords": "Cefotaxime resistance; Haemophilus influenzae; Penicillin-binding protein 3; ftsI gene; β-lactamases genes", "medline_ta": "New Microbes New Infect", "mesh_terms": null, "nlm_unique_id": "101624750", "other_id": null, "pages": "100690", "pmc": null, "pmid": "32489667", "pubdate": "2020-07", "publication_types": "D016428:Journal Article", "references": "24884375;28137937;7814470;30946954;20087619;9784503;19737286;18178031;23308379;7494007;17428889;11353613;16641114;17470649;25385097;16842955;19884366;29611493;12517878;772168;27436470;29579288;25523969;12069976;22538797;19135400", "title": "Polymorphism of ftsI gene in Haemophilus influenzae and emergence of cefotaxime resistance in two Tunisian hospitals.", "title_normalized": "polymorphism of ftsi gene in haemophilus influenzae and emergence of cefotaxime resistance in two tunisian hospitals" }

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{ "abstract": "A 39-year-old woman was admitted to our hospital with symptoms of general fatigue, nausea, and vomiting that appeared three months after she stopped seven years of medroxyprogesterone acetate (MPA) medication for endometrial stromal sarcoma. Laboratory tests demonstrated moderate hypercalcemia. Several tests demonstrated that she was suffering from adrenal insufficiency. Glucocorticoid supplementation decreased her calcium level to a normal range, indicating that hypercalcemia was induced by adrenal insufficiency. It was suggested that she was suffering from MPA-induced adrenal insufficiency, but hypocortisolemia was being compensated by a high dose of MPA; hypocortisolemia and hypercalcemia then became evident after MPA treatment was discontinued.", "affiliations": "Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan.", "authors": "Yuasa-Shibasaki|Erina|E|;Ishii|Sumiyasu|S|;Matsumoto|Shunichi|S|;Tomaru|Takuya|T|;Horiguchi|Kazuhiko|K|;Osaki|Aya|A|;Ozawa|Atsushi|A|;Shibusawa|Nobuyuki|N|;Satoh|Tetsurou|T|;Yamada|Masanobu|M|", "chemical_list": "D018931:Antineoplastic Agents, Hormonal; D017258:Medroxyprogesterone Acetate", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.9036-17", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2922524710.2169/internalmedicine.9036-17Case ReportHypercalcemia after the Discontinuation of Medroxyprogesterone Acetate Yuasa-Shibasaki Erina 1Ishii Sumiyasu 1Matsumoto Shunichi 1Tomaru Takuya 1Horiguchi Kazuhiko 1Osaki Aya 1Ozawa Atsushi 1Shibusawa Nobuyuki 1Satoh Tetsurou 1Yamada Masanobu 1\n1 Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, JapanCorrespondence to Dr.　Sumiyasu Ishii, sishii@gunma-u.ac.jp\n\n8 12 2017 15 2 2018 57 4 545 549 13 2 2017 27 7 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 39-year-old woman was admitted to our hospital with symptoms of general fatigue, nausea, and vomiting that appeared three months after she stopped seven years of medroxyprogesterone acetate (MPA) medication for endometrial stromal sarcoma. Laboratory tests demonstrated moderate hypercalcemia. Several tests demonstrated that she was suffering from adrenal insufficiency. Glucocorticoid supplementation decreased her calcium level to a normal range, indicating that hypercalcemia was induced by adrenal insufficiency. It was suggested that she was suffering from MPA-induced adrenal insufficiency, but hypocortisolemia was being compensated by a high dose of MPA; hypocortisolemia and hypercalcemia then became evident after MPA treatment was discontinued. \n\nhypercalcemiaadrenal insufficiencymedroxyprogesterone acetateglucocorticoid supplementation\n==== Body\nIntroduction\nHypercalcemia is a relatively common problem. In most cases, it is induced by primary hyperparathyroidism or malignancy (1), but a wide variety of diseases can potentially cause elevated levels of serum calcium as well. Patients with mild or chronic hypercalcemia might be asymptomatic, but severe or acute hypercalcemia can sometimes result in a coma. Other manifestations include nausea, vomiting, constipation, polyuria, depression, and fatigue. The treatment is determined by both the severity and the etiology of hypercalcemia.\n\nAdrenal insufficiency is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease due to impairment of the hypothalamic-pituitary axis (2). Patients exhibit fatigue, weight loss, nausea, vomiting, dry skin, and hypoglycemia. Glucocorticoid supplementation is essential for such patients.\n\nMedroxyprogesterone acetate (MPA) is commonly used as hormonal therapy for several diseases, including breast cancer, endometrial cancer, amenorrhea, and endometrial stromal sarcoma (3). High-dose MPA treatment can achieve long-term control of endometrial stromal sarcoma (4).\n\nWe herein report a case of hypercalcemia that emerged after discontinuation of MPA. Laboratory testing revealed adrenal insufficiency, which was suggested to be the result of long-term MPA treatment. We speculated that high-dose MPA administration had been compensating for adrenal insufficiency, and the symptoms became overt after discontinuation of MPA. Hypercalcemia appeared to be a manifestation of adrenal insufficiency, as glucocorticoid supplementation normalized the level of serum calcium.\n\nCase Report\nA 39-year-old woman was admitted to our hospital with complaints of general fatigue, nausea, and vomiting for the previous 3 months. She had undergone a hysterectomy because of an endometrial stromal sarcoma seven years earlier. Thereafter, she had been treated with 600 mg of MPA as adjuvant therapy; MPA had been discontinued 3 months before the admission because no recurrence of the sarcoma had been observed. Her symptoms appeared soon after she stopped MPA medication, suggesting a relationship between the MPA withdrawal and her sickness. She was receiving furosemide and spironolactone because of cardiomyopathy, but was not taking any medication or dietary supplement that might have increase the serum calcium level on admission. She did not have any history of urinary stones.\n\nHer blood pressure was slightly low (84/63 mmHg), and her skin was dry. Laboratory tests demonstrated moderate hypercalcemia with normal phosphorus and albumin levels (Table 1). Her serum creatinine level was slightly high, and the levels of sodium, chloride, and potassium were low, but these abnormal findings were rapidly normalized after saline infusion and food intake, suggesting dehydration and loss of minerals by diuretics and vomiting. The levels of intact parathyroid hormone (PTH), PTH-related protein (PTHrP), calcitriol (1,25-dihydroxyvitamin D3), and calcifediol (25-hydroxyvitamin D3) were low. Ultrasonography did not demonstrate parathyroid adenoma. Fractional excretion of calcium (FECa) was not low. She was not suffering from thyrotoxicosis. Markers for bone resorption were slightly elevated. No signs of malignant tumors were observed in her bones, as assessed by 18fluoro-deoxyglucose-positron emission tomography (FDG-PET) and bone scintigraphy. Serum protein electrophoresis did not suggest the presence of multiple myeloma.\n\nTable 1. Laboratory Findings on Admission.\n\nHematology\t\t\t\tBlood chemistry\t\t\t\tHormones\t\t\t\nHematocrit\t43.8\t%\t\tTotal protein\t6.7\tg/dL\t\tintact-PTH\t7.3\tpg/mL\t\nHemoglobin\t15.6\tg/dL\t\tAlbumin\t4.0\tg/dL\t\tPTHrP\t<1.1\tpmol/L\t\nRed blood cell\t493\t×104/μL\t\tAspartate aminotransferase\t56\tIU/L\t\tCalcitriol\t11\tpg/mL\t\nPlatelet\t19.8\t×104/μL\t\tAlanine aminotransferase\t33\tIU/L\t\tCalcifediol\t9\tng/mL\t\nWhite blood cell\t5,100\t/μL\t\tLactate dehydrogenase\t195\tIU/L\t\tCalcitonin\t<5.0\tpg/mL\t\nNeutrophil\t54.7\t%\t\tAlkaline phosphatase\t272\tIU/L\t\tThyrotropin\t9.52\tμU/mL\t\nEosinophil\t4.8\t%\t\tγ-glutamyl transpeptidase\t33\tIU/L\t\tFree thyroxine\t1.32\tng/dL\t\nBasophil\t0.5\t%\t\tBlood urea nitrogen\t16\tmg/dL\t\tGrowth hormone\t0.3\tng/mL\t\nMonocyte\t9.7\t%\t\tCreatinine\t1.12\tmg/dL\t\tIGF-1\t110\tng/mL\t\nLymphocyte\t11.3\t%\t\tSodium\t136\tmEq/L\t\t\t\t\t\n\t\t\t\tPotassium\t3.0\tmEq/L\t\tCalcium metabolism\t\t\t\nCoagulation\t\t\t\tChloride\t93\tmEq/L\t\tBone alkaline phosphatase\t26.5\tμg/L\t\nFibrinogen\t357\tmg/dL\t\tCalcium\t12.0\tmg/dL\t\tintact-P1NP\t478\tμg/L\t\nProthrombin time\t93\t%\t\tPhosphorus\t3.5\tmg/dL\t\tTRACP-5b\t887\tmU/dL\t\nAPTT\t28.7\tsec\t\tGlucose\t103\tmg/dL\t\tNTX\t131\tnMBCE/L\t\nFDP\t3.8\tμg/mL\t\tHbA1c\t5.3\t%\t\tUrinary calcium\t158\tmg/day\t\nD-dimer\t2.1\tμg/mL\t\tTotal cholesterol\t141\tmg/dL\t\tFECa\t1.23\t%\t\nAPTT: activated partial thromboplastin time, FDP: fibrin/ fibrinogen degradation product, HbA1c: hemoglobin A1c, PTH: parathyroid hormone, IGF-1: insulin-like growth factor 1, P1NP: N-terminal propeptide of type I procollagen, TRACP-5b: tartrate-resistant acid phosphatase form 5b, NTX: N-telopeptide of type I collagen, FECa: fractional excretion of calcium\n\nIn addition to hydration therapy, treatment with elcatonin lowered her calcium level, although it was still above the normal range, indicating that hypercalcemia was not solely due to dehydration. Her nausea and fatigue were alleviated but still persisted (Figure). Many types of disorders, including autoimmune diseases, infectious diseases and hormonal diseases such as infant hypothyroidism and adrenal insufficiency, are potential inducers of hypercalcemia, although these cases are not common (5). Among these diseases, we investigated whether or not she was suffering from adrenal insufficiency, because hypocortisolemia could explain all of her symptoms. Although the levels of serum cortisol and plasma corticotropin were within normal limits, the levels of urinary free cortisol and plasma dehydroepiandrosterone sulfate (DHEA-S) exhibited extremely low, suggesting adrenal insufficiency (Table 2A). Continuous glucose monitoring (CGM) revealed hypoglycemia during the nighttime, although she did not complain of any typical hypoglycemic symptoms, such as palpitations and sweating.\n\nFigure. Schematic presentation of the clinical course.\n\nTable 2. Adrenal Function.\n\n(A)\t\nAdrenal function\t\t\t\tHormones during hypoglycemia\t\nCorticotropin\t20.8\tpg/mL\t\tPlasma glucose\t49\tmg/dL\t\nCortisol\t8.0\tμg/dL\t\tInsulin\t1.6\tμU/mL\t\nDHEA-S\t30\tng/mL\t\tC-peptide\t1.03\tng/mL\t\n(normal range: 230-2,660)\t\tCorticotropin\t9.0\tpg/mL\t\nUrinary free cortisol\t10.9\tμg/day\t\tCortisol\t6.0\tμg/dL\t\nDHEA-S: dehydroepiandrosterone sulfate\t\n(B) Corticotropin (ACTH) test\t\nTime (min)\t0\t30\t60\t\nCortisol (μg/dL)\t23.8\t34.7\t42.3\t\n(C) Corticotropin-releasing hormone (CRH) test\t\nTime (min)\t0\t30\t60\t90\t120\t\nCorticotropin (pg/mL)\t13.0\t52.6\t51.6\t33.4\t18.2\t\nCortisol (μg/dL)\t4.4\t13.3\t14.9\t10.3\t7.2\t\nCorticotropin and cortisol are regarded as counterregulatory hormones in the hypoglycemic state and are usually up-regulated during hypoglycemia. However, reactive stimulation was not observed when we measured the levels of these hormones in the morning during hypoglycemia. Her serum insulin level was low, indicating that hypoglycemia was not induced by excessive secretion of insulin. Provocative tests demonstrated that cortisol secretion was normally stimulated by corticotropin (Table 2B). A corticotropin-releasing hormone (CRH) test demonstrated that corticotropin secretion was stimulated at a normal level, but that the peak of cortisol was not high enough considering the level of corticotropin present. In addition, the peak of corticotropin appeared to be slightly delayed, as the corticotropin level at 60 minutes was similar to that at 30 minutes (Table 2C). Magnetic resonance imaging (MRI) did not reveal any abnormal findings in the hypothalamus or pituitary gland. Calcification in the adrenal gland, which suggests adrenal tuberculosis, was not shown on computed tomography (CT). She tested negative for human immunodeficiency virus.\n\nShe was supplemented with hydrocortisone, and her symptoms rapidly disappeared (Figure). CGM demonstrated the recovery from nocturnal hypoglycemia. The serum calcium level decreased to the normal range without any other treatment, indicating that hypercalcemia had been induced by adrenal insufficiency. The levels of bone resorption markers, such as tartrate-resistant acid phosphatase form 5b (TRACP-5b) and N-telopeptide of type I collagen (NTX), were high even after hypercalcemia disappeared, but these markers gradually decreased (Table 3). She has been free of hypercalcemia and other manifestation for more than one year. She still needs glucocorticoid supplementation, probably due to long-term adrenal deficiency.\n\nTable 3. Time Course of Laboratory Data.\n\nHospital days\t1\t26\t(47)\t(375)\t\nCalcium (mg/dL)\t12.0\t11.6\t10.2\t9.8\t\nFECa (%)\t1.24\t\t1.16\t0.55\t\nBone alkaline phosphatase (μg/L)\t26.5\t\t34.1\t15.8\t\nTRACP-5b (mU/dL)\t887\t\t1130\t640\t\nNTX (nMBCE/L)\t131.0\t\t107.0\t30.1\t\nHemoglobin (g/dL)\t15.6\t12.5\t12.0\t13.7\t\nCreatinine (mg/dL)\t1.12\t0.64\t0.57\t0.55\t\nSodium (mEq/L)\t136\t138\t142\t142\t\nHydrocortisone supplementation started on day 27.\n\nFECa: fractional excretion of calcium, TRACP-5b: tartrate-resistant acid phosphatase form 5b, NTX: N-telopeptide of type I collagen\n\nDiscussion\nUnderstanding the etiology of hypercalcemia is essential for administering the proper treatment. Most cases are due to primary hyperparathyroidism or malignancy (1). However, it is not always easy to identify the reason for elevated levels of serum calcium, as many types of diseases may be responsible (6). In our case, the level of intact PTH was suppressed, indicating that the patient was not suffering from primary hyperparathyroidism or PTH-producing tumors. In addition, FECa was not low, eliminating the possibility of familial hypercalciuric hypercalcemia, which is caused by a mutation in the calcium-sensing receptor gene (7). Humoral hypercalcemia of malignancy, in which malignant tumors produce PTHrP (8), was not likely because PTHrP was not detected in her serum. A low level of calcitriol excluded the possibility of activation of 1-alpha hydroxylase by lymphoma or granulomatous diseases, such as tuberculosis and sarcoidosis (9). The calcifediol level, as well as her medication history, did not show any evidence of vitamin D intoxication. FDG-PET and bone scintigraphy did not suggest any signs of osteolytic malignant diseases (8) or recurrence of endometrial stromal sarcoma. Multiple myeloma can also increase the serum calcium level, but serum protein electrophoresis showed negative results for the presence of this disease. Therefore, we considered rare causes of hypercalcemia (5).\n\nAdrenal insufficiency is one of the diseases that can induce the elevation of the serum calcium level. It is reported that 6% of primary adrenal insufficiency cases exhibit hypercalcemia (2). The clinical manifestations of hypoadrenalism include fatigue, weight loss, nausea, vomiting, dry skin, and hypoglycemia, which are consistent with the symptoms of our case. Low levels of urinary free cortisol and plasma DHEA-S, and the nocturnal hypoglycemia demonstrated by CGM, supported the hypothesis that she was suffering from moderate hypoadrenalism, although her basal levels of serum cortisol and plasma corticotropin were normal. Cortisol secretion was normally stimulated by the administration of corticotropin. A CRH stimulation test suggested a delayed up-regulation of corticotropin with slightly weak activity, based on the peak level of cortisol. We did not perform an insulin tolerance test because we were able to measure the levels of corticotropin and cortisol during spontaneous hypoglycemia. The expected up-regulation of the pituitary-adrenal axis was not observed. Based on these findings, we speculate that our case was suffering from tertiary adrenal insufficiency, in which the hypothalamic function was disturbed. In addition to primary adrenal insufficiency, central adrenal insufficiency is also reported to induce hypercalcemia (10,11).\n\nThe precise mechanisms though which adrenal insufficiency induces hypercalcemia are not yet fully understood. Multiple factors are suggested to be involved, including increased bone resorption and decreased renal calcium excretion due to dehydration (12-14). Consistent with these reports, the levels of bone resorption markers were elevated in our patient (Table 1). However, high bone resorption marker levels persisted in our patient, even after the serum calcium level was normalized (Table 3). Indeed, previous reports have not mentioned whether or not the levels of bone resorption markers were rapidly decreased. However, histological studies of the bones in patients with hypercalcemia induced by Addison's disease have shown no signs of bone resorption (13). Therefore, it remains unclear whether or not increased bone resorption really contributes to hypercalcemia. In addition, our patient was also suffering from dehydration, although diuretics and vomiting likely contributed as well. However, saline infusion to correct dehydration did not fully correct the hypercalcemia (Figure), consistent with previous reports (13). Transient thyrotoxicosis is suggested to be involved in hypercalcemia in corticotropin-deficient patients (10,11), but this was not the case in our patient, as she presented with subclinical hypothyroidism. Supplementation with glucocorticoid normalized her serum calcium level, supporting the idea that her hypercalcemia was due to adrenal insufficiency.\n\nIt was not easy to identify the reason for adrenal insufficiency, as imaging studies did not suggest any causes for primary or central adrenal insufficiency. It has been reported that high-dose MPA can cause adrenal insufficiency (15). Therefore, we hypothesized that her history of MPA treatment was involved in the etiology. A high dose of MPA can result in both iatrogenic Cushing's syndrome and subsequent adrenal insufficiency at the same time (16,17), because MPA and glucocorticoid are both derivatives of steroids and are structurally similar. Thus, she may have been suffering from MPA-induced adrenal insufficiency, but her hypocortisolemia was compensated by the high dose of MPA, so hypocortisolemia and hypercalcemia only became evident after MPA treatment was discontinued.\n\nHypercalcemia was reported in four breast cancer patients with bone metastasis who were treated with MPA (18). The authors suggested some effects of MPA on bone lesions, although the mechanism was unknown. This does not seem to be the case in our patient, as she did not have any bone tumors. Those four patients might have also been suffering from adrenal insufficiency, as two of them recovered from hypercalcemia after the administration of steroids. Why our patient exhibited hypercalcemia despite hypercalcemia not being common in patients with adrenal insufficiency and the degree of her hypocortisolemia not being very severe is unclear, as the mechanisms underlying hypocortisolemia-induced hypercalcemia have yet to be elucidated, as discussed above. One hallmark of our case is the sudden onset of hypocortisolism after long-term treatment with MPA, which exhibits glucocorticoid-mimetic action. Indeed, hypercalcemia was reported in a patient who had undergone glucocorticoid withdrawal after unilateral adrenalectomy (19). In that case, hypercalcemia was due in part to increased renal tubular reabsorption of calcium as a result of glucocorticoid withdrawal, which is consistent with the present case. Therefore, MPA withdrawal might have contributed to the elevation of serum calcium levels in our case.\n\nTo our knowledge, this is the first report of hypercalcemia emerging after the discontinuation of MPA. Adrenal insufficiency induced by MPA was involved in the mechanism. Glucocorticoid supplementation should therefore be considered when a high dose of steroid-type hormone therapy is withdrawn.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nLafferty FW \nDifferential diagnosis of hypercalcemia . 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Clin Endocrinol (Oxf) \n41 : 261 -264 , 1994 .7923833 \n12. \nFujikawa M , Kamihira K , Sato K , Okamura K , Kidota S , Lida M \nElevated bone resorption markers in a patient with hypercalcemia associated with post-partum thyrotoxicosis and hypoadrenocorticism due to pituitary failure . J Endocrinol Invest \n27 : 782 -787 , 2004 .15636435 \n13. \nMontoli A , Colussi G , Minetti L \nHypercalcaemia in Addison's disease: calciotropic hormone profile and bone histology . J Intern Med \n232 : 535 -540 , 1992 .1474363 \n14. \nMuls E , Bouillon R , Boelaert J , et al \nEtiology of hypercalcemia in a patient with Addison's disease . Calcif Tissue Int \n34 : 523 -526 , 1982 .6819071 \n15. \nvan Veelen H , Willemse PH , Sleijfer DT , van der Ploeg E , Sluiter WJ , Doorenbos H \nMechanism of adrenal suppression by high-dose medroxyprogesterone acetate in breast cancer patients . Cancer Chemother Pharmacol \n15 : 167 -170 , 1985 .3160504 \n16. \nKrueger RB , Hembree W , Hill M \nPrescription of medroxyprogesterone acetate to a patient with pedophilia, resulting in Cushing's syndrome and adrenal insufficiency . Sex Abuse \n18 : 227 -228 , 2006 .16868842 \n17. \nSeo Y , Jeong EG , Kim ES \nCushing's syndrome with adrenal suppression and masked hyperandrogenism by high-dose medroxyprogesterone acetate for treatment of endometrial cancer in a young woman with polycystic ovarian syndrome . Endocrine \n50 : 519 -521 , 2015 .26298265 \n18. \nKaufman RJ , Rothschild EO , Escher GC , Myers WP \nHypercalcemia in mammary carcinoma following the administration of a progestational agent . J Clin Endocrinol Metab \n24 : 1235 -1243 , 1964 .14243164 \n19. \nSuzuki K , Nonaka K , Ichihara K , et al \nHypercalcemia in glucocorticoid withdrawal . Endocrinol Jpn \n33 : 203 -209 , 1986 .3757916\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "57(4)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "adrenal insufficiency; glucocorticoid supplementation; hypercalcemia; medroxyprogesterone acetate", "medline_ta": "Intern Med", "mesh_terms": "D000309:Adrenal Insufficiency; D000328:Adult; D018931:Antineoplastic Agents, Hormonal; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D017258:Medroxyprogesterone Acetate; D028761:Withholding Treatment", "nlm_unique_id": "9204241", "other_id": null, "pages": "545-549", "pmc": null, "pmid": "29225247", "pubdate": "2018-02-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "7916660;3160504;1763670;22569596;6819071;21830086;22446158;17371483;15636435;3757916;16368128;24503135;26713296;1474363;16131579;7923833;14243164;26298265;16868842", "title": "Hypercalcemia after the Discontinuation of Medroxyprogesterone Acetate.", "title_normalized": "hypercalcemia after the discontinuation of medroxyprogesterone acetate" }

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HYPERCALCEMIA AFTER THE DISCONTINUATION OF MEDROXYPROGESTERONE ACETATE. 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{ "abstract": "Coronavirus disease 19 (COVID-19) which is caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has been a problem worldwide, particularly due to the high rate of transmission and wide range of clinical manifestations. Acute respiratory distress syndrome (ARDS) and multiorgan failure are the most common events observed in severe cases and can be fatal. Cytokine storm syndrome emerges as one of the possibilities for the development of ARDS and multiorgan failure in severe cases of COVID-19. This case report describes a case of a 53-year-old male patient who has been diagnosed with COVID-19. Further evaluation in this patient showed that there was a marked increase in IL-6 level in blood accompanied with hyperferritinemia, which was in accordance with the characteristic of cytokine storm syndrome. Patient was treated with tocilizumab, a monoclonal antibody and is an antagonist to IL-6 receptor. The binding between tocilizumab and IL-6 receptors effectively inhibit and manage cytokine storm syndrome. Although this case report reported the efficacy of tocilizumab in managing cytokine storm syndrome, tocilizumab has several adverse effects requiring close monitoring. Further clinical randomized control trial is required to evaluate the efficacy and safety of tocilizumab administration in participants with various clinical characteristics and greater number of subjects.", "affiliations": "Fellow of the American College of Physicians; Division of Gastroenterology, Dept. of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia. ari_syam@hotmail.com.", "authors": "Syam|Ari Fahrial|AF|;Pitoyo|Ceva W|CW|;Suhendro|Suhendro|S|;Zulkarnain|Benny|B|;Indrasari|Nuri D|ND|;Aditianingsih|Dita|D|;Irawan|Cosphiadi|C|;Susilo|Adityo|A|;Rumende|Cleopas M|CM|;Wijaya|Ika P|IP|;Ibrahim|Fera|F|;Rasmin|Menaldi|M|;Alwi|Idrus|I|;Makmun|Dadang|D|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D015850:Interleukin-6; C502936:tocilizumab", "country": "Indonesia", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0125-9326", "issue": "53(2)", "journal": "Acta medica Indonesiana", "keywords": "COVID-19; SARS-CoV-2; Tocilizumab; acute respiratory distress syndrome (ARDS)", "medline_ta": "Acta Med Indones", "mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D000086382:COVID-19; D000080424:Cytokine Release Syndrome; D006801:Humans; D015850:Interleukin-6; D008297:Male; D008875:Middle Aged; D000086402:SARS-CoV-2", "nlm_unique_id": "7901042", "other_id": null, "pages": "194-201", "pmc": null, "pmid": "34251348", "pubdate": "2021-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Tocilizumab as a Treatment for 'Cytokine Storm Syndrome' in COVID-19: A Case Report.", "title_normalized": "tocilizumab as a treatment for cytokine storm syndrome in covid 19 a case report" }

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"drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZINC" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ENOXAPARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anticoagulant therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VITAMINS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Vitamin supplementation", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMINS" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Syam AF, Pitoyo CW, Suhendro S, Zulkarnain B, Indrasari ND, Aditianingsih D, et al. Tocilizumab as a treatment for ^cytokine Storm syndrome^ in COVID-19: A case report. Acta Medica Indonesiana. 2021;53(2):194-201", "literaturereference_normalized": "tocilizumab as a treatment for cytokine storm syndrome in covid 19 a case report", "qualification": "1", "reportercountry": "ID" }, "primarysourcecountry": "ID", "receiptdate": "20211006", "receivedate": "20211006", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19921900, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "BACKGROUND\nClostridium difficile causes diarrhea that ranges from a benign, self-limiting antibiotic use-associated disease to a life-threatening pseudomembranous colitis. Clostridium difficile has rarely been isolated in extraintestinal infections. Our objective was to characterize clinical features and risk factors of these infections. METHODS Extraintestinal C. difficile infections (CDIs) were searched for in an electronic database of all C. difficile-positive isolates found during a 10-year period. The medical records were reviewed retrospectively. Disease severity and comorbidities of the patients were evaluated using Horn disease severity and Charlson comorbidity indexes.\n\n\nRESULTS\nExtraintestinal CDI was found in 31 patients who comprised 0.17% of all CDIs. Two patients had bacteremic infections, 4 had abdominal infections without any prior surgery, 7 had abdominal infections after surgery, 4 had perianal abscesses, 13 had wound infections, and 1 had C. difficile in a urinary catheter. In most cases (85%), C. difficile was isolated together with other microbes. Most (81%) patients developed the infection when hospitalized and many had severe comorbidities. Sixteen (52%) had diarrhea. The 1-year mortality rate was 36% and it correlated with the severity of underlying diseases.\n\n\nCONCLUSIONS\nExtraintestinal CDIs occur mainly in hospitalized patients with significant comorbidities. Extraintestinal CDIs in the abdominal area may result from either intestinal perforation after infection or after intestinal surgery. Wound infections may result from colonization by feces. Clostridium difficile may reach distant sites via bacteremia. Mortality in extraintestinal CDIs is associated with the severity of underlying diseases.", "affiliations": "Department of Infectious Diseases, Department of Infectious Diseases, Helsinki University Central Hospital, Helsinki, Finland. eero.mattila@hus.fi", "authors": "Mattila|Eero|E|;Arkkila|Perttu|P|;Mattila|Petri S|PS|;Tarkka|Eveliina|E|;Tissari|Päivi|P|;Anttila|Veli-Jukka|VJ|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1093/cid/cit392", "fulltext": null, "fulltext_license": null, "issn_linking": "1058-4838", "issue": "57(6)", "journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", "keywords": "Clostridium difficile; abscess; bacteremia; postoperative complications; wound infection", "medline_ta": "Clin Infect Dis", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016470:Bacteremia; D016360:Clostridioides difficile; D003015:Clostridium Infections; D005260:Female; D005387:Finland; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index", "nlm_unique_id": "9203213", "other_id": null, "pages": "e148-53", "pmc": null, "pmid": "23771984", "pubdate": "2013-09", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Extraintestinal Clostridium difficile infections.", "title_normalized": "extraintestinal clostridium difficile infections" }

[ { "companynumb": "FI-PFIZER INC-2017185768", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFUROXIME" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFUROXIME." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLINDAMYCIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "050162", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE, HARD", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN HCL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA ASPIRATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Clostridium bacteraemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BYL, B.. EXTRAINTESTINAL CLOSTRIDIUM DIFFICILE INFECTIONS. CLIN INFECT DIS. 1996;22 (4):712", "literaturereference_normalized": "extraintestinal clostridium difficile infections", "qualification": "3", "reportercountry": "FI" }, "primarysourcecountry": "FI", "receiptdate": "20170510", "receivedate": "20170501", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13500611, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "Here the cases of three female patients who received long-term rituximab treatment for seropositive, erosive and deforming rheumatoid arthritis was reported. After rituximab treatment, they presented with recurrent sinusitis and pneumonia, followed by the subsequent development of bronchiectasis. A temporal relationship between rituximab treatment and the onset of respiratory complications was exposed as a possible pathogenic mechanism.", "affiliations": "GIRAT, Fundación Valle del Lili - Universidad Icesi, Cra. 98 18-49, 760026 Cali, Colombia. gtobon1@yahoo.com.", "authors": "Santos|Víctor A|VA|;Tobón|Gabriel J|GJ|;Cañas|Carlos A|CA|", "chemical_list": null, "country": "Poland", "delete": false, "doi": "10.5603/ARM.a2018.0050", "fulltext": null, "fulltext_license": null, "issn_linking": "2451-4934", "issue": null, "journal": "Advances in respiratory medicine", "keywords": "bronchiectasis; rheumatoid arthritis; rituximab; sinusitis", "medline_ta": "Adv Respir Med", "mesh_terms": null, "nlm_unique_id": "101697329", "other_id": null, "pages": null, "pmc": null, "pmid": "30594999", "pubdate": "2018-12-30", "publication_types": "D016428:Journal Article", "references": null, "title": "Development of bronchiectasis during long-term rituximab treatment for rheumatoid arthritis.", "title_normalized": "development of bronchiectasis during long term rituximab treatment for rheumatoid arthritis" }

[ { "companynumb": "CO-ROCHE-2240971", "fulfillexpeditecriteria": "1", "occurcountry": "CO", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2013", "drugstartdateformat": "602", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bronchiectasis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SANTOS V, TOBON G AND CANAS C. DEVELOPMENT OF BRONCHIECTASIS DURING LONG-TERM RITUXIMAB TREATMENT FOR RHEUMATOID ARTHRITIS. ADVANCES IN RESPIRATORY MEDICINE 2018 DEC 30?:-.", "literaturereference_normalized": "development of bronchiectasis during long term rituximab treatment for rheumatoid arthritis", "qualification": "3", "reportercountry": "CO" }, "primarysourcecountry": "CO", "receiptdate": "20190204", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15797238, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "CO-ROCHE-2258372", "fulfillexpeditecriteria": "1", "occurcountry": "CO", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS-LIKE SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2013", "drugstartdateformat": "602", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bronchiectasis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SANTOS V, TOBON G AND CANAS C. DEVELOPMENT OF BRONCHIECTASIS DURING LONG-TERM RITUXIMAB TREATMENT FOR RHEUMATOID ARTHRITIS. ADVANCES IN RESPIRATORY MEDICINE 2018 DEC 30?:-.", "literaturereference_normalized": "development of bronchiectasis during long term rituximab treatment for rheumatoid arthritis", "qualification": "3", "reportercountry": "CO" }, "primarysourcecountry": "CO", "receiptdate": "20190204", "receivedate": "20190204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15904842, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "CO-ROCHE-2258371", "fulfillexpeditecriteria": "1", "occurcountry": "CO", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TOFACITINIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOFACITINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2009", "drugstartdateformat": "602", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic sinusitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bronchiectasis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SANTOS V, TOBON G AND CANAS C. DEVELOPMENT OF BRONCHIECTASIS DURING LONG-TERM RITUXIMAB TREATMENT FOR RHEUMATOID ARTHRITIS. ADVANCES IN RESPIRATORY MEDICINE 2018 DEC 30?:-.", "literaturereference_normalized": "development of bronchiectasis during long term rituximab treatment for rheumatoid arthritis", "qualification": "3", "reportercountry": "CO" }, "primarysourcecountry": "CO", "receiptdate": "20190204", "receivedate": "20190204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15904785, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]

{ "abstract": "Rituximab maintenance therapy is indicated for the treatment of patients with non-Hodgkin's lymphoma (NHL) who responded to induction therapy. More than 10% of patients will develop rituximab-induced upper respiratory tract infections (URTIs). These infections are usually mild in patients receiving first-line or second-line treatment. Heavily pretreated patients sometimes undergo additional rituximab maintenance therapy. We describe three female patients aged 53, 43 and 42 years who were successfully treated with rituximab maintenance therapy after chemotherapy for three or more recurrences of NHL. These patients developed more serious recurrent URTIs due to rituximab-induced long-term hypogammaglobulinaemia. In one patient, serum IgG levels continued to decline for four years after rituximab therapy. Long-term immunoglobulin substitution was needed to treat these patients. Physicians should be aware that URTIs may develop in heavily pretreated patients even years after rituximab maintenance therapy and substitution with immunoglobulin may be warranted.", "affiliations": "Antoni van Leeuwenhoek, Amsterdam.", "authors": "Jacobs|Bart A W|BA|;Opdam|Frans L|FL|;Rodenhuis|Sjoerd|S|;Baars|Joke W|JW|", "chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0028-2162", "issue": "159()", "journal": "Nederlands tijdschrift voor geneeskunde", "keywords": null, "medline_ta": "Ned Tijdschr Geneeskd", "mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D012008:Recurrence; D012141:Respiratory Tract Infections; D000069283:Rituximab", "nlm_unique_id": "0400770", "other_id": null, "pages": "A8546", "pmc": null, "pmid": "25850451", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Recurrent upper respiratory tract infections during and after rituximab therapy.", "title_normalized": "recurrent upper respiratory tract infections during and after rituximab therapy" }

[ { "companynumb": "NL-MYLANLABS-2015M1027775", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "062337", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "UPPER RESPIRATORY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "UPPER RESPIRATORY TRACT INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "375 MG/M2 EVERY 3 MONTHS FOR OVER 2 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "UPPER RESPIRATORY TRACT INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tooth discolouration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JACOBS BA, OPDAM FL, RODENHUIS S, BAARS JW. RECURRENT UPPER RESPIRATORY TRACT INFECTIONS DURING AND AFTER RITUXIMAB THERAPY. NED-TIJDSCHR-GENEESKD 2015; 159:A8546.", "literaturereference_normalized": "recurrent upper respiratory tract infections during and after rituximab therapy", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20150817", "receivedate": "20150817", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11387730, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "BACKGROUND\nAs the opioid epidemic continues, state legislatures and clinicians increasingly utilize Prescription Drug Monitoring Programs (PDMPs). These programs record dates prescribed and filled for all controlled substances, attempting to identify high-risk prescribing. The aims of this study were to (i) examine data from individuals who died of accidental opioid overdose and (ii) compare differences between those with prescriptions documented in Kentucky's PDMP with individuals without recorded prescriptions.\n\n\nMETHODS\nThis was a retrospective, observational cohort study conducted in Jefferson County, Kentucky. We reviewed records for all opioid overdose death subjects from 2017 and 2018, cross-referencing with prescriptions in Kentucky's PDMP (Kentucky All Schedule Prescription Electronic Reporting System [KASPER]) back to 2014. We performed χ2 analyses for categorical variable comparisons and a separate univariate analysis for age.\n\n\nRESULTS\nOf the 575 individuals who died of accidental opioid overdose in Jefferson County during the study period, 379 (65.9%) had prescriptions documented in KASPER. Individuals had a high prevalence of fentanyl on postmortem toxicology. Only one individual had postmortem toxicology positive for buprenorphine, a medication for opioid use disorder (MOUD). Several subjects experienced what we termed see-saw MOUD prescribing (prescriptions alternating between MOUD and other controlled substances including full agonists), and multiple prescriptions were apparently written and/or filled for deceased subjects.\n\n\nCONCLUSIONS\nReview of PDMP data in deceased patients can prevent unnecessary opioid prescribing and optimize clinical practice. Buprenorphine may have a protective effect in opioid dependence, but access must be consistent. Providers should be aware of see-saw MOUD prescribing and understand the effects on patient care. In response to the prescriptions filled for deceased individuals, legislators could enact a policy such as Void All Prescriptions or VAP alerts to cancel all prescriptions for individuals who have died, reducing drug diversion. It is vital that providers routinely use PDMP data along with counseling and other treatment strategies to optimize patient care.", "affiliations": "Department of Emergency Medicine, University of Louisville, Louisville, Kentucky (Drs Shreffler, Shaw, and Huecker); and Kentucky Office of Inspector General, Cabinet for Health and Family Services, Frankfort, Kentucky (Dr Berrones).", "authors": "Shreffler|Jacob|J|;Shaw|Isaac|I|;Berrones|Adam|A|;Huecker|Martin|M|", "chemical_list": "D000701:Analgesics, Opioid; D009025:Morpholines; C033110:RV 538", "country": "United States", "delete": false, "doi": "10.1097/PHH.0000000000001210", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-4659", "issue": "27(4)", "journal": "Journal of public health management and practice : JPHMP", "keywords": null, "medline_ta": "J Public Health Manag Pract", "mesh_terms": "D000701:Analgesics, Opioid; D015331:Cohort Studies; D011307:Drug Prescriptions; D006801:Humans; D009025:Morpholines; D000083682:Opiate Overdose; D009293:Opioid-Related Disorders; D010818:Practice Patterns, Physicians'", "nlm_unique_id": "9505213", "other_id": null, "pages": "385-392", "pmc": null, "pmid": "32810066", "pubdate": "2021", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Prescription History Before Opioid Overdose Death: PDMP Data and Responsible Prescribing.", "title_normalized": "prescription history before opioid overdose death pdmp data and responsible prescribing" }

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PRESCRIPTION HISTORY BEFORE OPIOID OVERDOSE DEATH: PDMP DATA AND RESPONSIBLE PRESCRIBING. J PUBLIC HEALTH MANAG PRACT. 2020?000 (000):1?8.", "literaturereference_normalized": "prescription history before opioid overdose death pdmp data and responsible prescribing", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200908", "receivedate": "20200908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18243266, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-INDIVIOR US-INDV-126115-2020", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020732", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Accidental overdose", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "JACOB SHREFFLER, ISAAC SHAW, ADAM BERRONES, MARTIN HUECKER. PRESCRIPTION HISTORY BEFORE OPIOID OVERDOSE DEATH: PDMP DATA AND RESPONSIBLE PRESCRIBING. 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Prescription History Before Opioid Overdose Death: PDMP Data and Responsible Prescribing. 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{ "abstract": "BACKGROUND\nVertical transmission of coronavirus disease 2019 (COVID-19) from mother to newborn infant is doubtful, and very little is known about disease severity and neonatal outcome.\n\n\nMETHODS\nWe present a preterm Iranian infant born to a Persian mother with severe COVID-19 pneumonia. The mother underwent cesarean delivery, and amniotic fluid yielded a positive result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by real-time reverse transcription polymerase chain reaction (RT-PCR). The newborn infant showed early-onset infection with SARS-CoV-2 confirmed on pharyngeal swabs by RT-PCR assay within 24 hours after birth, suggesting vertical transmission. Unfortunately, the mother died 14 days after delivery. We describe the clinical course and outcome of the infant up to 7 months of age.\n\n\nCONCLUSIONS\nCOVID-19 infection in pregnant women may increase maternal morbidity, mortality and possibly vertical transmission in severe cases. However, it does not seem to progress to serious early or late neonatal complications.", "affiliations": "Pediatrics infectious diseases research center, Mazandaran University of Medical Sciences, Sari, Iran. dr.royafarhadi@gmail.com.;Pediatrics infectious diseases research center, Mazandaran University of Medical Sciences, Sari, Iran.;Pediatrics infectious diseases research center, Mazandaran University of Medical Sciences, Sari, Iran.;Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Obstetrics and Gynecology, Mazandaran University of Medical Sciences, Sari, Iran.", "authors": "Farhadi|Roya|R|http://orcid.org/0000-0002-6525-527X;Mehrpisheh|Shahrokh|S|;Ghaffari|Vajiheh|V|;Haghshenas|Mohammadreza|M|;Ebadi|Aghdas|A|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s13256-021-02835-0", "fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2835\n10.1186/s13256-021-02835-0\nCase Report\nClinical course, radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe COVID-19 pneumonia: a case report\nhttp://orcid.org/0000-0002-6525-527X\nFarhadi Roya dr.royafarhadi@gmail.com\n\n1\nMehrpisheh Shahrokh 1\nGhaffari Vajiheh 1\nHaghshenas Mohammadreza 2\nEbadi Aghdas 3\n1 grid.411623.3 0000 0001 2227 0923 Pediatrics infectious diseases research center, Mazandaran University of Medical Sciences, Sari, Iran\n2 grid.411623.3 0000 0001 2227 0923 Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran\n3 grid.411623.3 0000 0001 2227 0923 Department of Obstetrics and Gynecology, Mazandaran University of Medical Sciences, Sari, Iran\n23 4 2021\n23 4 2021\n2021\n15 21324 11 2020\n29 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nVertical transmission of coronavirus disease 2019 (COVID-19) from mother to newborn infant is doubtful, and very little is known about disease severity and neonatal outcome.\n\nCase presentation\n\nWe present a preterm Iranian infant born to a Persian mother with severe COVID-19 pneumonia. The mother underwent cesarean delivery, and amniotic fluid yielded a positive result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by real-time reverse transcription polymerase chain reaction (RT-PCR). The newborn infant showed early-onset infection with SARS-CoV-2 confirmed on pharyngeal swabs by RT-PCR assay within 24 hours after birth, suggesting vertical transmission. Unfortunately, the mother died 14 days after delivery. We describe the clinical course and outcome of the infant up to 7 months of age.\n\nConclusion\n\nCOVID-19 infection in pregnant women may increase maternal morbidity, mortality and possibly vertical transmission in severe cases. However, it does not seem to progress to serious early or late neonatal complications.\n\nKeywords\n\nCOVID-19\nSARS-CoV-2\nNeonate\nPreterm infant\nVertical transmission\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nPneumonia caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in Wuhan, China in December 2019 [1, 2]. On February 11, 2020, the World Health Organization (WHO) officially named the disease caused by the novel virus, coronavirus disease 2019 (COVID-19) [3, 4]. The outbreak was declared a pandemic by WHO as the virus spread rapidly to other countries including Japan, Korea, Thailand and Iran, with high mortality rates [3, 5]. It seems that due to physiological and immunological changes during pregnancy, pregnant women are susceptible to COVID-19 and more likely to have morbidity and mortality [1, 6]. At present, there is not enough data to ascertain the effects of COVID-19 infection on the fetus, and the main question is whether vertical transmission of COVID-19 from pregnant mother to fetus occurs and causes clinically significant infection in newborns [5, 7, 8]. Indeed, published case series and case reports have shown extensive variability in the rate of vertical transmission. As COVID-19 infection can potentially cause severe complications in neonates, continuous observance is necessary [9]. On the other hand, the disease severity when SARS-CoV-2 is transmitted vertically and the time of this transmission are still uncertain. Thus, WHO recently published a definition and categorization system for the timing and possibility of infection occurrence to enhance our understanding of SARS-CoV-2 vertical transmission and its clinical outcomes [10].\n\nIn this report, we present early-onset infection with SARS-CoV-2 in a preterm infant, born to a mother with severe COVID-19 pneumonia. The mother’s clinical characteristics have already been published in a research letter [11]. In this article we focus more on the clinical course and para-clinical evidence for the newborn, which indicates the possibility of vertical transmission of SARS-CoV-2 from mother to infant, and we describe the follow-up of the infant to 7 months of age.\n\nCase presentation\n\nOn March 11, 2020, the neonatal resuscitation team of Imam Khomeini Hospital in Sari (northern Iran) was alerted for the delivery by caesarean section of a mother with critical COVID-19 pneumonia. The mother was a 22-year-old, primigravid Persian woman suffering from fever, nonproductive cough, myalgia, anorexia and nausea for the preceding two weeks. She was a housewife and came from a middle-class family and had a history of exposure to a person with COVID-19 infection 1 week before the onset of symptoms. She did not smoke or drink alcohol. Prior to admission, she had received only oral azithromycin and acetaminophen. Diagnosis of COVID-19 pneumonia was confirmed by lung computed tomography (CT) scan and two positive nasal and throat sample real-time reverse transcription polymerase chain reaction (RT-PCR) tests (SuperScript III Platinum, Quantitative Real-Time PCR kit, Invitrogen, Waltham, MA, USA), and she underwent antiviral treatment and respiratory support. During admission, treatment with Kaletra (lopinavir/ritonavir 200 mg orally daily), azithromycin (500 mg intravenously every 12 hours), ceftriaxone (1000 mg every 12 hours), Tamiflu (oseltamivir orally, 400 mg every 12 hours) and hydroxychloroquine (400 mg daily) were initiated. The mother did not receive antenatal corticosteroid, and considering the rapid deterioration of her condition and the recommendation of a multidisciplinary working group, a decision was taken for an early caesarean delivery at 32 weeks of gestation.\n\nNeonatal resuscitation team members wore the recommended personal protective equipment (PPE) and followed the COVID-19 protocols for perinatal care. The mother only had a history of hypothyroidism without other underlying diseases such as diabetes. Hypothyroidism was controlled by treatment with levothyroxine 100 μg daily. Following the policy during the early first wave of COVID-19, we decided in advance to separate the baby from the mother immediately after birth and postpone skin-to-skin contact and delayed cord clamping.\n\nFive milliliters of amniotic fluid was aspirated into a sterile syringe with a needle after myometrial incision of the uterus, just before tearing of the membrane, for COVID-19 RT-PCR assay. A preterm female Persian infant was delivered uneventfully. She needed only initial steps of resuscitation and had APGAR scores of 8 and 9 at 1 and 5 minutes, respectively. Umbilical cord blood samples were obtained in sterile containers with viral transport media to immediate transfer to the specific virology center of the university for COVID-19 studies.\n\nThe newborn infant weighing 2350 gm was isolated in a single-occupancy room with an air filtration system in the neonatal intensive care unit (NICU). She had respiratory distress and required continuous positive airway pressure (CPAP) with positive end-expiratory pressure (PEEP) of 5 cmH2O and fraction of inspired oxygen (FiO2) of 21%. The first chest X-ray showed characteristic features of respiratory distress syndrome (RDS). According to the updated protocols, neonatal nasopharyngeal and oropharyngeal swab samples were collected at 2 and 24 hours after delivery and tested for SARS-CoV-2 using the SuperScript III Platinum Quantitative Real-Time PCR kit (Invitrogen, Waltham, MA, USA) at the medical virology laboratory of Mazandaran University of Medical Sciences. Twelve hours after birth, the infant was formula-fed because the mother was critically ill, and we did not have a milk bank in our hospital. Intravenously administered ampicillin (50 mg/kg/dose every 12 hours)  and gentamicin (4 mg/kg/dose every 48 hours)  were prescribed as empirical antibiotic therapy. Noninvasive respiratory support (nasal CPAP) was required for 2 days, with acceptable blood gas analysis. Umbilical cord and first oro/nasopharyngeal sample RT-PCR tests reported negative results; however, the results of amniotic fluid and the second pharyngeal swab done within 24 hours turned positive for SARS-CoV-2. The neonate’s blood gas analysis was acceptable, and blood oxygen saturation stayed above 92% without supplemental oxygen. Other laboratory results including complete blood count, C-reactive protein, creatine phosphokinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, thyroid-stimulating hormone and alkaline phosphatase were within the normal range. Two days after discontinuing the CPAP, while the neonate was afebrile, the baby became unwell with respiratory distress and increasing need for supplemental oxygen. The antibiotic regimen was changed to vancomycin (10 mg/kg/dose every 18 hours) and meropenem (20 mg/kg/dose every 12 hours). Chest X-ray showed a pneumomediastinum/pneumothorax needing chest drain insertion due to oxygen desaturation (Fig. 1). Subsequent to the chest drain removal, she remained stable on 30% supplemental nasal cannula oxygen, and a lung CT scan revealed patchy shadows in the peripheral parts of the lung (Fig. 2).Fig. 1 Chest radiograph of the newborn obtained on the fifth day of life\n\nFig. 2 Chest computed tomography of the baby obtained on the ninth day of life showing bilateral patchy shadows\n\nThe infant was not commenced on specific antiviral treatments. On day 14 of life (March 24), a repeat pharyngeal swab sample was obtained, and the result was positive. The results of repeated pharyngeal swab samples for SARS-CoV-2 on the 16th and 18th days of life were negative. When the baby's general condition improved, we decided to share the baby's pictures and videos with the mother in the ICU. This decision was made based on a quality improvement project in our unit [12]. We did not succeed because the mother underwent peritoneal dialysis, intubation and full sedation for ventilator therapy due to oxygen desaturation. Unfortunately, the mother died on March 26 due to the severity of her illness.\n\nThe neonate received a total of 14 days of antibiotics and was discharged home on day 30 of life. She was followed up with mobile communication and telemedicine clinics initially and subsequently through limited clinic visits. Eye examinations for retinopathy of prematurity were normal. Hearing screening test results showed clear response for both of the baby’s ears as well. The results of ultrasound of the brain and lungs performed at 2 months of age were normal. Neurodevelopmental status was appropriate for the corrected gestational age when reviewed in late October.\n\nDiscussion\n\nIn this report we present the case of a preterm baby, born to a mother with severe COVID-19 pneumonia. The newborn infant had positive RT-PCR tests on the first and 14th days of life and pulmonary involvement on lung CT scan. Although findings from a recent small group of cases indicate that there is currently no strong evidence for vertical transmission in women who develop COVID-19 pneumonia late in pregnancy, the possibility of maternal-to-fetal vertical transmission cannot be completely ruled out, given the small sample size reported, and poses a concern among neonatal societies [13, 14]. According to the WHO classification, the reasons suggesting vertical transmission in our neonate are the positive amniotic fluid test and positive RT-PCR testing of the baby within 24 hours of life [10]. In addition, the baby had respiratory distress, although it is difficult to differentiate COVID-19 symptoms from the symptoms of RDS, transient tachypnea of the newborn (TTN) and sepsis [14].\n\nThe possibility of vertical transmission of COVID-19 infection from mother to baby has already been proposed. Alzamora et al. reported a preterm infant born to a mother with severe COVID-19 from Peru. The infant’s nasopharyngeal swab at 16 hours after birth was positive for SARS-CoV-2 on RT-PCR. Immunoglobulins (IgM and IgG) for SARS-CoV-2 were negative. The authors did not test for the presence of the virus in the amniotic fluid. Similar to our case, they believe that the severity of maternal illness could be a possible explanation for vertical transmission [15]. Another report from India also highlighted the possibility of vertical transmission of COVID-19 from a mildly symptomatic mother [16].\n\nIn a report of nine pregnant women with laboratory-confirmed COVID-19 pneumonia in Wuhan, China, cord blood, amniotic fluid and neonatal throat swab were tested for the presence of SARS-CoV-2 and all samples were negative for the virus. Four mothers had preterm labor, but all were beyond 36 gestational weeks. The authors concluded that development of COVID-19 pneumonia in the third trimester could not lead to fetal infection or severe adverse outcome in neonates by intrauterine vertical transmission [13].\n\nDong et al. reported possible vertical transmission in a newborn with elevated IgM antibodies to SARS-CoV-2 born to a mother with COVID-19 in China. The baby was exposed for 23 days from the time of the mother’s diagnosis of COVID-19 to delivery, but the infant’s repeated RT-PCR nasopharyngeal swabs tests were reportedly negative, and PCR testing of amniotic fluid was not done [17]. Due to the limited number of confirmed neonatal cases, there is still a lack of clarity as to whether the duration of maternal infection affects the rate of positive test results in neonates [14]. On the other hand, the viral load and amount of virus may be another important factor for amplification of RT-PCR test results and transmission to infants [18, 19]. In our case, the mother exhibited severe pneumonia and subsequently died. It is possible that when the mother exhibits a severe disease course with the associated presence of the virus in the amniotic fluid, the vertical transmission potential also increases, probably due to the high viral load. In a cohort study, Zeng et al. recruited all 33 neonates born to mothers with COVID-19 from Wuhan Children’s Hospital in China. Of the three newborns who tested positive for COVID-19 infection, the first RT-PCR test for all three babies was taken on the second day of life. Therefore, the authors were unable to determine whether these babies caught the virus in the womb or were infected by contact transmission around the time of birth [20]. In our study, the first RT-PCR test was negative and the second was positive, raising the question of prenatal or postnatal timing of infection. On the other hand, the amniotic fluid test was positive, and the baby was born by cesarean section with our strict measures to reduce the risk of infection. We believe that it is unlikely that the infant was infected during the delivery.\n\nAt present, RT-PCR is considered the gold standard for the diagnosis of SARS-CoV-2 [21]. However, the positive detection rate of the nasopharyngeal swab test is reportedly less than 50% [7, 8].\n\nThe scope to which maternal COVID-19 infection increases the risk of preterm delivery remains uncertain, though based on several unpublished reports from Spain, prematurity was secondary to an obstetrics decision to terminate the pregnancy due to the severity of the disease in the mother [21]. In our case report, preterm delivery was due to severe pneumonia and respiratory insufficiency in the mother.\n\nThe limitation of our study is that we were not able to measure the neonatal SARS-CoV-2 IgM level because the serologic kits were not available to us in the early stages of the pandemic.\n\nConclusion\n\nThe case reported herein of an infected preterm neonate born to a mother with critical infection suggests that COVID-19 infection in pregnant woman may increase the risk of maternal mortality, and vertical transmission may be possible in severe cases. Therefore, the collection of additional evidence regarding perinatal infection is of significant interest for assessing the risk of vertical transmission of SARS-CoV-2 and its impact on neonatal outcomes.\n\nAcknowledgements\n\nThe authors of this paper would like to thank the baby’s father for his cooperation in all stages of the neonate’s treatment, and Professor Roy K. Philip, University Maternity Hospital Limerick, Ireland, for the editorial assistance.\n\nAuthors' contributions\n\nRF took the newborn’s history, performed management, organized the research ethics approval and developed the first draft manuscript. SM and VH performed the physical examination of the baby and provided the data regarding the follow-up. MH performed the virological examinations and revised the draft. AE was responsible for the mother’s data collection. All authors read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nAll data and material collected during this study are available from the corresponding author upon reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthical approval was obtained for this report from research ethics committee of Mazandaran University of Medical Sciences (No. 1399.8083).\n\nConsent for publication\n\nWritten informed consent was obtained from the patient‘s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that there are no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Wang S Guo L Chen L A case report of neonatal 2019 coronavirus disease in China Clin Infect Dis. 2020 71 15 853 857 10.1093/cid/ciaa225 32161941\n2. Yu N Li W Kang Q Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study Lancet Infect Dis. 2020 20 5 559 564 10.1016/S1473-3099(20)30176-6 32220284\n3. Karimi-Zarchi M Neamatzadeh H Dastgheib SA Vertical transmission of coronavirus disease 19 (COVID-19) from infected pregnant mothers to neonates: a review Fetal Pediatr Pathol. 2020 39 3 246 250 10.1080/15513815.2020.1747120 32238084\n4. Hui DS Azhar IE Madani TA The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health—the latest 2019 novel coronavirus outbreak in Wuhan, China Int J Infect Dis. 2020 91 264 266 10.1016/j.ijid.2020.01.009 31953166\n5. Mimouni F Lakshminrusimha S Pearlman SA Raju T Gallagher PG Mendlovic J Perinatal aspects on the covid-19 pandemic: a practical resource for perinatal-neonatal specialists J Perinatol. 2020 40 5 820 826 10.1038/s41372-020-0665-6 32277162\n6. Mardani M Pourkaveh B A controversial debate: vertical transmission of COVID-19 in pregnancy Arch Clin Infect Dis. 2020 15 1 e102286 10.5812/archcid.102286\n7. Lu Q Shi Y Coronavirus disease (COVID-19) and neonate: what neonatologist need to know J Med Virol. 2020 92 6 564 567 10.1002/jmv.25740 32115733\n8. Chen Y Peng H Wang L Infants born to mothers with a new coronavirus (COVID-19) Front Pediatr. 2020 8 104 10.3389/fped.2020.00104 32266184\n9. Goh XL Low YF Ng CH Amin Z Ng YPM Incidence of SARS-CoV-2 vertical transmission: a meta-analysis Arch Dis Child Fetal Neonatal Ed. 2021 106 1 112 113 10.1136/archdischild-2020-319791 32586828\n10. World Health Organization: Definition and categorization of the timing of mother-to-child transmission of SARS-CoV-2. 8 February 2021. Geneva: World Health Organization; 2021.\n11. Zamaniyan M Ebadi A Aghajanpoor S Rahmani Z Haghshenas M Azizi S Preterm delivery, maternal death, and vertical transmission in a pregnant woman with COVID-19 infection Prenat Diagn. 2020 10.1002/pd.5713 32304114\n12. Farhadi R Mehrpisheh S Philip RK Mobile-assisted virtual bonding enables breast milk supply in critically Ill mothers With COVID-19: a reflection on the feasibility of telelactation Cureus 2021 13 3 e13699 33833919\n13. Chen H Guo J Wang C Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records Lancet 2020 395 10226 809 815 10.1016/S0140-6736(20)30360-3 32151335\n14. Ma X Zhu J Du L Neonatal management during the coronavirus disease (COVID-19) outbreak: the Chinese experience NeoReviews 2020 21 5 e293 e297 10.1542/neo.21-5-e293 32358142\n15. Alzamora MC Paredes T Caceres D Webb CM Valdez LM La Rosa M Severe COVID-19 during pregnancy and possible vertical transmission Am J Perinatol. 2020 37 8 861 865 10.1055/s-0040-1710050 32305046\n16. Kulkarni R Rajput U Dawre R Early-onset symptomatic neonatal COVID-19 infection with high probability of vertical transmission Infection 2020 2 1 5\n17. Dong L Tian J He S Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn JAMA 2020 323 18 1846 1848 32215581\n18. Qiu L Liu X Xiao M SARS-CoV-2 is not detectable in the vaginal fluid of women with severe COVID-19 infection Clin Infect Dis. 2020 71 15 813 817 10.1093/cid/ciaa375 32241022\n19. Fan C Lei D Fang C Perinatal transmission of COVID-19 associated Sars-CoV-2: should we worry? Clin Infect Dis. 2021 72 5 862 864 10.1093/cid/ciaa226 32182347\n20. Zeng L, Xia S, Yuan W, et al. Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China (published online ahead of print, 2020 Mar 26). JAMA Pediatr. 2020; e200878.\n21. Chandrasekharan P Vento M Trevisanuto D Neonatal resuscitation and postresuscitation care of infants born to mothers with suspected or confirmed SARS-CoV-2 infection Am J Perinatol 2020 37 8 813 824 10.1055/s-0040-1709688 32268381\n\n", "fulltext_license": "CC BY", "issn_linking": "1752-1947", "issue": "15(1)", "journal": "Journal of medical case reports", "keywords": "COVID-19; Neonate; Preterm infant; SARS-CoV-2; Vertical transmission", "medline_ta": "J Med Case Rep", "mesh_terms": "D000653:Amniotic Fluid; D000086382:COVID-19; D002585:Cesarean Section; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D018445:Infectious Disease Transmission, Vertical; D007492:Iran; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D047928:Premature Birth; D012151:Resuscitation; D055815:Young Adult", "nlm_unique_id": "101293382", "other_id": null, "pages": "213", "pmc": null, "pmid": "33892788", "pubdate": "2021-04-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "32238084;32743723;32220284;32304114;32277162;32358142;32305046;32115733;32182347;32215598;32266184;31953166;32586828;33833919;32268381;32161941;32241022;32151335;32215581", "title": "Clinical course, radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe COVID-19 pneumonia: a case report.", "title_normalized": "clinical course radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe covid 19 pneumonia a case report" }

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"500 MILLIGRAM, Q 12 HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN USP" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MILLIGRAM, Q 12 HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203412", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN USP" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "COVID-19 pneumonia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "FARHADI R, MEHRPISHEH S, GHAFFARI V, HAGHSHENAS M, EBADI A.. CLINICAL COURSE, RADIOLOGICAL FINDINGS AND LATE OUTCOME IN PRETERM INFANT WITH SUSPECTED VERTICAL TRANSMISSION BORN TO A MOTHER WITH SEVERE COVID?19 PNEUMONIA: A CASE REPORT. JOURNAL OF MEDICAL CASE REPORTS. 2021?15:213:1?5", "literaturereference_normalized": "clinical course radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe covid 19 pneumonia a case report", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20210615", "receivedate": "20210615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19418538, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "IR-PFIZER INC-2021669657", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "OSELTAMIVIR PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, 2X/DAY (EVERY 12 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMIFLU" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 UG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "050670", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, 2X/DAY (EVERY 12 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "050670", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, 2X/DAY (EVERY 12 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "FARHADI, R.. CLINICAL COURSE, RADIOLOGICAL FINDINGS AND LATE OUTCOME IN PRETERM INFANT WITH SUSPECTED VERTICAL TRANSMISSION BORN TO A MOTHER WITH SEVERE COVID?19 PNEUMONIA: A CASE REPORT. JOURNAL OF MEDICAL CASE REPORTS. 2021?15 (1):10.1186/S13256?021?02835?0", "literaturereference_normalized": "clinical course radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe covid 19 pneumonia a case report", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20210621", "receivedate": "20210621", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19443398, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "IR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-308143", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "090923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OSELTAMIVIR PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMIFLU" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200311" } }, "primarysource": { "literaturereference": "FARHADI R, MEHRPISHEH S, GHAFFARI V, HAGHSHENAS M, EBADI A. CLINICAL COURSE, RADIOLOGICAL FINDINGS AND LATE OUTCOME IN PRETERM INFANT WITH SUSPECTED VERTICAL TRANSMISSION BORN TO A MOTHER WITH SEVERE COVID?19 PNEUMONIA: A CASE REPORT. J MED CASE REP. 2021?15(1):213", "literaturereference_normalized": "clinical course radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe covid 19 pneumonia a case report", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19713742, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-308154", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GENTAMICIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MILLIGRAM/KILOGRAM, 1DOSE/48HOUR", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GENTAMICIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OSELTAMIVIR PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMIFLU" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM/KILOGRAM, EVERY 18 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMPICILLIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM/KILOGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPICILLIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "090923", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200311" } }, "primarysource": { "literaturereference": "FARHADI R, MEHRPISHEH S, GHAFFARI V, HAGHSHENAS M, EBADI A. CLINICAL COURSE, RADIOLOGICAL FINDINGS AND LATE OUTCOME IN PRETERM INFANT WITH SUSPECTED VERTICAL TRANSMISSION BORN TO A MOTHER WITH SEVERE COVID?19 PNEUMONIA: A CASE REPORT. J MED CASE REP. 2021?15(1):213", "literaturereference_normalized": "clinical course radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe covid 19 pneumonia a case report", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20210818", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19713792, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "NVSC2021IR176052", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 UG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "40104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OSELTAMIVIR PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMIFLU" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FARHADI R., MEHRPISHEH S, GHAFFARI V, HAGHSHENAS M, EBADI A.. CLINICAL COURSE, RADIOLOGICAL FINDINGS AND LATE OUTCOME IN PRETERM INFANT WITH SUSPECTED VERTICAL TRANSMISSION BORN TO A MOTHER WITH SEVERE COVID?19 PNEUMONIA: A CASE REPORT. JOURNAL OF MEDICAL CASE REPORTS. 2021?15:1?5", "literaturereference_normalized": "clinical course radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe covid 19 pneumonia a case report", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20210816", "receivedate": "20210816", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19711762, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "IR-NOVARTISPH-NVSC2021IR176045", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "4", "drugadministrationroute": "015", "drugauthorizationnumb": "40104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Foetal exposure during pregnancy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LOPINAVIR\\RITONAVIR" }, "drugadditional": "4", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Foetal exposure during pregnancy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KALETRA" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN" }, "drugadditional": "4", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Foetal exposure during pregnancy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "4", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Foetal exposure during pregnancy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OSELTAMIVIR PHOSPHATE" }, "drugadditional": "4", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Foetal exposure during pregnancy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMIFLU" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "4", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Foetal exposure during pregnancy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Farhadi Roya, Mehrpisheh Shahrokh, Ghaffari Vajiheh, Haghshenas Mohammadreza, Ebadi Aghdas. Clinical course, radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe COVID-19 pneumonia: a case report. Journal of Medical Case Reports. 2021;15:1-5", "literaturereference_normalized": "clinical course radiological findings and late outcome in preterm infant with suspected vertical transmission born to a mother with severe covid 19 pneumonia a case report", "qualification": "3", "reportercountry": "IR" }, "primarysourcecountry": "IR", "receiptdate": "20211207", "receivedate": "20210811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19684233, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "Mixed connective tissue disease (MCTD) involves various clinical manifestations, and pulmonary hypertension (PH) is an important organ dysfunction defining the prognosis of MCTD. The pathology of PH is heterogeneous. Here, we present 2 cases of MCTD complicated by PH that had contrasting clinical courses. The first case involved a 54-year-old woman with Raynaud's phenomenon and dyspnoea on exertion. She was diagnosed with MCTD accompanied by pulmonary arterial hypertension (PAH) and was treated with ambrisentan and tadalafil in addition to high-dose glucocorticoid (GC) therapy and rituximab therapy. After treatment, her PH resolved. The second case involved a 64-year-old woman with Raynaud's phenomenon and dyspnoea on exertion. She was similarly diagnosed with MCTD accompanied by PAH and was treated with ambrisentan and tadalafil in addition to high-dose GC therapy and cyclophosphamide pulse therapy. However, she showed exacerbation of her respiratory condition and manifestation of pulmonary veno-occlusive disease (PVOD). Thus, the treatment was discontinued, and subsequently, her condition improved and eventually returned to that before treatment. The findings suggest that the presence or absence of latent PVOD might be an important factor for predicting the therapeutic responsiveness of MCTD-associated PH. Evaluation of chest radiography findings, computed tomography findings, percent vital capacity, and percent carbon monoxide diffusion capacity might be useful for predicting prognosis and might aid in treatment. PVOD could be underlying in patients with CTD-PH. When the complication of PVOD is suggested by chest CT or pulmonary function test, we need a careful introduction with pulmonary vasodilators. So, combination therapy of pulmonary vasodilators should not be applied in all patients with CTD-PH since underlying PVOD could deteriorate the patient's condition.", "affiliations": "The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.;The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.;The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.;The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.;The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.;The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.", "authors": "Kusaka|Katsuhide|K|;Nakano|Kazuhisa|K|;Iwata|Shigeru|S|;Kubo|Satoshi|S|;Nishida|Tomoya|T|;Tanaka|Yoshiya|Y|0000-0002-0807-7139", "chemical_list": "D007166:Immunosuppressive Agents; D014665:Vasodilator Agents", "country": "England", "delete": false, "doi": "10.1080/24725625.2020.1758388", "fulltext": null, "fulltext_license": null, "issn_linking": "2472-5625", "issue": "4(2)", "journal": "Modern rheumatology case reports", "keywords": "Pulmonary vasodilators; immunosuppressive therapy; mixed connective tissue disease; pulmonary hypertension; pulmonary veno-occlusive disease", "medline_ta": "Mod Rheumatol Case Rep", "mesh_terms": "D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D008947:Mixed Connective Tissue Disease; D000081029:Pulmonary Arterial Hypertension; D011668:Pulmonary Veno-Occlusive Disease; D012129:Respiratory Function Tests; D063189:Symptom Assessment; D016896:Treatment Outcome; D014665:Vasodilator Agents", "nlm_unique_id": "101761026", "other_id": null, "pages": "253-261", "pmc": null, "pmid": "33087021", "pubdate": "2020-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Two patients with mixed connective tissue disease complicated by pulmonary arterial hypertension showing contrasting responses to pulmonary vasodilators.", "title_normalized": "two patients with mixed connective tissue disease complicated by pulmonary arterial hypertension showing contrasting responses to pulmonary vasodilators" }

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TWO PATIENTS WITH MIXED CONNECTIVE TISSUE DISEASE COMPLICATED BY PULMONARY ARTERIAL HYPERTENSION SHOWING CONTRASTING RESPONSES TO PULMONARY VASODILATORS. MODERN RHEUMATOLOGY CASE REPORTS. 2020?UNK:UNK. 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failure", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Productive cough", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2019" } }, "primarysource": { "literaturereference": "KUSAKA K., NAKANO K., IWATA S., KUBO S., NISHIDA T., TANAKA Y... TWO PATIENTS WITH MIXED CONNECTIVE TISSUE DISEASE COMPLICATED BY PULMONARY ARTERIAL HYPERTENSION SHOWING CONTRASTING RESPONSES TO PULMONARY VASODILATORS.. MODERN RHEUMATOLOGY CASE REPORTS. 2020?UNK:UNK", "literaturereference_normalized": "two patients with mixed connective tissue disease complicated by pulmonary arterial hypertension showing contrasting responses to pulmonary vasodilators", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200617", "receivedate": "20190925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16852032, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "JP-ACCORD-207345", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMBRISENTAN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY ARTERIAL HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMBRISENTAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIXED CONNECTIVE TISSUE DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MIXED CONNECTIVE TISSUE DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE/CYCLOPHOSPHAMIDE MONOHYDRATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TADALAFIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "209167", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY ARTERIAL HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TADALAFIL." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "39.7", "reaction": [ { "reactionmeddrapt": "Pulmonary veno-occlusive disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory symptom", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KUSAKA K, NAKANO K, IWATA S, KUBO S, NISHIDA T, TANAKA Y. TWO PATIENTS WITH MIXED CONNECTIVE TISSUE DISEASE COMPLICATED BY PULMONARY ARTERIAL HYPERTENSION SHOWING CONTRASTING RESPONSES TO PULMONARY VASODILATORS. MOD RHEUMATOL CASE REP. 2020 JUL?4(2):253-261", "literaturereference_normalized": "two patients with mixed connective tissue disease complicated by pulmonary arterial hypertension showing contrasting responses to pulmonary vasodilators", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201107", "receivedate": "20201107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18476763, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210114" } ]

{ "abstract": "Prosthetic valve dehiscence and persistent infection are two complications following reconstruction of the aortic root in destructive endocarditis. A technique is described involving the principles of aggressive debridement, closure of large abscess cavities with biological material incorporating a slurry of antibiotic-impregnated biological sealant, and replacement of the aortic valve with an aortic allograft valve. This strategy appears to have been successful in preventing persistent endocarditis and valve dehiscence in a limited number of patients.", "affiliations": "Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, Alabama.", "authors": "McGiffin|David C|DC|;Davies|James E|JE|;Kirklin|James K|JK|", "chemical_list": "D000269:Adhesives; D000900:Anti-Bacterial Agents", "country": "United States", "delete": false, "doi": "10.1111/jocs.12292", "fulltext": null, "fulltext_license": null, "issn_linking": "0886-0440", "issue": "29(3)", "journal": "Journal of cardiac surgery", "keywords": null, "medline_ta": "J Card Surg", "mesh_terms": "D000038:Abscess; D000269:Adhesives; D064591:Allografts; D000900:Anti-Bacterial Agents; D001021:Aortic Valve; D004697:Endocarditis, Bacterial; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D019651:Reconstructive Surgical Procedures; D013529:Surgical Wound Dehiscence", "nlm_unique_id": "8908809", "other_id": null, "pages": "340-2", "pmc": null, "pmid": "24433228", "pubdate": "2014-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Reconstructing the infected aortic root with antibiotic impregnated biological glue.", "title_normalized": "reconstructing the infected aortic root with antibiotic impregnated biological glue" }

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{ "abstract": "Treatment of chronic hepatitis C virus (HCV) infection remains a priority in the veterans affairs (VA) health care system nationwide, as there is a high burden of liver disease due to HCV infection among US veterans. The combination of sofosbuvir and simeprevir was the first all-oral antiviral regimen used in clinical practice to treat veterans with HCV infection. In this study, we report a single-center experience showing both the feasibility and effectiveness of this all-oral combination to treat HCV genotype 1 infection. One hundred patients with HCV genotype 1 infection were treated between December 2013 and June 2014. Eighty-six patients were treated with sofosbuvir and simeprevir, with or without ribavirin, for 12 weeks; 12 patients were treated with sofosbuvir, pegylated interferon, and ribavirin for 12 weeks; and 2 patients were treated with sofosbuvir and ribavirin for 24 weeks. Overall, treatment was well tolerated and feasible, with compliance rates over 95% in patients treated with all-oral therapy. The sustained virologic response (SVR) rate for sofosbuvir and simeprevir (88.4%) was superior to the rate for sofosbuvir, pegylated interferon, and ribavirin (50.0%). Subgroup analysis showed diminished SVR rates in cirrhotic patients vs noncirrhotic patients. There were no significant differences in SVR when comparing treatment with or without ribavirin or among genotype subtypes. In conclusion, this study demonstrated excellent completion rates for all-oral treatment of veterans with chronic HCV infection. Additionally, treatment was highly effective, nearing a 90% cure rate. Thus, we recommend that the VA health care system continue to incorporate new HCV medications into its formulary so as to expand HCV treatment for US veterans.", "affiliations": "Dr Sclair is a transplant hepatology fellow at the University of Miami Miller School of Medicine in Miami, Florida. Drs Hernandez and Peyton are assistant professors of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and staff physicians in the Hepatology Section of the Miami VA Healthcare System in Miami, Florida. Ms Vance is a research associate in the Miami VA Healthcare System. Dr Gilinski is an internal medicine resident at the University of Miami Miller School of Medicine. Drs Youtseff and Toro are clinical pharmacists in the Pharmacy Service of the Miami VA Healthcare System. Ms Antoine is a nurse practitioner in the Medicine Service of the Miami VA Healthcare System. Dr Jeffers is a professor of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and chief of the Hepatology Section of the Miami VA Healthcare System.;Dr Sclair is a transplant hepatology fellow at the University of Miami Miller School of Medicine in Miami, Florida. Drs Hernandez and Peyton are assistant professors of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and staff physicians in the Hepatology Section of the Miami VA Healthcare System in Miami, Florida. Ms Vance is a research associate in the Miami VA Healthcare System. Dr Gilinski is an internal medicine resident at the University of Miami Miller School of Medicine. Drs Youtseff and Toro are clinical pharmacists in the Pharmacy Service of the Miami VA Healthcare System. Ms Antoine is a nurse practitioner in the Medicine Service of the Miami VA Healthcare System. Dr Jeffers is a professor of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and chief of the Hepatology Section of the Miami VA Healthcare System.;Dr Sclair is a transplant hepatology fellow at the University of Miami Miller School of Medicine in Miami, Florida. Drs Hernandez and Peyton are assistant professors of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and staff physicians in the Hepatology Section of the Miami VA Healthcare System in Miami, Florida. Ms Vance is a research associate in the Miami VA Healthcare System. Dr Gilinski is an internal medicine resident at the University of Miami Miller School of Medicine. Drs Youtseff and Toro are clinical pharmacists in the Pharmacy Service of the Miami VA Healthcare System. Ms Antoine is a nurse practitioner in the Medicine Service of the Miami VA Healthcare System. Dr Jeffers is a professor of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and chief of the Hepatology Section of the Miami VA Healthcare System.;Dr Sclair is a transplant hepatology fellow at the University of Miami Miller School of Medicine in Miami, Florida. Drs Hernandez and Peyton are assistant professors of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and staff physicians in the Hepatology Section of the Miami VA Healthcare System in Miami, Florida. Ms Vance is a research associate in the Miami VA Healthcare System. Dr Gilinski is an internal medicine resident at the University of Miami Miller School of Medicine. Drs Youtseff and Toro are clinical pharmacists in the Pharmacy Service of the Miami VA Healthcare System. Ms Antoine is a nurse practitioner in the Medicine Service of the Miami VA Healthcare System. Dr Jeffers is a professor of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and chief of the Hepatology Section of the Miami VA Healthcare System.;Dr Sclair is a transplant hepatology fellow at the University of Miami Miller School of Medicine in Miami, Florida. Drs Hernandez and Peyton are assistant professors of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and staff physicians in the Hepatology Section of the Miami VA Healthcare System in Miami, Florida. Ms Vance is a research associate in the Miami VA Healthcare System. Dr Gilinski is an internal medicine resident at the University of Miami Miller School of Medicine. Drs Youtseff and Toro are clinical pharmacists in the Pharmacy Service of the Miami VA Healthcare System. Ms Antoine is a nurse practitioner in the Medicine Service of the Miami VA Healthcare System. Dr Jeffers is a professor of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and chief of the Hepatology Section of the Miami VA Healthcare System.;Dr Sclair is a transplant hepatology fellow at the University of Miami Miller School of Medicine in Miami, Florida. Drs Hernandez and Peyton are assistant professors of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and staff physicians in the Hepatology Section of the Miami VA Healthcare System in Miami, Florida. Ms Vance is a research associate in the Miami VA Healthcare System. Dr Gilinski is an internal medicine resident at the University of Miami Miller School of Medicine. Drs Youtseff and Toro are clinical pharmacists in the Pharmacy Service of the Miami VA Healthcare System. Ms Antoine is a nurse practitioner in the Medicine Service of the Miami VA Healthcare System. Dr Jeffers is a professor of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and chief of the Hepatology Section of the Miami VA Healthcare System.;Dr Sclair is a transplant hepatology fellow at the University of Miami Miller School of Medicine in Miami, Florida. Drs Hernandez and Peyton are assistant professors of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and staff physicians in the Hepatology Section of the Miami VA Healthcare System in Miami, Florida. Ms Vance is a research associate in the Miami VA Healthcare System. Dr Gilinski is an internal medicine resident at the University of Miami Miller School of Medicine. Drs Youtseff and Toro are clinical pharmacists in the Pharmacy Service of the Miami VA Healthcare System. Ms Antoine is a nurse practitioner in the Medicine Service of the Miami VA Healthcare System. Dr Jeffers is a professor of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and chief of the Hepatology Section of the Miami VA Healthcare System.;Dr Sclair is a transplant hepatology fellow at the University of Miami Miller School of Medicine in Miami, Florida. Drs Hernandez and Peyton are assistant professors of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and staff physicians in the Hepatology Section of the Miami VA Healthcare System in Miami, Florida. Ms Vance is a research associate in the Miami VA Healthcare System. Dr Gilinski is an internal medicine resident at the University of Miami Miller School of Medicine. Drs Youtseff and Toro are clinical pharmacists in the Pharmacy Service of the Miami VA Healthcare System. Ms Antoine is a nurse practitioner in the Medicine Service of the Miami VA Healthcare System. Dr Jeffers is a professor of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and chief of the Hepatology Section of the Miami VA Healthcare System.;Dr Sclair is a transplant hepatology fellow at the University of Miami Miller School of Medicine in Miami, Florida. Drs Hernandez and Peyton are assistant professors of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and staff physicians in the Hepatology Section of the Miami VA Healthcare System in Miami, Florida. Ms Vance is a research associate in the Miami VA Healthcare System. Dr Gilinski is an internal medicine resident at the University of Miami Miller School of Medicine. Drs Youtseff and Toro are clinical pharmacists in the Pharmacy Service of the Miami VA Healthcare System. Ms Antoine is a nurse practitioner in the Medicine Service of the Miami VA Healthcare System. Dr Jeffers is a professor of medicine in the Division of Hepatology at the University of Miami Miller School of Medicine and chief of the Hepatology Section of the Miami VA Healthcare System.", "authors": "Sclair|Seth N|SN|;Hernandez|Maria Del Pilar|MD|;Vance|Evan|E|;Gilinski|Dani|D|;Youtseff|Helen|H|;Toro|Maribel|M|;Antoine|Marie|M|;Jeffers|Lennox J|LJ|;Peyton|Adam|A|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1554-7914", "issue": "12(8)", "journal": "Gastroenterology & hepatology", "keywords": "Hepatitis C virus; direct-acting antiviral agents; ribavirin; simeprevir; sofosbuvir", "medline_ta": "Gastroenterol Hepatol (N Y)", "mesh_terms": null, "nlm_unique_id": "101262648", "other_id": null, "pages": "490-497", "pmc": null, "pmid": "27917084", "pubdate": "2016-08", "publication_types": "D016428:Journal Article", "references": "23268517;25078309;23607594;24907225;26113432;23982366;24907224;21397729;24361415;24206566;26497081;24602923;23602817;22525303", "title": "Sofosbuvir and Simeprevir Combination Therapy for HCV Genotype 1 Infection: Results of a Single-Center VA Experience.", "title_normalized": "sofosbuvir and simeprevir combination therapy for hcv genotype 1 infection results of a single center va experience" }

[ { "companynumb": "US-JNJFOC-20160819347", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "FOR 12 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "(1000 MG FOR PATIENTS {75 KG AND 1200 MG FOR PATIENTS }75 KG)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "205123", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "FOR 12 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis C", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug prescribing error", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Photosensitivity reaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SCLAIR SN, DEL PILAR MH, VANCE E, GILINSKI D, YOUTSEFF H, TORO M, ET AL. SOFOSBUVIR AND SIMEPREVIR COMBINATION THERAPY FOR HCV GENOTYPE 1 INFECTION: RESULTS OF A SINGLE-CENTER VA EXPERIENCE. GASTROENTEROLOGY AND HEPATOLOGY AUG-2016;12(8):490-497.", "literaturereference_normalized": "sofosbuvir and simeprevir combination therapy for hcv genotype 1 infection results of a single center va experience", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160923", "receivedate": "20160826", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12690314, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "US-ROCHE-1823861", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021511", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "WEIGHT BASED RIBAVIRIN THERAPY (1000 MG DAILY FOR PATIENTS { 75 KG AND 1200 MG DAILY FOR PATIENTS }/", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, 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"reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SCLAIR S, DEL PILAR HERNANDEZ M, VANCE E, GILINSKI D, YOUTSEFF H, TORO M, ANTOINE M, JEFFERS L AND PEYTON A. SOFOSBUVIR AND SIMEPREVIR COMBINATION THERAPY FOR HCV GENOTYPE 1 INFECTION: RESULTS OF A SINGLE-CENTER VA EXPERIENCE. GASTROENTEROLOGY AND HEPATOLOGY 2016 AUG;12 (8):490-497.", "literaturereference_normalized": "sofosbuvir and simeprevir combination therapy for hcv genotype 1 infection results of a single center va experience", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160913", "receivedate": "20160913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12736324, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "Although PEGylated filgrastim-induced aortitis is very rare and unknown clinically, some cases were reported and increasing, especially in breast cancer patients. The present study investigated the prevalence, clinical features and treatment of aortitis induced by PEGylated filgrastim in patients with breast cancer. A total of 2068 consecutive patients who underwent neoadjuvant/adjuvant chemotherapy with PEGylated filgrastim for breast cancer were enrolled. From the medical record, clinical, laboratory, medication, and imaging evaluation findings were collected. PEGylated filgrastim-induced aortitis was established in 0.3% of the study population. Common clinical presentations included extremely high fever and chest/back pain with high levels of inflammatory markers without any signs of infection. Contrast-enhanced computed tomography scans revealed typical enhancing wall thickening and periaortic soft tissue infiltration at various levels of aorta. All patients improved rapidly after treatment with modest doses of prednisolone (0.5 mg/kg/day) without any complications. Clinicians should be aware of aortitis as a possible complication of granulocyte-colony stimulating factor therapy, especially PEGylated filgrastim, given the frequent misdiagnoses in neutropenic patients undergoing chemotherapy.", "affiliations": "Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.;Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea. ekbobi.kim@samsung.com.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.;Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.", "authors": "Lee|Sang Yoon|SY|;Kim|Eun Kyoung|EK|;Kim|Ji-Yeon|JY|;Park|Taek-Kyu|TK|;Choi|Seung-Hyuk|SH|;Im|Young-Hyuck|YH|;Kim|Min Yeong|MY|;Park|Yeon Hee|YH|;Kim|Duk-Kyung|DK|", "chemical_list": "D011092:Polyethylene Glycols; D000069585:Filgrastim", "country": "England", "delete": false, "doi": "10.1038/s41598-020-75620-6", "fulltext": "\n==== Front\nSci Rep\nSci Rep\nScientific Reports\n2045-2322 Nature Publishing Group UK London \n\n75620\n10.1038/s41598-020-75620-6\nArticle\nThe incidence and clinical features of PEGylated filgrastim-induced acute aortitis in patients with breast cancer\nLee Sang Yoon 1 Kim Eun Kyoung ekbobi.kim@samsung.com 1 Kim Ji-Yeon 2 Park Taek-kyu 1 Choi Seung-Hyuk 1 Im Young-Hyuck 2 Kim Min Yeong 3 Park Yeon Hee 2 Kim Duk-Kyung 1 1 grid.264381.a0000 0001 2181 989XDivision of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro, Gangnam-gu, Seoul, 06351 Republic of Korea \n2 grid.264381.a0000 0001 2181 989XDivision of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea \n3 grid.264381.a0000 0001 2181 989XDepartment of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea \n29 10 2020 \n29 10 2020 \n2020 \n10 1864716 4 2020 16 10 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Although PEGylated filgrastim-induced aortitis is very rare and unknown clinically, some cases were reported and increasing, especially in breast cancer patients. The present study investigated the prevalence, clinical features and treatment of aortitis induced by PEGylated filgrastim in patients with breast cancer. A total of 2068 consecutive patients who underwent neoadjuvant/adjuvant chemotherapy with PEGylated filgrastim for breast cancer were enrolled. From the medical record, clinical, laboratory, medication, and imaging evaluation findings were collected. PEGylated filgrastim-induced aortitis was established in 0.3% of the study population. Common clinical presentations included extremely high fever and chest/back pain with high levels of inflammatory markers without any signs of infection. Contrast-enhanced computed tomography scans revealed typical enhancing wall thickening and periaortic soft tissue infiltration at various levels of aorta. All patients improved rapidly after treatment with modest doses of prednisolone (0.5 mg/kg/day) without any complications. Clinicians should be aware of aortitis as a possible complication of granulocyte-colony stimulating factor therapy, especially PEGylated filgrastim, given the frequent misdiagnoses in neutropenic patients undergoing chemotherapy.\n\nSubject terms\nCardiologyMedical researchOncologyissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nAortitis is a rare clinical manifestation caused by multiple etiologies including infection or autoimmune disease1,2. While several drugs such as ergot alkaloids, dopaminergic drugs or methysergide have been known to be the primary cause of chronic aortitis, drugs that cause acute aortitis are very rarely reported2. Recombinant human granulocyte-colony stimulating factors (G-CSF) are widely used for primary or secondary prevention of chemotherapy-induced neutropenia in patients treated with anticancer agents. The use of G-CSF is generally considered safe with relatively mild side effects such as bone pain3. However, critical cardiovascular adverse events including arterial thrombosis or aortitis are rarely reported4–6.\n\n\nIn clinical field, there are several kinds of G-CSF agents. Filgrastim and lenograstim, which is a short-acting agent of G-CSF, have very similar biological structure and activity compared to endogenous human G-CSF; PEGylated filgrastim is a long-acting agent of G-CSF7. According to cases reported to date, several types of G-CSF (filgrastim, lenograstim, lipegfilgrastim and PEGylated filgrastim) can cause aortitis in patients with various types of malignancies6,8–20. The exact incidence of G-CSF related aortitis is unknown; however, it was more frequently detected in patients with breast cancer, ovarian cancer or lymphoma20. In particular, PEGylated filgrastim, usually used for primary prophylaxis of neutropenia in breast cancer patients, is known to be associated with the highest incidence of aortitis among G-CSF agents.\n\nDespite the small but increasing number of cases reported for the past 10 years, the incidence, clinical characteristics and management of G-CSF-related aortitis are still unclear. In the absence of large-scale data other than those derived from case reports or adverse drug reports, we sought to investigate the prevalence, clinical features and treatment of G-CSF-induced acute aortitis in patients treated with adjuvant or neoadjuvant chemotherapy and PEGylated filgrastim for breast cancer.\n\nMethods\nStudy population and design\nWe retrospectively reviewed the medical records of breast cancer patients who received PEGylated filgrastim during adjuvant or neoadjuvant chemotherapy from March 2015 to February 2020. In study population, two kinds of PEGylated filgrastim were used, which were pegfilgrastim (Neulasta-prefilled syringe 6 mg, Kyowa Hakko Kirin Co. Ltd) and tripegfilgrastim (Dulastin-prefilled syringe 6 mg, Dong-A ST Co. Ltd). The following baseline clinical data for PEGylated filgrastim-induced aortitis patients were collected: age, gender, comorbidity, chemotherapy regimen, G-CSF type, frequency of pegfilgrastim and other G-CSF administration before aortitis. Symptoms, time to onset, and extent of disease confirmed by computed tomography (CT) scans were retrieved as clinical manifestations. Laboratory tests including white blood cell counts, erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (CRP), procalcitonin, immunoglobulin, blood culture, and serologic markers of atypical pathogens and rheumatologic diseases were also conducted. This study was conducted in accordance with the Declaration of Helsinki and approved by the local institutional review board of Samsung Medical Center. (IRB File No. 2019-10-095-001) All of the methods were carried out in accordance with the approved guidelines and relevant regulations. Informed consent was waived for this retrospective study.\n\nDiagnosis of acute aortitis\nBased on clinical presentation including fever, myalgia, or chest/back pain without other infectious causes, CT scan of the entire aorta was performed with contrast enhancement. On CT scan, acute aortitis was defined by aortic inflammation as well as newly-developed enhancing aortic wall thickening with peri-aortic infiltration. To exclude other causes of aortitis, blood culture and serologic tests for atypical pathogens, autoimmune diseases or connective tissue diseases were also reviewed. The history of other treatment regimens, especially chemotherapy, was reviewed to exclude other drug-induced aortitis.\n\nStatistical analysis\nBaseline characteristics were described as numbers and percentages for all breast cancer patients treated with neoadjuvant or adjuvant chemotherapy. Continuous variables were presented as medians, standard deviation. Categorical variables were presented as percentages. All statistical analyses were performed using SPSS Statistics 23.0 (SPSS, Chicago, IL, USA).\n\nResults\nBaseline characteristics\nA total of 2068 patients who underwent neoadjuvant/adjuvant chemotherapy with PEGylated filgrastim for breast cancer were consecutively enrolled in this study. Among study population, 1438 patients (69.5%) received pegfilgrastim, 567 patients (27.4%) received tripegfilgrastim, which is a biosimilar of pegfilgrastim, and 63 patients (3.0%) had the history of both pegfilgrastim and tripegfilgrastim administration. Mean age of study populations was 49.9 years and 2065 patients (99.9%) were female. In the study population, 470 patients (22.7%) had a history of treatment with filgrastim due to febrile neutropenia. No lenograstim treatment history was found in the study population. These results are shown in Table 1.Table 1 Baseline characteristics of total study population.\n\n\tBreast cancer patients with PEGylated filgrastim\n(n = 2068)\t\nAge, years\t49.9 ± 11.1\t\nSex\t\nFemale\t2065 (99.9%)\t\nMale\t3 (0.1%)\t\nChemotherapy indication\t\nNeoadjuvant\t995 (48.1%)\t\nAdjuvant\t1073 (51.9%)\t\nChemotherapy regimen\t\nDoxorubicin + cyclophosphamide\t243 (11.8%)\t\nDocetaxel + cyclophosphamide\t383 (18.5%)\t\nDocetaxel + doxorubicin + cyclophosphamide\t724 (35.0%)\t\nDocetaxel + carboplatin\t369 (17.8%)\t\nOthers\t349 (16.9%)\t\nG-CSF with chemotherapy\t\n PEGylated filgrastim\t2068 (100%)\t\n  Pegfilgrastim\t1438 (69.5%)\t\n  Tripegfilgrastim\t567 (27.4%)\t\n  Pegfilgrastim and tripegfilgrastim\t63 (3.0%)\t\nG-CSF for febrile neuropenia\t\nFilgrastim\t470 (22.7%)\t\nLenograstim\t0 (0%)\t\n\n\nClinical manifestations\nAmong 2068 consecutive patients who were treated with PEGylated filgrastim once or more, six patients (0.3%) developed acute non-infectious aortitis. The median age of patients diagnosed with acute aortitis was 51.7 years. Two patients (Cases #1 and #2) developed aortitis during neoadjuvant chemotherapy, which was consist of docetaxel and carboplatin. And four patients (Cases #3–6) had aortitis during adjuvant chemotherapy. In past medical history, there was no specific features related with giant cell arteritis or Takayasu arteritis. Acute symptoms related to aortitis including extremely high fever, chest/back pain and severe myalgia occurred 13.4 ± 7.6 days after administration of pegfilgrastim. While three patients (Cases #3, #4 and #6) developed aortitis when the the first dose of PEGylated filgrastim was conducted, other patients (Cases #1, #2 and #5) developed aortitis after more than three times of PEGylated filgrastim injection. Except one patient (Case #1) who had filgrastim instead of PEGylated filgrastim after experience of aortitis, G-CSF was no longer administered for other patients. In that patient who had filgrastim injection, instead of pegfilgrastim afterwards, aortitis was recurred with symptoms similar to the first episode. And inflammatory change of the aorta was observed in the same location with the first episode.\n\nLaboratory and CT findings\nIn all patients, high fever (more than 39 °C) and high levels of CRP (24.1 ± 7.7 mg/dL) were identified without any infection-related signs. To evaluate infectious aortitis, blood and urine culture were done and assays for Bartonella Ab, Brucella Ab, and Q fever antibody were conducted to distinguish atypical pathogens. Diagnostic tests for fluorescent antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor and serum levels of immunoglobulin G4 (IgG4) subclass were also conducted for rheumatologic diseases, such as polyangiitis with granulomatosis or IgG4-related diseases. All serologic tests and cultures for infection or rheumatologic disease were negative in all cases.\n\nThe contrast-enhanced CT revealed enhanced segmental wall thickening of aorta with varying degrees of peri-aortic infiltration in all patients. These findings were consistently seen in the aortic arch (Fig. 1) and occasionally extended to branch arteries (Case #3–6, Fig. 2). Peri-aortic infiltration was extended to thoracoabdominal junction of the aorta in two patients (Case #1 and #2). One patient (Case #3) underwent positron-emission tomography-CT (PET-CT), which showed an increased FDG uptake (SUVmax = 3.2) along the wall of aortic arch confirming acute vasculitis (see Supplementary Fig. S1 online).Figure 1 Serial CT images of aortic arch before, during and after PEGylated filgrastim-induced aortitis. Irregular wall thickening with periaortic infiltration is commonly observed in the aortic arch (Case #1–#6). After steroid treament, inflammatory changes of aortic wall were significantly improved.\n\nFigure 2 Various level of the aorta involvement in PEGylated filgrastim-induced aortitis. Case #1 and Case#2: abdominal aorta was involved. Case #3–#6: branching arteries from the aortic arch were involved.\n\n\n\nTreatment of acute aortitis\nTreatment with pegfilgrastim was discontinued, and prednisolone 0.5 mg/kg/day was initiated. Initial symtoms and inflammatory markers were rapidly resolved within one week. After confirming the negative test results of infection and rheumatologic diseases, patients were discharged. Steroid treatment was tappered over 1–2 months. In one patient (Case #1) who recurred aortitis after injection of filgrastim, warranted additional steroid therapy for 2 weeks. No further G-CSF treatment was administered in all patients during the remainder of chemotherapy. No significant post-aortitis complications or delay of scheduled chemotherapy were observed. The follow-up CT scans after more than 1 month from onset revealed a remarkable improvement in wall thickening and infiltration. Detailed clinical features and the result of treatment are depicted in Table 2 and Fig. 3.Table 2 PEGylated filgrastim-induced aortitis among breast cancer patients treated with neoadjuvant or adjuvant chemotherapy.\n\n\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\t\nBaseline characteristics\t\nAge\t45 years\t66 years\t49 years\t50 years\t59 years\t53 years\t\nGender\tFemale\tFemale\tFemale\tFemale\tFemale\tFemale\t\nRace\tAsian\tAsian\tAsian\tAsian\tAsian\tAsian\t\nComorbidity\tNone\tHypertension\n\nHypothyroidism\n\n\tHypertension\tNone\tNone\tNone\t\nChemotherapy indication\tNeoadjuvant\tNeoadjuvant\tAdjuvant\tAdjuvant\tAdjuvant\tAdjuvant\t\nChemotherapy regimen\tDocetaxel\n\nCarboplatin\n\n\tDocetaxel\n\nCarboplatin\n\n\tDocetaxel\n\nCyclophosphamide\n\n\tDocetaxel\n\nCyclophosphamide\n\n\tDocetaxel\n\nCarboplatin\n\nTrastuzumab\n\nHertuzumab\n\n\tDocetaxel\n\nCyclophosphamide\n\n\t\nG-CSF type at the onset of aortitis\tPegfilgrastim\n\nFilgrastim(Recurrence)\n\n\tPegfilgrastim\tPegfilgrastim\tPegfilgrastim\tPegfilgrastim\tPegfilgrastim\t\nFrequency of pegfilgrastim before aortitis\t5\t3\t1\t1\t1\t4\t\nClinical manifestations\t\nSymptoms\tFever\n\nMyalgia\n\nChilling\n\nEpigastric discomfort\n\n\tFever\n\nChilling\n\nMyalgia\n\nNausea\n\n\tFever\n\nChest discomfort\n\nDyspepsia\n\nMyalgia\n\n\tFever\n\nChilling\n\nMyalgia\n\n\tFever\n\nMyalgia\n\nChilling\n\n\tFever\n\nChilling\n\nMyalgia\n\nHeadache\n\n\t\nPhysical examination\tAbdominal tenderness\tAbdominal tenderness\tUnremarkable\tUnremarkable\tUnremarkable\tUnremarkable\t\nTime to onset\t(1st) 12 days\n\n(2nd) 10 days\n\n\t13 days\t15 days\t12 days\t17 days\t14 days\t\nExtent of disease\tAortic arch\n\nAbdominal aorta\n\n\tAortic arch\n\nLeft CCA\n\nRight innominate artery\n\nThoracic aorta\n\nAbdominal aorta\n\n\tAortic arch\n\nLeft CCA\n\n\tAortic arch\n\nRight innominate artery\n\nLeft SCA\n\nLeft CCA\n\n\tAortic arch\n\nLeft CCA\n\nRight innominate artery\n\nThoracic aorta\n\nAbdominal aorta\n\n\tAortic arch\n\nLeft CCA\n\n\t\nLaboratory findings\t\nWBC count, × 103/μL\t7.46\n\n(Neutrophil-dominant)\n\n\t19.76\n\n(Neutrophil-dominant)\n\n\t12.33\n\n(Neutrophil-dominant)\n\n\t38.29\n\n(Neutrophil-dominant)\n\n\t16.91\n\n(Neutrophil-dominant)\n\n\t11.25\n\n(Neutrophil-dominant)\n\n\t\nESR, mm/h\t53\t118\t119\t69\t120\t64\t\nCRP, mg/dL\t23.11\t26.63\t21.76\t29.58\t32.86\t10.85\t\nProcalcitonin, ng/mL\t0.04\t0.26\t0.18\t0.05\t0.28\t0.04\t\nBlood culture\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\t\nInfection serologya\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\t\nRheumatologic markers\tRF/FANA/ANCA (–/–/–)\tRF/FANA/ANCA (–/–/–)\tRF/FANA/ANCA (–/–/–)\tRF/FANA/ANCA (–/–/–)\tRF/FANA/ANCA (–/–/–)\tNo data\t\nImmunoglobulin (IgG4)\tNo data\tNo data\tNormal\tNormal\tNegative\tNo data\t\nCCA common carotid artery, SCA subclavian artery.\n\naInfectious markers including following tests: syphilis, Salmonella, Borrelia, Mycoplasma, Chlamydia, Richettsia, Q fever, Brunella, Bartonella, Legionella, M. tuberculosis.\n\nFigure 3 Clinical course of PEGylated filgrastim-induced aortitis. C-reactive protein (CRP) and body temperature during the clinical course of PEGylated filgrastim-induced aortitis. CRP level and fever rapidly improved after steroid administration in cases #1, #4, #5 and #6. In cases #2 and #3, CRP and fever already improved at the time of steroid administration.\n\n\n\nDiscussion\nDrug-induced acute aortitis is extremely rare, but is a critical co-morbidity, especially in cancer patients requiring continuous chemotherapy. Here, we reported the incidence and clinical manifestations of PEGylated filgrastim-induced acute aortitis in breast cancer patients who underwent chemotherapy. Among the 2068 patients who received PEGylated filgrastim for prophylaxis of neutropenia, six patients developed acute aortitis (0.3%). Common clinical presentations included extremely high fever and chest/back pain with high levels of CRP without any signs of infection. The onset of aortitis usually occurred within 2 weeks after PEGylated filgrastim injection. The contrast-enhanced CT scans revealed aortic enhancing wall thickening and peri-aortic soft tissue infiltration at various levels of aorta, most commonly along the aortic arch. All patients rapidly improved after administration of a modest dose of prednisolone without any complications and returned to chemotherapy as scheduled. To the best of our knowledge, this is the first study to report detailed clinical features of PEGylated filgrastim-induced acute aortitis during chemotherapy in patients with breast cancer.\n\nIn breast cancer patients, dose-dense chemotherapy involving administration of chemotherapy agents more frequently than typical chemotherapy, resulted in a significant improvement of clinical outcomes21,22. However, this intensified chemotherapy induces additional neutropenia and infection-related complications23. To prevent chemotherapy-induced febrile neutropenia, G-CSF was added to chemotherapy regimen and chemotherapy with PEGylated filgrastim yielded favorable clinical outcomes in breast cancer patients24,25. Therefore, considering the fact that most of the breast cancer patients undergoes chemotherapy with PEGylated filgrastim, aortitis could occur more easily in breast cancer patients. However, for breast cancer, few data pertained to G-CSF-related aortitis including several case reports6,8–15,17–19 and two study from Adverse Drug Reporting (ADR) systems16,20. Data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) reported that the frequency of G-CSF-related aortitis was 0.0014%20. Another data based on the Japanese ADR database reported the incidence of G-CSF-induced aortitis as 0.47%20. Although those two results showed the association between G-CSF injection and the development of aortitis, they included the patients with malignancy and not exposed to chemotherapy with G-CSF in study population and did not report the detailed clinical courses including treatment of aortitis. Considering that chemotherapy with PEGylated filgrastim is widely used to treat breast cancer patients, one of the strengths of our study relates to the real-world incidence in consecutive patients and a comprehensive description regarding the clinical course of PEGylated filgrastim-induced aortitis in patients with breast cancer.\n\nG-CSF stimulates proliferation and diffrentiation of neutriphil precursors, enhances chemotaxis and mobilizes hematopoietic stem cells26. Aortitis might be triggered via increased pro-inflammatory reaction and neutrophil-mediated damage27. Additionally, G-CSF-induced autoimmune reactions mediated via IL-6 between Th17 cells and CD4+ T cells is also thought to result in aortitis, aneurysm or dissection9,10,28. In fact, blood tests at the onset of PEGylated induced-aortitis patients showed a significant increase in G-CSF as well as neutrophil and cytokine levels10. Based on this immune-related vascular inflammation as one of the main mechanisms underlying the development of aortitis, all our patients were treated with short-term steroids to induce immunosuppression. While some data showed spontaneous improvement of aortitis without anti-inflammatory agents8,11, we thought that the recovery without anti-inflammatory agents might take longer than for the use of glucocorticoid, and delay recovery could directly affect the anticancer treatment schedule. Anticipating no further delay in chemotherapy, it may be reasonable to consider short-term glucocorticoid treatment. Further studies are warranted to determine the appropriate duration of steroid administration and indications for the restart of chemotherapy.\n\nEarly diagnosis of G-CSF-induced aortitis can be established based on high fever and chest/back pain combined with remarkable elevation in inflammatory markers, when G-CSF administration is known. Despite the high levels of CRP and ESR, these patients appear to be stable without symptoms related to infection or autoimmune disease. There have been a difference of the time from G-CSF administration to the onset of aortitis among the studies. It might vary depending on how aortitis-indicating symptoms were defined. Because mild fever and general ache are frequently observed in cancer patients after chemotherapy regardless of G-CSF administration, we defined aortitis-indicating symptoms as extremely high fever and localizing chest/back pain without other infection-related signs. Therefore, the symptom onset time was longer than the previous data17. Immediate chest CT or CT aortography is indicated considering the risk of disease spread to proximal aorta, such as aortic arch or ascending thoracic aorta. Of course, even if G-CSF induced aortitis is suspected, the tests for infection and rheumatic disease are required at the same time. Procalcitonin, which is associated with the extent and severity of bacterial infection29, was within normal range despite the highly elevated ESR/CRP. This finding may facilitate to exclude the diagnosis of other suspected causes of fever and inflammation.\n\nA comprehensive review of past medications for the patients with aortitis are also important. Few case reports showed the aortitis caused by gemcitabine or bevacizumab30–32. Similary with the preivous data8,11–13,17–19, docetaxel was concorrently used in our aortitis patients. However, aortitis did not recur during the remainder of docetaxel chemotherapy without G-CSF after aortitis. Therefore, we thought docetaxel was not the primary cause of aortitis. Some data have suggested there might be a potential interaction between taxanes and G-CSF, and their synergistic effect might promote vasculitis17,33.\n\nCompared with the other cases discontinuing G-CSF treatment, Case #1 was exposed to filgrastim instead of pegfilgrastim after the resolution of the initial aortitis-related symptoms. Except our data (Case #1), no report of recurrent aortitis after administration of another type of G-CSF has been reported. Clinicians should be cautious when re-administration of G-CSF, even if it is a different type of G-CSF with the prior agent, considering the possibility of cross-reaction between drugs. Notably, in the present study, all cases of aortitis were induced by pegfilgrastim, which is an original PEGylated filgrastim made by Kyowa Hakko Kirin Co. Ltd. Among patients who received tripegfilgrastim, which is a biosimilar of pegfilgrastim, no aortitis occurred. According to previous studies including data from Japan ADR database6,8–20, the biosimilars of G-CSF did not cause aortitis. Taken together, although the mechanism is unknown, biosimilars of G-CSF can be the alternatives when G-CSF administration is inevitable for patients.\n\nAccording to the previous studies to date, the incidence of G-CSF induced aortitis is higher in East Asian. Pegfilgrastim is world widely used G-CSF, so the difference in the incidence of G-CSF induced aortitis might not be due to the difference in the rate of drug use. One of the possible explanation is that a certain genetic predisposition might be related to the increased incidence of G-CSF induced aortitis in Asian. Th17 cell pathway, which is considered as one of the pathogenesis of G-CSF induced aortitis, is also known to contribute to the systemic and vascular manifestations of Takayasu’s arteritis that is common in East Asia10,34. Genetic susceptibility to large vessel inflammatory change might have caused differences in the frequency of drug-related vasculitis between races. Underdiagnosis should be considered as another explanation for relatively low incidence of G-CSF induced aortitis in Western. In terms of G-CSF induced aortitis, it is difficult to diagnose without clinical suspicion and early imaging evaluation. Future large scale studies are warranted to identify the exact incidence of G-CSF induced aortitis and bring awareness to physicians.\n\nThe present study had several limitations. First, this was a single center retrospective study. Second, the number of patients was relatively small; however, all patients were enrolled consecutively and our study focused on discrete manifestations of aortitis. Lastly, among patients who presented with fever, chest/back pain and elevated inflammatory markers, patients were diagnosed with pegfilgrastim-related aortitis only when the newly developed aortic wall thickening was detected in imaging tests, the temporal relationship was evident following pegfilgrastim injection, and the exclusion of infection and autoimmune disease was established. Because of the strict diagnositc criteria for aortitis, the exact incidence might be underestimated.\n\nIn conclusion, among breast cancer patients who were treated with adjuvant/neoadjuvant chemotherapy including PEGylated filgrastim, the incidence of PEGylated filgrastim-induced acute aortitis was 0.3%. Although not established as a treatment of choice, short-term steroid administration and avoidance of all G-CSF types can be effective in these patients. In view of the remarkable systemic symptoms associated with aortitis, which can be misdiagnosed as infection in neutropenic patients undergoing chemotherapy, clinicians should be aware of aortitis as a possible complication of G-CSF therapy, especially in breast cancer patients treated with PEGylated filgrastim.\n\nSupplementary information\n\nSupplementary Figure.\n\n \n\nPublisher's note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nis available for this paper at 10.1038/s41598-020-75620-6.\n\nAuthor contributions\nL.S.Y., K.E.K., P.Y.H. and K.D.K. conceived the study. L.S.Y., K.J.Y., I.Y.H., P.T.K. and C.S.H. collected the data and perfored the statistical analysis. L.S.Y., K.E.K., K.M.Y. and K.J.Y. reviewed the data and wrote the main manuscript.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Gornik HL Creager MA Aortitis Circulation 2008 117 3039 3051 10.1161/circulationaha.107.760686 18541754 \n2. Bossone E Aortitis Vascul. Pharmacol. 2016 80 1 10 10.1016/j.vph.2015.11.084 26721213 \n3. Smith TJ Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update J. Clin. Oncol. 2015 33 3199 3212 10.1200/JCO.2015.62.3488 26169616 \n4. Conti JA Scher HI Acute arterial thrombosis after escalated-dose methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy with recombinant granulocyte colony-stimulating factor: a possible new recombinant granulocyte colony-stimulating factor toxicity Cancer 1992 70 2699 2702 10.1002/1097-0142(19921201)70:11<2699::AID-CNCR2820701122>3.0.CO;2-C 1384952 \n5. Kawachi Y Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor Br. J. Haematol. 1996 94 413 416 10.1046/j.1365-2141.1996.d01-1807.x 8759907 \n6. Darie C Aortite après injections de G-CSF La Revue de Médecine Interne 2004 25 225 229 10.1016/j.revmed.2003.10.015 14990294 \n7. Molineux G A new form of filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans Exp. Hematol. 1999 27 1724 1734 10.1016/S0301-472X(99)00112-5 10641590 \n8. Adiga GU Elkadi D Malik SK Fitzpatrick JD Madajewicz S Abdominal aortitis after use of granulocyte colony-stimulating factor Clin. Drug Investig. 2009 29 821 825 10.2165/11530790-000000000-00000 19888788 \n9. Miller EB Grosu R Landau Z Isolated abdominal aortitis following administration of granulocyte colony stimulating factor (G-CSF) Clin. Rheumatol. 2016 35 1655 1657 10.1007/s10067-016-3253-6 27094941 \n10. Sato Y Kaji S Ueda H Tomii K Thoracic aortitis and aortic dissection following pegfilgrastim administration Eur. J. Cardiothorac. Surg. 2017 52 993 994 10.1093/ejcts/ezx165 28549110 \n11. Kinjo Y Acute arteritis after G-CSF administration Int. Cancer Conf. J. 2019 8 77 80 10.1007/s13691-018-00357-z 31149552 \n12. Mukai T Kubo S Morita Y Yamamoto M Ikeda M Aortitis which developed after the administration of granulocyte-colony stimulating factor Mod. Rheumatol. Case Rep. 2019 10.1080/24725625.2019.1629570 33086976 \n13. Parodis I G-CSF-induced aortitis: two cases and review of the literature Autoimmun. Rev. 2019 18 615 620 10.1016/j.autrev.2018.12.011 30959218 \n14. Sasaki K Arteritis after administration of granulocyte colony-stimulating factor: a case series Int. J. Hematol. 2019 110 370 374 10.1007/s12185-019-02662-6 31090035 \n15. Yukawa K Mokuda S Yoshida Y Hirata S Sugiyama E Large-vessel vasculitis associated with PEGylated granulocyte-colony stimulating factor Neth. J. Med. 2019 77 224 226 31391329 \n16. Lardieri A McCulley L Christopher Jones S Woronow D Granulocyte colony-stimulating factors and aortitis: a rare adverse event Am. J. Hematol. 2018 93 E333 E336 10.1002/ajh.25220 30016548 \n17. Taimen K Granulocyte colony-stimulating factor- and chemotherapy-induced large-vessel vasculitis: six patient cases and a systematic literature review Rheumatol. Adv. Pract. 2020 4 rkaa004 10.1093/rap/rkaa004 32128475 \n18. Chino T A case of arteritis that developed after pegfilgrastim administration during chemotherapy for breast cancer Gan to Kagaku ryoho Cancer Chemother. 2018 45 1771 1774 \n19. Hoshina H Takei H Granulocyte-colony stimulating factor-associated aortitis in a woman with advanced breast cancer: a case report and review of the literature BMC Cancer 2019 19 1217 10.1186/s12885-019-6403-9 31842789 \n20. Oshima Y Takahashi S Tani K Tojo A Granulocyte colony-stimulating factor-associated aortitis in the Japanese adverse drug event report database Cytokine 2019 119 47 51 10.1016/j.cyto.2019.02.013 30875590 \n21. Citron ML Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of intergroup trial C9741/cancer and leukemia group B trial 9741 J. Clin. Oncol. 2003 21 1431 1439 10.1200/jco.2003.09.081 12668651 \n22. Kummel S Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer Br. J. Cancer 2006 94 1237 1244 10.1038/sj.bjc.6603085 16622463 \n23. Aapro MS EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours Eur. J. Cancer 2006 42 2433 2453 10.1016/j.ejca.2006.05.002 16750358 \n24. Vogel CL First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study J. Clin. Oncol. 2005 23 1178 1184 10.1200/JCO.2005.09.102 15718314 \n25. Holmes FA Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer J. Clin. Oncol. 2002 20 727 731 10.1200/JCO.2002.20.3.727 11821454 \n26. Semerad CL Liu F Gregory AD Stumpf K Link DC G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood Immunity 2002 17 413 423 10.1016/S1074-7613(02)00424-7 12387736 \n27. Cuchacovich R Immunopathogenesis of vasculitis Curr. Rheumatol. Rep. 2002 4 9 17 10.1007/s11926-002-0018-9 11798977 \n28. Anzai A Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture Circ. Res. 2015 116 612 623 10.1161/circresaha.116.304918 25563839 \n29. Schuetz P Albrich W Mueller B Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future BMC Med. 2011 9 107 10.1186/1741-7015-9-107 21936959 \n30. Hiranuma K Drug-induced aortitis in a patient with ovarian cancer treated with bevacizumab combination therapy Taiwan J. Obstet. Gynecol. 2018 57 750 752 10.1016/j.tjog.2018.08.026 30342665 \n31. Eyre TA Gemcitabine-induced large vessel vasculitis demonstrated by PET CT: a rare, important side effect Int. J. Hematol. 2014 99 798 800 10.1007/s12185-014-1555-5 24584910 \n32. Ramsay LB Gemcitabine-associated large vessel vasculitis presenting as fever of unknown origin JCR J. Clin. Rheumatol. 2010 16 181 182 10.1097/RHU.0b013e3181df91ad 20407388 \n33. Omidvari S Drug-induced vasculitis in a breast cancer patient receiving chemotherapy Rep. Radiother. Oncol. 2013 1 81 84 \n34. Saadoun D Th1 and Th17 cytokines drive inflammation in Takayasu arteritis Arthritis Rheumatol. 2015 67 1353 1360 10.1002/art.39037 25604824\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-2322", "issue": "10(1)", "journal": "Scientific reports", "keywords": null, "medline_ta": "Sci Rep", "mesh_terms": "D000208:Acute Disease; D001025:Aortitis; D001943:Breast Neoplasms; D005260:Female; D000069585:Filgrastim; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D011092:Polyethylene Glycols; D012189:Retrospective Studies", "nlm_unique_id": "101563288", "other_id": null, "pages": "18647", "pmc": null, "pmid": "33122662", "pubdate": "2020-10-29", "publication_types": "D016428:Journal Article", "references": "14990294;31842789;11798977;30959218;30587739;25563839;25604824;18541754;16622463;30016548;12668651;33086976;31391329;8759907;28549110;12387736;10641590;15718314;24584910;1384952;20407388;21936959;31149552;19888788;32128475;26721213;30875590;11821454;30342665;26169616;31090035;27094941;16750358", "title": "The incidence and clinical features of PEGylated filgrastim-induced acute aortitis in patients with breast cancer.", "title_normalized": "the incidence and clinical features of pegylated filgrastim induced acute aortitis in patients with breast cancer" }

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{ "abstract": "We report an unusual case of a Duchenne Muscular Dystrophy(DMD) patient who initiated a restless leg syndrome after the use of amytriptiline. The prescription and use of this medication for patients with persistent neuropathic pain is relatively common, especially for patients with DMD. Normally, this medication is well tolerated, however, we now report the occurrence of an induction or intensification of a restless leg syndrome case in a young patient with DMD, treated with amytriptiline for his chronic pain.", "affiliations": "Sector of Neuromuscular Diseases Treatment/AFIP, São Paulo, SP, Brazil.;Department of Neurology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Neurology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Neurology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.", "authors": "Akamine|Ricardo Tera|RT|;Grossklauss|Luis Fernando|LF|;Nozoe|Karen Tieme|KT|;Moreira|Gustavo Antonio|GA|;Bulle Oliveira|Acary Souza|AS|;Troccoli Chieia|Marco Antônio|MA|;Andersen|Monica Levy|ML|;Tufik|Sergio|S|", "chemical_list": null, "country": "Brazil", "delete": false, "doi": "10.1016/j.slsci.2014.09.010", "fulltext": "\n==== Front\nSleep SciSleep SciSleep Science1984-06591984-0063Elsevier S1984-0063(14)00048-010.1016/j.slsci.2014.09.010Case ReportRestless leg syndrome exacerbated by amytriptiline in a patient with Duchenne Muscular Dystrophy Akamine Ricardo Tera aGrossklauss Luis Fernando bNozoe Karen Tieme cMoreira Gustavo Antonio cBulle Oliveira Acary Souza bTroccoli Chieia Marco Antônio bAndersen Monica Levy ml.andersen12@gmail.commandersen@unifesp.brc⁎Tufik Sergio ca Sector of Neuromuscular Diseases Treatment/AFIP, São Paulo, SP, Brazilb Department of Neurology, Universidade Federal de São Paulo, São Paulo, SP, Brazilc Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil⁎ Corresponding author. Tel.: +55 11 2149 0155; fax: +55 11 5572 5092. ml.andersen12@gmail.commandersen@unifesp.br27 9 2014 9 2014 27 9 2014 7 3 178 180 9 4 2014 12 5 2014 14 5 2014 © 2014 Brazilian Association of Sleep. Production and Hosting by Elsevier B.V.2014Brazilian Association of SleepThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).We report an unusual case of a Duchenne Muscular Dystrophy(DMD) patient who initiated a restless leg syndrome after the use of amytriptiline. The prescription and use of this medication for patients with persistent neuropathic pain is relatively common, especially for patients with DMD. Normally, this medication is well tolerated, however, we now report the occurrence of an induction or intensification of a restless leg syndrome case in a young patient with DMD, treated with amytriptiline for his chronic pain.\n\nKeywords\nDuchenne Muscular DystrophyAmytriptilinRestless leg syndromeSleep\n==== Body\n1 Introduction\nDuchenne Muscular Dystrophy (DMD) is a neuromuscular disease linked to the X chromosome which afflicts 1 in every 3500 born boys. DMD is caused by a mutation on the dystrophin gene at locus Xp.21, leading to dystrophin absence or a production defect in the muscles. Affected individuals demonstrate progressive loss of muscle tone and respiratory, cardiac and orthopedic impairment. Loss of walking capacity usually occurs around 9–11 years of age and death between 20 and 30 years of age [1]. Neuromuscular diseases, in general, may be developed by chronic pain as a result of contractures, deformities and immobility, with great impact on the quality of life [2]. Pharmacological treatment with amytriptiline chloride constitutes one of the multimodal aspects of intervention for the pain treatment in patients with neuromuscular diseases [3]. There is a possible association between tricyclic antidepressants and the restless leg syndrome (RLS) [4].\n\nWe presently report a case where a patient with diagnostic of DMD demonstrated a marked worsening of his RLS, associated with the use of amytriptiline.\n\n2 Case report\nMale patient with 27 years of age, with diagnostic of Duchenne Muscular Dystrophy at the age of 7 years. Beginning of symptoms at the age of 6, with myopathic walk and difficulty in climbing stairs. Loss of walking ability at 10. With 19 years old, evolved to alveolar hypoventilation syndrome and the need of ventilatory support with non-invasive mechanical ventilation. At this age, the patient already demonstrated movement restriction, with global tetraparesis. At the age of 23, initiated with diffuse and continuous chronic pain, worsening of passive limb movements and daily chronic migraine resulted from analgesic abuse. We then initiated treatment with a tricyclic antidepressant (amytriptiline chloride 25 mg/night). After a few days of therapy the patient referred a feeling of undetermined discomfort in his inferior limbs, beginning every day in the evening, with intense will to move his legs, only relieved by passive movement of his legs (done by his caretaker since he was incapable of doing it himself). The phenomenon lasted for 2 h, making it difficult to sleep and with spontaneous remission. The patient had demonstrated similar symptoms previously although with less intensity, duration and frequency. There was no evidence of periodic limb movements (patient with global tetraparesis and motor strength grade 1, making it impossible to move the limbs), peripheral neuropathy, spinal radiculopathy or other associated conditions. He had positive familiar history (mother refers some characteristically similar episodes, not related to any drug usage, with low frequency and intensity). Blood tests were considered normal. With the interruption of the medication, after approximately 30 days, the patient showed marked improvement of this condition, with decrease of the episodes and symptoms, maintaining its eventual frequency. The punctuation of the Naranjo and cols Drug Adverse Reaction (DAR) probability scale (1981) was of 6 points, indicating a probable side effect of the drug (Table 1).\n\n3 Discussion\nPatients with DMD show high risk for the development of respiratory disorders related with sleep, mainly the sleep obstructive apnea syndrome and alveolar hypoventilation [5]. Other sleep disorders include difficulty in initiating and maintaining sleep. Many patients show important sleep fragmentation with frequent awakenings for decubital changes (by the caretakers) due to pain or discomfort [6]. There is very little information about movement disturbances during sleep in these patients.\n\nRLS is a motor-sensitive disorder related to sleep, characterized by discomforting or painful paresthetic sensations in the legs, between the ankle and the knee at rest, accompanied by the intense need to move the affected limbs. The RLS physiopathology is still not established; however, there are some hypothesis related to the mechanisms of central and peripheral nervous system processing and some elements of the motor system, as well as the dopaminergic and iron metabolisms systems. RLS may be classified as idiopathic, genetic with a dominant autosomic heritage pattern, or secondary to a subjacent clinical condition. The RLS diagnosis is exclusively clinical, obeying the minimal criteria in accordance to the International Restless Legs Syndrome Study Group – IRLSSG and of the International Sleep Disorders Classification of 2005, being essential criteria the following: irresistible and intense need to move the legs, generally accompanied by discomfort or inconvenience; the symptoms worsen or are exclusively present at rest or during inactivity, sitting or laying down; the symptoms are alleviated totally or partially with movement; symptoms worsen or occur exclusively at night. The described symptoms are not best explained by any other diseases of conditions. The support criteria for diagnostic of RLS are: elevated index of periodic leg movement during sleep; positive familiar history; therapeutic response to dopaminergic agents; clinical course [7,8].\n\nSeveral medications do appear to possess the potential to induce or intensify RLS, including antiemetics, antipsychotics and antidepressants (tricyclic, serotonin reuptake inhibitors, selective noradrenergic–serotonergics) [9]. Amytriptiline chloride is a potent antidepressant with sedative and anticholinergic properties, acting by inhibiting the membrane pump mechanism responsible for the norepinephrine and serotonin uptake by adrenergic and serotonergic neurons. It also shows, in less proportion, activity upon the blockage of dopamine reuptake, with possible psychomotor activation [12], this action being possibly related to the development of RLS. It is considered one of the drugs of first choice for the treatment of chronic pain, acting upon different nociceptive mechanisms. Some of its side effects include excessive sleepiness, insomnia, nightmares, paresthesias and extrapiramidal symptoms [3]. These effects might result in sleep disturbances.\n\nEstablishing a relationship cause/effect between a clinical event and the use of a medication presents intrinsic difficulties, bearing in mind inespecificity and the superimposition of several factors. One way of establishing a causal relationship with higher security is the use of algorithms with diagnostic criteria for DAR, such as the probability scale of DAR according to Naranjo et al. [11]. In this system, a punctuation between 5 and 8 indicates a probable causality, establishing that the reaction follows a reasonable chronological sequence from the initial administration of the drug, with a previously know response and which cannot be totally explained by the clinical course of the patient [10,11].\n\nThe patient here described demonstrated 4 of the 5 essential criteria for RLS and positive familiar history, associated with a relatively high probability of causality with a drug side effect. The criterion related to the beginning of the symptoms at rest or during inactivity periods, could not be evaluated or observed, due to the patient׳s global tetraparesis condition, making him totally restricted to bed during day and night timeframes. Considering the relaxation concept and incorporating the level of activity of the central nervous system with the decrease of the vigil level, then we determined that the patient really demonstrated all the essential criteria, once the symptoms only arose when the patient was beginning to sleep. This case describes a probable and rare side effect of amytriptiline related to sleep in a patient with DMD.\n\n4 Conclusion\nWe point out the importance of this association and identification due to its great discomfort described by the patient. This clinical symptom is of major importance since the patient with DMD is incapacitated of own motor mobility as a way to relieve his condition, therefore leading to a physical and emotional distress. In our knowledge, this is the first description of such association between tricyclic antidepressant and RLS in DMD. We point out that the association of medication with RLS is described in small series and case reports and the presently here described association must be interpreted with caution and be confirmed in other more structured studies in the future.\n\nAcknowledgements\nThe authors wish to acknowledge the Associação Fundo de Incentivo à Pesquisa (AFIP) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) of Brazil for financial support. ST and MLA are recipients of fellowships from CNPq.\n\nTable 1 Probability scale of DAR of Naranjo et al. [11].\n\nCriteria for the definition of causal relationship\tYes\tNo\tUndetermined\t\nAre there conclusive reports about this reaction?\t\t0\t\t\nHas the clinical event appeared after the administration of the suspected drug?\t+2\t\t\t\nHas the reaction disappeared when the suspected drug was discontinued or when the specific antagonist was administered?\t+1\t\t\t\nHas the reaction reappeared when the drug was reinstated?\t\t\t0\t\nAre there alternative causes (other than the drug) which could provoke that reaction?\t\t+2\t\t\nHas the reaction reappeared when a placebo is given?\t\t\t0\t\nHas the drug been detected in the bloodstream or in other biological fluids in well known toxic concentrations?\t\t\t0\t\nDoes the reaction increases with the increase of the drug dosage or becomes less severe with drug reduction?\t+1\t\t\t\nDoes the patient have a history of similar reaction to the same drug or a similar one in some previous exposure?\t\t\t0\n==== Refs\nReferences\n1 Bushby K. Finkel R. Birnkrant D.J. Case L.E. Clemens P.R. Cripe L. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management Lancet Neurol 9 2010 77 93 19945913 \n2 Jensen M.P. Abresch R.T. Carter G.T. McDonald C.M. Chronic pain in persons with neuromuscular diseases Arch Phys Med Rehabil 86 2005 1155 1163 15954054 \n3 Dharmshaktu P. Tayal V. Kalra B.S. Efficacy of antidepressants as analgesics: a review J Clin Pharmacol 52 2012 6 17 21415285 \n4 Thorpy M.J. New pardigms in the treatment of restless legs syndrome Neurology 64 2005 S28 S33 15994221 \n5 Wagner MH Berry RB. Disturbed sleep in a patient with Duchenne Muscular Dystrophy J Clin Sleep Med 4 2008 173 175 18468316 \n6 Bloetzer C. Jeannet P.Y. Lynch B. Newman C.J. Sleep disorders in boys with Duchenne muscular dystrophy Acta Paediatr 101 2012 1265 1269 23013479 \n7 International Restless Legs Syndrome Study Group. 2012 revised IRLSSG diagnostic criteria for RLS. Available from: http://irlssg.org/diagnostic-criteria [accessed March 2014].\n8 American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.\n9 Hoque R.L. Chesson A.L. Jr Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis J Clin Sleep Med 15 2010 79 83 20191944 \n10 Karch F.E. Lasagna L. Adverse drug reactions. A critical review JAMA 22 1975 1236 1241 1242749 \n11 Naranjo C.A. Busto U. Sellers E.M. Sandor P. Ruiz I. Roberts E.A. A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 30 1981 239 245 7249508 \n12 Moreno R. Moreno D. Soares M. Psicofarmacologia de antidepressivos Rev Bras Psiquiatr 21 1999 24 40\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1984-0063", "issue": "7(3)", "journal": "Sleep science (Sao Paulo, Brazil)", "keywords": "Amytriptilin; Duchenne Muscular Dystrophy; Restless leg syndrome; Sleep", "medline_ta": "Sleep Sci", "mesh_terms": null, "nlm_unique_id": "101598477", "other_id": null, "pages": "178-80", "pmc": null, "pmid": "26483924", "pubdate": "2014-09", "publication_types": "D002363:Case Reports", "references": "15994221;21415285;20191944;19945913;1242749;23013479;18468316;15954054;7249508", "title": "Restless leg syndrome exacerbated by amytriptiline in a patient with Duchenne Muscular Dystrophy.", "title_normalized": "restless leg syndrome exacerbated by amytriptiline in a patient with duchenne muscular dystrophy" }

[ { "companynumb": "BR-MYLANLABS-2015M1010958", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMITRIPTYLINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "086009", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25MG/NIGHT", "drugenddate": null, "drugenddateformat": null, "drugindication": "DUCHENNE MUSCULAR DYSTROPHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMITRIPTYLINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Restless legs syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "AKAMINE RT, GROSSKLAUSS LF, NOZOE KT, MOREIRA GA, OLIVEIRA ASB, CHIEIA MAT, ET AL. RESTLESS LEG SYNDROME EXACERBATED BY AMYTRIPTILINE IN A PATIENT WITH DUCHENNE MUSCULAR DYSTROPHY. SLEEP-SCI 2014; 7(3):178-180.", "literaturereference_normalized": "restless leg syndrome exacerbated by amytriptiline in a patient with duchenne muscular dystrophy", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20150406", "receivedate": "20150406", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10993017, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "Chromosome 6 abnormalities such as paternal uniparental isodisomy, paternal 6q24 duplication, and maternal DMR (differentially methylated region) hypomethylation are a common cause of transient neonatal diabetes mellitus (TNDM). Oral sulfonylurea (SU) is used off-label to treat permanent neonatal diabetes mellitus owing to potassium channel mutation but has not been evaluated in TNDM. Our objective was to evaluate the efficacy and safety of SU therapy in chromosome 6-related TNDM. Description of 3 case reports and literature review was the subject of the study. SU therapy was successful in 2 patients (initiated during neonatal life in 1 patient and during relapse in the other) but failed in the other despite the use of high dosage. The literature review identified 11 cases of patients with chromosome 6-related TNDM treated with SU, including 4 treated before remission and 7 after the relapse. SU therapy was consistently effective, although 4 patients treated after the relapse required multiple oral medications. None of the patients needed associated insulin therapy. No side effects of SU or complications of diabetes were reported. SU seems effective and safe in chromosome 6-related TNDM treatment when used to treat the initial episode of diabetes or the relapse. It improves patients' and families' quality of life. SU is available only as oral tablets. A pediatric dosage form would facilitate the treatment of neonates and infants.", "affiliations": "Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France.;Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France.;Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France.;Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Paris, France.;Service de Réanimation et Surveillance Continues de Pédiatrie, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Paris, France.;Faculté de Médecine Paris Descartes, Université Sorbonne Paris Cité, Paris, France.;Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Paris, France.;Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France.;Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France.", "authors": "Garcin|Laure|L|0000-0003-3605-5751;Kariyawasam|Dulanjalee|D|;Busiah|Kanetee|K|;Fauret-Amsellem|Anne-Laure|AL|;Le Bourgeois|Fleur|F|;Vaivre-Douret|Laurence|L|;Cavé|Hélène|H|;Polak|Michel|M|;Beltrand|Jacques|J|", "chemical_list": "D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds", "country": "Denmark", "delete": false, "doi": "10.1111/pedi.12635", "fulltext": null, "fulltext_license": null, "issn_linking": "1399-543X", "issue": "19(4)", "journal": "Pediatric diabetes", "keywords": "chromosome 6; monogenic diabetes; sulfonylureas; transient neonatal diabetes", "medline_ta": "Pediatr Diabetes", "mesh_terms": "D002869:Chromosome Aberrations; D002896:Chromosomes, Human, Pair 6; D003920:Diabetes Mellitus; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D008297:Male; D056687:Off-Label Use; D013453:Sulfonylurea Compounds; D016896:Treatment Outcome", "nlm_unique_id": "100939345", "other_id": null, "pages": "663-669", "pmc": null, "pmid": "29504184", "pubdate": "2018-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Successful off-label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities.", "title_normalized": "successful off label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities" }

[ { "companynumb": "FR-TEVA-2018-FR-921967", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GLYBURIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DRINKABLE FORM", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEONATAL DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GLIBENCLAMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "REDUCED PROGRESSIVELY AND DISCONTINUED ON THE 3RD DAY AFTER THE INITIATION OF GLIBENCLAMIDE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEONATAL DIABETES MELLITUS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".015", "drugstructuredosageunit": "028", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia neonatal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GARCIN L, KARIYAWASAM D, BUSIAH K, FAURET-AMSELLEM A-L, LE BOURGEOIS F, VAIVRE-DOURET L, ET AL. SUCCESSFUL OFF-LABEL SULFONYLUREA TREATMENT OF NEONATAL DIABETES MELLITUS DUE TO CHROMOSOME 6 ABNORMALITIES. PEDIATR-DIABETES 2018?19(4):663-669.", "literaturereference_normalized": "successful off label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20181024", "receivedate": "20180712", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15132917, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190204" } ]

{ "abstract": "Severe hypercalcemia is often caused by primary hyperparathyroidism (PHP), which is not commonly seen in patients with systemic lupus erythematosus (SLE). In this case report an adolescent girl with a history of SLE develops mild hypercalcemia secondary to unrecognized PHP that leads to a hypercalcemic crisis with a prolonged recovery. Therefore, early diagnostic evaluation of persistent hypercalcemia in patients with SLE is important for detection and appropriate treatment of PHP to avoid a hypercalcemic crisis and associated prolonged morbidity.", "affiliations": "Department of Child Health, Division of Endocrinology, University of Missouri Children’s Hospital, One Hospital Dr., DC058.00, Columbia, MO 65212, USA. choudhryk@health.missouri.edu", "authors": "Choudhry|K S|KS|;Malik|M Z|MZ|;Buggs-Saxton|C|C|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/0961203313491847", "fulltext": null, "fulltext_license": null, "issn_linking": "0961-2033", "issue": "22(8)", "journal": "Lupus", "keywords": "Primary hyperparathyroidism; SLE; hungry bones syndrome; hypercalcemic crisis; juvenile; severe hypercalcemia; systemic lupus erythematosus", "medline_ta": "Lupus", "mesh_terms": "D000293:Adolescent; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D049950:Hyperparathyroidism, Primary; D008180:Lupus Erythematosus, Systemic; D012720:Severity of Illness Index; D013997:Time Factors", "nlm_unique_id": "9204265", "other_id": null, "pages": "847-50", "pmc": null, "pmid": "23753296", "pubdate": "2013-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hypercalcemic crisis due to primary hyperparathyroidism in systemic lupus erythematosus (SLE).", "title_normalized": "hypercalcemic crisis due to primary hyperparathyroidism in systemic lupus erythematosus sle" }

[ { "companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-00451", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "018823", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERCALCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 ML/M2/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERCALCAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUID" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypernatraemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypercalcaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood urea increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypovolaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dehydration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "CHOUDHRY K,MALIK M,BUGGS-SAXTON C. HYPERCALCEMIC CRISIS DUE TO PRIMARY HYPERPARATHYROIDISM IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). LUPUS 2013;22:847-850.", "literaturereference_normalized": "hypercalcemic crisis due to primary hyperparathyroidism in systemic lupus erythematosus sle", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170220", "receivedate": "20170220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13251389, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" } ]

{ "abstract": "BACKGROUND\nNivolumab, a fully human IgG4 programmed cell death-1 checkpoint inhibitor, demonstrated its benefit of prolonged survival in advanced non-small cell lung cancer (NSCLC). However, nivolumab generated unique immune-related adverse events such as thyroid dysfunctions. Herein we assessed nivolumab-induced thyroid dysfunctions in patients with previously treated advanced NSCLC in our hospital.\n\n\nMETHODS\nThe medical records of 11 patients with advanced NSCLC who were initiated with nivolumab treatment between June 28, 2018, and January 15, 2019, in our hospital were reviewed. Serological tests of thyroid-stimulating hormone and free tetraiodothyronine were measured at baseline and every 8 weeks.\n\n\nRESULTS\nThree out of 11 patients developed new-onset hypothyroidism during the treatment, and two of three patients had transient hyperthyroidism first. Two patients were diagnosed with Grade 2 hypothyroidism and received levothyroxine therapy. The other one was Grade 1 hypothyroidism and asymptomatic. All these three patients continued nivolumab therapy.\n\n\nCONCLUSIONS\nNivolumab-induced thyroid dysfunctions in advanced NSCLC were mostly mild and controlled. Thyroid function needs to be monitored for early prediction and appropriate managements of thyroid dysfunctions.", "affiliations": "Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Clinical Laboratory, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China. jinghuiwang2006@163.com.;Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, 9 Beiguan Avenue, Tongzhou, Beijing, 101149, China. sczhang6304@163.com.", "authors": "Zhang|Xinyong|X|;Wu|Yuhua|Y|;Lv|Jialin|J|;Li|Xi|X|;Ma|Li|L|;Nong|Jingying|J|;Zhang|Hui|H|;Qin|Na|N|;Zhang|Quan|Q|;Shi|Guangli|G|;Yang|Xinjie|X|;Wang|Jinghui|J|;Zhang|Shucai|S|", "chemical_list": "D000077594:Nivolumab; D013972:Thyrotropin; D013974:Thyroxine", "country": "Germany", "delete": false, "doi": "10.1007/s12539-019-00337-8", "fulltext": null, "fulltext_license": null, "issn_linking": "1867-1462", "issue": "11(2)", "journal": "Interdisciplinary sciences, computational life sciences", "keywords": "Anti-PD-1 antibody; Dysfunction; Immunotherapy; Nivolumab; Non-small cell lung cancer; Thyroid", "medline_ta": "Interdiscip Sci", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D013961:Thyroid Gland; D013972:Thyrotropin; D013974:Thyroxine", "nlm_unique_id": "101515919", "other_id": null, "pages": "287-291", "pmc": null, "pmid": "31187431", "pubdate": "2019-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Nivolumab-induced Thyroid Dysfunctions in Patients with Previously Treated Non-small Cell Lung Cancer.", "title_normalized": "nivolumab induced thyroid dysfunctions in patients with previously treated non small cell lung cancer" }

[ { "companynumb": "CN-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-113223", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "125554", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperthyroidism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypothyroidism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Immune-mediated hepatic disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZHANG X, WU Y, LV J, LI X, MA L, NONG J, ET AL. NIVOLUMAB?INDUCED THYROID DYSFUNCTIONS IN PATIENTS WITH PREVIOUSLY TREATED NON?SMALL CELL LUNG CANCER. INTERDISCIPLINARY SCIENCES, COMPUTATIONAL LIFE SCIENCES. 2019?11(2):287?91", "literaturereference_normalized": "nivolumab induced thyroid dysfunctions in patients with previously treated non small cell lung cancer", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20210106", "receivedate": "20210106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18704346, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" } ]

{ "abstract": "Few clinical reports have addressed the use of the antihypertensive drug amlodipine during breastfeeding. The objective of this study is to characterize concentration-time profiles of amlodipine in maternal and infant plasma, and milk.\n\n\n\nPlasma and breast milk samples were obtained from eight nursing mothers and their nine newborn nursing infants (median postnatal age: 6.5 days, range 5-7 days). Participants were recruited from February 2009 to June 2009. Multiple blood and milk samples were obtained from the mothers over a 24 hours dosing interval. The blood of infants was also obtained at before and 8 hours after nursing. Amlodipine concentrations were determined by high-performance liquid chromatography. Relative infant dose (RID) was calculated by dividing the infant's dose via milk in mg/kg/day by the maternal dose in mg/kg/day, assuming that a daily intake of milk is 150 mL/kg/day in the infants.\n\n\n\nMaximal amlodipine concentrations in mothers ranged from 4.4 to 14.7 ng/mL in plasma, and 6.5 to 19.7 ng/mL in milk (Average milk/plasma ratio: 1.4). RID was 3.4% of the maternal weight-adjusted dose. All plasma concentrations in infants were under the quantitation limit (0.4 ng/mL).\n\n\n\nInfant exposure to amlodipine in breast milk appears very small, suggesting that amlodipine can be used with little influence on infants during breastfeeding.", "affiliations": "1 Department of Obstetrics and Gynecology, The Jikei University School of Medicine , Tokyo, Japan .;2 Japan Drug Information Institute in Pregnancy , National Center for Child Health and Development, Tokyo, Japan .;4 Division of Medicinal Safety Science, National Institute of Health Sciences , Kawasaki, Japan .;4 Division of Medicinal Safety Science, National Institute of Health Sciences , Kawasaki, Japan .;2 Japan Drug Information Institute in Pregnancy , National Center for Child Health and Development, Tokyo, Japan .;2 Japan Drug Information Institute in Pregnancy , National Center for Child Health and Development, Tokyo, Japan .;7 Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development , Tokyo, Japan .;2 Japan Drug Information Institute in Pregnancy , National Center for Child Health and Development, Tokyo, Japan .;1 Department of Obstetrics and Gynecology, The Jikei University School of Medicine , Tokyo, Japan .;8 Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children , Toronto, Ontario, Canada .", "authors": "Aoki|Hiroaki|H|;Ito|Naoki|N|;Kaniwa|Nahoko|N|;Saito|Yoshiro|Y|;Wada|Yuka|Y|;Nakajima|Ken|K|;Sago|Haruhiko|H|;Murashima|Atsuko|A|;Okamoto|Aikou|A|;Ito|Shinya|S|", "chemical_list": "D000959:Antihypertensive Agents; D017311:Amlodipine", "country": "United States", "delete": false, "doi": "10.1089/bfm.2018.0158", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-8253", "issue": "13(9)", "journal": "Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine", "keywords": "amlodipine; antihypertensive agents; breastfeeding; chromatography; human milk; infant", "medline_ta": "Breastfeed Med", "mesh_terms": "D000328:Adult; D017311:Amlodipine; D000959:Antihypertensive Agents; D001942:Breast Feeding; D002845:Chromatography; D005260:Female; D006801:Humans; D006973:Hypertension; D007231:Infant, Newborn; D008895:Milk, Human; D055815:Young Adult", "nlm_unique_id": "101260777", "other_id": null, "pages": "622-626", "pmc": null, "pmid": "30265578", "pubdate": "2018-11", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Low Levels of Amlodipine in Breast Milk and Plasma.", "title_normalized": "low levels of amlodipine in breast milk and plasma" }

[ { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08389", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "100", "reaction": [ { "reactionmeddrapt": "Maternal exposure during breast feeding", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471954, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08391", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "59", "reaction": [ { "reactionmeddrapt": "Maternal exposure during breast feeding", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471974, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08383", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RELATIVE DOSE 2.37% VIA BREAST MILK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure via breast milk", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471957, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08385", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "49", "reaction": [ { "reactionmeddrapt": "Maternal exposure during breast feeding", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471958, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08394", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RELATIVE DOSE 3.78% VIA BREAST MILK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (DURING PREGNANCY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure via breast milk", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471978, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08382", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "57", "reaction": [ { "reactionmeddrapt": "Maternal exposure during breast feeding", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471956, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08308", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "48", "reaction": [ { "reactionmeddrapt": "Maternal exposure during breast feeding", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471966, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08396", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RELATIVE DOSE 1.56% VIA BREAST MILK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure via breast milk", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471979, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08387", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "53", "reaction": [ { "reactionmeddrapt": "Maternal exposure during breast feeding", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471959, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08390", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RELATIVE DOSE 4.19% VIA BREAST MILK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure via breast milk", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471952, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08388", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RELATIVE DOSE 4.32% VIA BREAST MILK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure via breast milk", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471960, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08392", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RELATIVE DOSE 4.06% VIA BREAST MILK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure via breast milk", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471970, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08395", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "57", "reaction": [ { "reactionmeddrapt": "Maternal exposure during breast feeding", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471975, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08384", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RELATIVE DOSE 2.37% VIA BREAST MILK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure via breast milk", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471955, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08393", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "51", "reaction": [ { "reactionmeddrapt": "Maternal exposure during breast feeding", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471971, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08381", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RELATIVE DOSE 2.60% VIA BREAST MILK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure via breast milk", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471951, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-08386", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RELATIVE DOSE 3.89% VIA BREASTMILK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure via breast milk", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AOKI H, ITO N, KANIWA N, SAITO Y, ET AL.. LOW LEVELS OF AMLODIPINE IN BREAST MILK AND PLASMA. BREASTFEEDING MEDICINE. 2018?13(9):622-626", "literaturereference_normalized": "low levels of amlodipine in breast milk and plasma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16471953, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190711" } ]

{ "abstract": "BACKGROUND\nMucocutaneous leishmaniasis (MCL) is a complication of tegumentary leishmaniasis, causing potentially life-threatening lesions in the ear, nose, and throat (ENT) region, and most commonly due to Leishmania (Viannia) braziliensis. We report a case of relapsing MCL in an Italian traveler returning from Argentina.\n\n\nMETHODS\nA 65-year-old Italian male patient with chronic kidney disease, arterial hypertension, prostatic hypertrophy, and type-2 diabetes mellitus was referred for severe relapsing MCL acquired in Argentina. ENT examination showed severe diffuse pharyngolaryngeal edema and erythema, partially obstructing the airways. A nasopharyngeal biopsy revealed a lymphoplasmacytic inflammation and presence of Leishmania amastigotes, subsequently identified as L. (V.) braziliensis by hsp70 PCR-RFLP analysis and sequencing. Despite receiving four courses of liposomal amphotericine B (L-AmB) and two courses of miltefosine over a 2-year period, the patient presented recurrence of symptoms a few months after the end of each course. After the patient was referred to us, a combined treatment was started with intravenous pentamidine 4 mg/kg on alternate days for 10 doses, followed by one dose per week for an additional seven doses, intralesional meglumine antimoniate on the nasal lesion once per week for six doses, oral azoles for three months, and aerosolized L-AmB on alternate days for three months. The treatment led to regression of mucosal lesions and respiratory symptoms. Renal function temporarily worsened, and the addition of insulin was required to maintain glycemic compensation after pentamidine discontinuation.\n\n\nCONCLUSIONS\nThis case highlights the difficulties in managing a life-threatening refractory case of MCL in an Italian traveler with multiple comorbidities. Even though parenteral antimonial derivatives are traditionally considered the treatment of choice for MCL, they are relatively contraindicated in cases of chronic kidney disease.The required dose adjustment in cases of impaired renal function is unknown, therefore the use of alternative drugs is recommended. This case was resolved with combination treatment, including aerosolized L-AmB, which had never been used before for MCL.", "affiliations": "Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.;Otorhinolaryngology Unit, Careggi University Hospital, Florence, Italy.;Otorhinolaryngology Unit, Careggi University Hospital, Florence, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.;Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy.;Otorhinolaryngology Unit, Careggi University Hospital, Florence, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Otorhinolaryngology Unit, Careggi University Hospital, Florence, Italy.;Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy.;Unit of Vector-borne Diseases, Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.;Unit of Vector-borne Diseases, Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.;Unit of Vector-borne Diseases, Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.;Clinic of Infectious Diseases, Vita-Salute San Raffaele University, Milan, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy; Referral Center for Tropical Diseases of Tuscany, Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy; Referral Center for Tropical Diseases of Tuscany, Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy. Electronic address: lorenzo.zammarchi@unifi.it.", "authors": "Basile|Gregorio|G|;Cristofaro|Glauco|G|;Locatello|Luca Giovanni|LG|;Vellere|Iacopo|I|;Piccica|Matteo|M|;Bresci|Silvia|S|;Maggiore|Giandomenico|G|;Gallo|Oreste|O|;Novelli|Andrea|A|;Di Muccio|Trentina|T|;Gramiccia|Marina|M|;Gradoni|Luigi|L|;Gaiera|Giovanni|G|;Bartoloni|Alessandro|A|;Zammarchi|Lorenzo|L|", "chemical_list": "D000981:Antiprotozoal Agents; D001393:Azoles; C068538:liposomal amphotericin B; D010419:Pentamidine; D000077485:Meglumine Antimoniate; D000666:Amphotericin B", "country": "Canada", "delete": false, "doi": "10.1016/j.ijid.2020.06.003", "fulltext": null, "fulltext_license": null, "issn_linking": "1201-9712", "issue": "97()", "journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases", "keywords": "Aerosolized liposomal amphotericin B; Chronic kidney disease; Combination therapy; Mucocutaneous leishmaniasis; Pentamidine; Recurrent leishmaniasis", "medline_ta": "Int J Infect Dis", "mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000666:Amphotericin B; D000981:Antiprotozoal Agents; D001118:Argentina; D001393:Azoles; D004359:Drug Therapy, Combination; D006801:Humans; D007892:Leishmania braziliensis; D007897:Leishmaniasis, Mucocutaneous; D008297:Male; D000077485:Meglumine Antimoniate; D010419:Pentamidine; D012008:Recurrence", "nlm_unique_id": "9610933", "other_id": null, "pages": "204-207", "pmc": null, "pmid": "32505874", "pubdate": "2020-08", "publication_types": "D002363:Case Reports", "references": null, "title": "Refractory mucocutaneous leishmaniasis resolved with combination treatment based on intravenous pentamidine, oral azole, aerosolized liposomal amphotericin B, and intralesional meglumine antimoniate.", "title_normalized": "refractory mucocutaneous leishmaniasis resolved with combination treatment based on intravenous pentamidine oral azole aerosolized liposomal amphotericin b and intralesional meglumine antimoniate" }

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{ "abstract": "BACKGROUND\nIn the setting of metastatic or locally advanced adrenocortical carcinoma, a limited number of therapies are available and their efficacy is generally below modest. The backbone of treatment remains surgery, even for metastatic disease, whenever it is possible, and mitotane. Chemotherapy can be used with limited results. A small subset of patients with adrenocortical carcinoma may have high mutational burden and harbor mutations in mismatch-repair genes.\nWe report a 40-year old and a 28-year-old female patients with metastatic adrenocortical carcinoma refractory to multiple treatments.\n\n\nMETHODS\nNext-generation sequencing detected high mutational burden (>10 mutations/megabase) in both patients, one of them with MSH2 mutation.\n\n\nMETHODS\nThey were treated with pembrolizumab (100 to 200 mg every 3 weeks).\n\n\nRESULTS\nThe patient harboring a MSH2 mutation experienced a long-term complete response after pembrolizumab, while the patient with high mutational burden and absence of mismatch repair deficiency did not have any response.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first report in the literature of a durable complete response after pembrolizumab in a patient with metastatic adrenocortical carcinoma. Differences in therapy sequencing, possibly abscopal effect related to multiple previous radiotherapy exposition, predictive values of high mutational burden and mutations in mismatch-repair genes are discussed.", "affiliations": "Instituto do Cancer do Estado de São Paulo, University of Sao Paulo.;Instituto do Cancer do Estado de São Paulo, University of Sao Paulo.;Instituto do Cancer do Estado de São Paulo, University of Sao Paulo.;Instituto do Cancer do Estado de São Paulo, University of Sao Paulo.;Instituto do Cancer do Estado de São Paulo, University of Sao Paulo.;Hospital Sírio Libanes, Sao Paulo, Brazil.;Instituto do Cancer do Estado de São Paulo, University of Sao Paulo.;Instituto do Cancer do Estado de São Paulo, University of Sao Paulo.", "authors": "Mota|Jose Mauricio|JM|;Sousa|Luana Guimarães|LG|;Braghiroli|Maria Ignez|MI|;Siqueira|Luiz Tenório|LT|;Neto|João Evangelista Bezerra|JEB|;Chapchap|Paulo|P|;Hoff|Ana A de Oliveira|AAO|;Hoff|Paulo M|PM|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein", "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000013517", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30593126MD-D-18-0562210.1097/MD.0000000000013517135175700Research ArticleClinical Case ReportPembrolizumab for metastatic adrenocortical carcinoma with high mutational burden Two case reportsMota Jose Mauricio MD, PhDab∗Sousa Luana Guimarães MDabBraghiroli Maria Ignez MDabSiqueira Luiz Tenório MDabNeto João Evangelista Bezerra MD, PhDabChapchap Paulo MD, PhDcHoff Ana A. de Oliveira MD, PhDabHoff Paulo M. MD, PhDabNA. a Instituto do Cancer do Estado de São Paulo, University of Sao Paulob Instituto D’Or de Ensino e Pesquisa, Sao Pauloc Hospital Sírio Libanes, Sao Paulo, Brazil.∗ Correspondence: Jose Mauricio Mota, Division of Oncology, Instituto do Cancer do Estado de São Paulo, Universidade de Sao Paulo, Avenida Dr Arnaldo, 251, Cerqueira Cesar, São Paulo 01255-000, Brazil (e-mail: motajmsc@gmail.com).12 2018 28 12 2018 97 52 e1351715 8 2018 9 11 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nIn the setting of metastatic or locally advanced adrenocortical carcinoma, a limited number of therapies are available and their efficacy is generally below modest. The backbone of treatment remains surgery, even for metastatic disease, whenever it is possible, and mitotane. Chemotherapy can be used with limited results. A small subset of patients with adrenocortical carcinoma may have high mutational burden and harbor mutations in mismatch-repair genes.\n\nPatient concerns:\nWe report a 40-year old and a 28-year-old female patients with metastatic adrenocortical carcinoma refractory to multiple treatments.\n\nDiagnosis:\nNext-generation sequencing detected high mutational burden (>10 mutations/megabase) in both patients, one of them with MSH2 mutation.\n\nInterventions:\nThey were treated with pembrolizumab (100 to 200 mg every 3 weeks).\n\nOutcomes:\nThe patient harboring a MSH2 mutation experienced a long-term complete response after pembrolizumab, while the patient with high mutational burden and absence of mismatch repair deficiency did not have any response.\n\nLessons:\nTo the best of our knowledge, this is the first report in the literature of a durable complete response after pembrolizumab in a patient with metastatic adrenocortical carcinoma. Differences in therapy sequencing, possibly abscopal effect related to multiple previous radiotherapy exposition, predictive values of high mutational burden and mutations in mismatch-repair genes are discussed.\n\nKeywords\nadrenocortical carcinomahigh mutational burdenimmunotherapymetastaticpembrolizumabOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAdrenocortical carcinoma is a rare disease affecting approximately 0.7 to 2 individuals per million.[1,2] Historically, localized disease is treated with surgical resection. Although controversies for adjuvant therapy still exists, surgery may be followed by adjuvant mitotane in those patients considered to be at high-risk (eg, tumor rupture, Ki67 immunoexpression in greater than 10% of tumor cells, positive lymph nodes or positive margins).[3–7]\n\nMetastatic or inoperable disease is generally considered incurable, and treatment remains a challenge. The evidence to support everyday clinical decision-making process is still poor. Repeated resection of metastatic disease and/or other local treatments such as radiofrequency ablation are often attempted and might play a role in providing better clinical outcomes.[8–12] Patients with indolent inoperable disease are generally treated with high-dose mitotane, although toxicity may limit optimal dosing, and overall clinical responses are often poor.[13] Chemotherapy can be added to the adrenolytic agent, particularly in those patients considered to have more aggressive disease. In the FIRM-ACT trial, the first-line use of etoposide, doxorubicin and cisplatin (EDP) plus mitotane has shown increased rates of response and progression-free survival (PFS) when compared with streptozotocin plus mitotane.[14]\n\nMolecularly, adrenocortical carcinomas are characterized by a high heterogeneity and low mutational burden, in which driver implicated mutations may include CTNNB1, TP53, ZNFR3, CCNE1, and PRKRAR1A.[15–17] Whole genome doubling is a typical event in a subset of adrenocortical carcinomas, and is associated with aggressiveness. At least 3 different prognostic groups can be identified using DNA methylation profiling.[16] Interestingly, a hypermutator phenotype is detected in a small subset of patients, which is associated with mutations in DNA mismatch repair genes. Associations with Lynch syndrome and mutations in MHS2, MSH6, MLH1, and POLE have been identified in approximately 3% of cases.[15,18,19]\n\nRecently, anti-PD1/anti-PD-L1 agents have been shown effective for the treatment of many malignant neoplasms, such as melanoma, lung, kidney, and urothelial cancers. Strikingly, a fraction of these patients may experience solid long-term responses. Although the perfect predictive biomarker has not been identified, mutations in genes of DNA mismatch repair enzymes (or the lack of immunoexpression of these enzymes), high tumor mutational burden, increased ratios of tumor-infiltrating lymphocytes, or increased PD-L1 expression have been implicated in better outcomes after treatment with anti-PD-1/anti-PD-L1 agents in different clinical settings.[20,21]\n\nIn the present paper, we report the clinical cases of 2 patients with advanced adrenocortical carcinomas who received pembrolizumab. One of them, in which a splice mutation in MSH2 and high tumor mutational burden were detected, achieved a long-lasting complete response following pembrolizumab monotherapy, after the disease had progressed on multiple treatments, including radiotherapy and different chemotherapy regimens. The other patient had a progression after pembrolizumab treatment, although a high mutational burden was also detected in tumor samples. Insights on the predictive effect of mutational status of DNA repair-related genes, high tumor mutational burden, and possible abscopal effect after multiple radiotherapy treatments are discussed.\n\n2 Methodology\n2.1 Ethical statement\nAll procedures and protocols in this study were previously approved by the local Ethics Committee (protocol number: 2018-06) and were in accordance with the Declaration of Helsinki. Written informed consents were obtained from the patients for publication of the case reports and accompanying images.\n\n2.2 Design and data acquisition\nThis is a retrospective series of 2 patients with metastatic adrenocortical carcinoma harboring high mutational burden treated with pembrolizumab. Clinical data was retrospectively reviewed using electronic charts. Next-generation sequencing (NGS) analysis (Foundation, Roche) was retrospectively assessed and high mutational burden was considered if tumor mutational burden was higher than 10 mutations per megabase. All responses to treatment were assessed by RECIST version 1.1 criteria.[22]\n\n3 Case reports\n3.1 Case #1\nA 40-year old Latin female patient without any known comorbidities presented with a left adrenal mass on September 2008. 18F-FDG-PET/CT scans showed no metastatic disease, and she went through a left adrenalectomy with curative intent. Pathology analyses revealed a 9-cm adrenocortical carcinoma with vascular invasion. Table 1 summarizes the timeline of treatments for this patient.\n\nTable 1 Case #1: Timeline of administered treatment regimens.\n\nDisease relapsed 3 months later as a 18F-FDG-PET/CT showed 2 hepatic hypermetabolic nodules. Systemic treatment with mitotane (maximum tolerated daily dose: 3 g) was started with disease progression after 3 months. Decision was made to start capecitabine, dacarbazine and mitotane. After 2 cycles, she had a new disease progression on the liver. On July 2009, a hepatic enucleation within the segments 2, 4, and 6 was performed and mitotane (maximum tolerated daily dose: 8 g) was started. A new hepatic lesion appeared on segment 4a, which was treated by radiofrequency ablation (RFA) on June 2010. Six months later, restaging 18F-FDG-PET/CT scans detected a 0.8 cm lung nodule and a 2 cm hepatic nodule (segment 8), which were treated by RFA. After 11 months (November 2011), another RFA procedure was performed due to a novel apical lung nodule.\n\nOn May 2013, a left lung metastasectomy was performed to treat a new lung nodule. Pathology analysis confirmed metastatic adrenocortical carcinoma. A Next-Generation Sequencing analysis (NGS, Foundation One, Roche) of this lesion identified mutations on the following genes: MSH2, ATM, APC, DAXX, KDM5LC, as shown in Table 2. Importantly, this patient had no familial history suggestive of Lynch disorder. HER-2 was not hyperexpressed, and PD-L1 expression was 10%. Tumor mutational burden was 32.65 mutations/Mb. On January 2014, she had a stereotatic body radiation therapy (SBRT, 45 Grays divided into 3 daily fractions) for a new lung nodule. On January 2015, 18F-FDG-PET/CT scans showed many hypermetabolic lung and pleural nodules, and a hepatic hypermetabolic lesion on segment 4. For the next 3 months, she was on curcumin with metronomic cyclophosphamide, which were discontinued due to disease progression. Pazopanib was started and maintained until a new disease progression on January 2016.\n\nTable 2 Next generation sequencing findings of Case #1 and Case #2.\n\nOn January 2016, decision was made to start pembrolizumab (100 mg every 3 weeks), and a complete radiologic and metabolic response was detected after 5 cycles, until April 2016. Figure 1 depicts the 18F-FDG-PET/CT scans before and after pembrolizumab treatment. After the fifth cycle, the patient developed progressive shortness of breath and dry cough, and chest imaging suggested a diffuse pulmonary inflammatory process. Bronchoscopy put away possible infectious complications and a transbronchial biopsy showed an organizing pneumonia. Grade III pneumonitis was diagnosed and pembrolizumab was no longer administered. Patient is currently on follow-up without any evidence of relapse, with her last 18F-FDG-PET/CT scans on March 2018, as depicted in Figure 2.\n\nFigure 1 Representative cross-sectional fusion images of 18F-FDG PET scans before and after pembrolizumab treatment in Case #1. Cross-sectional images showing hypermetabolic pulmonary nodule and hilar lymph node before (A and B) and after (C and D) treatment with pembrolizumab. Arrows point towards hypermetabolic lesions.\n\nFigure 2 18F-FDG-PET scans of Case #1 on March/2018. As shown in the picture, 18F-FDG-PET-scans did not detect any hypermetabolic lesions 11 months after the last dose of pembrolizumab. This illustrates an unprecedented long-term response in adrenocortical carcinoma with an anti-PD1 agent.\n\n3.2 Case #2\nA 28-year-old Latin male patient without known comorbidities presented with a locally advanced adrenocortical carcinoma on August 2004. Combination of mitotane (8 mg daily) and chemotherapy (cisplatin, etoposide, and doxorubicin) was started. After 3 cycles, he developed limiting toxicity and treatment was changed to carboplatin plus paclitaxel, with partial response after 3 cycles. On August 2005, a successful right adrenalectomy was performed.\n\nAfter 8 months, the patient had a pulmonary recurrence. On August 2006, a regimen containing dacarbazine, capecitabine and imatinib was started, with a partial response, followed by capecitabine plus imatinibe until March 2008, when 2 new pulmonary nodules were detected. A surgical resection of these nodules was performed followed by “adjuvant” mitotane from May to November 2008.\n\nOn July 2013, a new pulmonary and pleural recurrence was detected and the regimen with dacarbazine, capecitabine and imatinib was restarted, until disease progression on July 2014. He had paclitaxel plus imatinib for 2 months, until a new disease progression in mediastinal lymph nodes.\n\nA NGS analysis (Foundation One, Roche) from the resected pulmonary nodule did not detect any predicted deleterious genomic alterations. Mutational tumor burden was 23 mutations/Mb. On October 2014, pazopanib 800 mg per day was started, without any detectable response. A left hilar radiotherapy was performed (30 Gy), followed by metronomic cyclophosphamide with disease progression after 3 months.\n\nOn February 2015, a decision was made to start pembrolizumab (200 mg every 3 weeks). After 5 cycles, there was hepatic, nodal, bone and pulmonary progression. On April 2015 he was treated with external beam radiotherapy (20 Gy) on the left costal arch, and on June 2015 he had radiotherapy on left thoracic wall (30 Gy). From June 2015 to October 2015, he had mitotane without clinical benefit. A hepatic radiosurgery was performed on October 2015, and patient had 2 cycles of liposomal doxorubicin plus carboplatin interrupted due to disease progression. On December 2015, the patient passed away due to progressive disease. Table 3 summarizes the treatments offered to this patient.\n\nTable 3 Case #2: Timeline of administered treatment regimens.\n\n4 Discussion\nIn the present paper, we reported 2 patients with metastatic adrenocortical carcinomas who were treated with pembrolizumab. While the patient reported as Case #1 had a complete long-term metabolic and radiologic response, Case #2 progressed after pembrolizumab and passed away several months later. Both of them had high mutational burden (Case #1: 32 mutations/Mb; Case #2: 23 mutations/Mb), although only Case #1 had a known mutation in MSH2 gene.\n\nTreatment of metastatic or locally advanced adrenocortical carcinoma usually relies on the use of the maximum tolerated dose of mitotane with or without chemotherapy. Whenever it is possible, local control of metastatic disease with surgery, radiofrequency ablation, or external beam radiotherapy is desired, and may be associated with better outcomes.[8–12] Patient described as Case #1 had hepatic enucleations, a lung metastasectomy, 3 procedures of radiofrequency ablation, and a SBRT of a lung lesion; while Case #2 had left hilar radiotherapy and hepatic radiosurgery to provide local control of metastatic disease, with long survivals.\n\nSelection of patients for chemotherapy is usually made on the basis of tumor aggressiveness, performance status, and presence of comorbidities. The combination of etoposide, doxorubicin and cisplatin plus mitotane showed increased response rates and PFS when compared with mitotane plus streptozotocin in a phase 3 trial.[14] Case #2 had EDP plus mitotane in the neoadjuvant setting, which was discontinued due to intolerance and toxicity.\n\nDifferent regimens have been tested as well, but solid evidence is still lacking, mainly due to disease rarity and high molecular complexity. In a phase I trial of the combination of imatinib, capecitabine, and dacarbazine in patients with advanced endocrine tumors, a response was seen in 1 of 6 patients with adrenocortical carcinomas.[23] The use of agents targeting the tyrosine kinase activity of the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase has been tested in early clinical trials with only limited effectiveness.[24,25] Interestingly, Case #1 had a period of stable disease during treatment with pazopanib. Furthermore, treatment against insulin growth factor 1 receptor (IGF-1R) has also been attempted without success. A phase 3 trial comparing linsitinib, an IGF-1R inhibitor, versus placebo in patients with refractory metastatic or locally advanced adrenocortical carcinoma was early terminated due to lack of benefit.[26]\n\nThe recent introduction of anti-PD1/anti-PD-L1 agents changed the landscape of the treatment for many tumors, particularly those with known mutations in genes related to DNA repair. Tumors deficient of mismatch repair enzymes (ie, MLH1, MSH2, MSH6, PMS2) may derive the greatest benefit from these immune checkpoint inhibitors. In a seminal phase 2 trial, Le and colleagues evaluated the use of pembrolizumab, an anti-PD-1 antibody, in 41 patients with metastatic carcinomas. Immune-related response rate was 71% in the mismatch-repair-deficient-noncolorectal cancer cohort, 40% in the mismatch-repair-deficient colorectal cancer cohort, and no responses were observed in the cohort of mismatch-repair-proficient colorectal cancer. These compelling findings led to the approval of anti-PD1 agents by the Food and Drug Administration in the setting of tumors harboring mutations in genes related to mismatch-repair enzymes.[21] Other predictive findings, such as high mutational burden, increased PD-L1 expression, and high presence of tumor infiltrating lymphocytes may be directly linked to response and better outcomes, although the ideal predictive biomarker remains elusive.[27]\n\nCase #1 had no familial history of Lynch, but NGS analysis showed a splice mutation in MSH2, along with a high mutational burden. This finding prompted us to treat the patient with pembrolizumab, and a complete long-term metabolic and radiologic response was achieved. To the best of our knowledge, this is the first report of a durable complete response after pembrolizumab in a patient with metastatic adrenocortical carcinoma. No mutations in mismatch repair genes were observed in Case #2. However, treatment with pembrolizumab was attempted supported by a high mutational burden detected by NGS analysis, without any success. This illustrates that tumor mutational burden might not be an impeccable biomarker for patient selection for anti-PD-1/PD-L1 agents, at least in the setting of advanced adrenocortical carcinomas.\n\nAnother difference between Case #1 and Case #2 was the number of radiotherapeutic treatments to which each case was submitted. Case #1 had 3 procedures of radiofrequency ablation, and a SBRT of a lung lesion before pembrolizumab; while Case #2 went through 1 procedure of left hilar radiotherapy before and 2 procedures after pembrolizumab. The abscopal effect is described as a T-cell-dependent response at tumor sites other than the site treated with radiotherapy. There is a growing body of evidence suggesting that the combination of radiotherapy and immune checkpoint inhibitors may boost the abscopal effect and promote greater antitumor responses.[28–30] Furthermore, Case #1 had received a low-dose cyclophosphamide for approximately 1 year before pembrolizumab treatment. Low-dose cyclophosphamide selective deplete T-regulatory lymphocytes, which might predispose one to an increased action of anti-PD1 antibodies in unleashing effector T cells, and possibly producing better outcomes.[31,32] Definitive conclusions cannot be drawn here, and we can only speculate if these differences could have affected the efficiency of pembrolizumab therapy in Case #1.\n\nIn summary, we described, for the first time in the literature, a clinical case of a patient with metastatic adrenocortical carcinoma who was treated with pembrolizumab and had a durable complete radiological, metabolic and clinical response. This patient had a splice mutation in MSH2 gene and a high mutational burden. The clinical case of another patient with high tumor mutational burden and no mutations in mismatch-repair genes had no response after pembrolizumab was here reported as well. These findings may help to support the role of immune checkpoint inhibitors in patients with adrenocortical carcinomas harboring mutations in mismatch-repair genes. Also, we speculate that the differences between the 2 cases described might help to improve the selection of patients with metastatic or locally advanced carcinoma for the treatment with current immunotherapeutic strategies.\n\nAcknowledgments\nThe authors are grateful to Michele Artioli for her technical assistance.\n\nAuthor contributions\nConceptualization: Jose Mauricio Mota, Luana Guimarães Sousa, Maria Ignez Braghiroli, João Evangelista Bezerra Neto, Ana A. de Oliveira Hoff, Paulo M. Hoff.\n\nData curation: Jose Mauricio Mota, Luana Guimarães Sousa, Paulo Chapchap.\n\nFormal analysis: Jose Mauricio Mota, Luana Guimarães Sousa, Luiz Tenório Siqueira, Paulo Chapchap.\n\nInvestigation: Jose Mauricio Mota, Luana Guimarães Sousa, Luiz Tenório Siqueira, Paulo Chapchap.\n\nMethodology: Jose Mauricio Mota, Luana Guimarães Sousa, Luiz Tenório Siqueira, Paulo Chapchap.\n\nProject administration: Jose Mauricio Mota, Paulo M. Hoff.\n\nResources: Jose Mauricio Mota, Paulo Chapchap, Paulo M. Hoff.\n\nSoftware: Jose Mauricio Mota.\n\nSupervision: Jose Mauricio Mota, Maria Ignez Braghiroli, João Evangelista Bezerra Neto, Ana A. de Oliveira Hoff, Paulo M. Hoff.\n\nValidation: Jose Mauricio Mota, Luiz Tenório Siqueira, Paulo M. Hoff.\n\nVisualization: Jose Mauricio Mota, Luiz Tenório Siqueira.\n\nWriting – original draft: Jose Mauricio Mota, Luana Guimarães Sousa, Luiz Tenório Siqueira.\n\nWriting – review & editing: Jose Mauricio Mota, Maria Ignez Braghiroli, Luiz Tenório Siqueira, João Evangelista Bezerra Neto, Paulo Chapchap, Ana A. de Oliveira Hoff, Paulo M. Hoff.\n\nJose Mauricio Mota orcid: 0000-0001-9510-6956.\n\nAbbreviations: EDP = Etoposide, doxorubicin, cisplatin, IGF-1R = Insulin growth factor 1 receptor, NGS = Next generation sequencing, PFS = Progression-free survival, RFA = Radiofrequency ablation, SBRT = Stereotatic body radiation therapy, VEGFR = Vascular endothelial growth factor receptor.\n\nThe authors declare no conflict of interest relevant to this manuscript.\n==== Refs\nReferences\n[1] Kerkhofs TM Verhoeven RH Van der Zwan JM \nAdrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993 . 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Eur J Immunol \n2014 ;44 :3614–20 . doi:10.1002/eji.201444879 .25251877 \n[32] Scurr M Pembroke T Bloom A \nLow-dose cyclophosphamide induces antitumor T-Cell responses, which associate with survival in metastatic colorectal cancer . Clin Cancer Res \n2017 ;23 :6771–80 . doi:10.1158/1078-0432.CCR-17-0895 .28855352\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0025-7974", "issue": "97(52)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000306:Adrenal Cortex Neoplasms; D018268:Adrenocortical Carcinoma; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D051718:MutS Homolog 2 Protein; D009154:Mutation; D016896:Treatment Outcome", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e13517", "pmc": null, "pmid": "30593126", "pubdate": "2018-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pembrolizumab for metastatic adrenocortical carcinoma with high mutational burden: Two case reports.", "title_normalized": "pembrolizumab for metastatic adrenocortical carcinoma with high mutational burden two case reports" }

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{ "abstract": "A retrospective, multicentre study involving 52 patients was carried out to define the causes and characteristics of pregnancy-related osteoporosis. The mean number of vertebral fractures occurring during the last trimester of pregnancy or at the time of delivery was 3.8. This is often promoted by risk factors before or during pregnancy.\n\n\n\nIn order to define the causes or predisposing factors of pregnancy-related osteoporosis and its clinical, radiological and bone density characteristics, laboratory findings, course and outcome, we carried out a retrospective multicentre study.\n\n\n\nThe records of 52 women hospitalised over the last 10 years in the rheumatology departments of six French university hospitals and with a diagnosis of pregnancy-related osteoporosis were examined.\n\n\n\nThe patients' mean age at time of fracture was 32.1 years. In 10 patients, the fractures had occurred during the last trimester of pregnancy, and in 36 at the time of delivery or during the first 2 months post-partum. The mean number of vertebral fractures was 3.8 ± 2.0. Thirty three of the 52 patients had a risk factor of low bone mass before pregnancy. Twelve had disorders or treatments (heparin) that might promote osteoporosis during pregnancy, while 14 had no trigger factors before or during pregnancy. Overall, phosphate and calcium levels were normal, except for hyperphosphoraemia in lactating women (90%). On DXA scan, osteoporosis predominated in the trabecular bone (spinal T-score - 3.4, hip T-score - 2). Only 10 patients had a repeat fracture, and the increase in bone mineral density during follow-up was considerable, and improved by bisphosphonates (annual gain + 10% in the spine) or teriparatide (+ 15%).\n\n\n\nPregnancy-related osteoporosis gives rise to multiple vertebral fractures. It is often promoted by risk factors before or during pregnancy. Its mechanism is still unknown. Treatment with bisphosphonates or teriparatide appears to improve the recovery of bone mineral density.", "affiliations": "Department of Rheumatology, Toulouse University Hospital, Toulouse, France. laroche.m@chu-toulouse.fr.;Department of Rheumatology, Toulouse University Hospital, Toulouse, France.;Department of Rheumatology, Cochin University Hospital, Paris, France.;Department of Rheumatology, Cochin University Hospital, Paris, France.;Department of Rheumatology, Rennes University Hospital, Amiens, France.;Department of Rheumatology, Toulouse University Hospital, Toulouse, France.", "authors": "Laroche|M|M|;Talibart|M|M|;Cormier|C|C|;Roux|C|C|;Guggenbuhl|P|P|;Degboe|Y|Y|", "chemical_list": "D050071:Bone Density Conservation Agents", "country": "England", "delete": false, "doi": "10.1007/s00198-017-4165-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0937-941X", "issue": "28(11)", "journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA", "keywords": "Osteoporosis; Pregnancy; Risk factors; Vertebral fractures", "medline_ta": "Osteoporos Int", "mesh_terms": "D015502:Absorptiometry, Photon; D000328:Adult; D015519:Bone Density; D050071:Bone Density Conservation Agents; D005260:Female; D006801:Humans; D008875:Middle Aged; D010024:Osteoporosis; D011247:Pregnancy; D011248:Pregnancy Complications; D012189:Retrospective Studies; D012307:Risk Factors; D016103:Spinal Fractures; D055815:Young Adult", "nlm_unique_id": "9100105", "other_id": null, "pages": "3135-3142", "pmc": null, "pmid": "28879474", "pubdate": "2017-11", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016454:Review", "references": "8118748;19377024;9438399;8593546;8012335;14714147;20230328;15754537;10067016;24102815;15711893;2860385;8156291;9255376;9166005;22547939;18217397;12380703;6738354;15295766;7872214;22763936;25285145;18790681;1424213;7781623;18633621;19082826;12689690;22855199;24014470;14769530;16730397;24020042;17318776;10912848;11859703;8088078;24423337;24357025;25138263;11716185;8287577;21243337", "title": "Pregnancy-related fractures: a retrospective study of a French cohort of 52 patients and review of the literature.", "title_normalized": "pregnancy related fractures a retrospective study of a french cohort of 52 patients and review of the literature" }

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PREGNANCY-RELATED FRACTURES: A RETROSPECTIVE STUDY OF A FRENCH COHORT OF 52 PATIENTS AND REVIEW OF THE LITERATURE. OSTEOPOROS INT. 2017;28(11):3135-3142", "literaturereference_normalized": "pregnancy related fractures a retrospective study of a french cohort of 52 patients and review of the literature", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171220", "receivedate": "20171220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14308814, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "FR-SHENZHEN TECHDOW PHARMACEUTICAL CO. LTD-FR-2017TEC0000066", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202732", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM INJECTION USP, PRESERVATIVE FREE" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Complication of pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteoporotic fracture", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAROCHE M, TALIBART M, CORMIER C, ROUX C, GUGGENBUHL P, DEGBOE Y. PREGNANCY-RELATED FRACTURES: A RETROSPECTIVE STUDY OF A FRENCH COHORT OF 52 PATIENTS AND REVIEW OF THE LITERATURE. OSTEOPOROS INT. 2017;28(11):3135-3142", "literaturereference_normalized": "pregnancy related fractures a retrospective study of a french cohort of 52 patients and review of the literature", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171220", "receivedate": "20171220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14308825, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "FR-SHENZHEN TECHDOW PHARMACEUTICAL CO. LTD-FR-2017TEC0000064", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202732", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN SODIUM INJECTION USP, PRESERVATIVE FREE" } ], "patientagegroup": null, "patientonsetage": "38", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteoporotic fracture", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Complication of pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAROCHE M, TALIBART M, CORMIER C, ROUX C, GUGGENBUHL P, DEGBOE Y. PREGNANCY-RELATED FRACTURES: A RETROSPECTIVE STUDY OF A FRENCH COHORT OF 52 PATIENTS AND REVIEW OF THE LITERATURE. OSTEOPOROS INTOSTEOPOROS-INT. 2017;28(11):3135-3142", "literaturereference_normalized": "pregnancy related fractures a retrospective study of a french cohort of 52 patients and review of the literature", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171220", "receivedate": "20171220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14308813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]

{ "abstract": "Cytokine release syndrome (CRS) is a phenomenon of immune hyperactivation described in the setting of cellular and bispecific T-cell engaging immunotherapy. Checkpoint blockade using anti-programmed cell death 1 (anti-PD-1) inhibitors is an approach to antitumor immune system stimulation. A 29-year-old female with alveolar soft part sarcoma developed severe CRS after treatment with anti-PD-1 therapy. CRS was characterized by high fevers, encephalopathy, hypotension, hypoxia, hepatic dysfunction, and evidence of coagulopathy, and resolved after infusion of the interleukin-6 inhibitor tocilizumab and corticosteroids.", "affiliations": "Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.", "authors": "Rotz|Seth J|SJ|;Leino|Daniel|D|;Szabo|Sara|S|;Mangino|Jennifer L|JL|;Turpin|Brian K|BK|;Pressey|Joseph G|JG|", "chemical_list": "D060890:B7-H1 Antigen; D016207:Cytokines", "country": "United States", "delete": false, "doi": "10.1002/pbc.26642", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "64(12)", "journal": "Pediatric blood & cancer", "keywords": "IL-6; PD-1 inhibitor; cytokine release syndrome; nivolumab; tocilizumab", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000328:Adult; D060890:B7-H1 Antigen; D016207:Cytokines; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D011650:Pulmonary Alveoli; D012509:Sarcoma; D013577:Syndrome", "nlm_unique_id": "101186624", "other_id": null, "pages": null, "pmc": null, "pmid": "28544595", "pubdate": "2017-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Severe cytokine release syndrome in a patient receiving PD-1-directed therapy.", "title_normalized": "severe cytokine release syndrome in a patient receiving pd 1 directed therapy" }

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{ "abstract": "Cisplatin is a very common chemotherapeutic agent used in the treatment of gynecologic malignancies, including cervical, ovarian, and endometrial cancers. Bradycardia is a rare, though potentially severe, side effect of this medication. Here we present the case of a young woman with ovarian cancer who demonstrated significant short-lived cardiotoxicity associated with cisplatin treatment.", "affiliations": "Division of Surgery, Banner MD Anderson Cancer Center, Gilbert, AZ, USA matthew.schlumbrecht@bannerhealth.com.;Division of Pharmacy, Banner MD Anderson Cancer Center, Gilbert, AZ, USA.", "authors": "Schlumbrecht|Matthew P|MP|;Hehr|Kristen|K|", "chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin", "country": "England", "delete": false, "doi": "10.1177/1078155214522314", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "21(2)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Cisplatin; arrhythmia; ovarian cancer", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000970:Antineoplastic Agents; D001919:Bradycardia; D002945:Cisplatin; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System; D006339:Heart Rate; D006801:Humans; D010051:Ovarian Neoplasms; D013997:Time Factors; D055815:Young Adult", "nlm_unique_id": "9511372", "other_id": null, "pages": "157-60", "pmc": null, "pmid": "24557923", "pubdate": "2015-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cisplatin-induced bradycardia and the importance of the QT interval.", "title_normalized": "cisplatin induced bradycardia and the importance of the qt interval" }

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CISPLATIN-INDUCED BRADYCARDIA AND THE IMPORTANCE OF THE QT INTERVAL. J-ONCOL-PHARM-PRACT 2015; 21(2):157-160.", "literaturereference_normalized": "cisplatin induced bradycardia and the importance of the qt interval", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150423", "receivedate": "20150423", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11060350, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" }, { "companynumb": "US-MYLANLABS-2015M1012343", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THREE CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THREE CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091062", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OVARIAN CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Bradycardia" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS OF NAUSEA AND VOMITING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SCHLUMBRECHT MP, HEHR K. CISPLATIN-INDUCED BRADYCARDIA AND THE IMPORTANCE OF THE QT INTERVAL. J-ONCOL-PHARM-PRACT 2015; 21(2):157-160.", "literaturereference_normalized": "cisplatin induced bradycardia and the importance of the qt interval", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150414", "receivedate": "20150414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11027605, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]

{ "abstract": "BACKGROUND\nChronic kidney disease (CKD) is associated with significant morbidity and mortality after lung transplantation (LTX). Calcineurin inhibitor (CNI) nephrotoxicity is the leading cause of CKD. After kidney transplantation, polyomavirus-associated nephropathy (PyVAN) is a well-recognized problem. This study aims to evaluate the role of polyomavirus in patients after LTX.\n\n\nMETHODS\nFrom January 2017 to January 2020, all lung transplant recipients who performed follow-up visits in our center were included in the study and retrospectively assessed. We measured renal function (creatinine levels before and after transplantation), JCPyV, and BKPyV load by polymerase chain reaction (PCR) in serum and urine samples after transplantation.\n\n\nRESULTS\nIn total, 104 consecutive patients (59 males, 56.7%) with a mean age of 49.6 ± 11.1 years were identified. JCPyV was found in urine of 36 patients (34.6%) and serum of 3 patients (2.9%). BKPyV was found in urine of 40 patients (38.5%) and serum of 4 patients (3.8%), respectively. Urine evidence for JCPyV (p < 0.001, coefficient: +21.44) and BKPyV (p < 0.001, coefficient: +29.65) correlated highly with further kidney function decline.\n\n\nCONCLUSIONS\nKidney function deterioration is associated with JCPyV and BKPyV viruria in patients after LTX. This might indicate a role of PyVAN in lung transplant recipients.", "affiliations": "Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany. Electronic address: dieter.munker@med.uni-muenchen.de.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Medicine IV, University hospital, LMU Munich, Germany.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Urology, University hospital, LMU Munich, Germany.;Department of Anesthesiology, University hospital, LMU Munich, Germany.;Department of Thoracic Surgery, University hospital, LMU Munich, Germany.;Transplant Center, University hospital, LMU Munich, Germany.;Department of Pneumology and Respiratory Medicine, Schillerhoehe Clinic (affiliated to Rober-Bosch-Hospital GmbG, Stuttgart), Solitudestr. 18, 70839, Gerlingen, Germany.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Pathology, University hospital, LMU Munich, Germany.;Department of Thoracic Surgery, University hospital, LMU Munich, Germany; Transplant Center, University hospital, LMU Munich, Germany.;Department of Internal Medicine II, University hospital, LMU Munich, Germany.;Department of Internal Medicine II, University hospital, LMU Munich, Germany.;Department of Medicine IV, University hospital, LMU Munich, Germany.;Transplant Center, University hospital, LMU Munich, Germany.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Medicine V, University hospital, LMU Munich; Comprehensive Pneumology Center (CPC-M); Member of the German Center for Lung Research (DZL), Munich, Germany.;Department of Virology, University hospital, LMU Munich, Germany; Department of Pneumology and Respiratory Medicine, Schillerhoehe Clinic (affiliated to Rober-Bosch-Hospital GmbG, Stuttgart), Solitudestr. 18, 70839, Gerlingen, Germany.", "authors": "Munker|Dieter|D|;Veit|Tobias|T|;Schönermarck|Ulf|U|;Arnold|Paola|P|;Leuschner|Gabriela|G|;Barton|Jürgen|J|;Mümmler|Carlo|C|;Briegel|Ignaz|I|;Mumm|Jan-Niclas|JN|;Zoller|Michael|M|;Kauke|Teresa|T|;Sisic|Alma|A|;Ghiani|Alessandro|A|;Walter|Julia|J|;Milger|Katrin|K|;Mueller|Susanna|S|;Michel|Sebastian|S|;Munker|Stefan|S|;Keppler|Oliver|O|;Fischereder|Michael|M|;Meiser|Bruno|B|;Behr|Jürgen|J|;Kneidinger|Nikolaus|N|;Neurohr|Claus|C|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jcv.2021.105029", "fulltext": null, "fulltext_license": null, "issn_linking": "1386-6532", "issue": "145()", "journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology", "keywords": "BK Virus; BK nephropathy; BKPyV; JC Virus; JCPyV; LTX; Lung transplantation; Polyomavirus associated nephropathy; PyVAN", "medline_ta": "J Clin Virol", "mesh_terms": null, "nlm_unique_id": "9815671", "other_id": null, "pages": "105029", "pmc": null, "pmid": "34798365", "pubdate": "2021-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Polyomavirus exerts detrimental effects on renal function in patients after lung transplantation.", "title_normalized": "polyomavirus exerts detrimental effects on renal function in patients after lung transplantation" }

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Polyomavirus exerts detrimental effects on renal function in patients after lung transplantation. Journal of Clinical Virology. 2021;145:1-11", "literaturereference_normalized": "polyomavirus exerts detrimental effects on renal function in patients after lung transplantation", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211227", "receivedate": "20211227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20232507, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "DE-ASTELLAS-2021US049545", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "50708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Formulation unknown", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "Lung transplant", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Formulation unknown", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "Lung transplant", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Formulation unknown", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antifungal prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vascular hyalinosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "BK virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "JC virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection viral", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Polyomavirus viraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Munker D, Veit T, Schonermarck U, Arnold P, Leuschner G, Barton J, et al. Polyomavirus exerts detrimental effects on renal function in patients after lung transplantation. 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Polyomavirus exerts detrimental effects on renal function in patients after lung transplantation. Journal of Clinical Virology. 2021;145:1-11", "literaturereference_normalized": "polyomavirus exerts detrimental effects on renal function in patients after lung transplantation", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211227", "receivedate": "20211227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20232660, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "DE-NOVARTISPH-NVSC2021DE276908", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Lung transplant", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Lung transplant", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Munker D, Veit T, Schonermarck U, Arnold P, Leuschner G, Barton J, et al.. Polyomavirus exerts detrimental effects on renal function in patients after lung transplantation. JOURNAL OF CLINICAL VIROLOGY. 2021;145:1-11", "literaturereference_normalized": "polyomavirus exerts detrimental effects on renal function in patients after lung transplantation", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211207", "receivedate": "20211207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20156105, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "DE-ASTELLAS-2021US049287", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "50708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Formulation unknown", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "Lung transplant", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Formulation unknown", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "Lung transplant", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Formulation unknown", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antifungal prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angiopathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "BK virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection viral", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Munker D, Veit T, Schonermarck U, Arnold P, Leuschner G, Barton J, et al. Polyomavirus exerts detrimental effects on renal function in patients after lung transplantation. Journal of Clinical Virology. 2021;145:1-11", "literaturereference_normalized": "polyomavirus exerts detrimental effects on renal function in patients after lung transplantation", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20211227", "receivedate": "20211227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20232683, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "OBJECTIVE\nTo evaluate our institutional experience with Mycobacterium abscessus infections occurring in lung transplant recipients (LTR).\n\n\nMETHODS\nWe retrospectively reviewed our prospectively collected institutional adult lung transplant database from 2001 to 2015 to identify patients with M. abscessus or Mycobacterium chelonae/abscessus infection before or after transplantation. Untreated, colonized patients were excluded from the study. Electronic health records of nine out of 516 lung recipients (1.74%) with clinical infection were reviewed to determine outcomes.\n\n\nRESULTS\nSeven patients acquired the infection after transplantation. Indications for transplantation were: idiopathic pulmonary fibrosis (in 6), chronic obstructive pulmonary disease (in 2), and cystic fibrosis (in 1). Five patients (55.5%) underwent bilateral lung transplantation; one patient required bilateral re-transplantation for complications from infection. M. abscessus was isolated from the respiratory tract with a median time of 7.5 months (range: 3 days to 13 months) from transplantation. All patients were treated using a multidrug regimen, with durations ranging from 3 days to 12 months. Complications from infection included death in one patient, bronchial anastomotic dehiscence in one patient, delayed bronchial occlusions in two patients, and osteomyelitis of the knee in one patient. Median survival time from transplantation was 39 months (range: 11-96 months) and from the date of first positive culture was 58 months (range: 3-91 months). Five patients (55.5%) were cured but two had re-infections >1 year later.\n\n\nCONCLUSIONS\nMycobacterium abscessus infection in LTR is rare and can lead to severe complications. Eradication is difficult and usually requires prolonged combination antibiotic therapy and occasionally surgical management.", "affiliations": "Clinical Research Internship Summer Program, Mayo Clinic, Jacksonville, FL, USA.;Department of Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA.;Department of Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA.;Department of Cardiothoracic Surgery, Mayo Clinic, Jacksonville, FL, USA.;Department of Cardiothoracic Surgery, Mayo Clinic, Jacksonville, FL, USA.", "authors": "Osmani|Morsal|M|;Sotello|David|D|;Alvarez|Salvador|S|;Odell|John A|JA|;Thomas|Mathew|M|http://orcid.org/0000-0003-4609-0833", "chemical_list": null, "country": "Denmark", "delete": false, "doi": "10.1111/tid.12835", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "20(2)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "\nMycobacterium abscessus\n; lung transplantation; mycobacterial infections; non-tuberculous mycobacterium; rapidly growing mycobacterium", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000328:Adult; D000368:Aged; D006761:Hospitals; D006801:Humans; D016040:Lung Transplantation; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D000073358:Mycobacterium abscessus; D012189:Retrospective Studies; D012307:Risk Factors; D066027:Transplant Recipients", "nlm_unique_id": "100883688", "other_id": null, "pages": "e12835", "pmc": null, "pmid": "29359872", "pubdate": "2018-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Mycobacterium abscessus infections in lung transplant recipients: 15-year experience from a single institution.", "title_normalized": "mycobacterium abscessus infections in lung transplant recipients 15 year experience from a single institution" }

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} ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mycobacterium abscessus infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteomyelitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bronchial obstruction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bronchiectasis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSMANI M, SOTELLO D, ALVAREZ S, ODELL JA, THOMAS M. MYCOBACTERIUM ABSCESSUS INFECTIONS IN LUNG TRANSPLANT RECIPIENTS: 15?YEAR EXPERIENCE FROM A SINGLE INSTITUTION. 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Obliterative bronchiolitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transplant failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mycobacterium abscessus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSMANI M, SOTELLO D, ALVAREZ S, ODELL JA, THOMAS M. MYCOBACTERIUM ABSCESSUS INFECTIONS IN LUNG TRANSPLANT RECIPIENTS: 15-YEAR EXPERIENCE FROM A SINGLE INSTITUTION. TRANSPL-INFECT-DIS 2018?20(2):E12835.", "literaturereference_normalized": "mycobacterium abscessus infections in lung transplant recipients 15 year experience from a single institution", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180516", "receivedate": "20180516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14899607, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "US-PFIZER INC-2018173509", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN SULFATE" }, "drugadditional": 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM CHELONAE INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMIPENEM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM ABSCESSUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TIGECYCLINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM ABSCESSUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIGECYCLINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "063264", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM ABSCESSUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN SULFATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050670", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM CHELONAE INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TIGECYCLINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021821", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM CHELONAE INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIGECYCLINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050670", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM ABSCESSUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050706", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM CHELONAE INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MEROPENEM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IMIPENEM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM ABSCESSUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMIPENEM" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "OSMANI, M.. MYCOBACTERIUM ABSCESSUS INFECTIONS IN LUNG TRANSPLANT RECIPIENTS: 15-YEAR EXPERIENCE FROM A SINGLE INSTITUTION. TRANSPLANT INFECTIOUS DISEASE. 2018?20 (2):10.1111/TID.12835", "literaturereference_normalized": "mycobacterium abscessus infections in lung transplant recipients 15 year experience from a single institution", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180427", "receivedate": "20180427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14822388, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "US-TEVA-2018-US-892559", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMIKACIN" }, 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PREOPERATIVE", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE IMMUNOSUPPRESSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MONTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM ABSCESSUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, 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"medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFOXITIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MONTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM ABSCESSUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFOXITIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM CHELONAE INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MONTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYCOBACTERIUM ABSCESSUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLARITHROMYCIN." } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Skin lesion", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mycobacterium abscessus infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bursitis infective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OSMANI M, SOTELLO D, ALVAREZ S, ODELL JA, THOMAS M. MYCOBACTERIUM ABSCESSUS INFECTIONS IN LUNG TRANSPLANT RECIPIENTS: 15?YEAR EXPERIENCE FROM A SINGLE INSTITUTION. TRANSPL?INFECT?DIS 2018?20(2):E12835.", "literaturereference_normalized": "mycobacterium abscessus infections in lung transplant recipients 15 year experience from a single institution", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180516", "receivedate": "20180516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14899606, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201105" }, { "companynumb": "US-PFIZER INC-2018173510", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN SULFATE" }, "drugadditional": "3", 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"reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "OSMANI M, SOTELLO D, ALVAREZ S, ODELL JA, THOMAS M. MYCOBACTERIUM ABSCESSUS INFECTIONS IN LUNG TRANSPLANT RECIPIENTS: 15?YEAR EXPERIENCE FROM A SINGLE INSTITUTION. TRANSPL?INFECT?DIS 2018?20(2):E12835.", "literaturereference_normalized": "mycobacterium abscessus infections in lung transplant recipients 15 year experience from a single institution", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180516", "receivedate": "20180516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14899605, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201105" }, { "companynumb": "US-PFIZER INC-2018172789", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN SULFATE" }, "drugadditional": 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"patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "OSMANI, M.. MYCOBACTERIUM ABSCESSUS INFECTIONS IN LUNG TRANSPLANT RECIPIENTS: 15-YEAR EXPERIENCE FROM A SINGLE INSTITUTION. TRANSPLANT INFECTIOUS DISEASE. 2018?20 (2):10.1111/TID.12835", "literaturereference_normalized": "mycobacterium abscessus infections in lung transplant recipients 15 year experience from a single institution", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180430", "receivedate": "20180430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14828175, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "US-TEVA-2018-US-892531", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "060", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PREOPERATIVE", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE IMMUNOSUPPRESSION", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "040232", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON CALL TO THE OPERATING ROOM, THEN INTRAOPERATIVELY DURING REPERFUSION OF LUNGS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mycobacterium abscessus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OSMANI M, SOTELLO D, ALVAREZ S, ODELL JA, THOMAS M. MYCOBACTERIUM ABSCESSUS INFECTIONS IN LUNG TRANSPLANT RECIPIENTS: 15-YEAR EXPERIENCE FROM A SINGLE INSTITUTION. TRANSPL-INFECT-DIS 2018?20(2):E12835.", "literaturereference_normalized": "mycobacterium abscessus infections in lung transplant recipients 15 year experience from a single institution", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180516", "receivedate": "20180516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14899595, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "US-PFIZER INC-2018173511", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, 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MYCOBACTERIUM ABSCESSUS INFECTIONS IN LUNG TRANSPLANT RECIPIENTS: 15-YEAR EXPERIENCE FROM A SINGLE INSTITUTION. TRANSPL-INFECT-DIS 2018?20(2):E12835.", "literaturereference_normalized": "mycobacterium abscessus infections in lung transplant recipients 15 year experience from a single institution", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180516", "receivedate": "20180516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14899613, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "This case illustrates the rare presentation of endogenous Klebsiella pneumoniae endophthalmitis with concomitant orbital cellulitis from an acute pyelonephritis. A 59-year-old Caucasian female with type 2 diabetes mellitus was transferred from a regional hospital with decreased visual acuity, periorbital edema, photophobia, proptosis and pain of the right eye, as well as suprapubic discomfort. Initial ocular examination and B-scan ultrasonography were consistent with endophthalmitis and orbital cellulitis which lead to a vitreous tap and intravitreal antibiotics injection and systemic antibiotherapy. Vitreous and blood cultures confirmed Klebsiella pneumoniae as the causative organism. An orbital MRI showed a panophthalmitis with optic neuritis and further imaging confirmed a concomitant pyelonephritis secondary to a septic nephrolithiasis. The patient was given treatment with high-does intravenous antibiotics, oral and topical corticotherapy, and an early core pars plana vitrectomy (PPV), performed 5 days after presentation with repeat injections of antibiotics and dexamethasone. Unfortunately, two weeks following PPV, despite an initial stable postoperative course, the patient deteriorated and presented with purulent discharge from one of the vitrectomy port incision site. An emergency evisceration was performed in order to control the infection, revealing a large subretinal abscess and necrosed sclerotic tissue around the prior vitrectomy incision sites. Conclusion: This is the first case report of Klebsiella pneumoniae endophthalmitis or panophthalmitis presenting with orbital cellulitis and optic neuritis from an urinary tract infection. Prognosis is poor despite treatment including early vitrectomy.", "affiliations": "Department of Ophthalmology, Université de Montréal, Montréal, Québec, Canada.;Department of Ophthalmology, Université de Montréal, Montréal, Québec, Canada.;Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montréal, Québec, Canada.;Department of Ophthalmology, Université de Montréal, Montréal, Québec, Canada.", "authors": "Bouhout|Soumaya|S|;Lacourse|Magaly|M|;Labbé|Annie-Claude|AC|;Aubin|Marie-Josée|MJ|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.idcr.2021.e01289", "fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00245-6\n10.1016/j.idcr.2021.e01289\ne01289\nCase Report\nA rare presentation of Klebsiella pneumoniae endogenous panophthalmitis with optic neuritis and orbital cellulitis from a urinary tract infection\nBouhout Soumaya marie-josee.aubin@umontreal.ca\na⁎1\nLacourse Magaly marie-josee.aubin@umontreal.ca\na⁎1\nLabbé Annie-Claude bc\nAubin Marie-Josée ade\na Department of Ophthalmology, Université de Montréal, Montréal, Québec, Canada\nb Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montréal, Québec, Canada\nc Division of Infectious Diseases and Microbiology, Hôpital Maisonneuve-Rosemont, CIUSSS de l’Est-de-l’Île-de-Montréal, Montréal, Québec, Canada\nd Centre universitaire d’ophtalmologie (CUO), Hôpital Maisonneuve-Rosemont (HMR), CIUSSS de l’Est-de-l’Île-de-Montréal, Montréal, Québec, Canada\ne Department of Social and Preventive Medicine, School of Public Health, Université de Montréal, Montréal, Québec, Canada\n⁎ Corresponding author. marie-josee.aubin@umontreal.camarie-josee.aubin@umontreal.ca\n1 Co-first authors: Soumaya Bouhout and Magaly Lacourse contributed equally to this paper.\n\n23 9 2021\n2021\n23 9 2021\n26 e0128914 8 2021\n18 9 2021\n22 9 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nThis case illustrates the rare presentation of endogenous Klebsiella pneumoniae endophthalmitis with concomitant orbital cellulitis from an acute pyelonephritis. A 59-year-old Caucasian female with type 2 diabetes mellitus was transferred from a regional hospital with decreased visual acuity, periorbital edema, photophobia, proptosis and pain of the right eye, as well as suprapubic discomfort. Initial ocular examination and B-scan ultrasonography were consistent with endophthalmitis and orbital cellulitis which lead to a vitreous tap and intravitreal antibiotics injection and systemic antibiotherapy. Vitreous and blood cultures confirmed Klebsiella pneumoniae as the causative organism. An orbital MRI showed a panophthalmitis with optic neuritis and further imaging confirmed a concomitant pyelonephritis secondary to a septic nephrolithiasis. The patient was given treatment with high-does intravenous antibiotics, oral and topical corticotherapy, and an early core pars plana vitrectomy (PPV), performed 5 days after presentation with repeat injections of antibiotics and dexamethasone. Unfortunately, two weeks following PPV, despite an initial stable postoperative course, the patient deteriorated and presented with purulent discharge from one of the vitrectomy port incision site. An emergency evisceration was performed in order to control the infection, revealing a large subretinal abscess and necrosed sclerotic tissue around the prior vitrectomy incision sites. Conclusion: This is the first case report of Klebsiella pneumoniae endophthalmitis or panophthalmitis presenting with orbital cellulitis and optic neuritis from an urinary tract infection. Prognosis is poor despite treatment including early vitrectomy.\n==== Body\npmcIntroduction\n\nKlebsiella species are facultative anaerobic Gram-negative bacilli, which can be part of the gastrointestinal and nasopharyngeal flora [1]. They are highly prevalent causative organisms for endogenous endophthalmitis (EE) in Asia (3–37%) and is often associated with a pyogenic liver abscess and diabetes mellitus [1]. By contrast, it is relatively rare in North America where it accounts for only 3.6% of endogenous endophthalmitis [1]. Indeed, most endogenous endophthalmitis in North America and Europe are caused by Streptococci (30–50%), other Gram-negative bacilli (30%) and Staphylococcus aureus (25%)[2].\n\nAs seen in Table 1, there are only few reported cases of endogenous Klebsiella panophthalmitis [3], [4] or endophthalmitis [5], [6], [7] with concomitant orbital cellulitis. This case report describes the first documented case of Klebsiella endogenous panophthalmitis, with associated optic neuritis and orbital cellulitis secondary to a urinary tract infection (UTI).Table 1 Review of the literature of endogenous Klebsiella optic neuritis or panophthalmitis and endophthalmitis with orbital cellulitis. AC: anterior chamber. DM: Diabetes mellitus. EVI: endoscopic variceal injections. IV: intravenous. IVDU: intravenous drug use. HM: Hand motion. LP: Light perception. NA: not available. OHT: ocular hypertension PPV: pars plana vitrectomy. RAPD: Relative afferent pupillary defect. RD: retinal detachment.\n\nTable 1Tyee of presentation\tCase\tAge/Sex\tUnderlying medical conditions\tSystemic infection foci\tInitial symptoms\tInitial VA\tOcular signs\tOrbital Imaging\tMedical management\tPars Plana Vitrectomy performed (timing / findings)?\tComplications\tFinal VA (timing)\t\nEndophthalmitis/panophthalmitis and orbital cellulitis\t1 [Hung et al.2]\t66 M\tLiver cirrhosis\tTranslocation from EVI\tFever, chills, decreased VA, ocular pain\tNA\tConjunctiva chemosis, edematous cornea, shallow AC with hypopyon, no vitreous view\tCT scan: abnormal enhancement around the orbit\tIntravitreal cefazolin and gentamicin.\nIV ceftriaxone for 4 weeks\tNo\tRecurrent infection despite IV and intravitreal antibiotics\tEnucleation (NA)\t\n2 [Suwan et al.5]*\t58 M\tDM\tNA\tDecreased vision, proptosis, diarrhea and fever.\tHM\tSignificant proptosis (9 mm), eyelid erythema and edema, RAPD, EOM restriction, severe AC inflammation, mature cataract, yellow subretinal mass\tOcular B-scan: dome shaped lesion.\nCT scan: orbital cellulitis, no abscess, no cavernous sinus abnormalities\tInitial IV ceftazidime and cloxacillin switch to IV ceftriaxone once organism identified.\nNo initial Tap/inject.\nFollowing PPV, second intravitreal injection vancomycin and ceftazidime\tYes (NA/NA) with intravitreal injection of vancomycin and ceftazidime\t–\tLP(NA)\t\n3 [Davies et al.6] *\t70 F\tHypertension\tKlebsiella pneumoniae liver pyogenic abscess\tNA\tHM\tRAPD, EOM restriction, 1 mm proptosis and 3 mm inferior globe displacement. Eyelid edema, conjunctival chemosis, 1 + AC cells. No fundus view.\tMRI: Superior and anterior orbital infiltrate, without involvement of intraconal space\tIntravitreal amikacin and cyclosporine. IV ceftriaxone then IV ertapenem and vancomycin. IV methylprednisolone (100 mg daily, total dose 1.4 g). Topical moxifloxacin and cyclopentolate.\tNo\tDense cataract\tLP (1 month)\t\n4 [Ghiam et al.11]\t34 M\tType 1 DM, IVDU\tPresumed skin abscesses\tProgressive ocular pain\tLP\tPtosis, EOM restriction, OHT, eyelid erythema and edema, chemosis, fibrin over the pupil, 0.5 mm hypopyon. No fundus view.\tOcular B-scan: hyperechoic material in the vitreous consistent with vitritis.\nCT scan: eye proptosis with orbital fat stranding focused primarily around the globe.\tTwo intravitreal injections (vancomycin/ceftazidime then Only ceftazidime).\nIV vancomycin and piperacillin/tazobactam then IV cefepime.\nTopical antihypertensive drops\tYes (NA/ dense vitritis, widespread retinal necrosis, RD)\tRefractive high IOP and significant proptosis requiring lateral canthotomy and cantholysis. Despite PPV, NLP and increase ocular pain.\tEvisceration (day 9)\t\nEndophthalmitis with optic neuritis\t5 [Chiba et al.7]\t79 F\tNA\tKlebsiella pneumoniae liver pyogenic abscess\tEyelid swelling, severe hyperemia and purulent conjunctival discharge\tNA\tHypopyon, cataract\tCT scan: nasal scleral rupture and orbital cellulitis. MRI: optic neuritis and ventriculitis\tNA\tNO\tDiseased (day 46)\tEnucleation (NA)\t\nIsolated optic neuritis\t6 [Lee and al.13]\t56 F\t–\tKlebsiella pneumoniae liver pyogenic abscess\tDecreased vision\tLP\tRAPD\tMRI: enhancement of the left optic nerve\tAt least 3 weeks of IV ceftriaxone and moxifloxacin.\nIV dexamethasone (20 mg/day) followed by oral prednisone\tNo\tSmall microabscesses in the left frontal and temporal lobes\tLP (4 months)\t\n*Although it was not explicitly described, Suwan et al. and Davies et al. described a RAPD which could represent either an extent retinal involvement or concomitant optic neuritis.\n\nCase report\n\nA 59-year-old woman known for a well-controlled type 2 diabetes mellitus with oral medication and prior bariatric surgery presented to a local community hospital with a two-day history of decreased visual acuity, periorbital edema, photophobia, proptosis and pain of the right eye. She was phakic bilaterally, had no prior medial nor surgical ocular history and no previous ocular trauma. Apart from her diabetes and prior bariatric surgery, she had no other risk factors for endogenous endophthalmitis (intravenous drug use, indwelling catheter, immunosuppression). She was seen by the local ophthalmologist who suspected a panuveitis with a hypopyon. The initial empiric treatment decision, awaiting further consultation at our tertiary hospital was oral cotrimoxazole (800 mg/160 mg twice a day) for possible toxoplasmosis, valacyclovir (1 g three times a day) for herpetic acute retinal necrosis and prednisolone acetate (Pred Forte) 1% drops hourly. The acute nature of the presentation with the presence of a hypopyon suggested an endogenous endophthalmitis, but from a yet unknown underlying source. A computerized tomography (CT) scan was performed and no sign of periorbital nor orbital cellulitis was initially seen. She was transferred to our tertiary hospital for further care. At our center, the initial visual acuity was hand motion on the right eye and 20/30 on the left. The presentation with painful ophthalmoplegia (Fig. 1) and a right relative afferent pupillary defect led to suspect concomitant orbital cellulitis (not only preseptal), cavernous sinus involvement or apex syndrome. In diabetics especially, cavernous sinus involvement can occur (other etiologies need to also be considered: ischemic, other infectious agents such as mucormycosis).Fig. 1 Extraocular movements 48 h following intravitreal antibiotic injection. Right eye showed important eyelid edema and erythema as well as important conjunctival erythema and chemosis. Extraocular movements were limited and painful in all directions.\n\nFig. 1\n\nFurther, there was erythema, warmth and edema of the right eyelids, and associated ptosis. Slit-lamp exam showed important chemosis and hyperemia of the conjunctiva, corneal edema, 3–4+ cells (according to the Standardization of Uveitis Nomenclature grading) and 2+ flare in the anterior chamber with a 1.5 mm hypopyon. A fundus exam was not feasible due to the anterior chamber findings, cataract and important vitreous haze. A B-scan ultrasonography showed dense heterogeneous intravitreal cellular debris suggesting the presence of significant vitritis. Her blood cultures done the day before had grown Klebsiella pneumoniae in line with the diagnostic impression of an endogenous endophthalmitis. A vitreous tap was performed with injection of ceftazidime 2.25 mg/0.1 mL and moxifloxacin 500 mg/0.1 mL. The vitreous culture confirmed K. pneumoniae as the causative organism, which was resistant to ampicillin but sensitive to ceftazidime, ceftriaxone, ciprofloxacin, cotrimoxazole and piperacillin/tazobactam. The minimal inhibitory concentrations were ≤0.25 mg/L for ceftriaxone, ≤ 0.06 mg/L for ciprofloxacin and ≤ 2.0 mg/L for amoxicillin-clavulanic acid. The patient was hospitalized, and further questioning revealed a suprapubic discomfort and a fever spike (38.8 oC) one week before hospitalization. On admission, inflammation markers were elevated with a white cell count (WBC) of 9.2 × 109/L and a C-reactive protein (CRP) of 74 mg/L. An abdominal CT scan showed the presence of an acute pyelonephritis secondary to a partially obstructive nephrolithiasis; no liver abscess was seen. The patient was treated empirically with meropenem 2 g IV every eight hours and PF 1% drops were continued hourly (Fig. 2).Fig. 2 Right eye 48 h following intravitreal antibiotic injection: conjunctival chemosis and erythema, corneal edema, cataract with fibrin on the anterior capsule, 3–4+ cells in the anterior chamber with a 1.5 mm hypopyon.\n\nFig. 2\n\nIndeed, despite early interventions and subjective improvement of the patient’s symptoms, her visual acuity on the right eye continued to deteriorate to no light perception (LP) within 72 h following her presentation. Repeated imaging of the orbits (CT and MRI) showed signs of right eye panophthalmitis with associated papillitis and orbital cellulitis, but no abscess collection, no sinusitis and no cavernous sinus involvement. Additional daily B-scan ultrasonography evaluations revealed a swollen optic nerve head, a thickened choroid, choroidal detachment, a densely organized vitreous and a possible retinal detachment. Given the clinical deterioration, oral prednisone (30 mg daily) was initiated and a core pars plana vitrectomy (PPV) was performed in order to debride the infectious and inflammatory load, with repeat antibiotic injections (vancomycin 1 mg/0.1 mL and ceftazidime 2.25 mg/0.1 mL) and dexamethasone (400 mg/0.1 mL).\n\nEarly postoperative course was favorable, with improved visual acuity to light perception, diminished periorbital edema and pain and decreased signs of cellulitis. According to antibiotic sensitivities, intravenous meropenem was tailored to intravenous ceftriaxone (2 g IV BID) for 3 days and then to oral ciprofloxacin (500 mg twice a day) for a 14 days antibiotic course. The last four days, ciprofloxacin was changed to amoxicillin-clavulanic acid (875 mg PO BID) because of nausea and vomiting. Her oral prednisone (30 mg daily) was tapered. One week following her PPV, proptosis was resolved, extraocular movements were complete and inflammatory markers normalized (WBC: 7.1 ×109/L and CRP: 2.4 mg/L). She was assessed by the urology service and double J-stent placement was planned on an outpatient basis. During the intake of oral prednisone, her glycemia mildly increased which was controlled with increase of her metformin dosage.\n\nTwo weeks following her PPV and five days after discontinuing antibiotics, she presented with recurrent periorbital edema and pain with extraocular movement. Visual acuity decreased from LP to no light perception, slit lamp exam showed flare in the anterior chamber with no hypopyon. B-scan ultrasonography showed an organized vitreous with an inferior choroidal detachment. Given the potential diagnosis of either recurrent infection or inflammation, oral ciprofloxacin (500 mg twice per day) was restarted and her oral prednisone (5 mg daily) was increased (10 mg daily). The next day, her clinical presentation worsened with increased erythema, periorbital edema and ocular pain. Her examination showed still trace of cells in the anterior chamber, 2 + of flare, no hypopyon but the new presence of anterior scleritis, and a rise of the CRP (4.4–28.9 mg/L). Ciprofloxacin was changed to intravenous meropenem (2 g IV three times a day), oral prednisone was increased to 40 mg daily and a second PPV was planned. Unfortunately, despite intravenous antibiotics, the patient rapidly developed a globe rupture at the previous vitrectomy trocar incision site with pustular discharge. An emergency evisceration was performed and showed a large inferior subretinal abscess, purulent vitreous and scleral necrosis. The vitreous culture was negative. Meropenem was changed to ceftriaxone (2 g IV daily) five days later, for a total of 12 days following her evisceration, and she remained stable until discharge. The dosage of ceftriaxone was decreased post-evisceration as it was considered as a soft-tissue infection.\n\nDiscussion\n\nKlebsiella endogenous panophthalmitis or endophthalmitis with associated orbital cellulitis are rare and have a dismal visual and anatomic prognosis despite treatment [3], [4], [5].\n\nK. pneumoniae virulence is partly explained by its production of a polysaccharide capsule, with some serotype (particularly serotype K1 or K2) offering a higher resistance to phagocytose by neutrophils, especially in poorly controlled diabetics [8]. The hypervirulent K. pneumoniae is mostly associated with pyogenic liver abscesses (68%) followed by urinary tract infections (13%) [4], [9]. Metastatic complications, such as endogenous endophthalmitis are highly prevalent compared to systemic infections caused by other organisms (7% versus < 1%) [9], [10]. Although highly prevalent in Eastern Asia and rare in Western countries, some reports have described an increase in the incidence of Klebsiella endogenous endophthalmitis [11].\n\nAs illustrated with this case, diabetes is a significant risk factor for developing ocular infection from Klebsiella bacteremia and is also a poor visual prognostic factor. Other published poor prognosis factors include concomitant immunosuppression, a presenting visual acuity of less than counting fingers, delayed diagnosis and treatment, the presence of an hypopyon, rapid onset of symptoms, panophthalmitis or orbital cellulitis, many of which were present in our patient [12].\n\nOur patient presented with classical signs and symptoms of both orbital cellulitis and endophthalmitis which include decreased visual acuity, ocular pain, limited extra-ocular movement, conjunctival chemosis and erythema, diffuse anterior chamber reaction with a hypopyon and diffuse vitritis which is comparable to the other cases described in the literature (Table 1) [3], [4], [5], [7]. Other specific characteristics of Klebsiella endogenous endophthalmitis is a rapid evolution course, production of a subretinal abscess, spontaneous globe rupture and bilateral involvement (13%) [13]. This case shows how virulent this pathogen is. Indeed, no significant pathology of the orbits was visible on the initial CT scan, 24 h before the patient was transferred to our tertiary hospital. Furthermore, early orbital MRI performed 3 days after transfer showed evidence of papillitis with retrobulbar nerve sheath involvement (Fig. 3). There are two reports describing optic neuritis, with or without endophthalmitis nor orbital cellulitis from a Klebsiella pyogenic liver abscess [6], [14]. In the best of our knowledge, this is the second described case of endogenous Klebsiella panophthalmitis with orbital cellulitis and optic neuritis. In the setting of orbital cellulitis, optic nerve involvement can be caused by inflammatory infiltration, mechanical compression by an orbital abscess, ischemia secondary to compression of feeding vessels or dissemination of infection (septic optic neuropathy) [15]. MRI findings include orbital abscess, optic nerve T2-hypersignaling in the setting of optic neuritis, perineuritis can be seen as optic nerve sheath thickening and enhancement in contrast-enhanced fat-suppressed T1-weighted sequence [16]. In B-scan ultrasonography, retrobulbar optic nerve thickening has been reported in both papillitis and retrobulbar optic neuritis whereas optic disc swelling is only seen in papillitis [17]. In retrospect, the finding of an inferior choroidal detachment in the B-scan prior to the evisceration correlates with the sub-retinal abscess found intraoperatively. Therefore, we recommend being alert for choroidal detachment in Klebsiella endogenous endophthalmitis, as it could represent a subretinal abscess.Fig. 3 Orbital MRI in the axial (A) and coronal (B) T1- SEFS post-gadolinium administration sequence, showing a right panophthalmitis with associated optic neuritis (papillitis) and orbital cellulitis. Diffuse enhancement of sclera and ciliary body, vitreous heterogeneity with diffuse enhancement pre-septal and post-septal orbital fat was noted, with important conjunctival edema. Enhancement of the optic nerve head (white arrow) of the retrobulbar optic nerve sheath. Retrobulbar optic nerve itself was normal. No signs of an orbital collection, cavernous sinus syndrome or orbital apex syndrome was seen. SEFS: Spin echo fat suppressed.\n\nFig. 3\n\nIn this case, orbital MRI showed signs of anterior neuritis with retrobulbar perineuritis (optic sheath enhancement) and no signs of retrobulbar optic nerve involvement or orbital abscess were seen. Those findings could be secondary to either inflammatory changes or infectious dissemination.\n\nFurthermore, bacterial infectious optic neuropathies are not typically associated with common pathogens of endophthalmitis such as Klebsiella, Staphylococci or Streptococci, but are more seen in the setting of tuberculosis, syphilis, rickettsioses and brucellosis [18].\n\nIn this particular case, the patient had no other systemic symptoms apart from mild suprapubic discomfort. It reiterates the challenge of suspecting endogenous endophthalmitis without obvious systemic infection, which can lead to delay in treatment [13] In fact, around 25–33% bacterial endogenous endophthalmitis might have a delay in establishing the diagnosis with an estimated average of 3 days delay [19].\n\nManagement of all endophthalmitis includes intravitreal antibiotics injection and some patients may require a vitrectomy. Some reports have suggested that early PPV for cases with Klebsiella pneumonia endophthalmitis might improve visual outcomes [13]. Vitrectomy is also associated with a smaller rate of evisceration or enucleation [10]. Multiple intravitreal antibiotic injections may be required as optimal antibiotic intravitreal concentration only lasts 24–48 h following the injection, but repeated injections can be limited by other factors such as retinal toxicity or risk of retinal detachment [20].\n\nManagement of endogenous endophthalmitis also includes systemic antibiotics and the duration depends on the cause of the bacteremia [10]. Management of orbital cellulitis includes systemic antibiotics for at least 2–3 weeks and can be ceased when all clinical signs of orbital cellulitis has been resolved [15] (Fig. 4).Fig. 4 Summary of medical and surgical management of our case # Topical anti-hypertensive drops were used during all the follow-ups. *A B-Scan ocular ultrasound was performed almost daily. PPV: pars plana vitrectomy. PF: Pred Forte. IV: intravenous. PO: per os. AP: Abdominal-Pelvic. DIE: daily. BID: two times per day. TID: three times per day. QID: four times per day. 1 Meropenem 2 g IV TID (on day 2, meropenem was switched for ceftriaxone for less than 24 h and was reintroduced). 2Ceftriaxone 2 g IV BID. 3Ciprofloxacin 500 mg PO BID. 4 Prednisone per OS. 5 Amoxicillin-clavulanic acid 875 mg PO BID. 6Ceftriaxone 2 g IV DIE. Please refer to the text for information regarding radiological findings.\n\nFig. 4\n\nThe visual outcome of endophthalmitis depends both on the virulence of the causative organism and on the time of initiation of the therapy. For Klebsiella endophthalmitis, unfortunately, the visual outcome is generally poor. Previous series have shown that 44–69% of eyes with Klebsiella endogenous endophthalmitis have a final VA less than counting fingers and 16–40% of eyes require an evisceration or enucleation [1].\n\nConclusion\n\nKlebsiella endogenous endophthalmitis is a devasting ocular disease with poor visual and anatomical outcomes despite early treatment. This case describes a rare presentation of Klebsiella endogenous panophthalmitis with concomitant optic neuritis and orbital cellulitis. We suggest that patients with known Klebsiella infection reporting with any ocular symptoms should be evaluated by an ophthalmologist given the high rate of endophthalmitis and the rapid progression. Multidisciplinary management is essential and early vitrectomy should be performed when possible. Further, in the case of KEE, clinicians should be alert for subretinal abscess when choroidal detachment is observed on B-Scan. In the case of concomitant orbital cellulitis, extended treatment should be considered with an extended course of antibiotics of at least 3 weeks.\n\nDeclaration of funding\n\nNone to declare.\n\nDeclaration of conflict of interest\n\nNone to declare.\n\nCRediT authorship contribution statement\n\nSoumaya Bouhout: Review of the literature, Retrospective chart review, Writing – original draft. Magaly Lacrouse: Review of the literature, Retrospective chart review, Writing – original draft. Marie-Josée Aubin: Supervision, Written – review & editing. Annie-Claude Labbé: Supervision, Written – review & editing.\n\nAcknowledgements\n\nWe would like to thank Dr. Sébastien Olivier and Dr Andrée-Anne Pistono for their contribution to this manuscript.\n\nWritten informed consent was obtained from the patient for publication of this case report and.\n\naccompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n==== Refs\nReferences\n\n1 Sridhar J. Flynn HW Jr Jr. Kuriyan A.E. Dubovy S. Miller D. Endophthalmitis caused by Klebsiella species Retina 34 9 2014 1875 1881 24801652\n2 Okada A.A. Johnson R.P. Liles W.C. D’Amico D.J. Baker A.S. Endogenous bacterial endophthalmitis. Report of a ten-year retrospective study Ophthalmology 101 5 1994 832 838 8190467\n3 Hung H.C. Chen W.C. Chao Y. Hou M.C. Lin H.C. Chang F.Y. Klebsiella pneumoniae panophthalmitis: a possible complication of endoscopic variceal injection sclerotherapy Am J Gastroenterol 93 12 1998 2603 2604 9860443\n4 Suwan Y. Preechawai P. Endogenous Klebsiella panophthalmitis: atypical presentation J Med Assoc Thai 95 6 2012 830 833 22774630\n5 Davies B.W. Fante R.G. Concurrent endophthalmitis and orbital cellulitis from metastatic Kebsiella pneumonia liver abscess Ophthalmic Plast Reconstr Surg 32 5 2016 e118 e119 25186218\n6 Chiba T. Yoneyama S. Nakagomi T. Takahashi H. Iijima H. A case of metastatic endophthalmitis resulting from liver abscess complicated with pyogenic ventriculitis via optic nerve Nippon Ganka Gakkai Zasshi 119 10 2015 686 692 26571629\n7 Ghiam B.K. Israelsen P. Wang A. Grob S. Esfahani M.R. Klebsiella pneumoniae endogenous endophthalmitis presenting as orbital cellulitis GMS Ophthalmol Cases 9 2019 30\n8 Lin J.C. Siu L.K. Fung C.P. Tsou H.H. Wang J.J. Chen C.T. Impaired phagocytosis of capsular serotypes K1 or K2 Klebsiella pneumoniae in type 2 diabetes mellitus patients with poor glycemic control J Clin Endocrinol Metab 91 8 2006 3084 3087 16720670\n9 Russo T.A. Marr C.M. Hypervirulent Klebsiella pneumoniae Clin Microbiol Rev 32 2019 3\n10 Durand M.L. Bacterial and fungal endophthalmitis Clin Microbiol Rev 30 3 2017 597 613 28356323\n11 Odouard C. Ong D. Shah P.R. Gin T. Allen P.J. Downie J. Rising trends of endogenous Klebsiella pneumoniae endophthalmitis in Australia Clin Exp Ophthalmol 45 2 2017 135 142 27564396\n12 Sheu S.J. Kung Y.H. Wu T.T. Chang F.P. Horng Y.H. Risk factors for endogenous endophthalmitis secondary to Klebsiella pneumoniae liver abscess: 20-year experience in Southern Taiwan Retina 31 10 2011 2026 2031 21499189\n13 Jackson T.L. Eykyn S.J. Graham E.M. Stanford M.R. Endogenous bacterial endophthalmitis: a 17-year prospective series and review of 267 reported cases Surv Ophthalmol 48 4 2003 403 423 12850229\n14 Lee H.S. Choi K.D. Lee J.E. Park H.K. Optic neuritis after Klebsiella pneumonitis and liver abscess J Neuroophthalmol 29 2 2009 134 135 19491637\n15 Tsirouki T. Dastiridou A.I. Ibánez Flores N. Cerpa J.C. Moschos M.M. Brazitikos P. Orbital cellulitis Surv Ophthalmol 63 4 2018 534 553 29248536\n16 Kapur R. Sepahdari A.R. Mafee M.F. Putterman A.M. Aakalu V. Wendel L.J. MR imaging of orbital inflammatory syndrome, orbital cellulitis, and orbital lymphoid lesions: the role of diffusion-weighted imaging AJNR Am J Neuroradiol 30 1 2009 64 70 18842758\n17 Stefanović I.B. Jovanović M. Krnjaja B.D. Veselinović D. Jovanović P. Influence of retrobulbar neuritis and papillitis on echographically measured optic nerve diameter Vojn Pregl 67 1 2010 32 35\n18 Kahloun R. Abroug N. Ksiaa I. Mahmoud A. Zeghidi H. Zaouali S. Infectious optic neuropathies: a clinical update Eye Brain 7 2015 59 81 28539795\n19 Jackson T.L. Paraskevopoulos T. Georgalas I. Systematic review of 342 cases of endogenous bacterial endophthalmitis Surv Ophthalmol 59 6 2014 627 635 25113611\n20 Brockhaus L. Goldblum D. Eggenschwiler L. Zimmerli S. Marzolini C. Revisiting systemic treatment of bacterial endophthalmitis: a review of intravitreal penetration of systemic antibiotics Clin Microbiol Infect 25 11 2019 1364 1369 30771529\n\n", "fulltext_license": "CC BY", "issn_linking": "2214-2509", "issue": "26()", "journal": "IDCases", "keywords": null, "medline_ta": "IDCases", "mesh_terms": null, "nlm_unique_id": "101634540", "other_id": null, "pages": "e01289", "pmc": null, "pmid": "34646733", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "30771529;28539795;12850229;21499189;19491637;31531276;8190467;20225632;26571629;29248536;9860443;27564396;24801652;28356323;18842758;16720670;31092506;25113611;25186218;22774630", "title": "A rare presentation of Klebsiella pneumoniae endogenous panophthalmitis with optic neuritis and orbital cellulitis from a urinary tract infection.", "title_normalized": "a rare presentation of klebsiella pneumoniae endogenous panophthalmitis with optic neuritis and orbital cellulitis from a urinary tract infection" }

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"PREDNISOLONE ACETATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Eye drops", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypopyon", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRED FORTE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800MG/160MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Toxoplasmosis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COTRIMOXAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM, TID", "drugenddate": null, 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"actiondrug": null, "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Evidence based treatment", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": "3", "drugtreatmentdurationunit": "804", "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK DOSE REDUCED", "drugenddate": null, "drugenddateformat": null, "drugindication": "Klebsiella infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Eye inflammation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eye infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Bouhout S, Lacourse M, Labb??? AC, Aubin MJ.. A rare presentation of Klebsiella pneumoniae endogenous panophthalmitis with optic neuritis and orbital cellulitis from a urinary tract infection. ID Cases. 2021;25:e01289", "literaturereference_normalized": "a rare presentation of klebsiella pneumoniae endogenous panophthalmitis with optic neuritis and orbital cellulitis from a urinary tract infection", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20211126", "receivedate": "20211126", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20117886, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "CA-MLMSERVICE-20211027-3187020-1", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "77859", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, TWO TIMES A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antibiotic therapy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": "10", "drugtreatmentdurationunit": "804", "medicinalproduct": "CIPROFLOXACIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTAZIDIME" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Injection", "drugdosagetext": "2.25 MG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antibiotic therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTAZIDIME" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antibiotic therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MOXIFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antibiotic therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MOXIFLOXACIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type 2 diabetes mellitus", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE ACETATE" }, "drugadditional": "3", "drugadministrationroute": "047", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Eye drops", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Uveitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRED FORTE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE ACETATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Eye drops", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypopyon", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRED FORTE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "Antibiotic therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eye pain", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Periorbital oedema", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Bouhout S, Lacourse M, Labb? AC, Aubin MJ.. A rare presentation of Klebsiella pneumoniae endogenous panophthalmitis with optic neuritis and orbital cellulitis from a urinary tract infection.. IDCases. 2021;25", "literaturereference_normalized": "a rare presentation of klebsiella pneumoniae endogenous panophthalmitis with optic neuritis and orbital cellulitis from a urinary tract infection", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20220321", "receivedate": "20220321", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20614470, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "CA-BAYER-2021A247197", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019537", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN" } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Periorbital oedema", "reactionmeddraversionpt": "24.1", "reactionoutcome": null }, { "reactionmeddrapt": "Eye pain", "reactionmeddraversionpt": "24.1", "reactionoutcome": null }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.1", "reactionoutcome": null }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "24.1", "reactionoutcome": null }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "24.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "Bouhout S, Lacourse M, Labbe A-C, Aubin M-J. A rare presentation of Klebsiella pneumoniae endogenous panophthalmitis with optic neuritis and orbital cellulitis from a urinary tract infection. IDCases. 2021;26:XX-XX", "literaturereference_normalized": "a rare presentation of klebsiella pneumoniae endogenous panophthalmitis with optic neuritis and orbital cellulitis from a urinary tract infection", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20211112", "receivedate": "20211112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20063221, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "Hypoglycaemia has been reported as an unusual complication of tramadol use and in a few cases of tramadol poisoning, but the exact mechanism is not known.\nAn ambulance crew was dispatched to an unconscious 46-year old man. A glucometer point-of-care measurement revealed a profound hypoglycaemia (1.9 mmol/L). Treatment with intravenous glucose was started and the patient was transported to the hospital. The patient had several episodes of pulseless electrical activity requiring cardiopulmonary resuscitation in the ambulance and upon arrival in the hospital. Despite continuous glucose infusion the hypoglycaemia was difficult to correct during the next few hours and the patient developed hypokalaemia. Further investigation to identify the cause of hypoglycaemia revealed that insulin and C-peptide were inappropriately raised. A toxicological investigation revealed the presence of tramadol and its metabolites in lethal concentrations. Also acetaminophen, ibuprofen and lormetazepam were present. Ethanol screening was negative (< 0.1 g/L) and no sulfonylurea were detected. The patient developed multiple organ failure, but eventually recovered.\nThe hypoglycaemia was caused by inappropriate stimulation of insulin secretion in a patient intoxicated with tramadol. The sudden hypokalaemia was caused by a massive intracellular shift of potassium in response to the hyperinsulinemia, triggered by the intravenous administration of glucose.\nTo our knowledge, we are the first to document a significant rise in endogenous insulin production in a hypoglycaemic patient presenting with tramadol intoxication. Our observation suggests that hyperinsulinemia could be the cause of the hypoglycaemia associated with tramadol use.", "affiliations": "Laboratory Medicine, University Hospitals Leuven; Department of cardiovascular Medicine, University of Leuven, Leuven, Belgium.;Anesthesiology, Ziekenhuis Oost-Limburg, Genk, Belgium.;Laboratory medicine, AZ Groeninge Hospital, Kortrijk, Belgium.;Laboratory medicine, Ziekenhuis Oost-Limburg, Genk, Belgium.;Laboratory Medicine, University Hospitals Leuven; Department of cardiovascular Medicine, University of Leuven, Leuven, Belgium.;Laboratory Medicine, University Hospitals Leuven; Department of cardiovascular Medicine, University of Leuven, Leuven, Belgium.;Laboratory Medicine, University Hospitals Leuven; Department of cardiovascular Medicine, University of Leuven, Leuven, Belgium.", "authors": "Schiemsky|Toon|T|;Vundelinckx|Guy|G|;Croes|Kathleen|K|;Penders|Joris|J|;Desmet|Koen|K|;Pauwels|Steven|S|;Vermeersch|Pieter|P|", "chemical_list": "D000701:Analgesics, Opioid; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D014147:Tramadol; D005947:Glucose", "country": "Croatia", "delete": false, "doi": "10.11613/BM.2020.010802", "fulltext": "\n==== Front\nBiochem Med (Zagreb)\nBiochem Med (Zagreb)\nBM\nBiochemia Medica\n1330-0962\n1846-7482\nCroatian Society of Medical Biochemistry and Laboratory Medicine\n\nbm-30-1-010802\n10.11613/BM.2020.010802\nCase Reports\nAn unconscious man with profound drug-induced hypoglycaemia\nSchiemsky Toon 1\nVundelinckx Guy 2\nCroes Kathleen 3\nPenders Joris 4\nDesmet Koen 1\nPauwels Steven 1\nVermeersch Pieter *1\n1 Laboratory Medicine, University Hospitals Leuven; Department of cardiovascular Medicine, University of Leuven, Leuven, Belgium\n2 Anesthesiology, Ziekenhuis Oost-Limburg, Genk, Belgium\n3 Laboratory medicine, AZ Groeninge Hospital, Kortrijk, Belgium\n4 Laboratory medicine, Ziekenhuis Oost-Limburg, Genk, Belgium\n* Corresponding author: Pieter.Vermeersch@uzleuven.be\n15 12 2019\n15 2 2020\n30 1 01080202 8 2019\n31 10 2019\nCroatian Society of Medical Biochemistry and Laboratory Medicine.\n2019\nCroatian Society of Medical Biochemistry\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction\n\nHypoglycaemia has been reported as an unusual complication of tramadol use and in a few cases of tramadol poisoning, but the exact mechanism is not known.\n\nCase description\n\nAn ambulance crew was dispatched to an unconscious 46-year old man. A glucometer point-of-care measurement revealed a profound hypoglycaemia (1.9 mmol/L). Treatment with intravenous glucose was started and the patient was transported to the hospital. The patient had several episodes of pulseless electrical activity requiring cardiopulmonary resuscitation in the ambulance and upon arrival in the hospital. Despite continuous glucose infusion the hypoglycaemia was difficult to correct during the next few hours and the patient developed hypokalaemia. Further investigation to identify the cause of hypoglycaemia revealed that insulin and C-peptide were inappropriately raised. A toxicological investigation revealed the presence of tramadol and its metabolites in lethal concentrations. Also acetaminophen, ibuprofen and lormetazepam were present. Ethanol screening was negative (< 0.1 g/L) and no sulfonylurea were detected. The patient developed multiple organ failure, but eventually recovered.\n\nWhat happened\n\nThe hypoglycaemia was caused by inappropriate stimulation of insulin secretion in a patient intoxicated with tramadol. The sudden hypokalaemia was caused by a massive intracellular shift of potassium in response to the hyperinsulinemia, triggered by the intravenous administration of glucose.\n\nMain lesson\n\nTo our knowledge, we are the first to document a significant rise in endogenous insulin production in a hypoglycaemic patient presenting with tramadol intoxication. Our observation suggests that hyperinsulinemia could be the cause of the hypoglycaemia associated with tramadol use.\n\nKeywords:\n\nhypoglycaemia\ntramadol\ninsulin\npoisoning\n==== Body\nIntroduction\n\nTramadol is a commonly prescribed weak, centrally acting opioid used for the treatment of moderate to severe pain. It has two main metabolites, O-desmethyltramadol and N-desmethyltramadol. The main activity of tramadol is mediated via activation of the µ-receptors and can mainly be ascribed to O-desmethyltramadol, which is 2 to 4 times more analgesic than the parent drug. The second mechanism acts by inhibiting the central serotonin and norepinephrine re-uptake, thereby interfering with the central nociceptive signal transmission (1). The most commonly described side effects of tramadol use are vomiting, nausea, drowsiness, dizziness, constipation, dry mouth, seizures, respiratory difficulties and cardiovascular problems. Hypoglycaemia has been reported as an unusual complication of tramadol use and in a few cases of tramadol poisoning (2-5). A recent study of more than 12 million reports from the United States Food and Drug Administration Adverse Event Reporting System found evidence of significant association of hypoglycaemia with tramadol and methadone use, but not with other opioids (6). Diabetes mellitus seems to be a risk factor for this side effect, but the mechanism underlying this association is not known.\n\nCase report\n\nIn response to an emergency call, an ambulance crew and an emergency physician were dispatched to an unconscious man. The 46-year old man had a cerebrovascular accident three years ago and a medical history of rheumatoid arthritis treated with leflunomide. The patient was found unconscious (Glasgow Coma Scale 3/15) in his bed and had vomited. Benzodiazepines were found near his bed. The patient was last seen awake 12 hours before by his wife. A point-of-care (POC) measurement with a glucometer (Accu-Chek Performa, Roche Diagnostics, Rotkreuz, Switzerland) revealed a profound hypoglycaemia (1.9 mmol/L). The patient had no prior history of diabetes mellitus.\n\nThe patient was intubated and an intravenous infusion with glucose was started to correct the hypoglycaemia. In the ambulance, the patient developed a pulseless electrical activity (PEA). Cardiopulmonary resuscitation (CPR) was started and 1 mg adrenaline was administered intravenously. This was followed by a return of spontaneous circulation. During transportation and upon arrival at the hospital, a number of additional PEA events occurred requiring CPR.\n\nUpon arrival in the hospital, initial POC arterial blood gas measurements (ABL90 FLEX, Radiometer, Copenhagen, Denmark) revealed profound hypoglycaemia (0.8 mmol/L), acidosis, increased lactate and pCO2, decreased O2 saturation, and a normal ionogram (Table 1). Oxygen was administered via an oxygen mask and the glucose infusion was continued. A new POC analysis 50 minutes later revealed that blood glucose had only increased to 3.6 mmol/L and that the patient now had hypokalaemia. A parallel venous blood sample analysed in the core laboratory confirmed these findings and also showed increased aspartate aminotransferase (AST), lactate dehydrogenase (LD), cardiac troponin T high sensitive (cTnT-hs) and renal failure (creatinine 180 mmol/L, estimated GFR (eGFR): 38 mL/min/1.73m2) (Table 2). Urine strip analysis showed ketonuria (1+).\n\nTable 1 Point-of-care laboratory results during the first four hours\n\nLaboratory test (unit)\tAt arrival\tAfter 50 min\tAfter 130 min\tAfter 240 min\tReference interval\t\nSodium (mmol/L)\t143\t140\t143\t143\t135 – 145\t\nPotassium (mmol/L)\t3.7\t2.1\t2.6\t2.3\t3.5 – 4.5\t\nCalcium ionized (pH 7.4) (mmol/L)\t1.16\t1.17\t0.98\t1.02\t1.12 – 1.23\t\nChloride (mmol/L)\t109\t109\t109\tND\t101 – 111\t\nGlucose (mmol/L)\t0.8\t3.6\t3.3\t5.8\t3.3 – 6.1\t\nLactate (mmol/L)\t11.0\t11.1\t9.9\t9.9\t0.4 – 2.0\t\npH (pH units)\t7.05\t6.99\t7.21\t7.21\t7.35 – 7.45\t\npCO2 (kPa)\t6.8\t7.2\t6.4\t6.7\t4.7 – 6.0\t\npO2 (kPa)\t8.7\t13.6\t11.8\t8.4\t11.3 – 13.8\t\nHCO3- (mmol/L)\t14\t13\t19\t19\t24 – 31\t\nBase excess (mmol/L)\t- 17\t- 19\t- 9\tND\t- 2 to + 3\t\nO2 saturation (%)\t86\t95\t95\t89\t97 – 98\t\nMeasurements were performed using the ABL 90 FLEX, Radiometer, Copenhagen, Denmark. ND - not determined. pCO2 - partial pressure of CO2. pO2 - partial pressure of O2.\t\n\nTable 2 Core laboratory results of a venous blood sample taken one hour after admission to the hospital\n\nLaboratory test (unit)\tResult\tReference interval\t\nGlucose (mmol/L)\t3.9\t4.1 – 5.9\t\nPotassium (mmol/L)\t2.2\t3.5 – 5.1\t\nAST (U/L)\t179\t< 40\t\nALT (U/L)\t219\t< 41\t\nLD (U/L)\t382\t135 - 225\t\nHigh-sensitive cardiac troponin T (ng/L)\t262\t≤ 13\t\nCreatinine (µmol/L)\t180\t62 – 106\t\neGFR (CKD-EPI) (mL/min/1.73m2)\t38\t90 – 120\t\nEthanol (g/L)\t< 0.1\t< 0.1\t\nInsulin (pmol/L)\t583.4\t17.8 - 173.0\t\nC-peptide (pmol/L)\t4.36\t0.37 - 1.47\t\nMeasurements were performed using the Cobas 6000, Roche Diagnostics, Rotkreuz, Switzerland. ALT - alanine aminotransferase. AST - aspartate aminotransferase. CKD-EPI - Chronic Kidney Disease Epidemiology Collaboration. LD - lactate dehydrogenase.\t\n\nDespite the continuous glucose infusion (a total of 18 g was administered during the first three hours), the emergency medicine physician had difficulties correcting the hypoglycaemia after 130 and 240 minutes. The hypokalaemia also persisted over the next three hours (Table 1). The emergency physician requested a urine toxicology screening (performed using gas chromatography-mass spectrometry, GC-MS) which revealed the presence of tramadol (++++), acetaminophen (+++), lormetazepam (++), citalopram (+), ibuprofen (+) and a trace amount salicylic acid. Serum ethanol and salicylic acid were negative, while the serum acetaminophen concentration was 109.5 mg/L (Table 3). The patient’s home medication included tramadol and lormetazepam.\n\nTable 3 Serum concentrations of drugs in a venous blood sample taken 1 hour after admission to the hospital\n\nLaboratory test (unit)\tResult\tTherapeutic range*\tAnalytical method\t\nAcetaminophen (mg/L)\t109.5\t10 - 25\tRoche Integra 400\t\nSalicylic acid (mg/L)\t< 1.35\t20 - 200\tRoche Integra 400\t\nTramadol (mg/L)\t9.4\t0.1 - 1.0\tUPLC-DAD\t\nO-desmethyltramadol (mg/L)\t1.3\t-\tUPLC-DAD\t\nN-desmethyltramadol (mg/L)\t3.3\t-\tUPLC-DAD\t\nIbuprofen (mg/L)\t15.5\t15 - 30\tUPLC-DAD\t\nCitalopram (mg/L)\tNot detected\t0.05 – 0.11\tUPLC-DAD\t\nLormetazepam (mg/L)\t0.092\t0.005 - 0.025\tLC-MS/MS\t\nSulfonylurea (glipizide, gliclazide, glibenclamide, glimepiride, gliquidone) (mg/L)\tNot detected\t-\tUPLC-DAD\t\n*Therapeutic ranges are based on reference 12. UPLC-DAD - reversed-phase ultra-performance liquid chromatography with diode array detection. LC-MS/MS - liquid chromatography-tandem mass spectrometry.\t\n\nTo exclude hypoglycaemia due to exogenous insulin administration, insulin and C-peptide were measured. Both were significantly increased (Table 2), pointing to increased endogenous production. An abdominal CT scan did, however, not show any evidence for an insulinoma. The hyperinsulinemia could also explain the sudden hypokalaemia via an intracellular shift of potassium. Other possible causes of an acute intracellular shift including alkalosis, increased β2-adrenergic stimulation, chloroquine intoxication, familial hypokalaemia periodic paralysis or thyrotoxic periodic paralysis were ruled out (7).\n\nTramadol and its main metabolites were quantified by reversed-phase ultra-performance liquid chromatography with diode array detection (UPLC-DAD) in a serum sample taken one hour after admission (see Table 3). Also ibuprofen, citalopram, lormetazepam and sulfonylurea were measured quantitatively (Table 3). A second measurement of serum acetaminophen five hours after admission gave a result of 79.0 mg/L, confirming that a peak level had occurred. Alanine aminotransferase (ALT) and AST were only moderately elevated after five hours (231 and 223 U/L) and 20 hours (403 and 388 U/L). After transfer to the intensive care unit, the patient developed a multiple organ dysfunction syndrome. The cTnT-hs increased to 1742 ng/L after six hours and 1127 ng/L after 19 hours. The patient also developed an aspiration pneumonia and acute respiratory distress syndrome. Eight days after admission, the patient had recovered remarkably and could leave the intensive care. The patient later admitted that he intentionally took an overdose. Informed consent was obtained from the patient.\n\nDiscussion\n\nInsulin and C-peptide were both significantly increased in our patient, pointing to increased endogenous production of insulin. When increased endogenous production is observed, the presence of an insulinoma or another tumour producing insulin like substances should be investigated. Furthermore, cortisol or glucagon insufficiency can cause hypoglycaemia. In addition, a relatively large number of drugs can induce hypoglycaemia and intoxication should be excluded. Most of these drugs, but not all, are used to treat diabetes mellitus (8). The probability of intoxication and the hypoglycaemic effect due to these drugs depends on availability to the patient, dose and co-administered drugs, and the time after administration. When these more common causes of hypoglycaemia are excluded, other causes of fasting hypoglycaemia such as inborn errors of metabolism (e.g. glycogen storage disorders, fatty acid oxidation disorders, gluconeogenesis disorders) should be investigated (9).\n\nDrugs can cause hypoglycaemia by stimulating insulin release, reducing insulin clearance or interfering with glucose metabolism (8). Because the liver plays a critical role in glycolysis and gluconeogenesis, hypoglycaemia may develop in patients with hepatic failure due to acute drug-induced liver toxicity (10). Based on the clinical presentation and toxicology results, tramadol was considered the most likely cause of the severe hypoglycaemia. Of the multiple drugs co-ingested by the patient, tramadol and acetaminophen were the only drugs present in toxic serum concentrations. In this case, an acetaminophen intoxication causing the hypoglycaemia is not expected since hypoglycaemia typically only occurs after 72 - 96 hours in stage III due to liver failure when liver enzymes are markedly elevated (AST and ALT typically > 10,000 U/L). The other drugs found by toxicology screening were also ruled out as cause of the severe hypoglycaemia. Intoxication with citalopram causing hypoglycaemia has only been described in combination with ethanol (11). No evidence in the literature supporting lormetazepam or ibuprofen causing profound hypoglycaemia was found. Salicylates have been described to cause hypoglycaemia in case of intoxication (8), but the low urinary concentration does not support this hypothesis.\n\nHypoglycaemia has been described as an unusual side effect of tramadol use occurring within five days after starting tramadol therapy and in a few cases of tramadol poisoning (2-5). Only one (fatal) case of tramadol poisoning presenting with hypoglycaemia and cardiac arrest has previously been reported with a plasma concentration of 5.2 mg/L (5). The tramadol concentration (9.4 mg/L) found in our patient is far above the therapeutic blood concentration (0.1 – 1.0 mg/L) and also exceeds 2.0 mg/L, which is considered lethal (12).\n\nBased on animal studies, two hypotheses have been suggested for the hypoglycaemia associated with tramadol use. The first hypothesis, based on a study with mice, suggests a serotoninergic-mediated mechanism based on the increase of serum insulin and subsequent hypoglycaemia after serotonin administration (13). The second hypothesis based on a study in diabetic rats suggests that tramadol lowers plasma glucose by binding to opioid µ-receptors, thereby increasing turn-over of glucose and/or decreasing gluconeogenesis (14). Our observation of increased serum insulin and C-peptide in a hypoglycaemic patient presenting with tramadol intoxication suggests that hyperinsulinemia due to adverse activation of the beta cells in the pancreas could be the cause of the known association between hypoglycaemia and tramadol. Since multiple drugs were co-ingested, however, a definite causality between tramadol and this hypoglycaemic cannot be proven.\n\nThe patient was prescribed tramadol for pain management. While tramadol is generally preferred for moderate pain in patients with chronic kidney disease (CKD) because it is not directly nephrotoxic, tramadol and its metabolite have been reported to accumulate with advanced CKD (eGFR < 30 mL/min/1.73 m2) (15). The decreased renal function in our patient might therefore have worsened the tramadol intoxication. Tramadol, like other opioids, has a small therapeutic index (12). Accidental tramadol intoxication can therefore occur when patients do not adhere to the prescribed dose.\n\nThe sudden hypokalaemia was caused by a massive intracellular shift of potassium in response to the hyperinsulinemia, triggered by the intravenous administration of glucose. Insulin causes this shift mainly via direct stimulation of the Na+/K+- ATPase. The moderate increase of troponin T one hour after admission and further increase to 1742 ng/L after six hours can be explained by myocardial injury due to CPR and acute cardiac ischemia due to circulatory failure as evidenced by a lactate of 11 mmol/L at arrival in the hospital.\n\nTo our knowledge, we are the first to document a remarkably raised endogenous insulin production in a hypoglycaemic patient presenting with tramadol intoxication by measuring serum insulin and C-peptide, suggesting that hyperinsulinemia could, at least sometimes, be the cause of the known association between hypoglycaemia and tramadol.\n\nConclusion\n\nWhen dealing with an unresponsive hypoglycaemic patient, this rare but potential life-threatening side effect of tramadol should be considered, and until the precise mechanism of this intoxication is clearly established, both insulin and C-peptide should be measured.\n\nAcknowledgments\n\nPV is a senior clinical investigator of the FWO-Vlaanderen.\n\nPotential conflict of interest: None declared.\n==== Refs\nReferences\n\n1 Golightly LK Simendinger BA Barber GR Stolpman NM Kick SD McDermott MT Hypoglycemic effects of tramadol analgesia in hospitalized patients: a case-control study. J Diabetes Metab Disord. 2017;16 :30. 10.1186/s40200-017-0311-9 28748177\n2 Bourne C Gouraud A Daveluy A Grandvuillemin A Auriche P Descotes J Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs. Br J Clin Pharmacol. 2013;75 :1063–7. 10.1111/j.1365-2125.2012.04451.x 22943675\n3 Fournier JP Azoulay L Yin H Montastruc JL Suissa S Tramadol Use and the Risk of Hospitalization for Hypoglycemia in Patients With Noncancer Pain. JAMA Intern Med. 2015;175 :186–93. 10.1001/jamainternmed.2014.6512 25485799\n4 Mugunthan N Davoren P Danger of hypoglycemia due to acute tramadol poisoning. Endocr Pract. 2012;18 :e151–2. 10.4158/EP12070.CR 22982791\n5 De Decker K Cordonnier J Jacobs W Coucke V Schepens P Jorens PG Fatal intoxication due to tramadol alone: Case report and review of the literature. Forensic Sci Int. 2008;175 :79–82. 10.1016/j.forsciint.2007.07.010 17875377\n6 Makunts TUA Atayee RS Abagyan R Retrospective analysis reveals significant association of hypoglycemia with tramadol and methadone in contrast to other opioids. Sci Rep. 2019;9 :12490. 10.1038/s41598-019-48955-y 31462666\n7 Palmer BF Clegg DJ Physiology and Pathophysiology of Potassium Homeostasis: Core Curriculum 2019. Am J Kidney Dis. 2019;74 :682–95. 10.1053/j.ajkd.2019.03.427 31227226\n8 Ben Salem C Fathallah N Hmouda H Bouraoui K Drug-induced hypoglycaemia: an update. Drug Saf. 2011;34 :21–45. 10.2165/11538290-000000000-00000 20942513\n9 Guerrero RB Salazar D Tanpaiboon P Laboratory diagnostic approaches in metabolic disorders. Ann Transl Med. 2018;6 :470. 10.21037/atm.2018.11.05 30740401\n10 Levine M Stellpflug SJ Pizon AF Peak DA Villano J Wiegand T Hypoglycemia and lactic acidosis outperform King’s College criteria for predicting death or transplant in acetaminophen toxic patients. Clin Toxicol (Phila). 2018;56 :622–5. 10.1080/15563650.2017.1420193 29301418\n11 Duncan RA Armstrong PA Paterson B Severe hypoglycaemia in citalopram overdose. Eur J Emerg Med. 2008;15 :234–5. 10.1097/MEJ.0b013e3282f47947 19078823\n12 Schulz M Iwersen-Bergmann S Andresen H Schmoldt A Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit Care. 2012;16 :R136. 10.1186/cc11441 22835221\n13 Yamada J Sugimoto Y Kimura I Takeuchi N Horisaka K Serotonin-induced hypoglycemia and increased serum insulin levels in mice. Life Sci. 1989;45 :1931–6. 10.1016/0024-3205(89)90547-X 2689822\n14 Cheng JT Liu IM Chi TC Tzeng TF Lu FH Chang CJ Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. Diabetes. 2001;50 :2815–21. 10.2337/diabetes.50.12.2815 11723065\n15 Pham PC Khaing K Sievers TM Pham PM Miller JM Pham SV 2017 update on pain management in patients with chronic kidney disease. Clin Kidney J. 2017;10 :688–97. 10.1093/ckj/sfx080 28979781\n\n", "fulltext_license": "CC BY", "issn_linking": "1330-0962", "issue": "30(1)", "journal": "Biochemia medica", "keywords": "hypoglycaemia; insulin; poisoning; tramadol", "medline_ta": "Biochem Med (Zagreb)", "mesh_terms": "D000701:Analgesics, Opioid; D001786:Blood Glucose; D002096:C-Peptide; D005947:Glucose; D006801:Humans; D007003:Hypoglycemia; D007328:Insulin; D008297:Male; D008875:Middle Aged; D010146:Pain; D014147:Tramadol", "nlm_unique_id": "9610305", "other_id": null, "pages": "010802", "pmc": null, "pmid": "31839727", "pubdate": "2020-02-15", "publication_types": "D002363:Case Reports", "references": "20942513;2689822;25485799;22943675;31462666;30740401;22835221;22982791;31227226;11723065;28748177;19078823;28979781;17875377;29301418", "title": "An unconscious man with profound drug-induced hypoglycaemia.", "title_normalized": "an unconscious man with profound drug induced hypoglycaemia" }

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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "020281", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SALICYLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALICYLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEFLUNOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEFLUNOMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperinsulinaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ketonuria", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SCHIEMSKY T, VUNDELINCKX G, CROES K, PENDERS J, DESMET K, PAUWELS S ET AL.. AN UNCONSCIOUS MAN WITH PROFOUND DRUG-INDUCED HYPOGLYCAEMIA.. BIOCHEM MED. 2020?30(1):010802", "literaturereference_normalized": "an unconscious man with profound drug induced hypoglycaemia", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200106", "receivedate": "20200106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17237689, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-232445", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "071214", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LORMETAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORMETAZEPAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL" } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Schiemsky T, Vundelinckx G, Croes K, Penders J, Desmet K, Pauwels S, et al. An unconscious man with profound drug-induced hypoglycaemia. Biochem Med Zagreb. 2020;30(1):010802/1-6", "literaturereference_normalized": "an unconscious man with profound drug induced hypoglycaemia", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20220311", "receivedate": "20200114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17266112, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "BE-BION-008471", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEFLUNOMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEFLUNOMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078682", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMADOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LORMETAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORMETAZEPAM" } ], "patientagegroup": "5", "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "PCO2 increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Troponin T increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pulseless electrical activity", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ketonuria", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyperinsulinaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood lactic acid increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Oxygen saturation decreased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood lactate dehydrogenase increased", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SCHIEMSKY T, VUNDELINCKX G, CROES K, PENDERS J, DESMET K, PAUWELS S, ET AL,. AN UNCONSCIOUS MAN WITH PROFOUND DRUG-INDUCED HYPOGLYCAEMIA. BIOCHEM MED (ZAGREB). 2020 FEB 15? 30 (1): 010802.", "literaturereference_normalized": "an unconscious man with profound drug induced hypoglycaemia", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200104", "receivedate": "20200104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17233470, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "A 53-year-old man with a history of Crohn's disease on infliximab, presented with several weeks of cough and dyspnoea. He had a right-sided pleural effusion, found to be exudative with lymphocytic predominance. He underwent right-sided video-assisted thoracic surgery (VATS) with biopsies and pleurodesis. Histopathology showed pleural-based non-caseating granulomas with unremarkable lung parenchyma. Cultures were only positive for Propionibacterium acnes 8 months later, he was found to have a left-sided exudative, lymphocytic predominant pleural effusion. Left-sided VATS and biopsies again showed pleural-based non-caseating granulomas with normal lung parenchyma. Having ruled out an active infection and malignant lesions, we diagnosed infliximab-induced pleural granulomas. Infliximab was stopped. The patient continues to do well at 6 years of follow-up. We believe this is the first report of tumour necrosis factor (TNF) inhibitor-induced isolated pleural granulomas. P. acnes and cytokine imbalance might be responsible for the pathogenesis of TNF inhibitor-induced granulomas.", "affiliations": "Medical College of Wisconsin, Wauwatosa, Wisconsin, USA.;Medical College of Wisconsin, Wauwatosa, Wisconsin, USA.;Colorado Springs Pulmonary Consultants, Colorado Springs, Colorado, USA.;Aurora St. Luke's Medical Center, Milwaukee, Wisconsin, USA.", "authors": "Ali|Muhammad Sajawal|MS|http://orcid.org/0000-0002-9343-1074;Franco|Rose|R|;Dhotre|Dheeraj|D|;Rao|Nagarjun|N|", "chemical_list": "D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-219883", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "Crohn's disease; Gastrointestinal system; Respiratory medicine", "medline_ta": "BMJ Case Rep", "mesh_terms": "D003371:Cough; D003424:Crohn Disease; D004417:Dyspnea; D005765:Gastrointestinal Agents; D016908:Gram-Positive Bacterial Infections; D006099:Granuloma; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D010996:Pleural Effusion; D018700:Pleurodesis; D011425:Propionibacterium acnes; D020775:Thoracic Surgery, Video-Assisted; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28630242", "pubdate": "2017-06-18", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10524689;12426295;14611117;15286007;15764796;16840744;16884970;16935484;17139647;17373994;17417999;17896899;17985415;18474661;18520114;19147181;19423648;24351617;27607191;27894280;4642731;6377763", "title": "Tumour necrosis factor (TNF) inhibitor-induced isolated pleural granulomas: a rare adverse effect.", "title_normalized": "tumour necrosis factor tnf inhibitor induced isolated pleural granulomas a rare adverse effect" }

[ { "companynumb": "US-JNJFOC-20170702613", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": "5", "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary granuloma", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ALI MS, FRANCO R, DHOTRE D, NAGARJUN R. TUMOUR NECROSIS FACTOR (TNF) INHIBITOR-INDUCED ISOLATED PLEURAL GRANULOMAS: A RARE ADVERSE EFFECT. BMJ CASE REP 2017; : .", "literaturereference_normalized": "tumour necrosis factor tnf inhibitor induced isolated pleural granulomas a rare adverse effect", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170707", "receivedate": "20170707", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13727042, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "We present a case of ioniazid poisoning in a two year old otherwise healthy male. Problems with history and diagnosis characteristical of such cases are discussed along with current views on the pathogenesis and therapy. A suggestion is put forward to help to avoid future similar accidents which--although very rare--are extremely dangerous.", "affiliations": null, "authors": "Walther|J U|JU|", "chemical_list": "D011736:Pyridoxine; D007538:Isoniazid", "country": "Germany", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0026-9298", "issue": "129(7)", "journal": "Monatsschrift Kinderheilkunde : Organ der Deutschen Gesellschaft fur Kinderheilkunde", "keywords": null, "medline_ta": "Monatsschr Kinderheilkd", "mesh_terms": "D006801:Humans; D011695:IgA Vasculitis; D007223:Infant; D007538:Isoniazid; D008297:Male; D011736:Pyridoxine; D006435:Renal Dialysis; D012640:Seizures", "nlm_unique_id": "8206462", "other_id": null, "pages": "418-9", "pmc": null, "pmid": "6115311", "pubdate": "1981-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Acute isoniazid poisoning in a young child (author's transl).", "title_normalized": "acute isoniazid poisoning in a young child author s transl" }

[ { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-01401", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "202610", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Walther J.. Acute isoniazid poisoning in a young child (author^s transl). Monatsschr Kinderheilkd. 1981;7:418-9", "literaturereference_normalized": "acute isoniazid poisoning in a young child author s transl", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211213", "receivedate": "20211213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20174487, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "Vancomycin-induced thrombocytopenia has only been reported once previously in the medical literature. We describe a patient in whom sudden severe reversible thrombocytopenia developed on two separate occasions after exposure to vancomycin hydrochloride. A 54-year-old man was admitted to the hospital for bilateral swelling and erythema of his extremities. At the time of admission he received 2 days of vancomycin therapy without incident. On day 14 he was reexposed to vancomycin and thrombocytopenia developed, with a nadir value of 17 x 10(9)/L. On day 30, a single dose of vancomycin was administered, and thrombocytopenia once again developed, with a nadir value of 11 x 10(9)/L. Hematologic cytopenias are infrequent adverse effects of vancomycin therapy. It is postulated that these effects may be due to an immunologically mediated mechanism. With the increasing use of vancomycin due to the emergence of methicillin-resistant Staphylococcus aureus, this case should alert clinicians to this rare but potentially lethal manifestation of vancomycin.", "affiliations": "University of Houston College of Pharmacy, TX.", "authors": "Zenon|G J|GJ|;Cadle|R M|RM|;Hamill|R J|RJ|", "chemical_list": "D014640:Vancomycin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0003-9926", "issue": "151(5)", "journal": "Archives of internal medicine", "keywords": null, "medline_ta": "Arch Intern Med", "mesh_terms": "D006801:Humans; D008297:Male; D008875:Middle Aged; D013921:Thrombocytopenia; D014640:Vancomycin", "nlm_unique_id": "0372440", "other_id": null, "pages": "995-6", "pmc": null, "pmid": "2025149", "pubdate": "1991-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Vancomycin-induced thrombocytopenia.", "title_normalized": "vancomycin induced thrombocytopenia" }

[ { "companynumb": "US-IGSA-SR10009903", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "125046", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "2000 MG/KG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "THROMBOCYTOPENIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2000", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HUMAN NORMAL IMMUNOGLOBULIN (IV)" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemolysis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NISHA ELIZABETH AJIT, SINDHU PRIYA DEVARASHETT, SAMIP MASTER. VANCOMYCIN INDUCED THROMBOCYTOPENIA ? PROTRACTED COURSE IN A HEMODIALYSIS PATIENT. CASE REPORTS IN ONCOLOGY. 2019?12:749?754", "literaturereference_normalized": "vancomycin induced thrombocytopenia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200221", "receivedate": "20200221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17446918, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-PENTEC HEALTH-2019PEN00061", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "000000", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PYREXIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOSYN" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Melaena", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ecchymosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemolysis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epistaxis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AJIT NE, DEVARASHETTY SP, MASTER S. VANCOMYCIN INDUCED THROMBOCYTOPENIA ? PROTRACTED COURSE IN A HEMODIALYSIS PATIENT. CASE REP ONCOL. 2019?749-754", "literaturereference_normalized": "vancomycin induced thrombocytopenia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191101", "receivedate": "20191101", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16985360, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-PFIZER INC-2021393190", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "079183", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Powder for injection", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Pancreatic carcinoma metastatic", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE HYDROCHLORIDE" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Staphylococcal sepsis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Govindarajan, R.. Vancomycin-induced thrombocytopenia. American Journal of Hematology. 1999;62(2):122-123", "literaturereference_normalized": "vancomycin induced thrombocytopenia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211118", "receivedate": "20210421", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19164783, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "Cardiomyopathy is a frequent complication in propionic acidemia. It is mostly rapidly fatal and independent of the metabolic control or medical intervention. Here, we present the reversal of a severe cardiomyopathy after liver transplantation in a patient with propionic acidemia and the long-term stability after ten years. Liver transplantation in patients with propionic acidemia may be considered a valid and long-lasting treatment when cardiomyopathy is progressive and unresponsive to medical therapy.", "affiliations": "Department of Paediatrics, Inselspital, University Hospital Bern, Bern, Switzerland.;Clinic of Visceral Surgery and Medicine, Hepatology, Inselspital, University Hospital Bern, Bern, Switzerland.;MD Internal Medicine and Cardiology, Massagno, Switzerland.;Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, Switzerland.;Department of Paediatrics, Inselspital, University Hospital Bern, Bern, Switzerland.;Department of Paediatrics, Inselspital, University Hospital Bern, Bern, Switzerland.", "authors": "Arrizza|Chiara|C|;De Gottardi|Andrea|A|http://orcid.org/0000-0002-4401-2340;Foglia|Ezio|E|;Baumgartner|Matthias|M|;Gautschi|Matthias|M|;Nuoffer|Jean-Marc|JM|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/tri.12677", "fulltext": null, "fulltext_license": null, "issn_linking": "0934-0874", "issue": "28(12)", "journal": "Transplant international : official journal of the European Society for Organ Transplantation", "keywords": "cardiomyopathy; metabolic decompensation; orthotopic liver transplantation; propionic acidemia", "medline_ta": "Transpl Int", "mesh_terms": "D000328:Adult; D009202:Cardiomyopathies; D005500:Follow-Up Studies; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D056693:Propionic Acidemia; D016896:Treatment Outcome; D016277:Ventricular Function, Left", "nlm_unique_id": "8908516", "other_id": null, "pages": "1447-50", "pmc": null, "pmid": "26358860", "pubdate": "2015-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Reversal of cardiomyopathy in propionic acidemia after liver transplantation: a 10-year follow-up.", "title_normalized": "reversal of cardiomyopathy in propionic acidemia after liver transplantation a 10 year follow up" }

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REVERSAL OF CARDIOMYOPATHY IN PROPIONIC ACIDEMIA AFTER LIVER TRANSPLANTATION A 10 YEAR FOLLOW UP.. TRANSPLANT INTERNATIONAL. 2015?28:1447-50", "literaturereference_normalized": "reversal of cardiomyopathy in propionic acidemia after liver transplantation a 10 year follow up", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20160329", "receivedate": "20160329", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12219258, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "CH-VALIDUS PHARMACEUTICALS LLC-CH-2016VAL000700", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTOLIC DYSFUNCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "METOPROLOL TARTRATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "017963", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTOLIC DYSFUNCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL TARTRATE." }, { "actiondrug": "4", "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARNITINA /00718101/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TORSEMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTOLIC DYSFUNCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TORASEMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": null, 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null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTOLIC DYSFUNCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENALAPRIL" }, { "actiondrug": "5", "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACENOCOUMAROL" } ], "patientagegroup": null, "patientonsetage": "18", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mitral valve incompetence", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Congestive cardiomyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pulmonary hypertension", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NUOFFER J, ARRIZZA C, GOTTARDI AD, FOGLIA E, BAUMGARTNER M, GAUTSCHI M. REVERSAL OF CARDIOMYOPATHY IN PROPIONIC ACIDEMIA AFTER LIVER TRANSPLANTATION A 10 YEAR FOLLOW UP.. TRANSPLANT INTERNATIONAL. 2015;28:1447-50", "literaturereference_normalized": "reversal of cardiomyopathy in propionic acidemia after liver transplantation a 10 year follow up", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20160405", "receivedate": "20160405", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12239061, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "BACKGROUND\nEsomeprazole, the pure S isomer form of omeprazole, is indicated for the treatment of peptic esophagitis. We report here a major episode of cytolytic hepatitis following a single administration.\n\n\nMETHODS\nA 41-year-old woman with infiltrating ductal carcinoma of the breast was undergoing chemotherapy with paclitaxel and trastuzumab. On the fourth day of the second course, she took 1 tablet of esomeprazole 20 mg for epigastric pain. Liver pain and asthenia followed, and liver function tests showed substantial cytolysis. These tests returned to normal levels despite continuation of the chemotherapy.\n\n\nCONCLUSIONS\nThis cytolytic hepatitis is very probably imputable to esomeprazole, but a synergistic hepatic toxicity of the chemotherapy with esomeprazole cannot be ruled out.", "affiliations": "Centre Paul Papin, Angers.", "authors": "Capitain|O|O|;Lortholary|A|A|;Abadie-Lacourtoisie|S|S|", "chemical_list": "D000897:Anti-Ulcer Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D064098:Esomeprazole; D000068878:Trastuzumab; D017239:Paclitaxel", "country": "France", "delete": false, "doi": "10.1016/s0755-4982(05)84163-6", "fulltext": null, "fulltext_license": null, "issn_linking": "0755-4982", "issue": "34(17)", "journal": "Presse medicale (Paris, France : 1983)", "keywords": null, "medline_ta": "Presse Med", "mesh_terms": "D000328:Adult; D000897:Anti-Ulcer Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D056486:Chemical and Drug Induced Liver Injury; D064098:Esomeprazole; D004941:Esophagitis; D005260:Female; D006801:Humans; D017239:Paclitaxel; D000068878:Trastuzumab", "nlm_unique_id": "8302490", "other_id": null, "pages": "1235-6", "pmc": null, "pmid": "16230965", "pubdate": "2005-10-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cytolytic hepatitis and esomeprazole during chemotherapy.", "title_normalized": "cytolytic hepatitis and esomeprazole during chemotherapy" }

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{ "abstract": "Hypertrophic obstructive cardiomyopathy (HOCM) increases the risk for mother and fetus during pregnancy. Alcohol septal ablation (ASA) is an established procedure in nonpregnant patients with HOCM. In this report, we present a case of a 29-year-old woman in her 29th gestational week with decompensated HOCM undergoing a successful ASA. (Level of Difficulty: Advanced.).", "affiliations": "Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.;Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.;Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.;Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.;Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.;Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.;Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.;Department of Obstetrics and Gynecology, Heidelberg University Hospital, Heidelberg, Germany.;Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.;Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany.", "authors": "Gi|Weng-Tein|WT|;Amr|Ali|A|;Sedaghat-Hamedani|Farbod|F|;Kayvanpour|Elham|E|;Mohr|Isabell|I|;Meder|Manuela|M|;Shirvani Samani|Omid|O|;Fluhr|Herbert|H|;Katus|Hugo A|HA|;Meder|Benjamin|B|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jaccas.2019.11.053", "fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(19)30596-0\n10.1016/j.jaccas.2019.11.053\nPeripartum Cardiovascular Disease Mini-Focus Issue\nCase Report: Clinical Case\nTwo Hearts at Risk\nEmergency Alcohol Septal Ablation in a Pregnant Woman With Decompensated HOCM\nGi Weng-Tein MD, MSc ab\nAmr Ali MD ab\nSedaghat-Hamedani Farbod MD ab\nKayvanpour Elham MD ab\nMohr Isabell BSc a\nMeder Manuela MD a\nShirvani Samani Omid MD ab\nFluhr Herbert MD c\nKatus Hugo A. MD ab\nMeder Benjamin MD Benjamin.Meder@med.uni-heidelberg.de\nabd∗\na Institute for Cardiomyopathy, Department of Medicine III, University of Heidelberg, Heidelberg, Germany\nb DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany\nc Department of Obstetrics and Gynecology, Heidelberg University Hospital, Heidelberg, Germany\nd Department of Genetics, Stanford University, Stanford, California\n∗ Address for correspondence: Dr. Benjamin Meder, Department of Medicine III, University of Heidelberg, INF 410, 69120 Heidelberg, Germany. Benjamin.Meder@med.uni-heidelberg.de\n15 1 2020\n1 2020\n15 1 2020\n2 1 139144\n15 10 2019\n25 11 2019\n25 11 2019\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHypertrophic obstructive cardiomyopathy (HOCM) increases the risk for mother and fetus during pregnancy. Alcohol septal ablation (ASA) is an established procedure in nonpregnant patients with HOCM. In this report, we present a case of a 29-year-old woman in her 29th gestational week with decompensated HOCM undergoing a successful ASA. (Level of Difficulty: Advanced.)\n\nGraphical abstract\n\nHypertrophic obstructive cardiomyopathy (HOCM) increases the risk for mother and fetus during pregnancy…\n\nKey Words\n\nalcohol septal ablation\ndecompensation\nhypertrophic obstructive cardiomyopathy\npregnancy\nAbbreviations and Acronyms\n\nASA, alcohol septal ablation / transcoronary ablation of septal hypertrophy\nHCM, hypertrophic cardiomyopathy\nHOCM, hypertrophic obstructive cardiomyopathy\nIVS, interventricular septum\nLV, left ventricle\nLVOT, left ventricular outflow tract\nLVOTO, left ventricular outflow tract obstruction\nSAM, systolic anterior motion\n==== Body\nHistory of Presentation\n\nA 29-year-old pregnant patient in her 29th week of gestation was referred to the intermediate care unit of our gynecology university clinic due to shortness of breath. She reported severe dyspnea after minimal exertion (New York Heart Association functional class III) and was hypotensive with a blood pressure of 95/60 mm Hg. Her heart rate was 100 beats/min. She had no chest pain, abdominal pain, or signs of infection. Her physical examination revealed a 3/6 mid-systolic murmur over the lower left sternal border and fine crackles over both lower lungs. She also exhibited mild pretibial pitting edema.Learning Objectives\n\n• ASA can be safely performed in pregnant patients with HOCM to achieve rapid improvement of hemodynamics and functional class if conservative treatment fails.\n\n• H(O)CM increases the risk for mother and child during pregnancy.\n\n• During the prenatal consultation, proactive invasive gradient reduction strategies before planned pregnancies should be considered in high-risk patients with HOCM.\n\nMedical History\n\nThe patient had a known, mostly asymptomatic hypertrophic obstructive cardiomyopathy (HOCM). She received an implantable cardiac defibrillator as primary prophylaxis 7 years ago and had previously given birth to 1 daughter without complications. The last echocardiogram before pregnancy showed a mild left ventricular outflow tract (LVOT) obstruction with an interventricular septum (IVS) thickness of 38 mm and a gradient of 36 mm Hg, both at rest and after Valsalva maneuver. During her early pregnancy, no echocardiograms were performed, nor was she admitted to a specialized center for observation. At 24 weeks of gestation, her yearly echocardiogram was performed, which demonstrated an increased LVOT obstruction (LVOTO) with a gradient of 58 mm Hg at rest and a gradient of 108 mm Hg after Valsalva maneuver. Four weeks later, the patient developed pronounced symptoms and had a maximal LVOT gradient of 121 mm Hg. Hence, she was promptly referred to our hospital.\n\nDifferential Diagnosis\n\nThe differential diagnosis included acute pulmonary embolism, acute pulmonary edema, or decompensated HOCM.\n\nInvestigation\n\nA 12-lead electrocardiogram revealed tall R waves in leads I and aVL as well as deep S waves in leads V2 and V3, suggesting hypertrophy of the left ventricle (LV). There were also T-wave inversions in leads II, III, aVF, and V6. Her echocardiogram showed an increased LVOT gradient of 65 mm Hg at rest, accompanied by an obvious systolic anterior motion of the mitral valve (SAM), which led to severe mitral regurgitation. The basal IVS was noticeably hypertrophied with a thickness of 38 mm. Her blood tests revealed markedly elevated N-terminal pro–B-type natriuretic peptide (3,965 ng/l) in the plasma. Based on these findings, the patient was diagnosed with acutely decompensated HOCM.\n\nManagement\n\nThe patient received steroid therapy to accelerate fetal lung maturation. After our cardiomyopathy team was informed and the patient was seen at bedside, the therapy with Metoprolol succinate was up-titrated to 237.5 mg/day (95 mg [morning], 47.5 mg [noon], 95 mg [evening]). We carefully evaluated the use of diuretics and decided against it, because the patient was hypotensive and tachycardiac, indicating imminent cardiogenic shock (shock index >1.1) and she had a very narrow LV cavity with severe outflow tract obstruction. In such cases, diuretics and other afterload-changing drugs could result in increased gradients and hemodynamic instability. Instead of using diuretics, the patient’s fluid intake and spontaneous diuresis were carefully balanced. Two echocardiographies were performed daily to monitor her LVOT gradient and vena cava inferior filling. Despite the ongoing therapy, her symptoms worsened rapidly. On the next day after admission, the patient developed orthopnea due to severe pulmonary edema, and required 8 liters of oxygen per minute to maintain an adequate oxygenation. Tachycardia and hypotension persisted. The edema in her lower extremities worsened. Her N-terminal pro–B-type natriuretic peptide surged to 8,748 ng/l. Furthermore, sonography showed a delayed intrauterine growth development of the fetus. Thus, an emergent cesarean delivery was considered by the gynecologists. To determine the ultimate management of the patient, the Institute for Cardiomyopathies Heidelberg organized an ad hoc interdisciplinary team discussion. After a comprehensive discussion among interventional cardiologists, gynecologists, anesthesiologists, and neonatologists, we decided to perform an urgent alcohol septal ablation (ASA). This was based on the fact that the conservative treatment was ineffective, our center has a high level of expertise in the ASA procedure with no cases of intrahospital death or anterior wall infarction, and an emergent cesarean delivery with (general) anesthesia could have resulted in hemodynamic instability. In addition, the patient was protected against heart block by her implantable cardiac defibrillator. The patient and her family were thoroughly informed about the ASA procedure and about the fact that to that date no published cases or recommendations concerning her medical situation existed. The family agreed to the procedure.\n\nThe ASA procedure was performed in a hybrid catheter laboratory, which was fully equipped in case of an emergency cesarean delivery. Aside from the cardiologists and catheter technicians, the treating gynecologist, an obstetrician, a neonatologist nurse, and an anesthesiologist were at the scene during the procedure. Not only the mother’s but also the fetus’s vital signs were continuously monitored. Before septal ablation, we hemodynamically measured the LVOT gradient by placing a pigtail catheter in the LV cavity (Figure 1) and performed a coronary angiogram to judge the anatomic suitability for ASA (Figure 2A). The total dosage of radiation during the complete procedure was only 0.75 mGy with the additional protection of the fetus by optimal radiation shielding. After selective occlusion of the first septal branch with an over-the-wire balloon (2-mm diameter, 6 psi occlusion pressure) (Figure 2B), we tested for retrograde leakage by applying contrast agent via the balloon’s lumen (Figure 2C) and verified the targeted region by selective contrast echocardiography with 1 ml Sonovue contrast agent also given via the balloon lumen. As seen in Figure 3B, the contrasted region corresponded to the basal septum, which we aimed to ablate. Based on the contrasted target region, we planned to use 2.5 ml of 99% medical alcohol (0.1 ml/mm myocardium). Then, under continuous monitoring of cardiac electrical conduction and hemodynamics, we slowly injected the alcohol over 5 min via the lumen of the balloon. The patient received opioids at a tolerable dose to treat her angina pectoris and to slightly sedate the fetus. The fetus was constantly monitored by cardiotocography throughout the whole procedure, showing no signs of accelerations or decelerations and the peri-interventional sonographic examination of the fetus showed unremarkable findings.Figure 1 Electrocardiogram and Hemodynamic Monitoring During ASA\n\n(A) Real-time electrocardiogram monitoring showing ventricular extra beats induced by the insertion of the pigtail catheter into the left ventricle. (B) Simultaneous monitoring of left ventricular pressure (red line) and aortic pressure (blue line) during catheterization. Induced premature ventricular contractions worsened the LVOT obstruction with a maximal gradient of 93 mm Hg (Brockenbrough-Braunwald-Morrow sign). ASA = alcohol septal ablation; LVOT = left ventricular outflow tract.\n\nFigure 2 Angiogram Before and During ASA\n\n(A) Angiogram showing the baseline anatomy of the left coronary arteries with the large first septal perforator branch (white arrow). (B) Angiogram demonstrating the inflated balloon in the septal branch resulting in shielding from antegrade blood flow. (C) To confirm the balloon position and guarantee the absence of retrograde leakage, contrast agent was injected into the first perforator branch via the lumen of the inflated over-the-wire balloon catheter. Abbreviation as in Figure 1.\n\nFigure 3 Echocardiogram Before and During ASA\n\n(A) A baseline 4-chamber view in transthoracic echocardiography. (B) Before the injection of alcohol, the perfusion area of the selected septal perforator was assessed in a contrast echocardiogram. The contrasted area of the basal interventricular septum (white arrow) suggested an optimal target for alcohol ablation. Importantly, no other region such as the free RV wall was contrasted, which could be due to collaterals. Suboptimal recordings have been tolerated in the severely dyspneic women. RV = right ventricle; other abbreviation as in Figure 1.\n\nOne hour after the procedure, the patient’s dyspnea improved considerably and the oxygen insufflation was reduced to 2 l/min. In her echocardiogram on the next day, the LVOT gradient had decreased from 65 mm Hg to 16 mm Hg, and only minor SAM of the mitral valve and trace mitral regurgitation could be seen (Figure 4). Pericardial effusion or a ventricular septum perforation were excluded. The patient’s 12-lead electrocardiogram presented a new complete right bundle branch block, but no atrioventricular blockage. The patient was mobilized the next day, and was transferred to the normal ward 2 days later without any limiting dyspnea (New York Heart Association functional class I). Six days after the ASA procedure, the patient was discharged home.Figure 4 Reduction of LVOT Gradient After ASA\n\n(A) Before ASA, transthoracic echocardiogram demonstrating an increased LVOT gradient of 67 mm Hg at rest, and (B) a hypertrophied left ventricle with SAM of the mitral valve resulting in severe mitral regurgitation. Arrows indicate the typical “split sign.” (C) After ASA, the LVOT gradient has decreased to almost physiological values (16 mm Hg), and (D) the previously observed SAM of the mitral valve and mitral regurgitation have regressed. SAM = systolic anterior motion; TASH = transcoronary ablation of septal hypertrophy; other abbreviations as in Figure 1.\n\nDiscussion\n\nThe number of child-bearing women diagnosed with HCM is growing, due to the use of cardiac investigations and screening in HCM families. Pregnancy in women with H(O)CM bears higher risk, both for the women and for the fetuses, as there is a 40% increase of volume load and a rise of heart rate during pregnancy (1). A systematic review of 237 women and 408 pregnancies from 9 cohorts reported that the maternal mortality in pregnant patients with HCM remains low at 0.5%. However, 29% of patients developed worsening of symptoms during pregnancy, and 26% of patients had to undergo premature delivery (2). Sadly, cases of fetal death were reported (3).\n\nDue to a thickened IVS, 37% of patients with HCM develop LVOTO at rest, defined by LVOT gradient ≥50 mm Hg (4). LVOTO with an associated mitral regurgitation is a pathological hallmark of HOCM, and an independent predictor of adverse events, including progressive heart failure and SCD (4). According to the current recommendations, there are only a few options available for pregnant patients with symptomatic HOCM (5). In most cases, the use of β-blockers is recommended, preferably metoprolol. Second-line drugs include disopyramide, verapamil, diltiazem, and amiodaron, which are all linked to possible adverse effects on the fetus, such as maternal uterine contractions, delayed fetal development, neurologic adverse effects, and thyroid toxicity.\n\nASA is an established catheter-based intervention in nonpregnant patients. It especially benefits high-risk patients, who have relevant LVOTO but are contraindicated to surgical myectomy due to the risks of general anesthesia. During ASA, alcohol is injected into a suitable (often the first) septal perforator branch of the left anterior descending artery, aiming to induce a regional myocardial infarction and consecutive scaring of the IVS. It was reported that up to 92% of patients showed an immediate reduction of LVOT gradient >50% after ASA when using intraprocedural contrast-echocardiographic monitoring, which is a standard method nowadays; 94% of the patients described improved symptoms within 3 months after ASA (6). These results are comparable to the outcomes of surgical myectomy (7).\n\nTo our knowledge, the present case is the first uncomplicated ASA performed as a rescue intervention in a pregnant woman with decompensated HOCM. Aside from our present case, there was only one other report that was published after performing this procedure in a pregnant patient, who had post-procedural complications (8). Notably, the patient in the present case had an LV septal thickness of 38 mm before ASA, in comparison with the patient in the other reported case with an LV septal thickness of 20 mm. Furthermore, the patient in the present case had received an implantable defibrillator 7 years before this event and hence we did not fear the consequences of a higher degree AV blockage, which is the major complication in up to 10% of patients with ASA.\n\nDuring follow-up examinations, the patient remained asymptomatic. Due to the slight growth delay of the fetus shown by the sonography before the ASA procedure, the gynecologists and the patient decided on a cesarean delivery in analgosedation at 34 weeks of gestation. The cesarean delivery was performed without complications and the patient gave birth to a healthy infant weighing 1,990 g. Three days later, the patient was discharged. Before her discharge, long-term birth control with effective contraception was discussed to avoid unplanned pregnancy. At the 3-month follow-up examination, the LVOT gradient in the echocardiogram was <10 mm Hg, and the basal IVS thickness was reduced from 38 mm to 30 mm.\n\nConclusions\n\nThe current case presents the possibility of safely performing ASA on high-risk pregnant patients, when conservative therapy is ineffective. The results of this case suggest that proactive invasive gradient reduction strategies before planned pregnancies in selected high-risk patients with HOCM could be an effective means to reduce the hazard of LVOTO deterioration during pregnancy. This option should be discussed during patient consultations.\n\nAll authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nInformed consent was obtained for this case.\n==== Refs\nReferences\n\n1 Krul S.P. van der Smagt J.J. van den Berg M.P. Sollie K.M. Pieper P.G. van Spaendonck-Zwarts K.Y. Systematic review of pregnancy in women with inherited cardiomyopathies Eur J Heart Fail 13 2011 584 594 21482599\n2 Schinkel A.F. Pregnancy in women with hypertrophic cardiomyopathy Cardiol Rev 22 2014 217 222 25093741\n3 Goland S. van Hagen I.M. Elbaz-Greener G. Pregnancy in women with hypertrophic cardiomyopathy: data from the European Society of Cardiology initiated Registry of Pregnancy and Cardiac disease (ROPAC) Eur Heart J 38 2017 2683 2690 28934836\n4 Maron M.S. Olivotto I. Zenovich A.G. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction Circulation 114 2006 2232 2239 17088454\n5 Authors/Task Force membersElliott P.M. Anastasakis A. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC) Eur Heart J 35 2014 2733 2779 25173338\n6 Faber L. Seggewiss H. Gleichmann U. Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: results with respect to intraprocedural myocardial contrast echocardiography Circulation 98 1998 2415 2421 9832486\n7 Alam M. Dokainish H. Lakkis N.M. Hypertrophic obstructive cardiomyopathy-alcohol septal ablation vs. myectomy: a meta-analysis Eur Heart J 30 2009 1080 1087 19233857\n8 Shaikh A. Bajwa T. Bush M. Tajik A.J. Successful alcohol septal ablation in a pregnant patient with symptomatic hypertrophic obstructive cardiomyopathy J Cardiol Cases 17 2018 151 154 30279879\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2666-0849", "issue": "2(1)", "journal": "JACC. Case reports", "keywords": "ASA, alcohol septal ablation / transcoronary ablation of septal hypertrophy; HCM, hypertrophic cardiomyopathy; HOCM, hypertrophic obstructive cardiomyopathy; IVS, interventricular septum; LV, left ventricle; LVOT, left ventricular outflow tract; LVOTO, left ventricular outflow tract obstruction; SAM, systolic anterior motion; alcohol septal ablation; decompensation; hypertrophic obstructive cardiomyopathy; pregnancy", "medline_ta": "JACC Case Rep", "mesh_terms": null, "nlm_unique_id": "101757292", "other_id": null, "pages": "139-144", "pmc": null, "pmid": "34316982", "pubdate": "2020-01", "publication_types": "D002363:Case Reports", "references": "17088454;21482599;19233857;9832486;25173338;28934836;25093741;30279879", "title": "Two Hearts at Risk: Emergency Alcohol Septal Ablation in a Pregnant Woman With Decompensated HOCM.", "title_normalized": "two hearts at risk emergency alcohol septal ablation in a pregnant woman with decompensated hocm" }

[ { "companynumb": "DE-TOPROL ACQUISITION LLC-2020-TOP-000179", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL SUCCINATE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "95 MG [MORNING], 47.5 MG [NOON], 95 MG [EVENING])", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL SUCCINATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANGINA PECTORIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OPIOID ANESTHETICS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL THERAPY TO ENHANCE FOETAL LUNG MATURITY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROID NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OPIOID ANESTHETICS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": "1", "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal growth restriction", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MEDER B, GI W-T, AMR A, SEDAGHAT-HAMEDANI F, KAYVANPOUR E, MOHR I.. TWO HEARTS AT RISK: EMERGENCY ALCOHOL SEPTAL ABLATION IN A PREGNANT WOMAN WITH DECOMPENSATED HOCM. JACC: CASE REPORTS. 2020?2(1):139-144", "literaturereference_normalized": "two hearts at risk emergency alcohol septal ablation in a pregnant woman with decompensated hocm", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200228", "receivedate": "20200228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17483716, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]

{ "abstract": "Our goal was to describe the management of pregestational diabetes in pregnant women in the United Kingdom.\n\n\n\nWe used electronic medical records from The Health Improvement Network database between January 1995 and June 2012 to identify the first pregnancy in women 15 to 45 years of age with pregestational diabetes type 1 or type 2. Information on lifestyle factors, demographic characteristics, prescription of specific antidiabetic medications, and glycemic control measures (HbA1c) was obtained from primary care provider records. We evaluated treatment patterns and HbA1c levels within 90 days before the last menstrual period (prepregnancy period) and within each trimester of pregnancy.\n\n\n\nIn a cohort of 1511 pregnant women with pregestational diabetes, 60% had type 1 and 40% type 2 diabetes. Among women with type 1 diabetes, 90% received antidiabetic medication (primarily insulin) prepregnancy and 92% during the first trimester. Among women with type 2 diabetes, 54% received antidiabetic medication (primarily metformin) during the prepregnancy period and 60% during the first trimester. Among women with nontreated diabetes type 2 before pregnancy, 22% initiated treatment by the first trimester (primarily insulin); those on noninsulin antidiabetic medications often switched to insulin. The proportion of women with at least 1 HbA1c value recorded within the prepregnancy period was 33% for type 1 (n = 299) and 31% for type 2 diabetes (n = 189); the corresponding proportions within the first trimester were 48% and 40%, respectively. Among women with recorded HbA1c, the prevalence of HbA1c > 7% prepregnancy was 70% for type 1 and 52% for type 2 diabetes; the proportions within the first trimester were 73% and 46%, respectively.\n\n\n\nManagement of pregnant women with diabetes seems to follow recommendations for pharmacological treatment. However, there is substantial room for improvement in HbA1c control, that is, in the planning of pregnancy in women with diabetes, in the initiation of antidiabetic medication among women with diabetes type 2 who may need it, and likely in the compliance with treatments in women with type 2 and type 1 diabetes.", "affiliations": "Department of Public Health and Maternal and Child Health, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain.;Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, Spain.;Global Epidemiology, Boehringer Ingelheim Pharmacuticals, Inc, Ridgefield, CT, USA.;Corp. Dept. Global Epidemiology, Boehringer Ingelheim GmbH, Ingelheim, Germany.;Corp. Dept. Global Epidemiology, Boehringer Ingelheim GmbH, Ingelheim, Germany.;Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.", "authors": "Cea-Soriano|Lucia|L|0000-0002-7051-0730;García-Rodríguez|Luis A|LA|;Brodovicz|Kimberly G|KG|0000-0001-8275-1649;Masso-Gonzalez|Elvira|E|;Bartels|Dorothee B|DB|;Hernández-Díaz|Sonia|S|", "chemical_list": "D001786:Blood Glucose; D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; D007328:Insulin", "country": "England", "delete": false, "doi": "10.1002/pds.4553", "fulltext": null, "fulltext_license": null, "issn_linking": "1053-8569", "issue": "27(8)", "journal": "Pharmacoepidemiology and drug safety", "keywords": "THIN; antidiabetic medications; pharmacoepidemiology; pregestational diabetes; pregnancy; treatment patterns", "medline_ta": "Pharmacoepidemiol Drug Saf", "mesh_terms": "D000293:Adolescent; D000328:Adult; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1; D003924:Diabetes Mellitus, Type 2; D057286:Electronic Health Records; D005260:Female; D006442:Glycated Hemoglobin A; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First; D011446:Prospective Studies; D012016:Reference Values; D016896:Treatment Outcome; D006113:United Kingdom; D055815:Young Adult", "nlm_unique_id": "9208369", "other_id": null, "pages": "940-948", "pmc": null, "pmid": "29740916", "pubdate": "2018-08", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Real world management of pregestational diabetes not achieving glycemic control for many patients in the UK.", "title_normalized": "real world management of pregestational diabetes not achieving glycemic control for many patients in the uk" }

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AL.. REAL WORLD MANAGEMENT OF PREGESTATIONAL DIABETES NOT ACHIEVING GLYCEMIC CONTROL FOR MANY PATIENTS IN THE UK. 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PHARMACOEPIDEMIOL DRUG SAF. 1?9", "literaturereference_normalized": "real world management of pregestational diabetes not achieving glycemic control for many patients in the uk", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15728236, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "ES-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-03611", "fulfillexpeditecriteria": "2", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CEA-SORIANO L, GARCIA-RODRIGUEZ LA, BRODOVICZ LG, GONZALEZ-MASSO E, ET. AL.. REAL WORLD MANAGEMENT OF PREGESTATIONAL DIABETES NOT ACHIEVING GLYCEMIC CONTROL FOR MANY PATIENTS IN THE UK. PHARMACOEPIDEMIOL DRUG SAF.. 2018", "literaturereference_normalized": "real world management of pregestational diabetes not achieving glycemic control for many patients in the uk", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15728239, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "ES-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-03608", "fulfillexpeditecriteria": "2", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CEA?SORIANO L, GARCIA?RODRIGUEZ LA, BRODOVICZ KG, GONZALEZ?MASSO E ET. AL.. REAL WORLD MANAGEMENT OF PREGESTATIONAL DIABETES NOT ACHIEVING GLYCEMIC CONTROL FOR MANY PATIENTS IN THE UK. PHARMACOEPIDEMIOL DRUG SAF.. 2018?1?9", "literaturereference_normalized": "real world management of pregestational diabetes not achieving glycemic control for many patients in the uk", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15728242, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "ES-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-03549", "fulfillexpeditecriteria": "2", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 1 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 1 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CEA?SORIANO L, GARCIA?RODRIGUEZ LA, BRODOVICZ KG, GONZALEZ?MASSO E ET. AL.. REAL WORLD MANAGEMENT OF PREGESTATIONAL DIABETES NOT ACHIEVING GLYCEMIC CONTROL FOR MANY PATIENTS IN THE UK. 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AL.. REAL WORLD MANAGEMENT OF PREGESTATIONAL DIABETES NOT ACHIEVING GLYCEMIC CONTROL FOR MANY PATIENTS IN THE UK. PHARMACOEPIDEMIOL DRUG SAF.. 2018?1?9", "literaturereference_normalized": "real world management of pregestational diabetes not achieving glycemic control for many patients in the uk", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15728241, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "ES-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-03610", "fulfillexpeditecriteria": "2", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091184", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CEA?SORIANO L, GARCIA?RODRIGUEZ LA, BRODOVICZ KG, GONZALEZ?MASSO E ET. AL.. REAL WORLD MANAGEMENT OF PREGESTATIONAL DIABETES NOT ACHIEVING GLYCEMIC CONTROL FOR MANY PATIENTS IN THE UK. PHARMACOEPIDEMIOL DRUG SAF.. 2018?1?9", "literaturereference_normalized": "real world management of pregestational diabetes not achieving glycemic control for many patients in the uk", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20181217", "receivedate": "20181217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15728243, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "Convulsive status epilepticus is a medical emergency. Prompt treatment has been shown to decrease progression to refractory convulsive status epilepticus. We aimed to reduce time to second-line anti-seizure medication through implementation of a standardized treatment protocol.\n\n\n\nQuality improvement project. We constructed a multidisciplinary team and completed Plan-Do-Study-Act cycles to achieve the project aim.\n\n\n\nA tertiary care children's hospital.\n\n\n\nPatients presenting to the Children's Hospital at Montefiore emergency department with convulsive status epilepticus or new-onset seizures during admission to Children's Hospital at Montefiore.\n\n\n\nImplementation of a standardized treatment protocol, uploading the protocol to the hospital's intranet, adding anti-seizure medications to the hospital's Pyxis system, and creating a standardized convulsive status epilepticus order set in the electronic medical record. The primary outcome measure was time from order to administration of second-line anti-seizure medication, and secondary outcome was total seizure time.\n\n\n\nSeventy-eight patients were analyzed, including 41 from the baseline period (January 2014 through June 2015) and 37 from the postintervention period (July 2015 through December 2016). The median time to administration of second-line anti-seizure medication decreased from 52 to 21 minutes (p = 0.001) and total seizure time from 65 to 31 minutes (p = 0.09).\n\n\n\nA standardized treatment protocol for convulsive status epilepticus decreased time to administration of second-line therapy by 60%, but there was no statistically significant decrease in total seizure time.", "affiliations": "Division of Critical Care, Department of Pediatrics, The Children's Hospital at Montefiore, Bronx, NY.;Division of Child Neurology, Department of Neurology, The Children's Hospital at Montefiore, Isabelle Rapin, Bronx, NY.;Division of Critical Care, Department of Pediatrics, Nemours Children's Hospital, Orlando, FL.;Division of Child Neurology, Department of Neurology, The Children's Hospital at Montefiore, Isabelle Rapin, Bronx, NY.;Division of Emergency Medicine, Department of Pediatrics, The Children's Hospital at Montefiore, Bronx, NY.;Division of Critical Care, Department of Pediatrics, The Children's Hospital at Montefiore, Bronx, NY.", "authors": "Cassel-Choudhury|Gina|G|;Beal|Jules|J|;Longani|Neha|N|;Leone|Bridget|B|;Rivera|Ruby|R|;Katyal|Chhavi|C|", "chemical_list": "D000927:Anticonvulsants", "country": "United States", "delete": false, "doi": "10.1097/PCC.0000000000001816", "fulltext": null, "fulltext_license": null, "issn_linking": "1529-7535", "issue": "20(1)", "journal": "Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies", "keywords": null, "medline_ta": "Pediatr Crit Care Med", "mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D002985:Clinical Protocols; D005260:Female; D006776:Hospitals, Pediatric; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010348:Patient Care Team; D058996:Quality Improvement; D013226:Status Epilepticus; D062606:Tertiary Care Centers; D061665:Time-to-Treatment", "nlm_unique_id": "100954653", "other_id": null, "pages": "47-53", "pmc": null, "pmid": "30461579", "pubdate": "2019-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Protocol-Driven Management of Convulsive Status Epilepticus at a Tertiary Children's Hospital: A Quality Improvement Initiative.", "title_normalized": "protocol driven management of convulsive status epilepticus at a tertiary children s hospital a quality improvement initiative" }

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{ "abstract": "OBJECTIVE\nHepatotoxic complications of long-term oral amiodarone therapy have been well described ; however, liver injury secondary to parenteral infusion of amiodarone is uncommon, potentially fatal, and poorly understood. The hepatotoxicity is thought to result from the diluent polysorbate 80 and not the amiodarone its self. Theories suggest an allergic or immunologic response leading to alterations in the hepatocellular membrane while some propose that ischemia, not a drug reaction, is truly to blame.\n\n\nMETHODS\nBoth the PubMed and Embase databases were searched for cases of acute hepatitis implicating intravenous amiodarone with a total of 25 cases from 1986 to 2012 identified. Each case was then carefully evaluated to determine the connection between parenteral amiodarone and acute hepatotoxicity while assessing for evidence of potential ischemia.\n\n\nRESULTS\nOf the 25 published cases of amiodarone induced acute hepatotoxicity available for review, only 10 provide evidence to conclusively implicate parenteral amiodarone as the etiology. We add the eleventh reported case of parenteral amiodarone induced acute severe hepatitis to the literature and report the most comprehensive review of this topic to date.\n\n\nCONCLUSIONS\nThere is sufficient evidence to support amiodarone induced acute hepatotoxicity as a unique entity separate from ischemic hepatitis. If suspected, parenteral amiodarone should be discontinued and held indefinitely.", "affiliations": null, "authors": "Stratton|A|A|;Fenderson|J|J|;Kenny|P|P|;Helman|D L|DL|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone", "country": "Belgium", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1784-3227", "issue": "78(2)", "journal": "Acta gastro-enterologica Belgica", "keywords": null, "medline_ta": "Acta Gastroenterol Belg", "mesh_terms": "D000369:Aged, 80 and over; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D008297:Male", "nlm_unique_id": "0414075", "other_id": null, "pages": "233-9", "pmc": null, "pmid": "26151694", "pubdate": "2015-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Severe acute hepatitis following intravenous amiodarone : a case report and review of the literature.", "title_normalized": "severe acute hepatitis following intravenous amiodarone a case report and review of the literature" }

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null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENECTEPLASE" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis acute", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "General physical health deterioration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STRATTON A, FENDERSON J, KENNY P, HELMAN D. SEVERE ACUTE HEPATITIS FOLLOWING INTRAVENOUS AMIODARONE : A CASE REPORT AND REVIEW OF THE LITERATURE. 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"drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "VENTRICULAR TACHYCARDIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL (MANUFACTURER UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "806", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL (MANUFACTURER UNKNOWN)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "075761", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "806", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "General physical health deterioration", "reactionmeddraversionpt": "19.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "STRATTON A,FENDERSON J,KENNY P,HELMAN D. SEVERE ACUTE HEPATITIS FOLLOWING INTRAVENOUS AMIODARONE: A CASE REPORT AND REVIEW OF THE LITERATURE. ACTA-GASTROENTEROL-BELG 2015?2:233-239.", "literaturereference_normalized": "severe acute hepatitis following intravenous amiodarone a case report and review of the literature", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160121", "receivedate": "20160114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11917732, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "US-APOTEX-2016AP005092", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIODARONE HYDROCHLORIDE" }, "drugadditional": null, 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1MG/MIN FOR 6 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL INJECTION" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "A TOTAL DOSE OF 1300MG IN THE PRECEDING 24 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PARACETAMOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATORVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE HCL INJECTION" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis acute", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "STRATTON A, FENDERSON J, KENNY P, HELMAN DL.. SEVERE ACUTE HEPATITIS FOLLOWING INTRAVENOUS AMIODARONE : A CASE REPORT AND REVIEW OF THE LITERATURE.. ACTA-GASTROENTEROL-BELG. 2015?78(2):233-239", "literaturereference_normalized": "severe acute hepatitis following intravenous amiodarone a case report and review of the literature", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160112", "receivedate": "20160112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11910223, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "Apparently, unexplained weight loss is a common symptom experienced by patients affected by Parkinson's disease, especially in those treated by levodopa-carbidopa infusion gel (LCIG) with a poor control of dyskinesias. Weight loss is considered part of gastrointestinal dysfunction seen in patients affected by Parkinson's disease, along with gastroparesis and reduced bowel peristalsis. In patients treated with LCIG, weight loss needs to be accurately evaluated, because of possible underlying life-threatening adverse events, like duodenum decubitus ulcer.", "affiliations": "SC Neurologia Universitaria-AOU Ospedali Riuniti of Foggia, Foggia, Italy. tommartin@hotmail.it.;SC Neurologia Universitaria-AOU Ospedali Riuniti of Foggia, Foggia, Italy.;Gastroenterology Unit-AOU Ospedali Riuniti of Foggia, Foggia, Italy.;Gastroenterology Unit-AOU Ospedali Riuniti of Foggia, Foggia, Italy.;SC Neurologia Universitaria-AOU Ospedali Riuniti of Foggia, Foggia, Italy.;SC Neurologia Universitaria-AOU Ospedali Riuniti of Foggia, Foggia, Italy.;SC Neurologia Universitaria-AOU Ospedali Riuniti of Foggia, Foggia, Italy.", "authors": "Martino|Tommaso|T|http://orcid.org/0000-0001-8877-4104;Melchionda|Donato|D|;Tonti|Paolo|P|;De Francesco|Vincenzo|V|;Lalla|Alessandra|A|;Specchio|Luigi Maria|LM|;Avolio|Carlo|C|", "chemical_list": "D000978:Antiparkinson Agents; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa", "country": "Austria", "delete": false, "doi": "10.1007/s00702-016-1618-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0300-9564", "issue": "123(12)", "journal": "Journal of neural transmission (Vienna, Austria : 1996)", "keywords": "Duodenal decubitus ulcer; Intestinal levodopa infusion; Parkinson’s disease", "medline_ta": "J Neural Transm (Vienna)", "mesh_terms": "D000368:Aged; D000978:Antiparkinson Agents; D002230:Carbidopa; D004338:Drug Combinations; D004381:Duodenal Ulcer; D004386:Duodenum; D020820:Dyskinesias; D020776:Endoscopes, Gastrointestinal; D006801:Humans; D007980:Levodopa; D008297:Male; D010300:Parkinson Disease; D014057:Tomography, X-Ray Computed; D015431:Weight Loss", "nlm_unique_id": "9702341", "other_id": null, "pages": "1395-1398", "pmc": null, "pmid": "27614656", "pubdate": "2016-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "22690905;24375496;25987282;25435387;25585993;17146589;24313838;25809301;16330147;20829091;26003410;24398781;25545465;23595879;1483417", "title": "Weight loss and decubitus duodenal ulcer in Parkinson's disease treated with levodopa-carbidopa intestinal gel infusion.", "title_normalized": "weight loss and decubitus duodenal ulcer in parkinson s disease treated with levodopa carbidopa intestinal gel infusion" }

[ { "companynumb": "IT-MYLANLABS-2017M1005147", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOXYMETHYLCELLULOSE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.95 % CARMELLOSE (CARBOXYMETHYLCELLULOSE; IN LEVODOPA/CARBIDOPA SUSPENSION)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARMELLOSE SODIUM" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBIDOPA\\LEVODOPA" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "075091", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LEVODOPA (20MG/ML)/CARBIDOPA (5 MG/ML)", "drugenddate": null, "drugenddateformat": null, "drugindication": "PARKINSON^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBIDOPA/LEVODOPA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Duodenal ulcer", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decubitus ulcer", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MARTINO T, MELCHIONDA D, TONTI P, DE FRANCESCO V, LALLA A, SPECCHIO LM, ET AL. WEIGHT LOSS AND DECUBITUS DUODENAL ULCER IN PARKINSON^S DISEASE TREATED WITH LEVODOPA-CARBIDOPA INTESTINAL GEL INFUSION. J-NEURAL-TRANSM 2016;123(12):1395-1398.", "literaturereference_normalized": "weight loss and decubitus duodenal ulcer in parkinson s disease treated with levodopa carbidopa intestinal gel infusion", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20170131", "receivedate": "20170131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13170142, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "Altered mental status is a common cause for presentation to the emergency department with a broad differential diagnosis.\n\n\n\nWe present a unique case of altered mental status in a previously healthy man that was found to be secondary to primary central nervous system acute lymphoblastic leukemia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Lumbar puncture remains a critical tool for emergency physicians in the diagnosis of central nervous system pathologies.", "affiliations": "Department of Emergency Medicine, Indiana University, Indianapolis, Indiana.;Department of Emergency Medicine, Indiana University, Indianapolis, Indiana.", "authors": "Monsef|Brenna|B|;Carpp|Nicole|N|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.jemermed.2021.07.008", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-4679", "issue": "61(4)", "journal": "The Journal of emergency medicine", "keywords": "acute lymphoblastic leukemia; altered mental status; central nervous system malignancy; lumbar puncture", "medline_ta": "J Emerg Med", "mesh_terms": null, "nlm_unique_id": "8412174", "other_id": null, "pages": "e51-e53", "pmc": null, "pmid": "34384665", "pubdate": "2021-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Primary Central Nervous System Leukemia Presenting as Altered Mental Status.", "title_normalized": "primary central nervous system leukemia presenting as altered mental status" }

[ { "companynumb": "US-AMGEN-USASP2021195166", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERENUMAB-AOOE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "761077", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Solution for injection in pre-filled syringe", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Migraine", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AIMOVIG" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIMEGEPANT SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Migraine", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NURTEC ODT" } ], "patientagegroup": "5", "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "B-cell type acute leukaemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Central nervous system leukaemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Carpp N. Primary Central Nervous System Leukemia Presenting as Altered Mental Status. Journal of Emergency Medicine. 2021;61 (4):e51-e53", "literaturereference_normalized": "primary central nervous system leukemia presenting as altered mental status", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211213", "receivedate": "20211213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20178234, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "Comprehensive medication review is a patient-centered approach to optimize medication use and improve patient outcomes. This study outlines a pilot model of care in which a remote corporate-based clinical pharmacist implemented comprehensive medication reviews for a cohort of medically complex home-based primary care (HBPC) patients.\n\n\n\nNinety-six medically complex patients were assessed for medication-related problems. Data collected on these patients were: number of chronic conditions, number of medications, appropriate indication for each medication, dose appropriateness, drug interactions, recommendations for medication optimization and deprescribing. The number of accepted recommendations by the HBPC practice was analyzed.\n\n\n\nOn average, the patients were 82 years old and had 13 chronic conditions. They were taking a median of 17 medications. Over a four-month pilot period, 175 medication recommendations were made, and 53 (30.3%) of them were accepted, with most common being medication discontinuation, deprescribing, and dose adjustments. Sixty-four (66.7%) patients were on a medication listed as potentially inappropriate for use in older adults. The most common potentially inappropriate medication was a proton-pump inhibitor (38.5%), followed by aspirin (24%), tramadol (15.6%), a benzodiazepine (13.5%) or an opioid (8.3%). Eighty-one medications were recommended for deprescribing and 27 medications were discontinued (33.3%). There were 24 recommended dose adjustments and 11 medications were dose adjusted (45.8%). Thirty-four medications were suggested as an addition to the current patient regimen, 2 medications were added (5.9%).\n\n\n\nPharmacist comprehensive medication review is a necessary component of the HBPC healthcare continuum. Additional research is needed to examine whether aligning pharmacists to deliver support to HBPC improves clinical outcomes, reduces healthcare expenditures and improves the patient's experience.", "affiliations": "Northwestern Medicine, Evanston, IL, United States of America.;Northwestern Medicine, Evanston, IL, United States of America.;Home Centered Care Institute, Schaumburg, IL, United States of America.;Northwestern Medicine, Evanston, IL, United States of America.", "authors": "Monzón-Kenneke|Michele|M|0000-0002-2128-495X;Chiang|Paul|P|;Yao|Nengliang Aaron|NA|0000-0001-9000-0378;Greg|Mark|M|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0252151", "fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nplosone\nPLoS ONE\n1932-6203\nPublic Library of Science San Francisco, CA USA\n\n10.1371/journal.pone.0252151\nPONE-D-20-32017\nResearch Article\nPeople and Places\nPopulation Groupings\nProfessions\nMedical Personnel\nPharmacists\nMedicine and Health Sciences\nGeriatrics\nMedicine and Health Sciences\nPharmacology\nDrugs\nMedicine and Health Sciences\nHealth Care\nHealth Care Providers\nAllied Health Care Professionals\nMedicine and Health Sciences\nHealth Care\nPrimary Care\nMedicine and Health Sciences\nEpidemiology\nMedical Risk Factors\nMedicine and Health Sciences\nPharmacology\nAdverse Reactions\nResearch and Analysis Methods\nResearch Design\nPilot Studies\nPharmacist medication review: An integrated team approach to serve home-based primary care patients\nMedication review in home-based primary care\nhttps://orcid.org/0000-0002-2128-495X\nMonzón-Kenneke Michele Conceptualization Data curation Writing – original draft Writing – review & editing 1\nChiang Paul Conceptualization Supervision Writing – review & editing 12\nhttps://orcid.org/0000-0001-9000-0378\nYao Nengliang (Aaron) Conceptualization Writing – original draft Writing – review & editing 234*\nGreg Mark Conceptualization Resources Supervision Writing – review & editing 1\n1 Northwestern Medicine, Evanston, IL, United States of America\n2 Home Centered Care Institute, Schaumburg, IL, United States of America\n3 Center For Health Management and Policy, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China\n4 Section of Geriatrics, University of Virginia, Charlottesville, VA, United States of America\nVaismoradi Mojtaba Editor\nNord University, NORWAY\nCompeting Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: NY is an advisor to Heal Inc and research director for Home Centered Care Institute. NY receives stock options from Heal Inc, unrelated to this work. These affiliations and employments do not alter our adherence to PLOS ONE policies on sharing data and materials. We declare no further competing interests.\n\n* E-mail: ayao@virginia.edu\n25 5 2021\n2021\n16 5 e025215112 10 2020\n11 5 2021\n© 2021 Monzón-Kenneke et al\n2021\nMonzón-Kenneke et al\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nBackground\n\nComprehensive medication review is a patient-centered approach to optimize medication use and improve patient outcomes. This study outlines a pilot model of care in which a remote corporate-based clinical pharmacist implemented comprehensive medication reviews for a cohort of medically complex home-based primary care (HBPC) patients.\n\nMethod\n\nNinety-six medically complex patients were assessed for medication-related problems. Data collected on these patients were: number of chronic conditions, number of medications, appropriate indication for each medication, dose appropriateness, drug interactions, recommendations for medication optimization and deprescribing. The number of accepted recommendations by the HBPC practice was analyzed.\n\nResults\n\nOn average, the patients were 82 years old and had 13 chronic conditions. They were taking a median of 17 medications. Over a four-month pilot period, 175 medication recommendations were made, and 53 (30.3%) of them were accepted, with most common being medication discontinuation, deprescribing, and dose adjustments. Sixty-four (66.7%) patients were on a medication listed as potentially inappropriate for use in older adults. The most common potentially inappropriate medication was a proton-pump inhibitor (38.5%), followed by aspirin (24%), tramadol (15.6%), a benzodiazepine (13.5%) or an opioid (8.3%). Eighty-one medications were recommended for deprescribing and 27 medications were discontinued (33.3%). There were 24 recommended dose adjustments and 11 medications were dose adjusted (45.8%). Thirty-four medications were suggested as an addition to the current patient regimen, 2 medications were added (5.9%).\n\nConclusion\n\nPharmacist comprehensive medication review is a necessary component of the HBPC healthcare continuum. Additional research is needed to examine whether aligning pharmacists to deliver support to HBPC improves clinical outcomes, reduces healthcare expenditures and improves the patient’s experience.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper. Patient-level data cannot be shared publicly because of the HIPAA requirements.\nData Availability\n\nAll relevant data are within the paper. Patient-level data cannot be shared publicly because of the HIPAA requirements.\n==== Body\nIntroduction\n\nClinical pharmacists play an essential role within interdisciplinary teams in optimizing medication use, alerting providers to gaps in care, decreasing inappropriate prescribing practices and improving medication safety [1, 2]. Comprehensive medication review is a patient-centered approach to optimize medication use and improve patient outcomes by ensuring each patient’s medication is assessed for indication, effectiveness and safety given patient status and comorbidities [3]. Physicians in ambulatory settings often have limited access to a dedicated pharmacist resource [1–3]. This study sought to implement a remote corporate-based pharmacist into a home-based primary care practice to facilitate comprehensive medication reviews.\n\nAbout 2 to 4 million Americans have difficulty obtaining office-based primary care because they are frail, functionally limited, chronically-ill and/or homebound [4, 5]. These “invisible” people are the most expensive patients [6], and they fall through the cracks of our current healthcare delivery system. When in need, they often turn to emergency services for medical help but have no continuous, follow-up care [7]. This continues a cycle of poor health management and high expenses. This population is expected to grow dramatically as our society continues to age. The home-based primary care (HBPC) model offers an opportunity to meet their demand and save healthcare costs [5]. HBPC brings the expertise of primary care providers and the technology of a health care clinic directly to medically complex patients, providing comprehensive, coordinated care in the comfort of their home.\n\nLimited knowledge exists on the integration of pharmacist support in private sector HBPC practice [8]. Clinical pharmacist’s role is widely known within outpatient retail settings and hospital inpatient interdisciplinary teams. However, clinical pharmacy support of ambulatory based medical practices is limited [9], including in HBPC [10]. As the population ages and the option of many medical services being made available from home, it is important to include all of the services available to patients who standardly seek care in traditional settings. A remote-pharmacist functions as a liaison transcending novel healthcare landscapes providing oversight essential for safe medication use. Comprehensive medication management is a critical function that assists in improving medication use, especially in those utilizing many medications to manage their multiple coexisting disease states. Older adults using multiple medications may be at risk of medication-related problems leading to adverse health outcomes [11]. Comprehensive medication management in the HBPC population is crucial as these patients have multiple comorbidities and most fit the criteria for polypharmacy. Polypharmacy’s definition can be variable but is commonly considered to be the use of five or more medications [12]. Polypharmacy has been associated with increased risks of adverse events and poor health outcomes [12]. Polypharmacy can also lead to countless medication-related problems (MRP).\n\nLiterature searches for remote-pharmacist medication management in home-based primary care did not yield any studies. The demographic of the HBPC patient in this pilot is characterized as having multiple comorbidities, elderly and overwhelmed by polypharmacy. Globally, medication safety in older adults impacts health outcomes and is an enduring health issue. Medication-related problems can be the cause of hospital admissions and cause significant morbidity and mortality. Thirty percent of hospital admissions may be a result of an adverse drug reaction, of which 53.4% are considered preventable [13]. Adverse drug reactions cause significant morbidity and mortality especially as patients age, with a patient aged 75 years or older at the greatest risk [14].\n\nThis pilot population of HCBP was compromised of persons of advanced aged and medically vulnerable. Utilizing a remote-pharmacist service can support a HBCP practice by assisting in illuminating medication-related problems. In a study by Vink et al. pharmacists were able to identify medication-related problems in home care patients that were not identified from other providers [15]. In that study the most common problems identified were suboptimal therapy and using of unnecessary medications [15]. A review article describing medication-related problems in home care, commonly noted MRPs were due to potentially inappropriate medications, medication errors and adverse drug reactions [16]. In that same study, it was relayed that teams lacking an interdisciplinary model had patients who were at risk for experiencing MRPs [16].\n\nThe Northwestern Medicine Physician Network (NMPN) Accountable Care Organization (ACO) includes over 3,100 providers and approximately 400,000 covered lives. Many of these providers, including HBPC physicians and nurse practitioners, have expressed the need for pharmacist resources to assist with general drug information and patient specific medication consult support. This pilot study was a collaboration with Northwestern Medicine (NM) Regional Medical Group (RMG) Home Care Physicians who provide primary care to medically complex patients in their homes. The majority of these patients are older adults who live alone and have functional disabilities making it difficult to travel or leave their homes to obtain medical care. As strong proponents of team-based healthcare, Home Care Physicians requested assistance from the NMPN Pharmacy Team to review and offer feedback on their patient’s medication regimens. The aim of this study was to describe this pilot program and examine the degree of medication recommendation acceptance by the HBPC practice.\n\nMethods\n\nPilot innovation\n\nThis program was created to assist our pilot providers with medication management. Our ACO members expressed the need for pharmacist intervention in assisting with their patient care. Many of our members have no dedicated pharmacy resource and have stated that inpatient and outpatient pharmacists do not have the time or access to the patient medical records to provide comprehensive medication reviews. This program is innovative because this is the first program to incorporate a remote-pharmacist into a HBPC practice. There are no studies that have examined this type of team structure.\n\nNo clinical pharmacist service existed at the practice prior to the intervention. The pharmacist performing the medication reviews was employed by the ACO. The pharmacist performing the reviews has two board certifications: A Board-Certified Pharmacotherapy Specialist and a Board-Certified Geriatric Pharmacist with extensive experience in the ambulatory care setting managing patient with complex conditions.\n\nThe NM RMG Home Care Physician Team includes 2 physicians and 3 advanced practice nurses that serve approximately 750 patients.\n\nMedication review\n\nOver a four-month pilot period, a total of 96 patient charts were reviewed by one clinical pharmacist. The average time spent on each patient’s chart review and medication history was approximately 45 minutes. The total time allotted to the project was about 100 hours or 1 hour per patient. This time included chart review, literature review and guideline research in support of recommendations, messaging providers, and recording interventions in a Microsoft Excel spreadsheet.\n\nThe program workflow emanated from a weekly email received by the pharmacist containing a list of new Home Care patients on 5 or more medications to review for that week. Patient name, medical record number, and date of birth were forwarded to the pharmacist. The pharmacist would research the patient in the electronic medical record (EMR). Review consisted of reading patient notes, history and physical, laboratory (lab) results, and the medication list. Initially, the pharmacist would review all the patient’s medications and medical history and ensure that each medication prescribed for that patient was appropriate. Medication reviews were performed in a systematic manner by a single pharmacist. As part of a pharmacist’s training, they perform prospective reviews and determine indications for medication use, correct dosage and directions, duplication of therapy, medication effective for condition (based on current patient status and lab results), symptom management recommendations, and patient-centered considerations (affordability, alternative formulations).\n\nA Microsoft Excel spreadsheet was created and consensus regarding outcomes of interest was agreed upon by the pilot team. The spreadsheet contained several headings allowing for methodical review of each patient capturing demographics; provider name; number of chronic conditions; number of medications; renal/hepatic dosing appropriate; patient currently on a American Geriatric Society Beers List medication; name of American Geriatric Society Beers List medication; drug-drug interaction; number of medications recommended for deprescribing; name of medication recommended for deprescribing; additional medication recommended; name of medication recommended; number of total recommendations; number of recommendations taken and intervention taken by provider.\n\nDetermination of the number of chronic diseases a patient had was achieved by reviewing the Problem List in the EMR. Chronic medical conditions were defined mirroring the definition as described by the Centers for Disease Control and Prevention (CDC), a condition lasting one or more years that requires ongoing medical attention and/or limits the activities of daily living.\n\nAll medications that were current on the patient medication list in the EMR were totaled and considered the patient’s total medication count. This included regularly scheduled medications, as needed medications and medications taken during a specific time period such as an antibiotic.\n\nThe completed Excel spreadsheet was sent back to the providers each week. In addition to the spreadsheet, individual messages were sent to providers alerting them of patients in which the pharmacist recommended adjustments for hepatic/renal dosing, significant drug-interactions, and changes in medications based on laboratory results. Additionally, patients were also brought to the provider’s attention if they had a chronic condition that could benefit from dose titration or augmentation of therapy. PubMed and disease specific guidelines were used in assisting with recommendations. Information for recommendations to augment current treatment was gleaned from the pharmacist’s knowledge and experience in ambulatory care. Knowledge was supported by practice guidelines for major chronic illnesses. For example, for diabetes (American Diabetes Association–ADA Standards of Medical Care in Diabetes), chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease—GOLD Guidelines), hyperlipidemia (American College of Cardiology/American Heart Association Cholesterol Practice Guidelines), chronic kidney disease (Kidney Disease Improving Global Outcomes–KIDIGO), depression (American Psychiatric Association).\n\nDrug interactions were reviewed using Micromedex. Dose adjustments were based on estimated glomerular filtration rate (eGFR) or Cockcroft-Gault Equation for creatinine clearance (CrCl) as suggested by the medication prescribing information.\n\nMeasures\n\nPatients were assessed for number of chronic conditions, number of active medications prescribed, appropriate indication for each medication, dose appropriate for renal, hepatic, age or other specific monitoring parameters, medication listed on the American Geriatric Society Beers Criteria, drug-drug interactions, medications to consider for deprescribing, medications to add to current therapy to optimize disease state treatment.\n\nAt the end of the pilot program, the charts of those patients were re-reviewed to determine how many of the recommendations provided were accepted.\n\nAnalysis and approach\n\nWe first performed a frequency analysis of the baseline characteristics of the HBPC patients that received pharmacist medication review. At the end of the pilot period, a cross-table was created to show the number of recommendations per patient and accepted recommendations. A frequency table of the potentially inappropriate medications was included in the analysis. We then selected three patients to describe a detailed report of their medication deprescribing and optimization.\n\nSummary of the pilot results was shared with the providers at NM RMG Home Care. The senior medical advisor (physician champion) reviewed findings with his staff to better understand the reasons why many of the recommendations from the pharmacist were not accepted. The senior advisor interviewed the providers to understand the common barriers in implementing the recommendations. They also discussed the role a pharmacist has to assist with medication optimization and deprescribing. We have summarized their discussions in the results section.\n\nResults\n\nThe average age of the pilot population was 82 years. Table 1 shows that over a third of the patients were 85 years or older. About 61% are female. About 71% of them were enrolled in the traditional Medicare program. On average, the patients had 13 chronic conditions and were taking a median of 17 medications. About 70% of these patients were taking 15 or more medications (Table 1).\n\n10.1371/journal.pone.0252151.t001 Table 1 Baseline characteristics of the home-based primary care patients received pharmacist medication review (N = 96).\n\n\tN\tStd\t\nAge, N (%)\t\t\t\n    Younger than 65\t22\t22.9%\t\n    65–74\t17\t17.7%\t\n    75–84\t23\t24.0%\t\n    85 or older\t34\t35.4%\t\nSex, N (%)\t\t\t\n    Male\t37\t38.5%\t\n    Female\t59\t61.5%\t\nPayers, N (%)\t\t\t\n    Traditional Medicare\t68\t70.8%\t\n    Medicare Advantage\t20\t20.8%\t\n    Medicaid\t8\t8.3%\t\nChronic Conditions, N (%)\t\t\t\n    5–8\t23\t24.0%\t\n    9–12\t41\t42.7%\t\n    13–32\t32\t33.3%\t\nMedications, N (%)\t\t\t\n    8–14\t29\t30.2%\t\n    15–19\t35\t36.5%\t\n    20–47\t32\t33.3%\t\n\nThe clinical pharmacist made 175 recommendations, and 53 (30%) were accepted by the HBPC providers. While about 19% of patients did not receive any recommendations, about 28% and 29% of patients have received one and two recommendations, respectively (Table 2). Among 78 patients receiving recommendations, HBPC providers accepted at least one recommendation for 40% of these patients.\n\n10.1371/journal.pone.0252151.t002 Table 2 Recommendations from pharmacist medication review and acceptance by home-based primary care providers.\n\n\tNumber of Accepted Recommendations, N (Row %)\tRow Total (Column %)\t\n\tZero\tOne\tTwo\tFour\tSeven\t\nNumber of Recommendations\t\t\t\t\t\t\t\n    Zero\t18 (100%)\t\t\t\t\t18 (18.8%)\t\n    One\t17 (63.0%)\t10 (37.0%)\t\t\t\t27 (28.1%)\t\n    Two\t18 (64.3%)\t5 (17.9%)\t5 (17.9%)\t\t\t28 (29.2%)\t\n    Three\t7 (58.3%)\t3 (25.0%)\t2 (16.7%)\t\t\t12 (12.5%)\t\n    Four\t3 (50.0%)\t2 (33.3%)\t\t1 (16.7%)\t\t6 (6.3%)\t\n    Five\t2 (100%)\t\t\t\t\t2 (2.1%)\t\n    Seven\t\t1 (50%)\t\t\t1 (50%)\t2 (2.1%)\t\n    Eight\t\t\t\t\t1 (100%)\t1 (1.0%)\t\nColumn Total (Row %)\t65 (67.7%)\t21 (21.9%)\t7 (7.3%)\t1 (1.0%)\t2 (2.1%)\t96 (100%)\t\n\nThe most commonly heeded intervention was medication discontinuance or deprescribing and dose adjustments. Eighty-one medications were recommended for deprescribing and 27 medications were discontinued (33%). There were 24 recommended dose adjustments and 11 medications were dose adjusted (46%). Eleven medications were suggested as an addition to the current patient regimen.\n\nSixty-four (67%) of the 96 patients were on medication listed as potentially inappropriate on the American Geriatric Society Beers Criteria, 11 patients were not on a Beers List medication and in 21 patients the criteria were not applicable given current age. Fig 1 shows the most common potentially inappropriate medication was a proton-pump inhibitor (41%), followed by aspirin (24%), tramadol (16%), a benzodiazepine (14%) and an opioid (8%).\n\n10.1371/journal.pone.0252151.g001 Fig 1 Frequency of potentially inappropriate medications in home care patients (N = 96).\n\nPharmacist intervention in HBPC improved patient safety and had financial implications. Table 3 describes three examples of pharmacist recommendations that were accepted. In the first example, a 79-year-old patient on eltrombopag required medication dose adjustment based on their lab results to prevent potential thromboembolism; the second accepted recommendation was for medication consolidation and tapers in a 49-year-old patient taking several central nervous system (CNS) depressants who was at high risk for adverse drug reactions due to concomitant cannabis use and multiple comorbidities. In the third example, a 93-year-old patient on concomitant warfarin and torsemide was switched to apixaban to avert a drug interaction which prior to the modification was the cause of months of not achieving the international normalized ratio (INR) goal. Financial implications are added to each recommendation to emphasize how these interventions could have resulted in health care cost avoidance.\n\n10.1371/journal.pone.0252151.t003 Table 3 Three case studies of accepted medication recommendations.\n\n79-year-old patient on eltrombopag for idiopathic thrombocytopenia (ITP)\t\n• Labs—platelets– 451 x 10 (3) uL\t\n• Per Micromedex drug information on eltrombopag [17], dose adjustment required for platelet counts above 400 x 10(9)/L, in ITP.\t\n• Provider messaged potential dose adjustment required.\t\nSafety: Thromboembolism (venous or arterial) may occur with excessive increases in platelet levels. Incidence of thrombosis in ITP– 6%.\t\nFinancial Implications:\t\n“Treatment of an acute VTE on average appears to be associated with incremental direct medical costs of $12,000 to $15,000 (2014 US dollars) among first-year survivors, controlling for risk factors. Subsequent complications are conservatively estimated to increase cumulative costs to $18,000–23,000 per incident case. Annual incident VTE events conservatively cost the US healthcare system $7–10 billion each year for 375,000 to 425,000 newly diagnosed, medically treated incident VTE cases [18].”\t\n49-year-old patient on multiple CNS depressants, opioids, benzodiazepines, SSRI and z-drug at high doses\t\n• Recommendation to consider medication tapers and consolidation of therapy.\t\n• Patient mentions to provider they had previously used cannabis. Provider tests patient and they are positive for cannabis.\t\n• Note to provider that components in marijuana can interfere with CYP450 enzymes competitively inhibiting the metabolism of other compounds [19]. This interaction could impact benzodiazepines, opioids and CYP2D6 which metabolizes SSRIs and could potentially explain need for increased doses.\t\nSafety: With the legalization of marijuana in many states, it is imperative for providers to question patients regarding the use of cannabis products. Medically complex patients with multiple comorbidities are at risk for adverse drug reactions.\t\nFinancial Implications:\t\n“The average direct costs per patient caused by ADEs were USD $444.90 [95% CI: 264.4 to 625.3], corresponding to USD $21 million per 100,000 adult inhabitants per year. Inpatient care accounted for 53.9% of all direct costs caused by ADEs. For patients with ADEs, the average societal cost of illness was USD $6,235.00 [5,442.8 to 7,027.2], of which direct costs were USD $2,830.1 [2,260.7 to 3,399.4] (45%), and indirect costs USD $3,404.9 [2899.3 to 3910.4] (55%). The societal cost of illness was higher for patients with ADEs compared to other patients. ADEs caused 9.5% of all direct healthcare costs in the study population [20].”\t\n93-year-old patient on warfarin with unstable INR\t\n• Patient on concomitant torsemide.\t\n• Messaged provider regarding torsemide/warfarin interaction.\t\n• Patient transitioned to apixaban after months of INR not within goal–INR supratherapeutic.\t\nSafety: Patient at risk of bleeding, increased fall risk and potential hemorrhage.\t\nFinancial Implications:\t\n“Most hospitalization expenditures after an anticoagulant-associated ADR were attributable to nursing costs (mean $33,189 per ADR) followed by pharmacy costs (mean $7,451 per ADR). ADRs which were determined to add incremental expense were associated with significant increases in total hospitalization cost (mean $118,429 vs. $54,858, p = 0.02) as well as cost after the ADR (mean $89,733 vs. $23,680, p = 0.004) compared with ADRs in which no incremental cost was determined to be incurred [21].”\t\n\nThe provider interview shows that the barriers to implementation of recommended changes include (1) provider decision to continue medications based on clinical judgement and patient need; (2) patient/family/provider reluctance to institute changes (“don’t rock the boat”); (3) medical mindset of prescribing medication to address clinical complaints; (4) determining who is responsible for deprescribing when multiple specialists are involved; (5) lack of clinical time; and (6) lack of clear guidelines for deprescribing.\n\nThe NM RMG Home Care group identified the need for a pharmacist to assist with medication optimization and deprescribing by offering step by step guidance through the process. The group also believe a pharmacist would be an asset to the team if they would reach out and discuss changes directly with patients, family and caregivers. This would provide patients and caregivers with a dedicated pharmacist treatment team member allowing for immediate access to address uncertainty, understanding and apprehension.\n\nDiscussion\n\nThe forefront goal of the program was to implement and integrate a clinical pharmacist presence in a HBPC practice. Establishing this clinical pharmacy pilot demonstrated that pharmacist integration in HBPC identified opportunities to optimize patient care and potentially reduce or avoid additional healthcare spending. Another important aspect of this study was to describe a demographic that is serviced by home-care providers. As outlined, these patients are medically vulnerable, aged and have an increased utilization of medications. As the number of medications, a patient takes increases, so does the potential risk of adverse reactions or complications. It may be the perception that pharmacists review patient’s medications each time a new medication is added to their regimen. While this is true, many outpatient pharmacists lack access to patient’s EMR. Complicating this scenario, is patients who, due to cost, need to obtain medications from multiple different pharmacies. Fragmenting and the siloing of care follows. This adds complexity when attempting to perform a medication review from the outpatient pharmacy perspective. Having a pharmacist as a sentinel of where prescribing originates allows for the most comprehensive review to occur. In this pilot, about 81% of the patients received at least one medication recommendation. Of the 175 recommendations provided, 53 (30.3%) were accepted.\n\nComprehensive medication review has the unique ability to help identify medication problems. In an article from Castelli et al., it was noted that pharmacist inclusion in patient-centered medical homes (PCMH) is not widespread due to a lack of knowledge of the skill set and benefits [22]. In that study, in using comprehensive medication management, pharmacists were able to identify and work with the provider to resolve various medication therapy problems. There was a 98% acceptance rate of pharmacist interventions [22].\n\nHBPC teams within the Veteran’s Health Administration have clinical pharmacy specialists [10]. They provide comprehensive medication management services to HBPC veterans [10]. A study of 79 HBPC veterans examined medication appropriateness and the degree of recommendation acceptance [23]. The acceptance rates for primary care providers were 69% [23], in contrast with 30% in our study. A recent study in the private sector had pharmacy resident-provider pairs making home visits to 25 homebound patients [24]. However, their study focused on developing a screening tool that identifies identify HBPC patients likely to benefit from in-home pharmacist review.\n\nIn our pilot study, the HBPC provider group agreed to the pharmacist recommendation 33.3% of the time for deprescribing recommendations and 45.8% of the time on dosing recommendations. When reviewing the results, the provider group felt that additional deprescribing would have occurred if the pharmacist was readily available to provide step by step instructions how to de-escalate therapy for the treatment team. Providers also agreed that recommendations would be followed if the pharmacist would act as a liaison discussing changes with the family directly. An integrated pharmacist would be an asset allowing for patient and caregiver buy-in when there is resistance or hesitancy to make changes.\n\nImproving recommendation acceptance can occur by the pharmacist and the providers entering into a collaborative practice agreement (CPA). Initially focusing on a select few disease states, the CPA would outline a defined protocol under which the pharmacist would function to perform medication monitoring, initiating and adjusting medication regimens. Additionally, educating HBPC patients on the services provided by a pharmacist would encourage the patient to reach out to the pharmacist directly when they have any medication related problems. Patient care services provided by pharmacists and facilitated by CPA usage can assist in improving patient outcomes and reduction in the fragmentation of care [25].\n\nRecommendation acceptance could also be increased by implementing a weekly virtual team huddle to discuss the patients sent to the pharmacist for review. Under this practice, team dialog may help to alleviate any unanswered questions that may hinder recommendation acceptance. Healthcare huddles are known for promoting patient safety, enhancing communication and fostering trust and relationship building amongst the team [26].\n\nHome care providers are generally the sole clinician visiting the home with no additional care team members present in the home for support. The setting in which visits occur can become overwhelming depending on the environment in the home and the number of caregivers and family members present during the visit. Having immediate access to a pharmacist to assist with speaking with the family/caregiver about changes in medication therapy can be extremely valuable. This approach could become a standard of care which home care patients will grow to expect from their providers.\n\nOur pilot program was predicated on volunteered pharmacist time, which limited the number of patients that could be reviewed on a weekly basis. Patient chart review is extremely labor-intensive as evidenced by the total and average time required to review each case. Given the population that NM RMG Home Care currently has, there exists a divide between pharmacist clinical support and the ambulatory providers/patients who may benefit from pharmacist intervention. Without access and the integration of pharmacists into the treatment team providing this type of service, providers in the field lack expert point of care access and decision-making abilities to optimize patient’s complex medication regimens and conditions.\n\nAs evidenced from comments from our own providers, seeking input from various inpatient hospital or retail pharmacists has not been a consistent or ideal state. There needs to be provision and advocacy for pharmacists embedded in the health system that can act as liaisons and consultants to provide this type of support to the multitude of patients seeking care. As the future of reimbursement shifts away from fee for service and to pay-for-performance, a pharmacist is uniquely qualified to assist providers in providing optimal care. A remote-pharmacist model permits a larger landscape than just focusing on a single disease state or discipline. It also allows for support of multiple provider practices. Many times, embedded pharmacists are fraught with assisting with insurance coverage dilemmas, prior authorizations and other administrative tasks resulting in a decrease in the time available to provide pharmacist-specific clinical interventions. The remote-pharmacist model can serve as global resource for patient referrals or questions for complex patients and oversight for essential medication management.\n\nWhile many HBPC providers state they would value the addition of a pharmacist to their team, the limiting factor frequently stated are the financial resources needed to support a pharmacist. A commonly mentioned barrier is the ability to quantify and assign a dollar value to the myriad of clinical services the pharmacist provides. Using conservative estimates, pharmacist intervention in this pilot program may have resulted in health care cost avoidance in the three patient cases described estimated to be $53,000 in direct medical costs. The estimated annual cost of drug-related morbidity and mortality resulting from non-optimized medication therapy was $528.4 billion, equivalent to 16% of total United States health care expenditures in 2016 [27]. As the population ages, there will be a growing population of patients who will require multiple medications. Older adults taking multiple medications are at increased risk of adverse events as the number of their prescribed medication increases [28].\n\nThe pharmacy profession has historically been challenged to demonstrate their value with improving patient care. How is that accomplished? For the patient who has a better outcome due to pharmacist intervention, how can one quantify how the patient’s quality of life is impacted by avoiding an emergency room visit or hospitalization, better tolerating their medications or avoiding an adverse drug reaction, improved adherence and reducing overall medical cost? To paraphrase an excerpt from the book, The Little Prince by Antoine de Saint-Exupéry, many of the most impactful things in the world cannot be measured, seen or touched, they are just felt [29].\n\nThis study has several limitations. A small sample size was largely due to the limited staff and time available to direct toward this pilot. One pharmacist performed all the chart reviews which limited the number of patients that could be reviewed on a weekly basis. Additionally, since only one pharmacist performed each medication review, there may be biases in the types of interventions that were recommended. Patients selected represent a single HBPC practice. This cohort resides in a geographic area where there is expanded access to healthcare, this population could have better overall health status than other HBPC patients living in a different area. A noted contributor to disparities in health is differential access to care [30]. Patients selected for pharmacist review were taking several medications and considered extremely complex. Selection bias may have pushed these patients to the pharmacist for review and may not represent the majority HBPC population. Standardization criteria may help in determining which patients are candidates for review. A home-care provider screening tool could aid to streamline the process of patient referral. We relied on estimated or potential cost-avoidance from the pharmacist medication review. While additional research is needed to investigate what that actual dollar value may truly be, there are added benefits of an integrated pharmacist team member in the management of medically complex patients.\n\nConclusions\n\nComprehensive medication review is a critical component of the healthcare continuum. The dynamic of a home-bound patient who is being serviced at home interlaces well with a remote-pharmacist model. Many HBPC patients are medically vulnerable, due to multiple comorbidities necessitating many medications. Pharmacists have a unique skill set allowing them to provide medication support to ensure HBPC patients have optimal medication regimens. However, pharmacist integration into HBPC is lacking.\n\nPharmacist intervention in this pilot program may have resulted in health care cost avoidance. Aligning pharmacist services to deliver support to HBPC providers can ensure the patient is treated holistically. About 81% of patients selected by HBPC providers received medication recommendations, and 30% of these recommendations were accepted by the HBPC providers. Additional research is needed to discover ways to improve recommendation acceptance and determine if aligning pharmacists to deliver support to home-based primary care providers improve the patient experience, improve clinical outcomes and reduce healthcare expenditure.\n\nThank you to all the providers at Northwestern Medicine RMG Home Care Providers who requested pharmacy partnership to improve their patient experience.\n==== Refs\nReferences\n\n1 Kovačević SV , Simišić M , Rudinski SS , Ćulafić M , Vučićević K , Prostran M , et al . Potentially Inappropriate Prescribing in Older Primary Care Patients. PLOS ONE. 2014;9 : e95536. 10.1371/journal.pone.0095536 24763332\n2 Hanlon JT , Weinberger M , Samsa GP , Schmader KE , Uttech KM , Lewis IK , et al . 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Am J Geriatr Pharmacother. 2007;5 : 40–47. 10.1016/j.amjopharm.2007.03.003 17608246\n24 Stewart AE , Lovato JF , Zimmer R , Stewart AP , Hinely MT , Yang M . Development of a screening tool to identify patients likely to benefit from clinical pharmacist review in a home-based primary care population. J Am Pharm Assoc. 2020;0. 10.1016/j.japh.2020.03.008 32482500\n25 Giberson S , Yoder S , Lee MP . Improving Patient and Health System Outcomes Through Advanced Pharmacy Practice: A Report to the Surgeon General 2011. Rockville, MD: Office of the Chief Pharmacist, US Public Health Service; 2011. Available: https://www.pharmacist.com/improving-patient-and-health-system-outcomes-through-advanced-pharmacy-practice-report-surgeon\n26 Provost SM , Lanham HJ , Leykum LK , McDaniel RR , Pugh J . Health care huddles: managing complexity to achieve high reliability. Health Care Manage Rev. 2015;40 : 2–12. 10.1097/HMR.0000000000000009 24589926\n27 Watanabe JH , McInnis T , Hirsch JD . Cost of Prescription Drug-Related Morbidity and Mortality. Ann Pharmacother. 2018;52 : 829–837. 10.1177/1060028018765159 29577766\n28 Maher RL , Hanlon J , Hajjar ER . Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13 : 57–65. 10.1517/14740338.2013.827660 24073682\n29 Saint-Exupéry A de . The Little Prince. Wordsworth Editions; 1995.\n30 Lurie N , Dubowitz T . Health Disparities and Access to Health. JAMA. 2007;297 : 1118–1121. 10.1001/jama.297.10.1118 17356034\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "16(5)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000069340:Deprescriptions; D005260:Female; D006801:Humans; D057970:Inappropriate Prescribing; D008297:Male; D010595:Pharmacists; D000067561:Potentially Inappropriate Medication List; D011320:Primary Health Care", "nlm_unique_id": "101285081", "other_id": null, "pages": "e0252151", "pmc": null, "pmid": "34033661", "pubdate": "2021", "publication_types": "D016428:Journal Article; D016454:Review", "references": "17608246;25039690;11456032;31908421;30084141;24589926;24763332;29322475;22253191;30215820;30766361;8610730;21729848;24073682;31288397;25371236;24637879;24191087;26010119;29017448;17356034;26654719;32482500;29577766;22114827;25561640", "title": "Pharmacist medication review: An integrated team approach to serve home-based primary care patients.", "title_normalized": "pharmacist medication review an integrated team approach to serve home based primary care patients" }

[ { "companynumb": "US-AUROBINDO-AUR-APL-2022-022718", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TORSEMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "78249", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TORSEMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "93", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anticoagulation drug level above therapeutic", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Monzon-Kenneke M, Chiang P, Yao NA, Greg M.. Pharmacist medication review: An integrated team approach to serve home-based primary care patients. 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Pharmacist medication review: An integrated team approach to serve home-based primary care patients. [Review]. PLOS-One 2021;16(5):1-13.", "literaturereference_normalized": "pharmacist medication review an integrated team approach to serve home based primary care patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220614", "receivedate": "20220614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20956059, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220720" } ]

{ "abstract": "OBJECTIVE\nTrastuzumab improves overall survival for women with HER2-positive breast cancer but is associated with cardiotoxicity, especially when administered after anthracyclines. Use of non-anthracycline trastuzumab-based regimens is rising, particularly for patients with low-risk disease or with multiple cardiovascular risk factors. We performed a single-center retrospective cohort study to assess the cardiac safety of trastuzumab without anthracyclines outside of a clinical trial setting.\n\n\nMETHODS\nA retrospective chart review was conducted of patients with HER2-positive early-stage breast cancer receiving non-anthracycline trastuzumab-based therapy between January 2010 and June 2014. Cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. The primary outcome was a cardiac event (CE), defined by New York Heart Association class III or IV heart failure or cardiac death. The secondary outcome was a significant asymptomatic decline of LVEF (>10% to <55% or >16% from baseline).\n\n\nRESULTS\nA total of 165 patients were identified with a median age of 59 years (range 32-85 years). Seventy (42%) had hypertension, 52 (32%) had hyperlipidemia, 29 (18%) had diabetes, and 5 (3%) had coronary artery disease. All patients had a LVEF >50% (median 67%; range 50-80%) at baseline. Two (1.2%) patients with multiple cardiovascular risk factors developed a CE. After discontinuation of trastuzumab, both patients had recovery of LVEF to >50% and resolution of heart failure symptoms. Ten (6.1%) patients developed significant asymptomatic LVEF decline during trastuzumab therapy.\n\n\nCONCLUSIONS\nThe overall incidence of symptomatic heart failure and asymptomatic LVEF decline among patients receiving trastuzumab without anthracyclines remains low. These findings suggest that less intensive cardiac monitoring may be appropriate during trastuzumab therapy without anthracyclines.", "affiliations": "Department of Medicine, Cardiology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. yua3@mskcc.org.;Department of Medicine, Cardiology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Cardiology, Maimonides Medical Center, Brooklyn, NY, USA.;Department of Medicine, Cardiology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Division of Survivorship and Supportive Care, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Cardiology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, Brooklyn, NY, USA.;Department of Medicine, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, Brooklyn, NY, USA.", "authors": "Yu|Anthony F|AF|;Mukku|Roy B|RB|;Verma|Shivani|S|;Liu|Jennifer E|JE|;Oeffinger|Kevin C|KC|;Steingart|Richard M|RM|;Hudis|Clifford A|CA|;Dang|Chau T|CT|", "chemical_list": "D018943:Anthracyclines; D014408:Biomarkers, Tumor; D018719:Receptor, ErbB-2; D000068878:Trastuzumab", "country": "Netherlands", "delete": false, "doi": "10.1007/s10549-017-4362-x", "fulltext": null, "fulltext_license": null, "issn_linking": "0167-6806", "issue": "166(1)", "journal": "Breast cancer research and treatment", "keywords": "Cardio-oncology; Cardiotoxicity; Heart failure; Trastuzumab", "medline_ta": "Breast Cancer Res Treat", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms; D066126:Cardiotoxicity; D005260:Female; D006333:Heart Failure; D006334:Heart Function Tests; D006801:Humans; D008875:Middle Aged; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D012307:Risk Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left", "nlm_unique_id": "8111104", "other_id": null, "pages": "241-247", "pmc": null, "pmid": "28710537", "pubdate": "2017-11", "publication_types": "D016428:Journal Article", "references": "19561291;26392097;22987084;21991949;23158536;24912899;16236738;20530269;24007746;22949432;16376782;26539793;24584736;25564897;22614986;25172399;26240135;27091709;22614988", "title": "Cardiac safety of non-anthracycline trastuzumab-based therapy for HER2-positive breast cancer.", "title_normalized": "cardiac safety of non anthracycline trastuzumab based therapy for her2 positive breast cancer" }

[ { "companynumb": "US-MYLANLABS-2018M1004867", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091540", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRASTUZUMAB" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRASTUZUMAB." } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary oedema", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "YU AF, MUKKU RB, VERMA S, LIU JE, OEFFINGER KC, STEINGART RM, ET AL. CARDIAC SAFETY OF NON-ANTHRACYCLINE TRASTUZUMAB-BASED THERAPY FOR HER2-POSITIVE BREAST CANCER. BREAST-CANCER-RES-TREAT 2017?166(1):241-247.", "literaturereference_normalized": "cardiac safety of non anthracycline trastuzumab based therapy for her2 positive breast cancer", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180123", "receivedate": "20180123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14424948, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "BACKGROUND\nPerforation of intramural metastasis to the stomach (IMS) from esophageal cancer during chemotherapy has not been reported.\n\n\nMETHODS\nA 68-year-old male consulted our hospital due to appetite loss. He was diagnosed with advanced esophageal squamous cell carcinoma in the lower thoracic esophagus along with a large IMS in the upper stomach. The patient received preoperative chemotherapy of docetaxel, cisplatin, and 5-fluorouracil (DCF). During the second cycle of DCF, he had upper abdominal pain and was diagnosed with gastric perforation. Omental implantation repair for the perforation, peritoneal drainage, tube-gastrostomy, and tube-jejunostomy were performed. At 24 days after emergency surgery, he underwent thoracoscopic radical esophagectomy with total gastrectomy and reconstruction with colonic interposition. Pathological findings in the esophagus demonstrated complete replacement of the tumor by fibrosis. The gastric tumor was replaced by scar tissue with multinucleated giant cells along with a small amount of viable cancer cells. The patient was alive and healthy at 14 months after the radical operation, without tumor recurrence.\n\n\nCONCLUSIONS\nThe gastric perforation occurred due to rapid regression of the IMS which had involved the whole gastric wall before chemotherapy. Close monitoring to detect rapid tumor shrinkage during chemotherapy in patients with IMS may be warranted. A two-step operation was proposed to achieve safe curative treatment in patients with perforation of IMS during preoperative chemotherapy.\n\n\nCONCLUSIONS\nWe describe the first reported case of a patient with esophageal squamous cell carcinoma who showed perforation of IMS during preoperative chemotherapy.", "affiliations": "Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 2630 Sugitani, Toyama City, Toyama 930-0194, Japan. Electronic address: okumura@med.u-toyama.ac.jp.;Department of Nanobio Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.;Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 2630 Sugitani, Toyama City, Toyama 930-0194, Japan.;Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 2630 Sugitani, Toyama City, Toyama 930-0194, Japan.;Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 2630 Sugitani, Toyama City, Toyama 930-0194, Japan.;Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 2630 Sugitani, Toyama City, Toyama 930-0194, Japan.;Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama2630 Sugitani, Toyama City, Toyama 930-0194, Japan.;Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 2630 Sugitani, Toyama City, Toyama 930-0194, Japan.;Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 2630 Sugitani, Toyama City, Toyama 930-0194, Japan.", "authors": "Okumura|Tomoyuki|T|;Shimada|Yutaka|Y|;Hojo|Shozo|S|;Sekine|Shinich|S|;Hirano|Katsuhisa|K|;Moriyama|Makoto|M|;Miwa|Shigeharu|S|;Nagata|Takuya|T|;Tsukada|Kazuhiro|K|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": null, "fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(15)00460-510.1016/j.ijscr.2015.10.024Case ReportPerforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma Okumura Tomoyuki okumura@med.u-toyama.ac.jpa⁎Shimada Yutaka bHojo Shozo aSekine Shinich aHirano Katsuhisa aMoriyama Makoto aMiwa Shigeharu cNagata Takuya aTsukada Kazuhiro aa Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 2630 Sugitani, Toyama City, Toyama 930-0194, Japanb Department of Nanobio Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japanc Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama2630 Sugitani, Toyama City, Toyama 930-0194, Japan⁎ Corresponding author. Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama 2630 Sugitani, Toyama City, Toyama 930-0194, Japan. Fax: +81 76 434 5043. okumura@med.u-toyama.ac.jp21 10 2015 2015 21 10 2015 17 23 27 19 9 2015 12 10 2015 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• A case showed perforation of gastric intramural metastasis from esophageal cancer.\n\n• Rapid tumor regression by preoperative chemotherapy may cause the perforation.\n\n• Minimally invasive curative resection was achieved by a two-step operation.\n\n\n\nIntroduction\nPerforation of intramural metastasis to the stomach (IMS) from esophageal cancer during chemotherapy has not been reported.\n\nPresentation of case\nA 68-year-old male consulted our hospital due to appetite loss. He was diagnosed with advanced esophageal squamous cell carcinoma in the lower thoracic esophagus along with a large IMS in the upper stomach. The patient received preoperative chemotherapy of docetaxel, cisplatin, and 5-fluorouracil (DCF). During the second cycle of DCF, he had upper abdominal pain and was diagnosed with gastric perforation. Omental implantation repair for the perforation, peritoneal drainage, tube-gastrostomy, and tube-jejunostomy were performed.\n\nAt 24 days after emergency surgery, he underwent thoracoscopic radical esophagectomy with total gastrectomy and reconstruction with colonic interposition. Pathological findings in the esophagus demonstrated complete replacement of the tumor by fibrosis. The gastric tumor was replaced by scar tissue with multinucleated giant cells along with a small amount of viable cancer cells. The patient was alive and healthy at 14 months after the radical operation, without tumor recurrence.\n\nDiscussion\nThe gastric perforation occurred due to rapid regression of the IMS which had involved the whole gastric wall before chemotherapy. Close monitoring to detect rapid tumor shrinkage during chemotherapy in patients with IMS may be warranted. A two-step operation was proposed to achieve safe curative treatment in patients with perforation of IMS during preoperative chemotherapy.\n\nConclusion\nWe describe the first reported case of a patient with esophageal squamous cell carcinoma who showed perforation of IMS during preoperative chemotherapy.\n\nKeywords\nEsophageal cancerIntramural gastric metastasisNeoadjuvant chemotherapy\n==== Body\n1 Introduction\nIntramural metastasis to the stomach (IMS) from esophageal cancer is rare [1], [2], but is considered to be one of the most important poor-prognosis factors associated with a higher risk of distant metastasis [3].\n\nGastro-intestinal perforations during chemotherapy can be caused by rapid tumor shrinkage and necrosis due to chemotherapy [4]. The incidence and high mortality rate associated with surgery for patients with perforation of gastric cancer or gastric lymphoma during chemotherapy have been reported [4], [5]; however, no article could be found that described perforation of IMS from esophageal cancer.\n\nHere, we report a case of esophageal squamous cell carcinoma (ESCC) which showed perforation of IMS during preoperative chemotherapy.\n\n2 Case report\nA 68-year-old male consulted one of our hospitals due to appetite loss in May 2014. An upper gastrointestinal (GI) endoscopy revealed an advanced tumor in the lower thoracic esophagus (Fig. 1A) along with a submucosal tumor-like lesion in the upper stomach (Fig. 1B). Endoscopic biopsy from both tumors revealed moderately differentiated squamous cell carcinoma (Fig. 1C). Computed tomography (CT) showed high-density tumors in the lower thoracic esophagus (Fig. 1D) and upper stomach (Fig. 1E), but no evidence of lymph node involvement. The disease was diagnosed as ESCC with IMS, T3N0M1b Stage IVB, according to the classification of the Union for International Cancer Control (UICC, version 7).\n\nThe patient received preoperative chemotherapy of docetaxel, cisplatin, and 5-fluorouracil (DCF), which consisted of i.v. docetaxel (70 mg/m2) and cisplatin (70 mg/m2) on day 1, and the continuous infusion of fluorouracil (750 mg/m2/day) on days 1–5 [6]. The regimen was planned to be repeated every 3 weeks with a maximum of three cycles. The patient showed the nadir of immunosuppression on day 10 with febrile neutropenia (neutrophils:450/mm3) and recovered by treatment with granulocyte-colony stimulating factor and antibiotics.\n\nOn day 5 of the second cycle of DCF, the patient had sudden upper abdominal pain. CT demonstrated tumor regression in the lower esophagus (Fig. 2A). Free air and limited ascites were seen around the regressed tumor in the upper part of the stomach (Fig. 2B).\n\nHe was diagnosed with acute panperitonitis due to gastric perforation and received emergency surgery. Surgical findings revealed a 7-mm perforation at the centre of the induration in the upper part of the anterior wall of the stomach (Fig. 2C). There was no tumor mass in the gastric wall. Peritoneal lavage, peritoneal drainage, omental implantation repair for the perforation, tube gastrostomy for gastric drainage and tube jejunostomy for feeding were performed. The patient recovered from surgery without any complications.\n\nAt 24 days after the emergency surgery, he underwent thoracoscopic radical esophagectomy with total gastrectomy, followed by reconstruction with colonic interposition. The patient again recovered from surgery without complications.\n\nThe gross appearance of the resected specimen revealed tumor regression both in the lower esophagus and stomach (Fig. 3). Pathological findings in the lesion of the lower esophagus demonstrated complete re-epithelialization and the replacement of submucosa and muscularis propria by fibrosis (Fig. 4A). Multinucleated giant cells that had phagocytosed cornified substances were observed scattered throughout the muscularis propria, indicating that squamous cell carcinoma which had involved the deep part of the muscularis propria had completely regressed with chemotherapy (Fig. 4A). Pathological findings in the perforated ulcer scar in the stomach demonstrated that the gastric wall had been replaced by scar tissue containing multinucleated giant cells, indicating the involvement of squamous carcinoma in all layers of the gastric wall before chemotherapy (Fig. 4B). Although a small number of viable cancer cells were seen at the horizontal margin of the scar, there was no evidence of the residual tumor.\n\nNo metastasis was observed in any of the dissected mediastinal or abdominal lymph nodes. Peritoneal lavage cytology showed no malignant cells. The patient has been closely observed as an outpatient and was alive and healthy at 14 months after the radical operation, without any evidence of tumor recurrence.\n\n3 Discussion\nIMS from esophageal cancer is rare with an incidence of 1–1.7% in surgically resected cases [1], [2], but the incidence increases up to 15% in autopsy cases [7]. The predominant location of the primary esophageal carcinomas and IMS have been reported to be the middle/lower thoracic esophagus and gastric body close to the esophagocardial junction, respectively [1]. Histologically, the incidence of moderately differentiated squamous cell carcinoma has been reported to be the highest [1], with all findings consistent with our present case.\n\nMicrolymphatics in the esophageal submucosa which are continuous with those of the gastric submucosa are considered to play a key role in IMS [8].\n\nThe prognosis for esophageal cancer patients with IMS has been reported to be poor, with an 11.9% postoperative 5-year survival rate due to a higher rate of distant metastasis [3]. Therefore, IMS from esophageal cancer is categorized as a distant metastasis described as M1b Stage IVB, according to the UICC Classification.\n\nOn the other hand, recent progress in preoperative chemotherapy has facilitated an improved postoperative prognosis even in advanced esophageal cancer patients. Based on the results of a Japan Clinical Oncology Study Group trial (JCOG 9907), preoperative chemotherapy with cisplatin and 5-fluorouracil (CF) is regarded as a standard treatment for Stage II/III ESCC in Japan [9]. To further improve survival, a phase II trial demonstrated the feasibility of preoperative DCF for Stage II/III ESCC with an overall response rate of 64.3% [6]. DCF also led to improvement in both rapid tumor shrinkage and the survival benefit [6]. Accordingly, a randomized controlled trial comparing CF versus DCF versus chemoradiation as neoadjuvant therapy for locally advanced esophageal cancer is in progress [10]. In addition, preoperative DCF was also reported to be effective in patients with Stage IV (M1-lymph) disease of esophageal cancer [11]. Based on this reported evidence, the present case with IMS received preoperative DCF.\n\nOncological gastrointestinal perforation has several causes, such as spontaneous tumor rupture with rapid tumor progression, mucosal epithelial cytotoxicity of the anticancer agents or corticosteroids, and rapid tumor shrinkage or necrosis due to chemotherapy [6], [7], [12]. In the present case, the pathological findings of the perforated stomach demonstrated total replacement of the gastric wall by fibrosis containing multinucleated giant cells which phagocytosed squamous cell carcinoma, indicating that the perforation occurred due to rapid regression of the IMS which had involved in the whole gastric wall before chemotherapy.\n\nIn the present case, we started the second cycle of DCF without imaging diagnosis to assess the response to the first cycle. A close observation using CT or upper GI endoscopy is proposed before starting the next cycle of chemotherapy, not only to rule out the progression of the tumor due to a poor therapeutic response, but also to rule out too rapid tumor regression of large IMS.\n\nThe mortality rate following surgery for perforated gastric cancer during chemotherapy was reported to be 40 to 80%, because of immunosuppression and/or undernutrition [6]. In the present case, considering that the nadir of neutropenia was predicted at 5 days after perforation, we performed a two-step operation. Firstly, we performed repair of the perforation, peritoneal drainage, gastric drainage, and tube jejunostomy for feeding to support recovery with minimal surgical invasion. Then, we could safely perform a radical resection after the recovery of the general status without any perioperative complications.\n\n4 Conclusions\nHere, we describe, to our knowledge, the first reported case of a patient with esophageal squamous cell carcinoma who showed perforation of IMS during chemotherapy. Close monitoring to detect rapid tumor shrinkage during chemotherapy in patients with large IMS may be warranted. A two-step operation was proposed to achieve curative treatment with safety and minimal surgical invasion in a patient with perforation of IMS during preoperative chemotherapy.\n\nAuthors’ contributions\nTomoyuki Okumura: Played a role in the study conception and design, obtained informed consent, performed the surgical procedures and patient care, and wrote the manuscript.\n\nYutaka Shimada: Played a role in the study conception and design and wrote the manuscript.\n\nShozo Hojo: Played a role in the study conception and design and performed the surgical procedures and patient care.\n\nKatsuhisa Hirano: Played a role in the study conception and design, performed the surgical procedures and patient care, and wrote the manuscript.\n\nShinich Sekine: Played a role in the study conception and design, performed the surgical procedures and patient care, and wrote the manuscript.\n\nMakoto Moriyama: Played a role in the study conception and design, performed the surgical procedures and patient care, and wrote the manuscript.\n\nShigeharu Miwa: Performed pathological diagnosis.\n\nTakuya Nagata: Played a role in the study conception and design, performed the surgical procedures and patient care, and wrote the manuscript.\n\nKazuhiro Tsukada: Played a role in the study conception and design, performed the surgical procedures and patient care, and wrote the manuscript.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAcknowledgment\nThis work was partly supported by theGrant-in-Aid for Scientific Research (C)MEXT KAKENHIGrant number 15K10088.\n\nFig. 1 (a) Upper gastrointestinal endoscopy showed an advanced tumor in the lower thoracic esophagus. (b) Upper gastrointestinal endoscopy showed a submucosal tumor-like lesion in the upper stomach. (c) Endoscopic biopsy from both tumors revealed moderately differentiated squamous cell carcinoma. (d) CT showed high-density tumors in the lower thoracic esophagus. (e) CT showed high-density tumors in the upper stomach.\n\nFig. 2 (a) CT demonstrated tumor regression in the lower esophagus on day 5 of the second cycle of DCF. (b) CT demonstrated free air and limited ascites around the regressed tumor in the upper part of the stomach. (c) Surgical findings showed perforation in the upper part of the stomach.\n\nFig. 3 The gross appearance of the resected specimen revealed tumor regression in both the lower esophagus and stomach.\n\nFig. 4 (a) Pathological findings in the lesion of the lower esophagus demonstrated complete re-epithelialization, and replacement of the submucosa and muscularis propria by fibrosis. Multinucleated giant cells that had phagocytosed cornified substances were observed scattered throughout the muscularis propria. (b) Pathological findings in the perforated ulcer scar in the stomach demonstrated that the gastric wall had been replaced by scar tissue containing multinucleated giant cells. A small number of viable cancer cells were seen at the horizontal margin of the scar.\n==== Refs\nReferences\n1 Saito T. Iizuka T. Kato H. Watanabe H. Esophageal carcinoma metastatic to the stomach: a clinicopathologic study of 35 cases Cancer 56 1985 2235 2241 4052968 \n2 Ebihara Y. Hosokawa M. Kondo S. Katoh H. Thirteen cases with intramural metastasis to the stomach in 1259 patients with oesophageal squamous cell carcinoma Eur. J. Cardiothorac. Surg. 26 2004 1223 1225 15541989 \n3 Kato H. Tachimori Y. Watanabe H. Intramural metastasis of thoracic esophageal carcinoma Int. J. Cancer 50 1992 49 52 1728612 \n4 Chao T. Wang C. Chen M. Gastroduodenal perforation in cancer patients Hepatogastroenterology 46 1999 1878 1881 \n5 Spectre G. Libster D. Grisariu S. Da'as N. Yehuda D.B. Gimmon Z. Bleeding, obstruction, and perforation in a series of patients with aggressive gastric lymphoma treated with primary chemotherapy Ann. Surg. Oncol. 13 2006 1372 1378 17009162 \n6 Hara H. Tahara M. Daiko H. Kato K. Igaki H. Kadowaki S. Phase II. feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma Cancer Sci. 104 2013 1455 1460 23991649 \n7 Anderson L.L. Lad T.E. Autopsy findings in squamous-cell carcinoma of the esophagus Cancer 50 1982 1587 1590 7116290 \n8 Uehara M. Manaka D. Matsutani Y. Oji Y. Takemura K. Shimizu M. Gastric wall metastasis from esophageal carcinoma: report of a case Jpn. J. Gastroenterol. Surg. 41 2008 41 45 \n9 Ando N. Kato H. Igaki H. Shinoda M. Ozawa S. Shimizu H. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907) Ann. Surg. Oncol. 19 2012 68 74 21879261 \n10 Nakamura K. Kato K. Igaki H. Ito Y. Mizusawa J. Ando N. Three-arm phase III. trial comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer (JCOG1109, NExT study) Jpn. J. Clin. Oncol. 43 2013 752 755 23625063 \n11 Ui T. Fujii H. Hosoya Y. Nagase M. Mieno M.N. Mori M. Comparison of preoperative chemotherapy using docetaxel, cisplatin and fluorouracil with cisplatin and fluorouracil in patients with advanced carcinoma of the thoracic esophagus Dis. Esophagus 28 2015 180 187 24529073 \n12 Rose P.G. Piver M.S. Intestinal perforation secondary paclitaxel Gynecol. Oncol. 57 1995 270 272 7729749\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2210-2612", "issue": "17()", "journal": "International journal of surgery case reports", "keywords": "Esophageal cancer; Intramural gastric metastasis; Neoadjuvant chemotherapy", "medline_ta": "Int J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101529872", "other_id": null, "pages": "23-7", "pmc": null, "pmid": "26519812", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "7729749;15541989;24529073;4052968;21879261;17009162;23625063;1728612;23991649;7116290", "title": "Perforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma.", "title_normalized": "perforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma" }

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PERFORATION OF INTRAMURAL GASTRIC METASTASIS DURING PREOPERATIVE CHEMOTHERAPY IN A PATIENT WITH THORACIC ESOPHAGEAL SQUAMOUS CELL CARCINOMA. INT-J-SURG-CASE-REP 2015?1723-1727.", "literaturereference_normalized": "perforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11828209, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" }, { "companynumb": "JP-TEVA-616152ISR", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MG/M2 DAILY; ON DAYS 1-5.", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "203877", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70 MG/M2 ON DAY 1.", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74656", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70 MG/M2 ON DAY 1.", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastric perforation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peritonitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKUMURA T, SHIMADA Y, HOJO S, SEKINE S, HIRANO K, MORIYAMA M, ET AL. PERFORATION OF INTRAMURAL GASTRIC METASTASIS DURING PREOPERATIVE CHEMOTHERAPY IN A PATIENT WITH THORACIC ESOPHAGEAL SQUAMOUS CELL CARCINOMA. INT-J-SURG-CASE-REP 2015? 17:23-27.", "literaturereference_normalized": "perforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151209", "receivedate": "20151209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11814362, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" }, { "companynumb": "JP-MYLANLABS-2015M1042148", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "70 MG/M2 ON DAY 1.", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MG/M2/DAY ON DAYS 1-5.", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091062", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "70 MG/M2 ON DAY 1.", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastric perforation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peritonitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKUMURA T, SHIMADA Y, HOJO S, SEKINE S, HIRANO K, MORIYAMA M, ET AL. PERFORATION OF INTRAMURAL GASTRIC METASTASIS DURING PREOPERATIVE CHEMOTHERAPY IN A PATIENT WITH THORACIC ESOPHAGEAL SQUAMOUS CELL CARCINOMA. INT-J-SURG-CASE-REP 2015? 17:23-27.", "literaturereference_normalized": "perforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151209", "receivedate": "20151201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11789750, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" }, { "companynumb": "JP-SA-2015SA185453", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, 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}, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "020449", 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"medicinalproduct": "FLUOROURACIL." } ], "patientagegroup": "6", "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Gastric perforation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peritonitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKUMURA T, SHIMADA Y, HOJO S, SEKINE S, HIRANO K, MORIYAMA M, ET AL. PERFORATION OF INTRAMURAL GASTRIC METASTASIS DURING PREOPERATIVE CHEMOTHERAPY IN A PATIENT WITH THORACIC ESOPHAGEAL SQUAMOUS CELL CARCINOMA. INT J SURG CASE REP. 2015 JAN 01?17:23-7. AVAILABLE FROM: HTTP://DX.DOI.ORG/10/1016.J.IJSCR.2015.10.024.", "literaturereference_normalized": "perforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151230", "receivedate": "20151123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11767460, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "JP-ACCORD-035417", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "201195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "040743", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "CONTINUOUS INFUSION OF FLUOROURACIL (750 MG/M^2/DAY) ON DAYS 1-5.", "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA STAGE IV", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastric perforation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Immunosuppression", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peritonitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OKUMURA T, SHIMADA Y, HOJO S, SEKINE S, HIRANO K, MORIYAMA M, ET AL. PERFORATION OF INTRAMURAL GASTRIC METASTASIS DURING PREOPERATIVE CHEMOTHERAPY IN A PATIENT WITH THORACIC ESOPHAGEAL SQUAMOUS CELL CARCINOMA. INT J SURG CASE REP. 2015 OCT 21?17:23-27.", "literaturereference_normalized": "perforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151117", "receivedate": "20151117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11745010, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "Sporadic Creutzfeld Jakob Disease is a rare disease with diagnostic challenges. While there is very little human data regarding this disease, some studies have indicated that certain medications may be useful in slowing its progression. Case study data implies psychiatric and cognitive symptoms preceding the diagnosis. This single case report presents a 68-year-old male with suspected late-onset bipolar disorder, later found to have sporadic Creutzfeld Jakob Disease. The patient was treated with lithium for this purported bipolar disorder. Approximately 2 years later, the patient met the Center for Disease Control (CDC) diagnostic criteria for prion disease following a rapid decline in cognition. This case provides an example of a medical mimic of bipolar disorder in the geriatric population.", "affiliations": "Union Hospital Family Medicine Residency, Terre Haute, IN, USA.;Union Hospital Family Medicine Residency, Terre Haute, IN, USA.;Union Hospital Family Medicine Residency, Terre Haute, IN, USA.", "authors": "Cadick|Amber L|AL|https://orcid.org/0000-0002-8585-3031;Ehresman|Robert M|RM|;Jones|Jonathan A|JA|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/00912174211010529", "fulltext": null, "fulltext_license": null, "issn_linking": "0091-2174", "issue": null, "journal": "International journal of psychiatry in medicine", "keywords": "Creutzfed Jakob Disease; geriatric; mania; mimic; prion", "medline_ta": "Int J Psychiatry Med", "mesh_terms": null, "nlm_unique_id": "0365646", "other_id": null, "pages": "912174211010529", "pmc": null, "pmid": "33853439", "pubdate": "2021-04-14", "publication_types": "D016428:Journal Article", "references": null, "title": "Identifying medical mimics for late-life mania: A case of prion disease.", "title_normalized": "identifying medical mimics for late life mania a case of prion disease" }

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{ "abstract": "Case 1: An 80-year-old man was diagnosed with cecal cancer plus multiple liver metastases and peritoneal disseminations. He underwent surgical resection of the primary tumor to prevent bowel obstruction. Initially, hepatic arterial infusion(HAI) plus cetuximab(Cmab)was administered to reduce the size of the metastatic tumors and prevent liver failure. A partial response(PR)was observed in the liver metastases after 12 courses of treatment and S-1 plus oxaliplatin(SOX)plus bevacizumab was started. Case 2: A 44-year-old man was diagnosed with sigmoid colon cancer with multiple liver, lung and bone metastases, and with obstructive jaundice and cholangitis due to severe liver hilum lymph node metastases. His performance status(PS)score was 3 because of severe liver damage. Initially, he underwent endoscopic nasobiliary drainage for obstructive jaundice, and HAI plus Cmab was started to prevent liver dysfunction and to control all metastases. A PR in the metastatic liver tumors was observed after 18 courses. His PS increased to 1 and he was treated with mFOLFOX6 plus Cmab. HAI plus Cmab might be a treatment option for patients who have RAS-wild type tumors with severe liver dysfunction due to multiple liver metastases; HAI is intended to have few side effects and has a high local control rate.", "affiliations": "Dept. of Colorectal Surgery, Tokyo Medical and Dental University, Medical Hospital.", "authors": "Orita|Fukuichiro|F|;Ishikawa|Toshiaki|T|;Sasaki|Megumi|M|;Miura|Tomiyuki|T|;Tokura|Michiyo|M|;Hanaoka|Marie|M|;Yamauchi|Shinichi|S|;Kikuchi|Akifumi|A|;Ishiguro|Megumi|M|;Yasuno|Masamichi|M|;Uetake|Hiroyuki|H|", "chemical_list": "D000068818:Cetuximab", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "44(12)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001063:Appendiceal Neoplasms; D000068818:Cetuximab; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms; D008297:Male; D012811:Sigmoid Neoplasms", "nlm_unique_id": "7810034", "other_id": null, "pages": "1245-1247", "pmc": null, "pmid": "29394595", "pubdate": "2017-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Two Cases of Colon Cancer with Severe Liver Dysfunction Due to Multiple Liver Metastases Effectively Treated with Hepatic Arterial Infusion Chemotherapy plus CetuximabFollowed by Systemic Chemotherapy.", "title_normalized": "two cases of colon cancer with severe liver dysfunction due to multiple liver metastases effectively treated with hepatic arterial infusion chemotherapy plus cetuximabfollowed by systemic chemotherapy" }

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TWO CASES OF COLON CANCER WITH SEVERE LIVER DYSFUNCTION DUE TO MULTIPLE LIVER METASTASES EFFECTIVELY TREATED WITH HEPATIC ARTERIAL INFUSION CHEMOTHERAPY PLUS CETUXIMABFOLLOWED BY SYSTEMIC CHEMOTHERAPY. 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JPN J CANCER CHEMOTER. 2017?NOV? 44(12):1245-1247", "literaturereference_normalized": "two cases of colon cancer with severe liver dysfunction due to multiple liver metastases effectively treated with hepatic arterial infusion chemotherapy plus cetuximabfollowed by systemic chemotherapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180628", "receivedate": "20180628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15080281, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" } ]

{ "abstract": "An 11-year-old boy with Down syndrome and acute lymphoblastic leukemia developed hepatic dysfunction after only 10 months of treatment. MRI revealed severe iron deposition in the liver, pancreas, and heart. In stark contrast to what is seen in hemoglobinopathies, pancreatic and cardiac iron overload occurred with relatively low transfusion exposure and in a very short time period in this patient. Although extensive experience managing iron overload in hemoglobinopathies informs our approach in other diseases, it is clear that factors not present in hemoglobinopathies may be operative in patients with malignancy undergoing intense chemotherapy that lead to high levels of free iron and rapid loading of the heart and endocrine organs.", "affiliations": "Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California; and.;Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California; and Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California tcoates@chla.usc.edu.;Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California; and Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California.", "authors": "Reitman|Aaron J|AJ|;Coates|Thomas D|TD|;Freyer|David R|DR|", "chemical_list": "D000970:Antineoplastic Agents", "country": "United States", "delete": false, "doi": "10.1542/peds.2014-3770", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-4005", "issue": "136(3)", "journal": "Pediatrics", "keywords": null, "medline_ta": "Pediatrics", "mesh_terms": "D000970:Antineoplastic Agents; D001803:Blood Transfusion; D002648:Child; D006801:Humans; D019190:Iron Overload; D008297:Male; D009206:Myocardium; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D065227:Transfusion Reaction; D016896:Treatment Outcome", "nlm_unique_id": "0376422", "other_id": null, "pages": "e697-700", "pmc": null, "pmid": "26283784", "pubdate": "2015-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "21072815;9375751;19059052;18413890;20846597;25048454;19912219;22404220;18039957;18334672;16138345;17599610;24726864;17385941;18650452;20974500;18623223;19557769;12937413;23861216;11134212;24962841;17899187;12416732", "title": "Early Cardiac Iron Overload in a Child on Treatment of Acute Lymphoblastic Leukemia.", "title_normalized": "early cardiac iron overload in a child on treatment of acute lymphoblastic leukemia" }

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{ "abstract": "Polyarteritis nodosa (PAN) is a rare vasculitis affecting medium-sized vessels. Cutaneous PAN is a clinical variant, and we report the first case of empagliflozin-induced cutaneous PAN in a 69-year-old man. After starting empagliflozin, the patient presented with tender subcutaneous nodules on his legs, which showed a medium-sized vessel vasculitis on histopathology. Upon cessation of this medication, he had full resolution of these nodules. This case illustrates that empagliflozin can induce cutaneous PAN, and further attention to this medication's association with cutaneous PAN is warranted.", "affiliations": "1 Division of Dermatology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada.;2 Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, Canada.;1 Division of Dermatology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada.", "authors": "To|Derek|D|;Bradshaw|Scott|S|;Lipson|Jennifer|J|", "chemical_list": "D001559:Benzhydryl Compounds; D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin", "country": "United States", "delete": false, "doi": "10.1177/1203475418760457", "fulltext": null, "fulltext_license": null, "issn_linking": "1203-4754", "issue": "22(5)", "journal": "Journal of cutaneous medicine and surgery", "keywords": "cutaneous polyarteritis nodosa; drug induced; empagliflozin", "medline_ta": "J Cutan Med Surg", "mesh_terms": "D000368:Aged; D001559:Benzhydryl Compounds; D003924:Diabetes Mellitus, Type 2; D005960:Glucosides; D006801:Humans; D007866:Leg; D008297:Male; D010488:Polyarteritis Nodosa; D000077203:Sodium-Glucose Transporter 2 Inhibitors", "nlm_unique_id": "9614685", "other_id": null, "pages": "516-518", "pmc": null, "pmid": "29457486", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Case Report of Empagliflozin-Induced Cutaneous Polyarteritis Nodosa.", "title_normalized": "case report of empagliflozin induced cutaneous polyarteritis nodosa" }

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{ "abstract": "A 49-year-old man with no previous history of musculoskeletal or cutaneous problems who had a myocardial infarction (MI) was treated with atorvastatin, prasugrel, enoxaparine, and diltiazem following percutaneous coronary intervention. He was referred to our rheumatology outpatient clinic for rash and papules on the knuckles, face, and neck, as well as proximal muscle weakness. In the physical examination, a reddish rash on the face and Gottron's papules on the knuckles were detected. The skin biopsy performed indicated interface dermatitis with hydropic degeneration of basal keratinocytes, supporting the clinical impression of dermatomyositis. He was started on prednisolone 1 mg/kg/day. After 30 days of prednisolone therapy, all symptoms disappeared.", "affiliations": "Division of Internal Medicine, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey. dr.mertoztas@gmail.com.;Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey.;Department of Pathology, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey.", "authors": "Oztas|Mert|M|;Ugurlu|Serdal|S|;Aydin|Ovgu|O|", "chemical_list": "D005938:Glucocorticoids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011239:Prednisolone; D000069059:Atorvastatin", "country": "Germany", "delete": false, "doi": "10.1007/s00296-017-3658-9", "fulltext": null, "fulltext_license": null, "issn_linking": "0172-8172", "issue": "37(7)", "journal": "Rheumatology international", "keywords": "Atorvastatin; Dermatomyositis; Statin-induced dermatomyositis", "medline_ta": "Rheumatol Int", "mesh_terms": "D000069059:Atorvastatin; D001706:Biopsy; D003882:Dermatomyositis; D005938:Glucocorticoids; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D012074:Remission Induction; D016896:Treatment Outcome", "nlm_unique_id": "8206885", "other_id": null, "pages": "1217-1219", "pmc": null, "pmid": "28238074", "pubdate": "2017-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "9613910;14963215;22928274;26886523;16581329;11388341;7968073;19813188;26226717;25943841", "title": "Atorvastatin-induced dermatomyositis.", "title_normalized": "atorvastatin induced dermatomyositis" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DILTIAZEM." } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dermatomyositis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash generalised", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myopathy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201411" } }, "primarysource": { "literaturereference": "OZTAS M, UGURLU S, AYDIN O.. ATORVASTATIN-INDUCED DERMATOMYOSITIS.. RHEUMATOLOGY INTERNATIONAL. 2017;37(7):1217-9", "literaturereference_normalized": "atorvastatin induced dermatomyositis", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20170724", "receivedate": "20170724", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13784306, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "TR-MYLANLABS-2017M1045268", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ATORVASTATIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "091226", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATORVASTATIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DILTIAZEM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PRASUGREL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRASUGREL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ENOXAPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dermatomyositis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201411" } }, "primarysource": { "literaturereference": "OZTAS M, UGURLU S, AYDIN O. ATORVASTATIN-INDUCED DERMATOMYOSITIS. RHEUMATOL-INT 2017;37(7):1217-1219.", "literaturereference_normalized": "atorvastatin induced dermatomyositis", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20170729", "receivedate": "20170729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13813276, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "FR-PFIZER INC-2017476752", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ATORVASTATIN CALCIUM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "020702", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE IIA HYPERLIPIDAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATORVASTATIN CALCIUM." } ], "patientagegroup": null, "patientonsetage": "44", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dermatomyositis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NOEL, B.. ATORVASTATIN-INDUCED DERMATOMYOSITIS. THE AMERICAN JOURNAL OF MEDICINE. 2001;110 (8):670-671", "literaturereference_normalized": "atorvastatin induced dermatomyositis", "qualification": "1", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20171113", "receivedate": "20171106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14162502, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "TR-LANNETT COMPANY, INC.-TR-2017LAN000979", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PRASUGREL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRASUGREL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DILTIAZEM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ATORVASTATIN CALCIUM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "091624", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATORVASTATIN CALCIUM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ENOXAPARIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "160", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dermatomyositis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OZTAS M, UGURLU S, AYDIN O. ATORVASTATIN-INDUCED DERMATOMYOSITIS. RHEUMATOL-INT. 2017;37(7):1217-1219", "literaturereference_normalized": "atorvastatin induced dermatomyositis", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20170815", "receivedate": "20170815", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13870202, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "TR-CIPLA LTD.-2017TR29596", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PRASUGREL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL INFARCTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRASUGREL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, 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"ATORVASTATIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dermatomyositis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201411" } }, "primarysource": { "literaturereference": "OZTAS M, UGURLU S, AYDIN O. ATORVASTATIN INDUCED DERMATOMYOSITIS. RHEUMATOLOGY INTERNATIONAL. 2017?1 TO 3", "literaturereference_normalized": "atorvastatin induced dermatomyositis", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20180105", "receivedate": "20180105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14353260, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "A 90-year-old man with a previous history of brain infarction and diabetes mellitus presented with a gait disturbance. Although brain computed tomography (CT) showed no abnormalities, except for the old infarction, the patient experienced recurrent epileptic seizures. He was therefore admitted to our hospital for a further examination of the seizures. However, upon admission, he also presented with a fever and elevated C-reactive protein levels, indicating systemic inflammation. Based on the presence of bilateral infiltration visible on a chest X-radiograph, the patient was diagnosed with aspiration pneumonia. The administration of 4.5 g of sulbactam and ampicillin did not reduce the inflammation or resolve the abnormal lung findings. Therefore, he was intubated and placed on a ventilator. With the patient under ventilator management, we subsequently performed bronchoscopic alveolar lavage. Elevated neutrophil and lymphocyte counts were noted in the alveolar lavage fluid; therefore, we administered pulse steroid therapy with 500 mg of methylprednisolone. The sputum and alveolar lavage fluid samples collected 13 and 14 days, respectively, after admission were negative for Mycobacterium according to a smear test. In contrast, the cultured sputum samples collected on day 13 were positive for Mycobacterium tuberculosis; polymerase chain reaction testing confirmed the sputum culture results. A postmortem pathological examination of the lungs revealed neutrophilic exudative pneumonia as well as acute fibrinous and organizing pneumonia. Although Ziehl-Neelsen staining demonstrated a large number of positive bacteria, no epithelioid-cell granulomas were observed. M. tuberculosis lesions were also found in the liver, spleen, bones, and adrenal glands, suggesting hematogenous dissemination. Aspiration pneumonia is very common in elderly patients with a history of stroke, and these patients are also at risk of other pulmonary disorders and infections including M. tuberculosis. Prior to administering treatment for aspiration pneumonia, clinicians should consider the potential for other pulmonary infiltration disorders in the differential diagnosis, particularly in elderly post-stroke patients.", "affiliations": "Department of Internal Medicine, Hitachi, Ltd. Hitachinaka General Hospital.", "authors": "Matsuo|Tomohei|T|;Ishikawa|Hiroaki|H|;Tachi|Hiroaki|H|;Yoshida|Kazufumi|K|;Teramoto|Shinji|S|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.3143/geriatrics.51.460", "fulltext": null, "fulltext_license": null, "issn_linking": "0300-9173", "issue": "51(5)", "journal": "Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics", "keywords": null, "medline_ta": "Nihon Ronen Igakkai Zasshi", "mesh_terms": "D000369:Aged, 80 and over; D001344:Autopsy; D004827:Epilepsy; D006801:Humans; D008297:Male; D011015:Pneumonia, Aspiration; D020521:Stroke; D017211:Treatment Failure; D014376:Tuberculosis", "nlm_unique_id": "7507332", "other_id": null, "pages": "460-5", "pmc": null, "pmid": "25492676", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Development of exudative tuberculosis during treatment for aspiration pneumonia in an elderly post-stroke patient with symptomatic epilepsy.", "title_normalized": "development of exudative tuberculosis during treatment for aspiration pneumonia in an elderly post stroke patient with symptomatic epilepsy" }

[ { "companynumb": "JP-FRESENIUS KABI-FK201609618", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040583", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE (MANUFACTURER UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040583", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "90", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphocyte count decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary tuberculosis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MATSUO T,ISHIKAWA H,TACHI H,YOSHIDA K,TERAMOTO S. [DEVELOPMENT OF EXUDATIVE TUBERCULOSIS DURING TREATMENT FOR ASPIRATION PNEUMONIA IN AN ELDERLY POST-STROKE PATIENT WITH SYMPTOMATIC EPILEPSY]. NIPPON-RON-IGAK-ZASSHI-JPN-J-GERIATR 2014;5:460-5.", "literaturereference_normalized": "development of exudative tuberculosis during treatment for aspiration pneumonia in an elderly post stroke patient with symptomatic epilepsy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161209", "receivedate": "20161209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13012212, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" } ]

{ "abstract": "OBJECTIVE\nThe second-generation antipsychotics are associated with metabolic abnormalities in patients with schizophrenia. Elderly patients with Alzheimer's disease are frequently treated with these antipsychotics, but limited data are available on their metabolic effects.\n\n\nMETHODS\nThe authors assessed 186 male and 235 female Alzheimer's disease outpatients from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) for changes in weight, waist circumference, blood pressure, fasting glucose, and lipids in relation to duration of second-generation antipsychotic use (i.e., olanzapine, quetiapine, and risperidone) throughout the 36-week trial, using logistic regression and mixed-effects models.\n\n\nRESULTS\nWomen showed significant weight gain (0.14 lb/week of use) while change was nonsignificant in men. Clinically significant weight gain (i.e., > or = 7% of body weight) was seen among patients with antipsychotic use < or = 12 weeks (odds ratio [OR]=1.56, 95% CI=0.53 to 4.58), between 12 and 24 weeks (OR=2.89, 95% CI=0.97 to 8.64), and > 24 weeks (OR=3.38, 95% CI=1.24 to 9.23) relative to patients who did not use antipsychotics during the trial. Olanzapine and quetiapine treatments were significantly associated with weight gain (0.12 and 0.14 lb/week, respectively). In addition, olanzapine was significantly associated with decreases in HDL cholesterol (-0.19 mg/dl/week) and increased girth (0.07 inches/week) relative to the placebo group. No treatment effects were noted for changes in blood pressure, glucose, and triglycerides.\n\n\nCONCLUSIONS\nSecond-generation antipsychotic use was associated with weight gain in women, with olanzapine and quetiapine in particular, and with unfavorable change in HDL cholesterol and girth with olanzapine. The potential consequences of these effects suggest that patients with Alzheimer's disease treated with second-generation antipsychotics should be monitored closely.", "affiliations": "Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, USA.", "authors": "Zheng|Ling|L|;Mack|Wendy J|WJ|;Dagerman|Karen S|KS|;Hsiao|John K|JK|;Lebowitz|Barry D|BD|;Lyketsos|Constantine G|CG|;Stroup|T Scott|TS|;Sultzer|David L|DL|;Tariot|Pierre N|PN|;Vigen|Cheryl|C|;Schneider|Lon S|LS|", "chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D018967:Risperidone; D000077152:Olanzapine", "country": "United States", "delete": false, "doi": "10.1176/appi.ajp.2008.08081218", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-953X", "issue": "166(5)", "journal": "The American journal of psychiatry", "keywords": null, "medline_ta": "Am J Psychiatry", "mesh_terms": "D000368:Aged; D000544:Alzheimer Disease; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003987:Dibenzothiazepines; D004311:Double-Blind Method; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders; D009765:Obesity; D000077152:Olanzapine; D000069348:Quetiapine Fumarate; D018967:Risperidone", "nlm_unique_id": "0370512", "other_id": null, "pages": "583-90", "pmc": null, "pmid": "19369318", "pubdate": "2009-05", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural", "references": "12633121;14994733;16250069;14747245;16945212;10496251;16505124;11346192;18519523;11739062;11135780;17035647;10084637;16172203;14758577;17316169;16505133;11015815;16918818;7653692;16234500;16905684;16437455;18258416;16085789;15111472", "title": "Metabolic changes associated with second-generation antipsychotic use in Alzheimer's disease patients: the CATIE-AD study.", "title_normalized": "metabolic changes associated with second generation antipsychotic use in alzheimer s disease patients the catie ad study" }

[ { "companynumb": "US-JNJFOC-20090502651", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020272", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "36-WEEKS TRIAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "DEMENTIA ALZHEIMER^S TYPE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Total cholesterol/HDL ratio abnormal", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood triglycerides increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood glucose increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZHENG L, MACK WJ, DAGERMAN KS, HSIAO JK, LEBOWITZ BD, LYKESTOS CG, ET AL. METABOLIC CHANGES ASSOCIATED WITH SECOND-GENERATION ANTIPSYCHOTIC USE IN ALZHEIMER^S DISEASE PATIENTS: THE CATIE-AD STUDY. AMERICAN JOURNAL OF PSYCHIATRY MAY-2009;166(5):583-90.", "literaturereference_normalized": "metabolic changes associated with second generation antipsychotic use in alzheimer s disease patients the catie ad study", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150526", "receivedate": "20150322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10943489, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150821" } ]

{ "abstract": "BACKGROUND\nTransforaminal epidural steroid injection (TFESI) is a widely used nonsurgical procedure in the treatment of patients with radiculopathy. It is efficacious in relieving pain, but a number of complications are being reported. Recently, increasing frequency of major complications, such as spinal cord infarction and cerebral infarction, has been reported with the use of a particulate steroid within fluoroscopic-guided procedures.\n\n\nMETHODS\nWe report a 49-year-old man with a history of chronic cervical radiculopathy, who experienced a devastating complication after TFESI.\n\n\nRESULTS\nAfter 2 min of regular TFESI, the patient abruptly experienced muscle weakness in both upper extremities and within 5 min the patient became quadriplegic. Despite active rehabilitation, the patient remained bed-ridden 4 years after the catastrophic event. To our knowledge, this is the first reported case of spinal cord infarction that occurred after TFESI in Korea.\n\n\nCONCLUSIONS\nConsidering the risk of dreadful complications, which appear in an unpredictable manner, TFESI with fluoroscopic guidance should be done only with a nonparticulate steroid.", "affiliations": "Department of Neurology, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.;Department of Neurology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea.", "authors": "Moon|Jangsup|J|;Kwon|Hyung-Min|HM|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000455069", "fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000455069crn-0009-0001Case ReportSpinal Cord Infarction after Cervical Transforaminal Epidural Steroid Injection: Case Report and Literature Review Moon Jangsup aKwon Hyung-Min b*aDepartment of Neurology, Biomedical Research Institute, Seoul National University Hospital, Seoul, South KoreabDepartment of Neurology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea*Hyung-Min Kwon, MD, Department of Neurology, Seoul Metropolitan Government-Seoul National University, Boramae Medical Center, Seoul National University College of Medicine, Seoul 156-707 (South Korea), E-Mail hmkwon@snu.ac.krJan-Apr 2017 6 1 2017 6 1 2017 9 1 1 5 8 8 2016 13 12 2016 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Introduction\nTransforaminal epidural steroid injection (TFESI) is a widely used nonsurgical procedure in the treatment of patients with radiculopathy. It is efficacious in relieving pain, but a number of complications are being reported. Recently, increasing frequency of major complications, such as spinal cord infarction and cerebral infarction, has been reported with the use of a particulate steroid within fluoroscopic-guided procedures.\n\nMethods\nWe report a 49-year-old man with a history of chronic cervical radiculopathy, who experienced a devastating complication after TFESI.\n\nResults\nAfter 2 min of regular TFESI, the patient abruptly experienced muscle weakness in both upper extremities and within 5 min the patient became quadriplegic. Despite active rehabilitation, the patient remained bed-ridden 4 years after the catastrophic event. To our knowledge, this is the first reported case of spinal cord infarction that occurred after TFESI in Korea.\n\nConclusion\nConsidering the risk of dreadful complications, which appear in an unpredictable manner, TFESI with fluoroscopic guidance should be done only with a nonparticulate steroid.\n\nKeywords\nTransforaminal epidural steroid injectionSpinal cord infarctionComplication\n==== Body\nIntroduction\nTransforaminal epidural steroid injection (TFESI) is widely performed as a nonsurgical management of patients with radicular pain syndromes. This procedure allows direct delivery of injected corticosteroids to the nerve root and enables suppression of the surrounding inflammatory response, which is responsible for the radicular pain [1, 2]. While there are few complications after TFESI, an increasing number of devastating complications such as spinal cord infarction, cerebral infarction and death are being reported with the use of a particulate steroid within fluoroscopic-guided procedures [3, 4]. Here, we report the first case of a patient who experienced spinal cord infarction after cervical TFEFI in Korea.\n\nCase Report\nA 49-year-old man was transferred to our neurology department after abrupt onset of quadriparesis after a cervical TFESI. He was relatively healthy except for a long history of cervical radiculopathy. He visited the pain clinic of our hospital due to the persistent radiating pain and received a left-sided cervical TFESI at the C6-C7 level. The procedure was performed by an expert anesthesiologist. Fluoroscopy was utilized to guide the injection needle into the foramina. After confirmation of contrast around the nerve root and epidural space and the absence of vascular uptake, 20 mg of triamcinolone and 2 mL of 0.125% levobupivacaine were injected. Approximately 2 min after the procedure, the patient complained of weakness of both upper extremities. After 5 min, he described weakness of both lower extremities. On the initial neurological examination, he was quadriplegic with motor power less than grade I in all 4 extremities. His sensory function was absent below the C2 level. Cranial nerve examination was normal and respiration was intact. The initial diffusion magnetic resonance imaging (MRI) revealed an extensive ischemic lesion in the spinal cord, below C2 to the upper thoracic level. Follow-up MRI taken 3 days after the event demonstrated more significant signal changes in the diffusion-weighted images and T2-weighted images (Fig 1). The brain MRI was normal. Although the patient's motor power continued to improve with active rehabilitation, he remained bed-ridden 4 years after the catastrophic event.\n\nDiscussion\nTFESI is widely performed in patients with cervical and lumbosacral radiculopathy. TFESI reduces pain significantly – although the effect is transient – and decreases the need for surgery [3]. The reported incidence of periprocedural complications of TFESI is low. Complications include dural puncture, trauma to the spinal nerve, infection, and allergic reaction to the medication [3]. However, scrutiny of the literature reveals the existence of more severe procedure-related complications, which can leave permanent sequelae. To date, more than 15 cases of spinal cord infarction and 30 cases of cerebral infarction have been reported after TFESI. Fifteen deaths associated with this procedure have been reported [4]. However, the accurate rate of the major complication is unknown, because a lot of cases may not have been reported [3, 4].\n\nThe suggested mechanism of the ischemic complications of the central nervous system is that inadvertent intra-arterial injection of a particulate corticosteroid creates an embolus and subsequently leads to ischemic lesions in the anterior spinal or vertebral artery territories [3, 5]. A few prospective studies and case reports support the embolic mechanism via the intra-arterial injection of a particulate steroid [6, 7]. Although intravascular injections most likely result from incorrect needle placement, a number of studies have demonstrated that the intra-arterial injection of a steroid into a radicular artery is possible, even with proper needle placement [7]. The type of needle used for the procedure can also influence the rate of the intravascular injection [8]. Moreover, variable anastomoses exist between vertebral and cervical arteries, so that steroid particles could enter into the vertebral circulation via cervical arteries and cause cerebellar and brainstem infarcts [9]. Two reports have described patients who had a previous history of spinal surgery and experienced spinal cord infarction after TFESI [9, 10]. Previous surgery may have given rise to more anastomoses around the spinal canal in these patients. The corticosteroid seems to play a main role in the ischemic complications, with the steroid subtype being influential. Particulate steroids, such as methylprednisolone, triamcinolone, and betamethasone, have been reported to cause ischemic complications, while the nonparticulate steroid, dexamethasone, has not. The large particle size of some steroids may drive coalescence into larger aggregates that could induce embolic infarcts [3].\n\nOther proposed mechanisms are vertebral artery dissection resulting from a direct needle injury or malposition of the needle to intramedullar spinal cord [11]. Also, accidental laceration of an intervertebral disc by the needle may lead to fibrocartilaginous embolus [12] and accidental intraosseous injection of the steroid due to osteopenia may cause intravascular penetration of the steroid [5]. However, our patient showed normal appearance of the vertebral artery.\n\nTo date, no major ischemic complication has been reported after TFESI in Korea. One patient had experienced cervical subdural hematoma after cervical TFESI, which led to transient quadriplegia [13]. Another patient had experienced motor weakness in both lower extremities 2 days after cervical TFESI [14]. Spinal cord diffusion MRI was not performed, but considering the delayed onset of symptoms, spinal cord infarction was not suspected.\n\nOur patient encountered a catastrophic complication although the procedure was performed in the same manner as routine procedures. We suppose that a particulate steroid, triamcinolone, inadvertently entered the arterial system of the spinal cord and subsequently induced massive embolic infarction of the spinal cord. In 2015, a multidisciplinary working group announced a safeguard recommendation in effort to improve the safety of epidural steroid injections [11]. According to the recommendation, all cervical procedures should be performed using image guidance, and contrast medium should be injected under real-time fluoroscopy before injecting any substance. Particulate steroids should not be used in cervical TFESI. Computed tomography (CT) guidance offers several advantages over fluoroscopic guidance [15]. CT guidance can avoid cannulation of small arteries such as vertebral artery and also radical-medullar and other muscular cervical arteries that can sometimes give anatomic branches to radical-medullar arteries. Intramedullar needle placement can be avoided by CT guidance but not by fluoroscopic guidance alone.\n\nConsidering the risk of dreadful complications with a particulate steroid, and in this case triamcinolone, TFESI with fluoroscopic guidance should be done only with a nonparticulate steroid, like dexamethasone. CT guidance of the procedure can further decrease the chance of major complications.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThere are no conflicts of interest to disclose.\n\nFig. 1 Spine MRI data of the patient. A diffusion-weighted image (a) and an apparent diffusion coefficient image (b) show an extensive ischemic infarction in the spinal cord, below C2 to the upper thoracic level. A T2-weighted image (c) demonstrates high signal changes and swelling of the spinal cord.\n==== Refs\nReferences\n1 Boswell MV Hansen HC Trescot AM Hirsch JA Epidural steroids in the management of chronic spinal pain and radiculopathy Pain Physician 2003 6 319 334 16880879 \n2 Park SY An HS Moon SH Lee HM Suh SW Chen D Neuropathic pain components in patients with lumbar spinal stenosis Yonsei Med J 2015 56 1044 1050 26069129 \n3 Scanlon GC Moeller-Bertram T Romanowsky SM Wallace MS Cervical transforaminal epidural steroid injections: more dangerous than we think? Spine 2007 32 1249 17495784 \n4 Benny B Azari P Briones D Complications of cervical transforaminal epidural steroid injections Am J Phys Med Rehabil 2010 89 601 20567139 \n5 Wybier M Transforaminal epidural corticosteroid injections and spinal cord infarction Joint Bone Spine 2008 75 523 18801685 \n6 Baker R Dreyfuss P Mercer S Bogduk N Cervical transforaminal injection of corticosteroids into a radicular artery: a possible mechanism for spinal cord injury Pain 2003 103 211 215 12749976 \n7 Verrills P Nowesenitz G Barnard A Penetration of a cervical radicular artery during a transforaminal epidural injection Pain Med 2010 11 229 231 20447301 \n8 Hong J Jung S Chang H Whitacre needle reduces the incidence of intravascular uptake in lumbar transforaminal epidural steroid injections Pain Physician 2015 18 325 331 26218935 \n9 Huntoon MA Martin DP Paralysis after transforaminal epidural injection and previous spinal surgery Reg Anesth Pain Med 2004 29 494 495 15372396 \n10 Houten JK Errico TJ Paraplegia after lumbosacral nerve root block: report of three cases Spine J 2002 2 70 75 14588291 \n11 Rathmell JP Benzon HT Dreyfuss P Huntoon M Wallace M Baker R Safeguards to prevent neurologic complications after epidural steroid injections: consensus opinions from a multidisciplinary working group and national organizations Anesthesiology 2015 122 974 984 25668411 \n12 Meyer HJ Monticelli F Kiesslich J Fatal embolism of the anterior spinal artery after local cervical analgetic infiltration Forensic Sci Int 2005 149 115 119 15749350 \n13 Lee JK Chae KW Ju CI Kim BW Acute cervical subdural hematoma with quadriparesis after cervical transforaminal epidural block J Korean Neurosurg Soc 2015 58 483 486 26713152 \n14 Han M Low extremity weakness after cervical epidural steroid injection in previous spinal surgery patient: a case report Korean J Anesthesiol 2008 54 593 597 \n15 Wald JT Maus TP Diehn FE Kaufmann TJ Morris JM Murthy NS CT-guided cervical transforaminal epidural steroid injections: technical insights J Neuroradiol 2014 41 211 215 24074559\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-680X", "issue": "9(1)", "journal": "Case reports in neurology", "keywords": "Complication; Spinal cord infarction; Transforaminal epidural steroid injection", "medline_ta": "Case Rep Neurol", "mesh_terms": null, "nlm_unique_id": "101517693", "other_id": null, "pages": "1-5", "pmc": null, "pmid": "28203184", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "20567139;15372396;16880879;24074559;25668411;14588291;20447301;26069129;17495784;12749976;26218935;18801685;15749350;26713152", "title": "Spinal Cord Infarction after Cervical Transforaminal Epidural Steroid Injection: Case Report and Literature Review.", "title_normalized": "spinal cord infarction after cervical transforaminal epidural steroid injection case report and literature review" }

[ { "companynumb": "KR-SA-2019SA040192", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "020468", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, LEFT-SIDED CERVICAL TRANSFORAMINAL EPIDURAL STEROID INJECTION AT THE C6-C7 LEVEL", "drugenddate": null, "drugenddateformat": null, "drugindication": "CERVICAL RADICULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOBUPIVACAINE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 ML, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CERVICAL RADICULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOBUPIVACAINE" } ], "patientagegroup": "5", "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Spinal cord infarction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MOON J, KWON HM.. SPINAL CORD INFARCTION AFTER CERVICAL TRANSFORAMINAL EPIDURAL STEROID INJECTION: CASE REPORT AND LITERATURE REVIEW.. CASE REPORTS IN NEUROLOGY. 2017?9(1):1-5", "literaturereference_normalized": "spinal cord infarction after cervical transforaminal epidural steroid injection case report and literature review", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20190215", "receivedate": "20190215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15968707, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "KR-GLENMARK PHARMACEUTICALS-2017GMK028403", "fulfillexpeditecriteria": "1", "occurcountry": "KP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "206379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG, (LEFT-SIDED CERVICAL TRANSFORAMINAL EPIDURAL STEROID INJECTION AT THE C6-C7 LEVEL)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CERVICAL RADICULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOBUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "2 ML, (LEFT-SIDED CERVICAL TRANSFORAMINAL EPIDURAL STEROID INJECTION AT THE C6-C7 LEVEL)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CERVICAL RADICULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOBUPIVACAINE" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Spinal cord infarction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MOON J, KWON HM.. SPINAL CORD INFARCTION AFTER CERVICAL TRANSFORAMINAL EPIDURAL STEROID INJECTION: CASE REPORT AND LITERATURE REVIEW.. CASE REPORTS IN NEUROLOGY.. 2017;9(1):1-5", "literaturereference_normalized": "spinal cord infarction after cervical transforaminal epidural steroid injection case report and literature review", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20170807", "receivedate": "20170807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13839525, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "KR-MYLANLABS-2017M1048986", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRIAMCINOLONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "011601", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "CERVICAL RADICULOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVOBUPIVACAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "2 ML OF 0.125%", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOBUPIVACAINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Spinal cord infarction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MOON J, KWON H-M. SPINAL CORD INFARCTION AFTER CERVICAL TRANSFORAMINAL EPIDURAL STEROID INJECTION: CASE REPORT AND LITERATURE REVIEW. CASE-REP-NEUROL 2017;9(1):1-5.", "literaturereference_normalized": "spinal cord infarction after cervical transforaminal epidural steroid injection case report and literature review", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20170810", "receivedate": "20170810", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13856013, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "To determine the likelihood of antidepressant response in older adults with major depression as a function of their prior antidepressant trials.\n\n\n\n500 older adults with major depression as diagnosed by DSM-IV criteria for major depressive episode were treated with venlafaxine extended release for 12 weeks. Participants were recruited from July 2009 to January 2014. For each participant, we collected detailed data on prior antidepressant trials for the current episode of depression. We examined the prospective remission rates as a function of number and class of prior antidepressant trials in a post hoc analysis of pooled data from 2 prior trials.\n\n\n\nRemission rates with venlafaxine were inversely correlated with the number of prior adequate medication trials (66% for no prior adequate trials, 45% for 1 prior adequate trial, 23% for 2 or more prior adequate trials; P < .0001). Additionally, if prior treatment trials included a serotonin-norepinephrine reuptake inhibitor, participants were even less likely to achieve remission with venlafaxine (32% for 1 prior adequate trial, 18% for 2 or more prior adequate trials; P < .0001). Those with prior adequate trials were also more likely to require a higher dosage of venlafaxine to achieve remission.\n\n\n\nInformation on an individual patient's number and class of prior adequate antidepressant trials can be used to predict the likelihood of a successful treatment outcome with a given antidepressant in older adults with major depression. Further work is needed to refine this approach to provide personalized antidepressant treatment.\n\n\n\nClinicalTrials.gov identifiers: NCT00892047 and NCT02263248.", "affiliations": "Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA.;Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA.;Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA.;Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA.;Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA.;Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.;Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.;Department of Psychiatry, CAMH, 250 College St, Toronto, ON, M5T 1R8 Canada. benoit.mulsant@utoronto.ca.", "authors": "Buchalter|Erica L F|ELF|;Oughli|Hanadi Ajam|HA|;Lenze|Eric J|EJ|;Dixon|David|D|;Miller|J Philip|JP|;Blumberger|Daniel M|DM|;Karp|Jordan F|JF|;Reynolds|Charles F|CF|;Mulsant|Benoit H|BH|", "chemical_list": "D000928:Antidepressive Agents; D003692:Delayed-Action Preparations; D000069470:Venlafaxine Hydrochloride; D000068180:Aripiprazole", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0160-6689", "issue": "80(6)", "journal": "The Journal of clinical psychiatry", "keywords": null, "medline_ta": "J Clin Psychiatry", "mesh_terms": "D000465:Algorithms; D000928:Antidepressive Agents; D001008:Anxiety Disorders; D000068180:Aripiprazole; D000081415:Clinical Decision Rules; D015897:Comorbidity; D003692:Delayed-Action Preparations; D003865:Depressive Disorder, Major; D061218:Depressive Disorder, Treatment-Resistant; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006801:Humans; D016013:Likelihood Functions; D011446:Prospective Studies; D012008:Recurrence; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride", "nlm_unique_id": "7801243", "other_id": null, "pages": null, "pmc": null, "pmid": "31846575", "pubdate": "2019-12-10", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Predicting Remission in Late-Life Major Depression: A Clinical Algorithm Based Upon Past Treatment History.", "title_normalized": "predicting remission in late life major depression a clinical algorithm based upon past treatment history" }

[ { "companynumb": "US-OTSUKA-2020_011881", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ARIPIPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021436", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARIPIPRAZOLE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Buchalter ELF, Oughli HA, Lenze EJ, Dixon D, Miller JP, Blumberger DM et al. Predicting Remission in Late-Life Major Depression: A Clinical Algorithm Based Upon Past Treatment History. Journal of Clinical Psychiatry. 2019;80(6):NIL_0154-160", "literaturereference_normalized": "predicting remission in late life major depression a clinical algorithm based upon past treatment history", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211004", "receivedate": "20211004", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19916182, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "BACKGROUND\nType V osteogenesis imperfecta is characterized by hyperplastic callus formation and interosseus membrane calcification.\n\n\nMETHODS\nA 16-year-old boy who presented with history of recurrent fractures, had hard persistent swellings at fracture sites, and had radiographic features of hyperplastic callus and interosseus membrane calcification.\n\n\nRESULTS\nSequence analysis of the IFITM5 gene revealed the c.-14 C>T mutation. The patient had significant exacerbation of callus hyperplasia after initiation of bisphosphonate therapy, which reversed following cessation of the treatment.\n\n\nCONCLUSIONS\nBisphosphonates may exacerbate callus hyperplasia, and may therefore have to be used with caution in patients with type V osteogenesis imperfecta.", "affiliations": "Departments of Medical Genetics and *Orthopaedics, Nizams Institute of Medical Sciences, Hyderabad, Telangana; and Department of Medical Genetics, SGPGIMS, Lucknow, Uttar Pradesh; India. Correspondence to: Dr Prajnya Ranganath, Department of Medical Genetics, Nizams Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500 082, India. prajnyaranganath@gmail.com.", "authors": "Ranganath|Prajnya|P|;Stephen|Joshi|J|;Iyengar|Raju|R|;Phadke|Shubha R|SR|", "chemical_list": "D004164:Diphosphonates", "country": "India", "delete": false, "doi": "10.1007/s13312-016-0830-3", "fulltext": null, "fulltext_license": null, "issn_linking": "0019-6061", "issue": "53(3)", "journal": "Indian pediatrics", "keywords": null, "medline_ta": "Indian Pediatr", "mesh_terms": "D000293:Adolescent; D002146:Bony Callus; D004164:Diphosphonates; D005269:Femur; D050723:Fractures, Bone; D006801:Humans; D006965:Hyperplasia; D008297:Male; D010013:Osteogenesis Imperfecta", "nlm_unique_id": "2985062R", "other_id": null, "pages": "250-2", "pmc": null, "pmid": "27029692", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Worsening of Callus Hyperplasia after Bisphosphonate Treatment in Type V Osteogenesis Imperfecta.", "title_normalized": "worsening of callus hyperplasia after bisphosphonate treatment in type v osteogenesis imperfecta" }

[ { "companynumb": "IN-MYLANLABS-2016M1032864", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ALENDRONATE SODIUM" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "076584", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1MG/KG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OSTEOGENESIS IMPERFECTA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALENDRONATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OSTEOGENESIS IMPERFECTA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bone callus excessive", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "RANGANATH P, STEPHEN J, IYENGAR R, PHADKE SR. WORSENING OF CALLUS HYPERPLASIA AFTER BISPHOSPHONATE TREATMENT IN TYPE V OSTEOGENESIS IMPERFECTA. INDIAN-PEDIATR 2016;53(3):250-252.", "literaturereference_normalized": "worsening of callus hyperplasia after bisphosphonate treatment in type v osteogenesis imperfecta", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20160811", "receivedate": "20160811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12645567, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "We report the case of a 25-year-old female presenting to the emergency department after committing suicide by ingesting 100 mg amlodipine. The patient was initially treated with intravenous fluids, calcium gluconate, catecholamines and glucagone without effect. The clinical condition of the patient improved quickly and dramatically on the 20th minute of intravenous lipid emulsion (ILE) therapy. Different treatment methods have been developed for calcium channel blocker intoxication over the last years. Among these, lipid emulsion therapy has risen over the last decade as a salvation in cases which do not respond to other treatments. However, given the paucity of data, there are conflicting recommendations about the indications, dose and timing of ILE in the literature. In the light of this case report, we review the literature and discuss whether ILE therapy can find itself a place among first-line therapy recommendations.", "affiliations": "Department of Emergency Medicine, Faculty of Medicine, Ege University, 035100, Bornova, Izmir, Turkey. fkarbek2003@yahoo.com.;Department of Emergency Medicine, Faculty of Medicine, Ege University, 035100, Bornova, Izmir, Turkey.;Department of Emergency Medicine, Faculty of Medicine, Ege University, 035100, Bornova, Izmir, Turkey.", "authors": "Karbek Akarca|Funda|F|0000-0003-2455-8044;Akceylan|Ece|E|;Kıyan|Selahattin|S|", "chemical_list": "D002121:Calcium Channel Blockers; D005217:Fat Emulsions, Intravenous; D017311:Amlodipine", "country": "United States", "delete": false, "doi": "10.1007/s12012-017-9421-3", "fulltext": null, "fulltext_license": null, "issn_linking": "1530-7905", "issue": "17(4)", "journal": "Cardiovascular toxicology", "keywords": "Amlodipine toxicity; Calcium channel blocker; Intravenous lipid emulsion; Lipid emulsion therapy", "medline_ta": "Cardiovasc Toxicol", "mesh_terms": "D000328:Adult; D017311:Amlodipine; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D013406:Suicide, Attempted; D016896:Treatment Outcome", "nlm_unique_id": "101135818", "other_id": null, "pages": "482-486", "pmc": null, "pmid": "28766181", "pubdate": "2017-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Treatment of Amlodipine Intoxication with Intravenous Lipid Emulsion Therapy: A Case Report and Review of the Literature.", "title_normalized": "treatment of amlodipine intoxication with intravenous lipid emulsion therapy a case report and review of the literature" }

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TREATMENT OF AMLODIPINE INTOXICATION WITH INTRAVENOUS LIPID EMULSION THERAPY: A CASE REPORT AND REVIEW OF THE LITERATURE. 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TREATMENT OF AMLODIPINE INTOXICATION WITH INTRAVENOUS LIPID EMULSION THERAPY: A CASE REPORT AND REVIEW OF THE LITERATURE. 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TREATMENT OF AMLODIPINE INTOXICATION WITH INTRAVENOUS LIPID EMULSION THERAPY: A CASE REPORT AND REVIEW OF THE LITERATURE. 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TREATMENT OF AMLODIPINE INTOXICATION WITH INTRAVENOUS LIPID EMULSION THERAPY: A CASE REPORT AND REVIEW OF THE LITERATURE. CARDIOVASCULAR TOXICOLOGY. 2017?17 (4):482-486", "literaturereference_normalized": "treatment of amlodipine intoxication with intravenous lipid emulsion therapy a case report and review of the literature", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20190220", "receivedate": "20170809", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13850252, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "TR-ORCHID HEALTHCARE-2033954", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078453", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrioventricular block complete", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atrioventricular block first degree", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atrioventricular block second degree", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KARBEK AKARCA F, AKCEYLAN E, KIYAN S. TREATMENT OF AMLODIPINE INTOXICATION WITH INTRAVENOUS LIPID EMULSION THERAPY: A CASE REPORT AND REVIEW OF THE LITERATURE. CARDIOVASC TOXICOL. 2017 AUG 1.", "literaturereference_normalized": "treatment of amlodipine intoxication with intravenous lipid emulsion therapy a case report and review of the literature", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20171114", "receivedate": "20171114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 14185935, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "TR-ACCORD-057476", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202553", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" } ], "patientagegroup": null, "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intentional overdose", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrioventricular block", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Suicide attempt", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KARBEK AKARCA F, AKCEYLAN E, KIYAN S. TREATMENT OF AMLODIPINE INTOXICATION WITH INTRAVENOUS LIPID EMULSION THERAPY: A CASE REPORT AND REVIEW OF THE LITERATURE. CARDIOVASC TOXICOL. 2017 AUG 1.", "literaturereference_normalized": "treatment of amlodipine intoxication with intravenous lipid emulsion therapy a case report and review of the literature", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20190223", "receivedate": "20170821", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13884583, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190417" } ]

{ "abstract": "BACKGROUND\nAcute generalized exanthematous pustulosis (AGEP) is an acute pustular eruption with unique clinical features, a rapid clinical course and a typical histopathology. The causative agents are mostly drugs but other triggers have also been described.\n\n\nMETHODS\nA 52 year-old woman with a history of diabetes mellitus type II, dyslipidemia and osteomyelitis was treated for about a year with metformin (Glucophage) and simvastatin (Simovil) tablets. Due to the osteomyelitis, the patient was started on a regimen of intravenous vancomycin as well as furosemide tablets (Fusid) for pedal edema. About seventeen days after beginning treatment with vancomycin and a week after starting furosemide the patient was hospitalized due to an acute pruritic pustular eruption, involving most of her body surface area. Both vancomycin and furosemide treatment were discontinued, and topical treatment was provided. The clinical course was rapid with spontaneous resolution of the pustules followed by a characteristic pin-point post-pustular desquamation. The morphological, clinical and histological findings suggested a definite case of AGEP based on the EuroSCAR scoring system. The latent period between the initiation of medication intake and the appearance of AGEP, as well as a literature search, suggest that furosemide might be the incriminated drug.\n\n\nCONCLUSIONS\nWe have described a rare case of typical AGEP most probably induced by furosemide.", "affiliations": "Department of Dermatology and Institute of Pathology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.", "authors": "Davidovici|Batya B|BB|;Naveh|Hadas Prag|HP|;Cagnano|Emanuella|E|;Halevy|Sima|S|;|||", "chemical_list": "D004232:Diuretics; D005665:Furosemide", "country": "Israel", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0017-7768", "issue": "145(7)", "journal": "Harefuah", "keywords": null, "medline_ta": "Harefuah", "mesh_terms": "D003924:Diabetes Mellitus, Type 2; D004232:Diuretics; D004487:Edema; D005260:Female; D005665:Furosemide; D006801:Humans; D008875:Middle Aged; D010019:Osteomyelitis; D011565:Psoriasis", "nlm_unique_id": "0034351", "other_id": null, "pages": "477-9, 552", "pmc": null, "pmid": "16900732", "pubdate": "2006-07", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Acute generalized exanthematous pustulosis (AGEP) following intake of furosemide.", "title_normalized": "acute generalized exanthematous pustulosis agep following intake of furosemide" }

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{ "abstract": "We report the case of a 66-year-old man with primary diffuse large B-cell lymphoma of the prostate presenting with urinary retention and dyschezia as first manifestation. Although a colostomy was needed due to rectal obstruction, rituximab-combined chemotherapy resulted in complete remission. He underwent stoma closure safely and has remained in complete remission for over 3years. Primary prostatic lymphoma is extremely rare, presenting as 0.1% of newly diagnosed lymphomas, but rituximab-containing chemotherapy seems to be as effective as for nodal lymphoma.", "affiliations": "Dept. of Hematology, Osaka City General Hospital.", "authors": "Manabe|Masahiro|M|;Hayashi|Yoshiki|Y|;Yoshii|Yumi|Y|;Mukai|Satoru|S|;Sakamoto|Erina|E|;Kanashima|Hiroshi|H|;Nakao|Takafumi|T|;Hayama|Takuma|T|;Fukushima|Hiroko|H|;Inoue|Takeshi|T|;Yamane|Takahisa|T|;Teshima|Hirofumi|H|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "39(11)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003248:Constipation; D003520:Cyclophosphamide; D004317:Doxorubicin; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D011241:Prednisone; D011467:Prostate; D012004:Rectal Neoplasms; D012074:Remission Induction; D000069283:Rituximab; D016055:Urinary Retention; D014750:Vincristine", "nlm_unique_id": "7810034", "other_id": null, "pages": "1733-5", "pmc": null, "pmid": "23152030", "pubdate": "2012-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Primary diffuse large B-Cell lymphoma of the prostate presenting with urinary retention and dyschezia for which rituximab-combined CHOP therapy was effective-a case presentation.", "title_normalized": "primary diffuse large b cell lymphoma of the prostate presenting with urinary retention and dyschezia for which rituximab combined chop therapy was effective a case presentation" }

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PRIMARY DIFFUSE LARGE B-CELL LYMPHOMA OF THE PROSTATE PRESENTING WITH URINARY RETENTION AND DYSCHEZIA FOR WHICH RITUXIMAB-COMBINED CHOP THERAPY WAS EFFECTIVE: A CASE PRESENTATION. GAN-TO-KAGAKU-RYOHO 2012;39(11):1733-1735.", "literaturereference_normalized": "primary diffuse large b cell lymphoma of the prostate presenting with urinary retention and dyschezia for which rituximab combined chop therapy was effective a case presentation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160427", "receivedate": "20160427", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12309731, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" }, { "companynumb": "JP-MYLANLABS-2016M1015480", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "2", 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{ "abstract": "Quetiapine, an atypical antipsychotic, has been extensively used in patients with bipolar disorder. Overdose of quetiapine can result in severe complications, such as coma, seizure, respiratory depression, arrhythmia, and even death. However, the paucity of toxicological evaluation in adolescence causes more potential risks in this population. Herein, we present a case of hypotension and convulsive syncope after exposure to a small dose of quetiapine in a 16-year-old who was diagnosed with bipolar disorder. After cessation of quetiapine, no additional convulsive movements were reported. This case indicates that even in young patients without predisposing factors, close monitoring of adverse effects should be warranted for safety concerns, especially at the initiation of quetiapine treatment.", "affiliations": "Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine.;Department of Internal Medicine, Zhejiang University School of Medicine, Hangzhou, China.;Department of Internal Medicine, Zhejiang University School of Medicine, Hangzhou, China.;Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine.;Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine.", "authors": "Lai|Jianbo|J|;Lu|Qiaoqiao|Q|;Huang|Tingting|T|;Hu|Shaohua|S|;Xu|Yi|Y|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/NDT.S137923", "fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S137923ndt-13-1905Case ReportConvulsive syncope related to a small dose of quetiapine in an adolescent with bipolar disorder Lai Jianbo 12Lu Qiaoqiao 3Huang Tingting 3Hu Shaohua 12Xu Yi 12\n1 Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine\n2 Key Laboratory of Mental Disorder Management in Zhejiang Province\n3 Department of Internal Medicine, Zhejiang University School of Medicine, Hangzhou, ChinaCorrespondence: Shaohua Hu; Yi Xu, Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Mental Disorder Management, 79 Qingchun Road, Hangzhou, Zhejiang 310003, China, Tel +86 571 5672 3002; 138 0574 6579, Fax +86 571 5672 3001, Email dorhushaohua@zju.edu.cn; xuyizju61@163.com2017 19 7 2017 13 1905 1908 © 2017 Lai et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Quetiapine, an atypical antipsychotic, has been extensively used in patients with bipolar disorder. Overdose of quetiapine can result in severe complications, such as coma, seizure, respiratory depression, arrhythmia, and even death. However, the paucity of toxicological evaluation in adolescence causes more potential risks in this population. Herein, we present a case of hypotension and convulsive syncope after exposure to a small dose of quetiapine in a 16-year-old who was diagnosed with bipolar disorder. After cessation of quetiapine, no additional convulsive movements were reported. This case indicates that even in young patients without predisposing factors, close monitoring of adverse effects should be warranted for safety concerns, especially at the initiation of quetiapine treatment.\n\nKeywords\nquetiapinebipolar disorderhypotensionconvulsive syncope\n==== Body\nIntroduction\nQuetiapine, a second-generation antipsychotic, is approved by US Food and Drug Administration to treat young patients (age ≥10 years) with acute depressive or manic episodes and maintenance of bipolar disorder.1 Quetiapine seems to be a promising agent, well tolerated in the short and medium term in children and adolescents, and has low potential to elicit extrapyramidal effects.2 However, extremely limited guidelines for its use are available in this population. A recent nationwide report demonstrated that off-label use of quetiapine in children and adolescents is prevalent in Denmark, and life-threatening adverse events involved seizure, QT-interval prolongation, and cerebral hemorrhage.3 Besides, this study implied that quetiapine could induce hyperprolactinemia, especially in minors.3 Moreover, in some susceptible individuals, exposure to quetiapine overdoses can result in severe complications, such as coma, seizure, respiratory depression, arrhythmia, and even death.4 Therefore, great care should be taken when initiating quetiapine treatment in young patients.\n\nFor example, new-onset seizure has been reported in two young patients after taking small doses of quetiapine.5 One of these two patients was a 16-year-old girl with ornithine transcarbamylase deficiency and mental retardation, who was prescribed quetiapine to manage her behavioral instability. She developed a generalized tonic–clonic seizure after ingesting 50 mg quetiapine for 2 consecutive days.5 Another was a 7-year-old boy with autism and mental retardation, who was prescribed quetiapine at a dose of 25 mg/day for his behavioral problems. Generalized tonic–clonic seizure occurred as early as the first time quetiapine was taken.5 According to the literature available, most cases of seizure secondary to quetiapine exposure occur in adult patients or present as acute intoxication because of overdoses.6–8 Evidence of severe adverse events associated with quetiapine treatment in children and adolescents is fairly rare.\n\nHerein, we depict an adolescent with bipolar disorder who developed hypotension and syncope with convulsive movements after ingestion of quetiapine without concomitant medications. This case enriches our knowledge of quetiapine toxicity in young people.\n\nCase presentation\nA 16-year-old high school teenager was admitted to our hospital because of episodic mood swings for almost 4 years. Periods of depression were predominant in his course of disease and lasted for 1 or 2 months. When depressed, this patient complained of waning interest, poor academic performance, bad memory, and loss of appetite. Sometimes, this patient would have suicidal ideations, and had once attempted suicide by holding his breath. He had auditory hallucinations and delusions of persecution. Comparatively, when his mood elevated, this patient would become energetic, conversant, and generous, and gradually became euthymic after nearly 1 week. Two weeks before admission, this patient was sent to the outpatient service by his family. No physical illness, epilepsy, history of head trauma, or family history of mental disorders was reported. He had lost his mother because of a traffic accident. He denied experience of smoking, drinking alcohol, or taking any toxic or illicit substance. Neurological examination was normal, as well as laboratory tests (eg, routine blood test, urine, thyroid hormones, reproductive hormones, biochemical indices, and infectious profiles). Magnetic resonance imaging of the brain indicated an enlarged left lateral ventricle (Figure 1). According to the Diagnostic and Statistical Manual of Mental Disorders (fifth edition), this patient matched with the diagnosis of bipolar II disorder and depressive episodes, with psychotic features. Consequently, quetiapine was prescribed and started at a dosage of 50 mg per night. However, when this patient took the first 50 mg, he slept for almost 12 hours and felt feeble in the daytime. Since then, he had decided to stop this medication. His depressive condition did not improve, and hospitalization was suggested by his psychiatrist.\n\nOn admission, all vital signs of this patient were normal. His grandmother stayed in hospital to look after him. This patient tried to take an afternoon nap, but failed to fall asleep, and was given 50 mg quetiapine as a sleeping aid by his grandmother. About 2 hours after quetiapine exposure, this patient was taken to the nurses’ desk and educated with notes on security as a new inpatient. All of a sudden, his complexion became pale. Immediate blood glucose was 5.5 mmol/L, heart rate was 72 beats per minute, and blood pressure 118/80 mmHg. The psychiatrist arrived quickly and tried to measure blood pressure again, but failed to get any result. On his way back to the ward when supported by others, this patient fell abruptly to the floor, followed by tics of limbs and opisthotonos, which lasted for 2–3 seconds, and lay on the floor unconscious. No foaming at the mouth, urinary incontinence, or tongue biting was observed. About 1 minute later, he stood up by himself and asked, “What happened just now? My mind went blank.” At this moment, his complexion gradually became fresh and rosy. Blood pressure was at 88/53 mmHg, and heart rate was at 61 beats per minute. As the patient’s condition had improved, he was given low-flow oxygen therapy with close electrocardiography monitoring. Serum creatinine kinase after this event was 1,960 units/L (reference range 38–174 units/L). We did not examine the quetiapine concentration in the blood, as the patient had taken a small dosage of this medication. He was told not to take this medication again. A combination of valproate and olanzapine was used as his therapeutic regimen. Electroencephalography (EEG) was conducted 5 days after the event, and no epileptiform activity was captured. This patient recovered well in the next 2 weeks and remained syncope-free before hospital discharge. During outpatient visits, no more convulsive syncope was reported.\n\nThe Institute Ethical Committee of the First Affiliated Hospital, Zhejiang University School of Medicine approved this case study. Written informed consent for publication of the case and any accompanying image was obtained from the patient and his guardian.\n\nDiscussion\nIn this study, we present a case of extreme hypotension, transient convulsive movements, and unconsciousness after quetiapine exposure, suggesting relevant adverse effects to a small dosage of quetiapine (50 mg) in an adolescent with bipolar disorder. No predisposing factors were identified in this patient. To our knowledge, this is the first case study suggesting convulsive syncope secondary to a small dosage of quetiapine (50 mg) in an adolescent with bipolar disorder.\n\nQuetiapine functions as a multireceptor antipsychotic involved in the dopamine, serotonin, and adrenergic pathways. It also has antihistamine and anticholinergic properties. Hypotension is known as a common adverse effect, which is considered to be elicited by inhibition of adrenergic α1-receptors.9 However, the mechanism behind quetiapine-induced seizure remains unclear. Structurally similar to quetiapine, the dose-dependent potential of clozapine to mediate seizure by lowering the threshold of seizure is more definite.10 The risk of seizure provocation induced by first-generation antipsychotics or second-generation antipsychotics is inconsistent across different studies. In a nest-control study, when applied to patients with affective disorders, medium- to high-potency first-generation antipsychotics were more likely to elicit seizure than all other antipsychotics.11 Nevertheless, other findings suggested second-generation antipsychotics, rather than first-generation antipsychotics, had a higher risk of seizure.12 In addition, abnormal alterations on EEG have been observed in psychiatric patients taking second-generation antipsychotics, which were particularly high under clozapine and olanzapine treatment.13 None of the patients with quetiapine treatment showed EEG abnormalities in the same study.13 Interestingly, in a rat model with malformations of cortical development, quetiapine was found to rescue its cognitive impairment and reduce seizure susceptibility, possibly by maintaining the integrity of myelin.14\n\nIn our patient, we noted that extremely low blood pressure was associated with convulsive movements. In individuals with quetiapine abuse, severe complications, such as hypotension, respiratory depression, and seizure, have also been observed.15 Unfortunately, the interrelationship between hypotension and seizure has always been neglected. In a rare case of seizure presenting as refractory hypotension, the authors provided sufficient evidence to support acute hypotension as an atypical manifestation of seizure.16 Hypotension during the onset of seizure may cause cerebral hypoperfusion and further worsen autonomic dysfunction.16\n\nOf note, we would like to differentiate the manifestations of convulsive syncope from those of seizure attacks. In our patient, acute onset of limb spasm, opisthotonos, and transient unconsciousness was observed without other typical symptoms of seizure, such as foaming at the mouth, loss of urine, or biting of the tongue. Therefore, the seizure-like movements in our patient were not typical, and were more likely to be a syncopal attack secondary to hypotension. Convulsive syncope, or in academic terms, reflex asystolic syncope, occurs predominantly in young people and can manifest as loss of consciousness, loss of postural tone, myoclonic movements, and nonepileptic spasms.17\n\nIn the present case study of a patient with bipolar disorder, hypotension associated with convulsive movements was observed nearly 2 hours after exposure to a small dose of quetiapine. This is in accordance with the serum peak time after taking quetiapine orally.18 No obvious predisposing factors were reported, and no other medications were coingested. However, the undetected quetiapine concentration in blood seemed to be a major limitation of our study. In individuals with specific polymorphisms in CYP3A4 enzymes, unpredictable adverse reactions were associated with decreased enzyme activity and increased blood concentration.19 Moreover, no additional convulsive movements were observed after discontinuing quetiapine treatment. According to a scale evaluating possible drug-related adverse effects, the relationship between reported adverse reactions and quetiapine in our patient was assigned to the “probable” category.20 Finally, we hypothesize that the convulsive movements were consequences of hypotension induced by quetiapine.\n\nIn conclusion, this single case report enriches our understanding of quetiapine-associated adverse reactions in young patients. Special concerns are essential to evaluate the risk of hypotension and convulsive syncope in children and adolescents before starting quetiapine treatment. Continuous monitoring of acute adverse events is also needed after the initiation of treatment.\n\nAcknowledgments\nThis work was supported by the grants of the National Natural Science Foundation of China (81671357), the Project of Health Department in Zhejiang Province (2014ZDA008), the National Key Basic Research Program (2016YFC1307102, 2016YFC1307104), the Public Welfare Project of Science Technology Department of Zhejiang Province (2015C33133), National Clinical Research Center for Mental Health Disorders (2015BAI13B02), and the Key Research Project of Zhejiang Province (2015C03040). We appreciate the patient and his guardians for their understanding. We acknowledge Dr Pornkanok Prukpitikul for her help to polish our paper.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Magnetic resonance imaging showing an enlarged left lateral ventricle (orange arrow).\n==== Refs\nReferences\n1 Grande I Berk M Birmaher B Vieta E Bipolar disorder Lancet 2016 387 10027 1561 1572 26388529 \n2 Masi G Milone A Veltri S Iuliano R Pfanner C Pisano S Use of quetiapine in children and adolescents Paediatr Drugs 2015 17 2 125 140 25686575 \n3 Jakobsen KD Wallach-Kildemoes H Bruhn CH Adverse events in children and adolescents treated with quetiapine: an analysis of adverse drug reaction reports from the Danish Medicines Agency database Int Clin Psychopharmacol 2017 32 2 103 106 27685179 \n4 Eyer F Pfab R Felgenhauer N Strubel T Saugel B Zilker T Clinical and analytical features of severe suicidal quetiapine overdoses: a retrospective cohort study Clin Toxicol (Phila) 2011 49 9 846 853 22077248 \n5 Yalug I Tufan AE Kayaalp L Quetiapine may be associated with new-onset seizures in patients with seizurogenic conditions J Neuropsychiatry Clin Neurosci 2007 19 3 341 342 17827425 \n6 Dogu O Sevim S Kaleagasi HS Seizures associated with quetiapine treatment Ann Pharmacother 2003 37 9 1224 1227 12921503 \n7 Ngo A Ciranni M Olson KR Acute quetiapine overdose in adults: a 5-year retrospective case series Ann Emerg Med 2008 52 5 541 547 18433934 \n8 Young AC Kleinschmidt KC Wax PM Late-onset seizures associated with quetiapine poisoning J Med Toxicol 2009 5 1 24 26 19191211 \n9 Dev V Raniwalla J Quetiapine: a review of its safety in the management of schizophrenia Drug Saf 2000 23 4 295 307 11051217 \n10 Alldredge BK Seizure risk associated with psychotropic drugs: clinical and pharmacokinetic considerations Neurology 1999 53 5 Suppl 2 S68 S75 10496236 \n11 Bloechliger M Rüegg S Jick SS Meier CR Bodmer M Antipsychotic drug use and the risk of seizures: follow-up study with a nested case-control analysis CNS Drugs 2015 29 7 591 603 26242478 \n12 Lertxundi U Hernandez R Medrano J Domingo-Echaburu S García M Aguirre C Antipsychotics and seizures: higher risk with atypicals? Seizure 2013 22 2 141 143 23146619 \n13 Centorrino F Price BH Tuttle M EEG abnormalities during treatment with typical and atypical antipsychotics Am J Psychiatry 2002 159 1 109 115 11772698 \n14 Ma L Yang F Zhao R Quetiapine attenuates cognitive impairment and decreases seizure susceptibility possibly through promoting myelin development in a rat model of malformations of cortical development Brain Res 2015 1622 443 451 26188240 \n15 Klein L Bangh S Cole JB Intentional recreational abuse of quetiapine compared to other second-generation antipsychotics West J Emerg Med 2017 18 2 243 250 28210359 \n16 Vimala S Unnikrishnan P Gautham NS Intraoperative seizures presenting as refractory hypotension J Neurosurg Anesthesiol 2017 29 2 184 185 26669839 \n17 Iyer A Appleton R Management of reflex anoxic seizures in children Arch Dis Child 2013 98 9 714 717 23814085 \n18 Balit CR Isbister GK Hackett LP Whyte IM Quetiapine poisoning: a case series Ann Emerg Med 2003 42 6 751 758 14634598 \n19 Klein K Zanger UM Pharmacogenomics of cytochrome P450 3A4: recent progress toward the “missing heritability” problem Front Genet 2013 4 12 23444277 \n20 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 7249508\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1176-6328", "issue": "13()", "journal": "Neuropsychiatric disease and treatment", "keywords": "bipolar disorder; convulsive syncope; hypotension; quetiapine", "medline_ta": "Neuropsychiatr Dis Treat", "mesh_terms": null, "nlm_unique_id": "101240304", "other_id": null, "pages": "1905-1908", "pmc": null, "pmid": "28790826", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "22077248;27685179;10496236;11051217;26242478;26669839;11772698;26188240;23814085;26388529;7249508;14634598;23444277;25686575;12921503;17827425;23146619;18433934;19191211;28210359", "title": "Convulsive syncope related to a small dose of quetiapine in an adolescent with bipolar disorder.", "title_normalized": "convulsive syncope related to a small dose of quetiapine in an adolescent with bipolar disorder" }

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CONVULSIVE SYNCOPE RELATED TO A SMALL DOSE OF QUETIAPINE IN AN ADOLESCENT WITH BIPOLAR DISORDER. NEUROPSYCHIATRIC DISEASE AND TREATMENT. 2017;13:1905-1908.", "literaturereference_normalized": "convulsive syncope related to a small dose of quetiapine in an adolescent with bipolar disorder", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20170822", "receivedate": "20170822", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13891096, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "CN-UNICHEM LABORATORIES LIMITED-UCM201708-000208", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "202674", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Syncope", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LAI J,HU S,XU Y,LU Q,HUANG T. CONVULSIVE SYNCOPE RELATED TO A SMALL DOSE OF QUETIAPINE IN AN ADOLESCENT WITH BIPOLAR DISORDER. NEUROPSYCHIATRIC DISEASE AND TREATMENT 2017 JUL 19;13:1905-1908.", "literaturereference_normalized": "convulsive syncope related to a small dose of quetiapine in an adolescent with bipolar disorder", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20170824", "receivedate": "20170816", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13870906, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "CN-MYLANLABS-2017M1051835", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090323", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "090323", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "IN NIGHT", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR II DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Heart rate decreased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Syncope", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAI J, LU Q, HUANG T, HU S, XU Y. CONVULSIVE SYNCOPE RELATED TO A SMALL DOSE OF QUETIAPINE IN AN ADOLESCENT WITH BIPOLAR DISORDER. NEUROPSYCH-DIS-TREAT 2017;13:1905-1908.", "literaturereference_normalized": "convulsive syncope related to a small dose of quetiapine in an adolescent with bipolar disorder", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20170823", "receivedate": "20170823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13897370, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "CN-ALKEM LABORATORIES LIMITED-CN-ALKEM-2017-00544", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201504", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, AT NIGHT", "drugenddate": null, "drugenddateformat": null, "drugindication": "BIPOLAR II DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201504", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INSOMNIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Medication error", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tic", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Intellectual disability", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pallor", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood creatinine increased", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LAI J, LU Q, HUANG T, HU S, XU Y. CONVULSIVE SYNCOPE RELATED TO A SMALL DOSE OF QUETIAPINE IN AN ADOLESCENT WITH BIPOLAR DISORDER. NEUROPSYCHIATRIC DISEASE AND TREATMENT. 2017;13:1905-1908", "literaturereference_normalized": "convulsive syncope related to a small dose of quetiapine in an adolescent with bipolar disorder", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20170818", "receivedate": "20170818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13879751, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" } ]

{ "abstract": "Stroke mimics, especially those involving chemotherapy related neurotoxicity, can confound the clinical diagnosis of acute stroke. Here we describe the case of a 63year-old male with a recent history of stage IIIC colon cancer who presented with confusion on the second day of modified FOLFOX6 (5-fluorouracil/oxaliplatin) chemotherapy and subsequently received alteplase, tissue plasminogen activator therapy (tPA), for presumed ischemic stroke. Magnetic resonance imaging scans after tPA administration did not reveal evidence of an infarction and the patients' neurological symptoms resolved completely after discontinuation of 5-fluorouracil (5-FU). Although this patient did not experience any side effects from tPA, fibrinolytic therapy may have been avoided with a better understanding of potential chemotherapy related adverse reactions. Our experience suggests that 5-FU induced reversible encephalopathy can present with acute stroke-like symptoms and emergency medicine personnel evaluating patients for tPA treatment should be aware of this differential diagnosis.", "affiliations": "Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Department of Pharmacy, Robert Wood Johnson University Hospital Somerset, Somerville, NJ, USA. Electronic address: may.nguyen@rwjbh.org.;Department of Pharmacy, The University of Vermont Medical Center, Burlington, VT, USA.;Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Department of Pharmacy, Robert Wood Johnson University Hospital Somerset, Somerville, NJ, USA.", "authors": "Nguyen|May Thuy|MT|;Stoianovici|Robyn|R|;Brunetti|Luigi|L|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D005343:Fibrinolytic Agents; D009944:Organoplatinum Compounds; D010959:Tissue Plasminogen Activator; D002955:Leucovorin; D005472:Fluorouracil", "country": "United States", "delete": false, "doi": "10.1016/j.ajem.2017.07.022", "fulltext": null, "fulltext_license": null, "issn_linking": "0735-6757", "issue": "35(9)", "journal": "The American journal of emergency medicine", "keywords": null, "medline_ta": "Am J Emerg Med", "mesh_terms": "D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001037:Aphasia; D001927:Brain Diseases; D003110:Colonic Neoplasms; D003221:Confusion; D003937:Diagnosis, Differential; D005343:Fibrinolytic Agents; D005472:Fluorouracil; D006261:Headache; D006801:Humans; D002955:Leucovorin; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D020521:Stroke; D010959:Tissue Plasminogen Activator", "nlm_unique_id": "8309942", "other_id": null, "pages": "1389-1390", "pmc": null, "pmid": "28711275", "pubdate": "2017-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Chemotherapy induced stroke mimic: 5-Fluorouracil encephalopathy fulfilling criteria for tissue plasminogen activator therapy.", "title_normalized": "chemotherapy induced stroke mimic 5 fluorouracil encephalopathy fulfilling criteria for tissue plasminogen activator therapy" }

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CHEMOTHERAPY INDUCED STROKE MIMIC: 5-FLUOROURACIL ENCEPHALOPATHY FULFILLING CRITERIA FOR TISSUE PLASMINOGEN ACTIVATOR THERAPY. 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CHEMOTHERAPY INDUCED STROKE MIMIC: 5-FLUOROURACIL ENCEPHALOPATHY FULFILLING CRITERIA FOR TISSUE PLASMINOGEN ACTIVATOR THERAPY. AM-J-EMERG-MED 2017;35(9):1389-1390.", "literaturereference_normalized": "chemotherapy induced stroke mimic 5 fluorouracil encephalopathy fulfilling criteria for tissue plasminogen activator therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170925", "receivedate": "20170925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14007256, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171128" }, { "companynumb": "US-FRESENIUS KABI-FK201707902", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040278", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEUCOVORIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040258", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN CALCIUM (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078811", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "85", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "040", "drugauthorizationnumb": "040278", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLON CANCER STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "NGUYEN M,STOIANOVICI R,BRUNETTI L. CHEMOTHERAPY INDUCED STROKE MIMIC: 5-FLUOROURACIL ENCEPHALOPATHY FULFILLING CRITERIA FOR TISSUE PLASMINOGEN ACTIVATOR THERAPY.. AM-J-EMERG-MED 2017;35(9):1389-1390.", "literaturereference_normalized": "chemotherapy induced stroke mimic 5 fluorouracil encephalopathy fulfilling criteria for tissue plasminogen activator therapy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170922", "receivedate": "20170922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14002149, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171128" } ]

{ "abstract": "Data of our 254 patients who were treated with rt-PA between 1st of Jan, 2011 and 31st of Dec, 2014 were processed. We focused on angioneurotic oedema as allergic complication of thrombolysis which caused life threatening respiratory obstruction in two cases. We describe these two patients' history. Out of 254 patients six (2.3%) suffered angioneurotic edema caused respiratory obstruction in two (0.90%) cases. This occurrence is approximately 1.3-5.1% in literature. Five, out of six patients who suffered from angioneurotic oedema, had been treated with ACE inhibitors or ARB before. The role of ACE inhibitors is known in metabolism of bradykinin cascade. Plasmin which present during thrombolysis, precipitates biochemical mechanisms of this potential life threatening complication. Therefore rt-PA alone can be the cause of angioedema, but it can be more frequent together with ACE inhibitors therapy.", "affiliations": "BAZ Megyei Kórház, Stroke, Vascularis, Általános Neurológiai, Toxikológiai Osztály, Miskolc.;BAZ Megyei Kórház, Stroke, Vascularis, Általános Neurológiai, Toxikológiai Osztály, Miskolc.;BAZ Megyei Kórház, Stroke, Vascularis, Általános Neurológiai, Toxikológiai Osztály, Miskolc.;BAZ Megyei Kórház, Stroke, Vascularis, Általános Neurológiai, Toxikológiai Osztály, Miskolc.;Debreceni Egyetemi Centrum, ÁOK, Neurológiai Klinika, Debrecen.;BAZ Megyei Kórház, Radiológiai Intézet, Miskolc.;BAZ Megyei Kórház, Stroke, Vascularis, Általános Neurológiai, Toxikológiai Osztály, Miskolc.", "authors": "Lovász|Rita|R|;Sas|Attila|A|;Kollár|Tibor|T|;Petercsák|Edina|E|;Fekete|István|I|;Bilinszki|Erika|E|;Valikovics|Attila|A|", "chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator", "country": "Hungary", "delete": false, "doi": "10.18071/isz.69.0239", "fulltext": null, "fulltext_license": null, "issn_linking": "0019-1442", "issue": "69(7-8)", "journal": "Ideggyogyaszati szemle", "keywords": "ACE inhibitors; angioneurotic edema; bradykinin; rt-Pa; thrombolysis", "medline_ta": "Ideggyogy Sz", "mesh_terms": "D000799:Angioedema; D004342:Drug Hypersensitivity; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator", "nlm_unique_id": "17510500R", "other_id": null, "pages": "239-243", "pmc": null, "pmid": "29465888", "pubdate": "2016-07-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Angioneuritic edema in ischaemic stroke patients treated with rt-PA.", "title_normalized": "angioneuritic edema in ischaemic stroke patients treated with rt pa" }

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"reaction": [ { "reactionmeddrapt": "Angioedema", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Stridor", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RITA L, ATTILA S, TIBOR K, EDINA P, ISTVDN F, ERIKA B, ET AL. 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{ "abstract": "BACKGROUND Azithromycin is a macrolide antibiotic widely used to treat respiratory, urogenital, and other infections. Gastrointestinal upset, headache, and dizziness are common adverse effects, and prolongation of the rate-corrected electrocardiographic QT interval and malignant arrhythmias have been reported. There are rare reports of bradycardia and hypothermia but not in the same patient. CASE REPORT A 4-year-old boy given intravenous azithromycin as part of treatment for febrile neutropenia complicating leukemia chemotherapy developed hypothermia (rectal temperature 35.2°C) and bradycardia (65 beats/minute) after the second dose, which resolved over several days post-treatment, consistent with persistence of high tissue azithromycin concentrations relative to those in plasma. A sigmoid Emax pharmacokinetic/pharmacodynamic model suggested a maximal azithromycin-associated reduction in heart rate of 23 beats/minute. Monitoring for these potential adverse effects should facilitate appropriate supportive care in similar cases. CONCLUSIONS Recommended azithromycin doses can cause at least moderate bradycardia and hypothermia in vulnerable pediatric patients, adverse effects that should prompt appropriate monitoring and which may take many days to resolve.", "affiliations": "Department of Infection and Immunity, Monash Children's Hospital, Clayton, Victoria, Australia.;School of Medicine, University of Western Australia, Crawley, Western Australia, Australia.;School of Pharmacy, Curtin University of Technology, Bentley, Western Australia, Australia.;School of Medicine, University of Western Australia, Crawley, Western Australia, Australia.;Department of Infection and Immunity, Monash Children's Hospital, Clayton, Victoria, Australia.", "authors": "Benn|Kerri|K|;Salman|Sam|S|;Page-Sharp|Madhu|M|;Davis|Timothy M E|TME|;Buttery|Jim P|JP|", "chemical_list": "D000900:Anti-Bacterial Agents; D017963:Azithromycin", "country": "United States", "delete": false, "doi": "10.12659/ajcr.905400", "fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2879829010.12659/AJCR.905400905400ArticlesBradycardia and Hypothermia Complicating Azithromycin Treatment Benn Kerri ABDEF1Salman Sam CDE2Page-Sharp Madhu BE3Davis Timothy M.E. ADEF2Buttery Jim P. ABDE145\n1 Department of Infection and Immunity, Monash Children’s Hospital, Clayton, Victoria, Australia\n2 School of Medicine, University of Western Australia, Crawley, Western Australia, Australia\n3 School of Pharmacy, Curtin University of Technology, Bentley, Western Australia, Australia\n4 Department of Pediatrics, Monash University, Clayton, Victoria, Australia\n5 Surveillance of Adverse Events Following Vaccination In the Community (SAEFVIC), Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, AustraliaAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Timothy Davis, e-mail tim.davis@uwa.edu.au2017 11 8 2017 18 883 886 20 5 2017 31 5 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 4\n\nFinal Diagnosis: Febrile neutropenia\n\nSymptoms: Fever\n\nMedication: Azithromycin\n\nClinical Procedure: —\n\nSpecialty: Infectious Diseases\n\nObjective:\nUnusual or unexpected effect of treatment\n\nBackground:\nAzithromycin is a macrolide antibiotic widely used to treat respiratory, urogenital, and other infections. Gastrointestinal upset, headache, and dizziness are common adverse effects, and prolongation of the rate-corrected electrocardiographic QT interval and malignant arrhythmias have been reported. There are rare reports of bradycardia and hypothermia but not in the same patient.\n\nCase Report:\nA 4-year-old boy given intravenous azithromycin as part of treatment for febrile neutropenia complicating leukemia chemotherapy developed hypothermia (rectal temperature 35.2°C) and bradycardia (65 beats/minute) after the second dose, which resolved over several days post-treatment, consistent with persistence of high tissue azithromycin concentrations relative to those in plasma. A sigmoid Emax pharmacokinetic/pharmacodynamic model suggested a maximal azithromycin-associated reduction in heart rate of 23 beats/minute. Monitoring for these potential adverse effects should facilitate appropriate supportive care in similar cases.\n\nConclusions:\nRecommended azithromycin doses can cause at least moderate bradycardia and hypothermia in vulnerable pediatric patients, adverse effects that should prompt appropriate monitoring and which may take many days to resolve.\n\nMeSH Keywords\nAzithromycinBradycardiaHypothermia\n==== Body\nBackground\nAzithromycin is a broad-spectrum macrolide antibiotic used to treat respiratory, urogenital, and other infections [1]. Gastrointestinal upset, headache, and dizziness are common adverse effects, and prolongation of the rate-corrected electrocardiographic QT interval (QTc) and malignant arrhythmias have been reported [2], as have rare instances of bradycardia [3,4] and hypothermia [5].\n\nWe report the case of a child who developed both hypothermia and bradycardia after administration of therapeutic azithromycin doses.\n\nCase Report\nA 4-year-old boy in the delayed intensification phase of treatment for B cell lymphoblastic leukemia was admitted with fever, cough, and coryza. He had no other illnesses and had taken no recent corticosteroid therapy. He was started on 1.7 g intravenous piperacillin (100 mg/kg) plus tazobactam every 6 hours for febrile neutropenia [6], but this was changed to intravenous ceftriaxone 850 mg daily after 1 dose when admission hematology showed he was not neutropenic. His fever continued and he developed neutropenia (0.5×109/L) on the third day of hospitalization. His leukemia chemotherapy was withheld and piperacillin/tazobactam plus 380 mg of intravenous amikacin daily was recommenced. Thoracic CT scan appearances at that time were consistent with a fungal/atypical respiratory infection and he was started on 60 mg intravenous liposomal amphotericin B daily plus 170 mg (10 mg/kg) intravenous azithromycin followed by 85 mg (5 mg/kg) daily as a result. Piperacillin, tazobactam, and amikacin were continued.\n\nWithin 3 hours of the second azithromycin dose, he developed bradycardia (heart rate 75 beats/minute) when asleep. Five hours later, the bradycardia had worsened (65 beats/minute), his systolic blood pressure had fallen (110 to 80 mmHg), and he had become hypothermic (rectal temperature 35.2°C). Septic shock was diagnosed and, after intravenous fluids, the pulse rate and blood pressure increased. Blood cultures proved sterile, and serum electrolytes and venous blood gas analysis were normal. A nasopharyngeal aspirate showed picornavirus and parainfluenza RNA detected by PCR. Over the next 24 hours the patient experienced further episodes of bradycardia and hypothermia requiring use of a temperature management system. Electrocardiographic monitoring showed a QTc ≤480 msec−0.5. Liposomal amphotericin B was withheld and 310 mg intravenous vancomycin was added on the seventh day of hospitalization. The azithromycin was ceased after the third dose and the bradycardia and hypothermia improved over the next 72 hours. The bradycardia had resolved by the tenth day of admission and the hypothermia by the eleventh day.\n\nAzithromycin was measured in available plasma samples using liquid chromatography-mass spectrometry [7] and pharmacokinetic/pharmacodynamic (PK/PD) modelling was performed using NONMEM (v 7.2.0, ICON Development Solutions, Ellicott City, MD). Plasma azithromycin concentrations and clinical data were available at 16 time-points (Figure 1). A two-compartment PK model with first-order elimination from the central compartment provided the best fit (Table 1). Overall azithromycin exposure, the simulated Cmax, and the terminal elimination half-life were consistent with values after intravenous dosing based on data from studies of oral azithromycin in this age group [8]. A PK/PD model was developed incorporating heart rate during sleep. Observations before the final azithromycin dose were excluded to minimize the confounding effect of active infection. A negative sigmoid Emax model adequately described the association between plasma azithromycin and heart rate (Figure 1), the maximal azithromycin effect being a reduction of 23 beats/min.\n\nDiscussion\nThere have been 2 previously reported cases of severe bradycardia associated with azithromycin [3,4], and 3 additional cases of hypothermia in a brief report from 1 pediatric unit [5]. Of the 2 bradycardia cases, 1 was a 9-month-old infant who was accidentally given a high (50 mg/kg) dose of azithromycin and then developed a wide-complex bradycardia, prolonged QTc, and complete heart block [4]. The second involved a man with human immunodeficiency virus infection who developed marked QT prolongation and sinus bradycardia after a single 500-mg dose of intravenous azithromycin [3]. The 3 cases of azithromycin-associated hypothermia were all in children [5]. The first was a 3.5-year-old girl with tonsillopharyngitis who became unresponsive and had a rectal temperature of 34.4°C after the third daily 10 mg/kg azithromycin dose. The azithromycin was ceased on the fifth day and her hypothermia resolved. The second case was a 5-year-old girl who developed a rectal temperature of 35°C after the second daily dose of 200 mg azithromycin for tonsillopharyngitis. The hypothermia persisted for 4 days after treatment was discontinued. The third case was a 5-year-old boy treated with 200 mg azithromycin daily for otitis media, whose rectal temperature was 35.7°C 12 hours after the third dose. The hypothermia resolved over the next 24 hours.\n\nThe present case is the first to show a clear dose-response relationship between plasma azithromycin concentrations after therapeutic doses and bradycardia in a severely ill child. This observation, and the rarity of previous reports of azithromycin-associated bradycardia [3,4], suggest that our patient had underlying latent disease of the sinus and/or atrio-ventricular node which was unmasked by azithromycin treatment, albeit not severe enough to warrant cardiologic intervention [9]. Although azithromycin has a relatively weak pro-arrhythmic potential through inhibition of the rapid component of delayed rectifier K+ current channel compared with other macrolides [10] and our patient’s QTc prolongation was not marked compared with that in other severely ill pediatric patients [11], bradycardia is a risk factor for azithromycin-associated malignant arrhythmias when the QTc is prolonged [12]. In addition to electrocardiographic monitoring in cases such as ours, management should include withdrawal of other medications associated with QTc prolongation and correction of significant electrolyte abnormalities, including hypokalemia.\n\nThe potential causes of non-environmental hypothermia include infections, shock, and pharmacotherapy [13]. Whether our patient’s hypothermia was due to azithromycin rather than other factors is unknown, but, in addition to similar pediatric cases [5] and reports of hypothermia with other macrolides [14], the resolution of hypothermia was protracted in parallel with that for bradycardia and consistent with the persistence of high tissue concentrations of azithromycin relative to those in plasma [15]. Although bradycardia was not a reported feature of the 4 previously reported cases of macrolide-associated hypothermia in children [5,14], hypothermia is a recognized cause of bradycardia [16] and a bidirectional relationship cannot be excluded in our case. Hypothermia can cause or contribute to multi-organ failure but cardiotoxic effects appear rare, at least in adults [17]. Thus, coexistent bradycardia and hypothermia, as in our patient, who responded to supportive care, may not increase the risk of adverse outcomes.\n\nConclusions\nThis case provides evidence that recommended azithromycin doses can cause at least moderate bradycardia and hypothermia in vulnerable pediatric patients, which are adverse effects that may take days to resolve. Monitoring, including rectal temperature, heart rate, and QTc, should allow identification of these potential complications and facilitate appropriate supportive care.\n\nConflicts of interest\n\nNone.\n\nFigure 1. (A) Time vs. concentration (black open circles) and resting heart rate (grey crosses) plotted with model curves (black solid line and grey dashed line, respectively). (B) Pharmacodynamic relationship between resting heart rate and azithromycin concentration with actual observations as black crosses and model as solid black line.\n\nTable 1. Model parameters for the pharmacokinetic/pharmacodynamic model along with secondary pharmacokinetic variables.\n\nParameter\tValue\tPublished range [8]\t\nPharmacokinetic model\t\t\t\n  Clearance (L/h)\t18.1\t\t\n  Central volume of distribution (L)\t305\t\t\n  Inter-compartmental clearance (L/h)\t46.2\t\t\n  Peripheral volume of distribution (L)\t451\t\t\n  Proportional residual variability (%)\t12.8\t\t\n  Additive residual variability (μg/L)\t8.54\t\t\nSecondary parameters\t\t\t\n  Distribution half-life (h)\t2.4\t\t\n  Terminal elimination half-life (h)\t33\t31.6±6.6*\t\n  Simulated maximum concentration (μg/L)\t\t\t\n    First dose\t530\t224±120*\t\n    Second dose\t368\t\t\n    Third dose\t378\t\t\n  Total area under the curve to infinity (μg.h/L)\t18.785\t7.364±2.604*\t\nPharmacodynamic model\t\t\t\n  Baseline heart rate (beats/min)\t92.9\t\t\n  Half maximal effective concentration (EC50) (μg/L)\t105\t\t\n  Maximal effect (Emax) (beats/min)\t−23.4\t\t\n  Hill coefficient\t11\t\t\n  Additive residual variability (beats/min)\t26.8\t\t\n* Children aged 0.5–5 years receiving multiple doses of azithromycin suspension (10mg/kg then 5 mg/kg Days 2–5) with values based on sampling after the last dose (steady state) and to be interpreted against oral bioavailability of 40–50%.\n==== Refs\nReferences:\n1. Parnham MJ Erakovic Haber V Giamarellos-Bourboulis EJ Azithromycin: Mechanisms of action and their relevance for clinical applications Pharmacol Ther 2014 143 225 45 24631273 \n2. McMullan BJ Mostaghim M Prescribing azithromycin Aust Prescr 2015 38 87 89 26648627 \n3. Santos N Oliveira M Galrinho A LQT interval prolongation and extreme bradycardia after a single dose of azithromycin Rev Port Cardiol 2010 29 139 42 20391905 \n4. Tilelli JA Smith KM Pettignano R Life-threatening bradyarrhythmia after massive azithromycin overdose Pharmacother 2006 26 147 50 \n5. Kavukcu S Uguz A Aydin A Hypothermia from azithromycin J Toxicol Clin Toxicol 1997 35 2 225 26 9120898 \n6. The Royal Children’s Hospital Melbourne Clinical practice guidelines. Fever and suspected or confirmed neutropenia Available at: https://www.rch.org.au/clinicalguide/guideline_index/Fever_and_suspected_or_confirmed_neutropenia/ \n7. Salman S Davis TM Page-Sharp M Pharmacokinetics of transfer of azithromycin into the breast milk of african mothers Antimicrob Agents Chemother 2016 60 1592 99 \n8. Nahata MC Koranyi KI Luke DR Foulds G Pharmacokinetics of azithromycin in pediatric patients with acute otitis media Antimicrob Agents Chemother 1995 39 1875 77 7486938 \n9. Ovsyshcher IE Barold SS Drug induced bradycardia: to pace or not to pace? Pacing Clin Electrophysiol 2004 27 1144 47 15305965 \n10. Kezerashvili A Khattak H Barsky A Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors J Interv Card Electrophysiol 2007 18 243 46 17546486 \n11. Van Dorn CS Johnson JN Taggart NW QTc values among children and adolescents presenting to the emergency department Pediatrics 2011 128 e1395 401 22123891 \n12. Howard PA Azithromycin-induced proarrhythmia and cardiovascular death Ann Pharmacother 2013 47 1547 51 24285766 \n13. Brown DJ Brugger H Boyd J Paal P Accidental hypothermia N Engl J Med 2012 367 1930 38 23150960 \n14. Hassel B Hypothermia from erythromycin Ann Intern Med 1991 115 69 70 \n15. Wildfeuer A Laufen H Zimmermann T Uptake of azithromycin by various cells and its intracellular activity under in vivo conditions Antimicrob Agents Chemother 1996 40 75 79 8787883 \n16. Reuler JB Hypothermia: Pathophysiology, clinical settings, and management Ann Intern Med 1978 89 519 27 358883 \n17. Schober A Sterz F Handler C Cardiac arrest due to accidental hypothermia – a 20 year review of a rare condition in an urban area Resuscitation 2014 85 749 56 24513157\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "18()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000900:Anti-Bacterial Agents; D017963:Azithromycin; D001919:Bradycardia; D002675:Child, Preschool; D064147:Febrile Neutropenia; D006801:Humans; D007035:Hypothermia; D007938:Leukemia; D008297:Male", "nlm_unique_id": "101489566", "other_id": null, "pages": "883-886", "pmc": null, "pmid": "28798290", "pubdate": "2017-08-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "24285766;8787883;2048867;7486938;26711756;15305965;22123891;23150960;26648627;16506357;9120898;24513157;20391905;24631273;17546486;358883", "title": "Bradycardia and Hypothermia Complicating Azithromycin Treatment.", "title_normalized": "bradycardia and hypothermia complicating azithromycin treatment" }

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{ "abstract": "Calcineurin inhibitors (CNIs) are effective agents used for prevention of graft-vs-host disease after allogeneic hematopoietic stem cell transplant or for organ rejection in solid-organ transplant. However, CNIs have a wide range of adverse effects that may necessitate changing to another CNI or immunosuppressive agent. We report a case of acute myeloid leukemia in which achalasia developed after exposure to tacrolimus, as revealed by esophagram results. The patient's symptoms and signs were ameliorated after a change to cyclosporine. This case is the first in the literature to reveal achalasia associated with tacrolimus. Achalasia should be part of a differential diagnosis of upper gastrointestinal symptoms in patients undergoing transplant, and changing to another CNI may be a useful therapeutic intervention.", "affiliations": "Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.;Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.;Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.;Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD.;Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.;Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.;Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.", "authors": "Goklemez|Sencer|S|;Curtis|Lauren M|LM|;Hawwa|Alao|A|;Ling|Alexander|A|;Avila|Daniele|D|;Heller|Theo|T|;Pavletic|Steven Z|SZ|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.mayocpiqo.2017.06.004", "fulltext": "\n==== Front\nMayo Clin Proc Innov Qual OutcomesMayo Clin Proc Innov Qual OutcomesMayo Clinic Proceedings. Innovations, Quality & Outcomes2542-4548Elsevier S2542-4548(17)30038-310.1016/j.mayocpiqo.2017.06.004Case ReportAchalasia in a Patient Undergoing Hematologic Stem Cell Transplant After Exposure to Tacrolimus Goklemez Sencer aCurtis Lauren M. MDaHawwa Alao MDbLing Alexander MDcAvila Daniele CRNPaHeller Theo MDbPavletic Steven Z. MDpavletis@mail.nih.gova∗a Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MDb Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MDc Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD∗ Correspondence: Address to Steven Z. Pavletic, MD, 10 Center Dr, Bethesda, MD 20892. pavletis@mail.nih.gov02 8 2017 9 2017 02 8 2017 1 2 198 201 © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.2017Mayo Foundation for Medical Education and ResearchThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Calcineurin inhibitors (CNIs) are effective agents used for prevention of graft-vs-host disease after allogeneic hematopoietic stem cell transplant or for organ rejection in solid-organ transplant. However, CNIs have a wide range of adverse effects that may necessitate changing to another CNI or immunosuppressive agent. We report a case of acute myeloid leukemia in which achalasia developed after exposure to tacrolimus, as revealed by esophagram results. The patient's symptoms and signs were ameliorated after a change to cyclosporine. This case is the first in the literature to reveal achalasia associated with tacrolimus. Achalasia should be part of a differential diagnosis of upper gastrointestinal symptoms in patients undergoing transplant, and changing to another CNI may be a useful therapeutic intervention.\n\nAbbreviations and Acronyms\nCMV, cytomegalovirusCNI, calcineurin inhibitorGVHD, graft-vs-host diseaseHSCT, hematopoietic stem cell transplantIV, intravenousNO, nitric oxideNOS, nitric oxide synthase\n==== Body\nCalcineurin inhibitors (CNIs) are commonly used for prophylaxis of graft-vs-host disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) and for rejection in solid-organ transplant.1 They are known to be associated with many adverse effects, including nephrotoxicity, hypertension, vulnerability to infection, and neurotoxicity.2, 3 The gastrointestinal adverse effects of CNIs are mostly limited to nausea, vomiting, decreased oral intake, and elevation of liver enzyme levels. We present a compelling case of symptomatic achalasia likely induced by tacrolimus after allogeneic HSCT.\n\nReport of Case\nA 57-year-old male patient from Pakistan, with a history of acute promyelocytic leukemia and subsequent treatment-related acute myelocytic leukemia, received a reduced-intensity, 10 out of 10 human leukocyte antigen–matched, unrelated donor transplant. Conditioning pretransplant included administration of fludarabine and cyclophosphamide. For GVHD prophylaxis, tacrolimus and sirolimus were both started on day –3, with goal levels of 5 to 10 ng/mL for tacrolimus and 3-12 ng/ml for sirolimus; 5 mg/m2 intravenous (IV) methotrexate was given on days +1, +3, +6, and +11 posttransplant. In addition, the patient was taking ursodiol, acyclovir, fluconazole, ceftriaxone, tamsulosin, and metoprolol. On day –1 from transplant, the patient reported odynophagia, which at the time was attributed to mucositis. Given that the patient’s amylase and lipase levels were elevated (amylase peak value, 185 U/L; lipase, 223 U/L) and a computed tomography scan of the abdomen revealed mild stranding around the pancreas suspicious for pancreatitis, bowel rest, IV hydration, and pain medications were initiated. By day +15, he had resumed oral intake but started experiencing worsening dysphagia with pills and solid food. Results of an oropharyngeal barium swallow test on day +19 were normal, except for mildly reduced motility of the proximal esophagus. By day +22, he was discharged home, although most of his medications were changed to liquid formulations, owing to persistent dysphagia.\n\nOn day +33, the patient was readmitted to the hospital for IV antibiotic treatment of an abscess on his right arm that was related to a peripherally inserted central catheter line. While the patient was in the hospital, he complained of dysphagia and retrosternal discomfort. A barium swallow test, this time assessing the entire esophagus, was obtained on day +35 (Figure, A). Results revealed persistent, marked, smooth narrowing of the lower esophageal sphincter, with substantially delayed emptying of liquid barium, in a manner consistent with achalasia. After administration of twice-daily pantoprazole, the patient’s chest and abdominal pain improved. He began to tolerate pills and small quantities of food and was discharged from the hospital.Figure A, Results of esophagram at day +35 after transplant, with decreased peristalsis and spasm of the lower esophageal sphincter, consistent with the diagnosis of achalasia. B, Esophagram results at day +96 after transplant, with improved tertiary peristalsis soon after changing tacrolimus to cyclosporine for graft-vs-host disease prophylaxis. C, Esophagram results at day +140 after transplant, with improved esophageal motility pattern and minimally delayed emptying of contrast medium. D, Esophagram results at day +180 after transplant, with resolution of achalasia as seen from near-normal peristalsis as well as widely patent lower esophageal sphincter.\n\n\n\nHis improvement in oral intake was short-lived, and by day +50, his dysphagia once again worsened. To evaluate for GVHD vs pseudoachalasia, the patient underwent endoscopy on day +77. Results revealed mild duodenitis, but pathology test results were negative for GVHD and cytomegalovirus (CMV). Esophageal manometry results on day +78 were consistent with achalasia, with a lower esophageal sphincter pressure of 22 mm Hg (normal range, 8-12 mm Hg), and his esophagus was aperistaltic.\n\nThe patient also began to experience severe generalized bone and muscle pain, which was suspected of being secondary to tacrolimus. In an effort to relieve his pain, on day +84, tacrolimus was changed to cyclosporine. On day +96, the patient underwent another outpatient esophagram, results of which were consistent with those of the previous one, except that they revealed more tertiary peristalsis (Figure, B). At a follow-up visit on day +140, the esophagram was repeated, and this time results revealed a much better esophageal motility pattern, with only minimally delayed emptying, and rapid progression of contrast into the esophagus (Figure, C). However, the patient continued to complain of dysphagia, reflux, and upper abdominal pain. His appetite was poor because of these difficulties, and his weight was 64.5 kg (a 19% decrease from his pretransplant weight). Options for treatment of the achalasia were considered, including Heller myotomy, onabotulinum toxin A injection, and endoscopic balloon dilation. Given that less than 6 months had passed since the HSCT, invasive surgery was undesirable because of infection and wound-healing risks. A repeated endoscopy with onabotulinum toxin A injection was planned, owing to his ongoing weight loss and gastrointestinal symptoms.\n\nAt the patient’s 6-month visit, he presented for his pre–onabotulinum toxin A assessment and, surprisingly, reported marked improvement in his symptoms, with increased ability to eat solids and liquids. A repeated esophagram was obtained (Figure, D). Results revealed a complete absence of lower esophageal sphincter narrowing, with peristaltically coordinated, normal prompt passage of contrast materials from the distal esophagus into the stomach and only minor dysmotility, as evidenced by only minimal and transient tertiary peristalsis. The patient reported corresponding improvement in his symptoms, and onabotulinum toxin A therapy was cancelled. A review of his history revealed that the only recent intervention or medication change was switching from tacrolimus to cyclosporine 3 months before the dramatic improvement in his esophageal motility.\n\nDiscussion\nTo our knowledge, this case report is the first to discuss a new diagnosis of achalasia after allogeneic HSCT. Given the temporal relationship of development of an exacerbation of achalasia soon after starting tacrolimus and complete resolution after stopping, we suspect that starting tacrolimus was the most likely inciting cause. Koch et al4 reported on a liver transplant recipient who experienced achalasia 3 months after transplant and for whom cyclosporine was started for organ rejection prophylaxis. When cyclosporine was changed to tacrolimus, the patient’s esophageal mobility returned to normal. The authors speculated that this result may have occurred via inhibition of nitric oxide synthase (NOS) by CNIs.\n\nNitric oxide (NO) is present at the neurons along the entire esophageal lining, including the lower esophageal sphincter, and is not only responsible for appropriate relaxation of the sphincter to allow passage of food and liquid but also contributes to peristaltic movements of the body. Nitric oxide is synthesized by NOS. The inhibitory nonadrenergic noncholinergic neurons at the esophagus secrete NO (using their NOS) as a neurotransmitter,5 causing hyperpolarization of the innervated muscle, inhibiting its contraction. If this mechanism is somehow disrupted, the unopposed activity of the activator neurons secreting acetylcholine may prevent proper relaxation, causing a stiff lower esophageal sphincter and a body with unsynchronized peristalsis. Several reports suggest that CNIs may decrease NO levels in other diseases, including hypertension,6 inflammatory bowel disease,7 and renal diseases.8 Observations in the current case very likely result from decreased NO levels in the postganglionic neurons of the esophageal tract, leading to unopposed contractile activity. Changing from one drug to another was associated with resolution of achalasia within 3 months, in both our patient and the case reported by Koch et al.4 Owing to the difference in chemical structure between tacrolimus and cyclosporine, various drugs within the same class may have widely varying effects in different patients.9 This useful therapeutic substitution of one CNI for another is reported in thrombotic microangiopathy, or posterior reversible encephalopathy syndrome; several reports reveal that changing the CNI can lead to resolution or improvement of symptoms.10, 11, 12 If achalasia symptoms do not improve, however, CNI cessation should be considered in certain cases.\n\nConclusion\nUpper gastrointestinal symptoms after allogeneic HSCT can have multiple causes, including chemotherapy-related mucositis, gastrointestinal GVHD, CMV reactivation, and reflux-related gastritis.13 Achalasia could have been an underdiagnosed, drug-induced cause of gastrointestinal symptoms and should be considered in patients who have abdominal pain, reflux, dysphagia, and/or anorexia. If endoscopy with biopsy results are negative for GVHD and CMV and the work-up is otherwise unrevealing, an esophagram should be obtained. In this patient, a temporal association was found between the presence of achalasia and the starting and stopping of tacrolimus. Achalasia may be a rare adverse effect of CNIs, which may disrupt esophageal motility via decreasing NO levels in the postganglionic neurons of the esophageal tract. Once achalasia is diagnosed, changing from one CNI to another may be an effective management strategy.\n\nAcknowledgments\nThe opinions expressed in this article are those of the authors and do not represent the official position of the National Institutes of Health, National Cancer Institute, or the United States Government.\n\nGrant Support: This work was supported by the National Institutes of Health, National Cancer Institute, Intramural Program Center for Cancer Research.\n\nPotential Competing Interests: The authors report no competing interests.\n==== Refs\nReferences\n1 Ferrara J.L. Levine J.E. Reddy P. Holler E. Graft-versus-host disease Lancet 373 9647 2009 1550 1561 19282026 \n2 Kahan B.D. Cyclosporine N Engl J Med 321 25 1989 1725 1738 2687689 \n3 Scott L.J. McKeage K. Keam S.J. Plosker G.L. Tacrolimus: a further update of its use in the management of organ transplantation Drugs 63 12 2003 1247 1297 12790696 \n4 Koch R. Zoller H. Graziadei I. Propst A. Vogel W. Cyclosporine A-induced achalasia-like esophageal motility disorder in a liver transplant recipient: successful conversion to tacrolimus Transplantation 76 4 2003 744 745 12973123 \n5 Mashimo H. Goyal R.K. Physiology of esophageal motility https://www.nature.com/gimo/contents/pt1/full/gimo3.html Accessed July 26, 2017 \n6 Cook L.G. Chiasson V.L. Long C. Wu G.-Y. Mitchell B.M. Tacrolimus reduces nitric oxide synthase function by binding to FKBP rather than by its calcineurin effect Kidney Int 75 7 2009 719 726 19177155 \n7 Hämäläinen M. Lahti A. Moilanen E. Calcineurin inhibitors, cyclosporin A and tacrolimus inhibit expression of inducible nitric oxide synthase in colon epithelial and macrophage cell lines Eur J Pharmacol 448 2-3 2002 239 244 12144947 \n8 Baran D.A. Galin I.D. Gass A.L. Calcineurin inhibitor-associated early renal insufficiency in cardiac transplant recipients: risk factors and strategies for prevention and treatment Am J Cardiovasc Drugs 4 1 2004 21 29 14967063 \n9 Schreiber S.L. Chemistry and biology of the immunophilins and their immunosuppressive ligands Science 251 4991 1991 283 287 1702904 \n10 Kaufman D.B. Kaplan B. Kanwar Y.S. Abecassis M. Stuart F.P. The successful use of tacrolimus (FK506) in a pancreas/kidney transplant recipient with recurrent cyclosporine-associated hemolytic uremic syndrome Transplantation 59 12 1995 1737 1739 7541579 \n11 Abdalla A.H. Al-Sulaiman M.H. Al-Khader A.A. FK 506 as an alternative in cyclosporin-induced hemolytic uremic syndrome in a kidney transplant recipient Transpl Int 7 5 1994 382 384 7527640 \n12 Apuri S. Carlin K. Bass E. Nguyen P.T. Greene J.N. Tacrolimus associated posterior reversible encephalopathy syndrome—a case series and review Mediterr J Hematol Infect Dis 6 1 2014 e2014014 24678391 \n13 McDonald G.B. How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver Blood 127 12 2016 1544 1550 26729898\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2542-4548", "issue": "1(2)", "journal": "Mayo Clinic proceedings. Innovations, quality & outcomes", "keywords": "CMV, cytomegalovirus; CNI, calcineurin inhibitor; GVHD, graft-vs-host disease; HSCT, hematopoietic stem cell transplant; IV, intravenous; NO, nitric oxide; NOS, nitric oxide synthase", "medline_ta": "Mayo Clin Proc Innov Qual Outcomes", "mesh_terms": null, "nlm_unique_id": "101728275", "other_id": null, "pages": "198-201", "pmc": null, "pmid": "30225417", "pubdate": "2017-09", "publication_types": "D002363:Case Reports", "references": "7541579;14967063;24678391;1702904;12144947;19177155;12790696;19282026;2687689;7527640;26729898;12973123", "title": "Achalasia in a Patient Undergoing Hematologic Stem Cell Transplant After Exposure to Tacrolimus.", "title_normalized": "achalasia in a patient undergoing hematologic stem cell transplant after exposure to tacrolimus" }

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"drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMSULOSIN" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oesophageal achalasia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone pain", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GOKLEMEZ S, CURTIS LM, HAWWA A, LING A, AVILA D, HELLER T, ET AL. ACHALASIA IN A PATIENT UNDERGOING HEMATOLOGIC STEM CELL TRANSPLANT AFTER EXPOSURE TO TACROLIMUS. UNKNOWN 2017;1(2):198-201.", "literaturereference_normalized": "achalasia in a patient undergoing hematologic stem cell transplant after exposure to tacrolimus", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171129", "receivedate": "20171129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14235128, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "US-ACCORD-061034", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL." } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oesophageal achalasia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bone pain", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GOKLEMEZ S, CURTIS LM, HAWWA A, LING A, AVILA D, HELLER T ET AL. ACHALASIA IN A PATIENT UNDERGOING HEMATOLOGIC STEM CELL TRANSPLANT AFTER EXPOSURE TO TACROLIMUS. MAYO CLINIC PROCEEDINGS: INNOVATIONS, QUALITY AND OUTCOMES. 2017;1(2):198-201.", "literaturereference_normalized": "achalasia in a patient undergoing hematologic stem cell transplant after exposure to tacrolimus", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171116", "receivedate": "20171116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14194019, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "US-DRREDDYS-USA/USA/17/0094504", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": 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"literaturereference": "GOKLEMEZ S, CURTIS L, HAWWA A, LING A, AVILA D, HELLER T, ET AL. ACHALASIA IN A PATIENT UNDERGOING HEMATOLOGIC STEM CELL TRANSPLANT AFTER EXPOSURE TO TACROLIMUS.. MAYO CLIN PROC INN QUAL OUT. 2017;1(2):198-201.", "literaturereference_normalized": "achalasia in a patient undergoing hematologic stem cell transplant after exposure to tacrolimus", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20171115", "receivedate": "20171112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14181165, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "Insulin autoimmune syndrome or Hirata's disease is an extremely rare condition leading to hypoglycaemia of variable severity due to autoantibodies against insulin. We present the first case documented in the Czech Republic.", "affiliations": "4th Department of Internal Medicine, University Hospital and Faculty of Medicine Hradec Králové, Charles University, Hradec Králové, Czech Republic. katerina.zibridova@fnhk.cz.;4th Department of Internal Medicine, University Hospital and Faculty of Medicine Hradec Králové, Charles University, Hradec Králové, Czech Republic.;4th Department of Internal Medicine, University Hospital and Faculty of Medicine Hradec Králové, Charles University, Hradec Králové, Czech Republic.;4th Department of Internal Medicine, University Hospital and Faculty of Medicine Hradec Králové, Charles University, Hradec Králové, Czech Republic.;4th Department of Internal Medicine, University Hospital and Faculty of Medicine Hradec Králové, Charles University, Hradec Králové, Czech Republic.;4th Department of Internal Medicine, University Hospital and Faculty of Medicine Hradec Králové, Charles University, Hradec Králové, Czech Republic.", "authors": "Žibřidová|Kateřina|K|;Havlínová|Barbora|B|;Svobodová|Eliška|E|;Žák|Pavel|P|;Čáp|Jan|J|;Gabalec|Filip|F|", "chemical_list": "D001323:Autoantibodies; D015415:Biomarkers; D005938:Glucocorticoids; D007155:Immunologic Factors; D000069283:Rituximab; D011241:Prednisone", "country": "Czech Republic", "delete": false, "doi": "10.14712/18059694.2021.9", "fulltext": null, "fulltext_license": null, "issn_linking": "1211-4286", "issue": "64(1)", "journal": "Acta medica (Hradec Kralove)", "keywords": "Hirata’s disease; hyperinsulinemic hypoglycaemia; insulin autoantibodies; insulin autoimmune syndrome", "medline_ta": "Acta Medica (Hradec Kralove)", "mesh_terms": "D000328:Adult; D001323:Autoantibodies; D001327:Autoimmune Diseases; D015415:Biomarkers; D018153:Czech Republic; D004359:Drug Therapy, Combination; D005938:Glucocorticoids; D006801:Humans; D007003:Hypoglycemia; D007155:Immunologic Factors; D008297:Male; D011241:Prednisone; D000069283:Rituximab; D013577:Syndrome", "nlm_unique_id": "9705947", "other_id": null, "pages": "50-54", "pmc": null, "pmid": "33855960", "pubdate": "2021", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hirata's Disease: Rare Cause of Hypoglycaemia in Caucasian Male.", "title_normalized": "hirata s disease rare cause of hypoglycaemia in caucasian male" }

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"drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOCETIRIZINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Seasonal allergy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOCETIRIZINE" } ], "patientagegroup": "5", "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", 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{ "abstract": "We sought to determine whether conversion from tacrolimus/mycophenolate mofetil (TAC-MMF) into tacrolimus/mTOR inhibitor (TAC-mTOR) immunosuppression would reduce the incidences of BK and CMV viremia after kidney/pancreas (KP) transplantation.\n\n\n\nIn this single-center review, the TAC-mTOR cohort (n = 39) was converted at 1 month post-transplant to an mTOR inhibitor and reduced-dose tacrolimus. Outcomes were compared to a cohort of KP recipients (n = 40) maintained on TAC-MMF.\n\n\n\nAt 3 years post-transplant, KP survivals and incidences of kidney/pancreas rejection were equivalent between mTOR and MMF-treated cohorts. (P = ns). BK viremia-free survival was better for the mTOR vs MMF-treated group (P = .004). In multivariate analysis, MMF vs mTOR immunosuppression was an independent risk factor for BK viremia (hazard ratio 12.27, P = .02). Similarly, mTOR-treated recipients displayed better CMV infection-free survival compared to the MMF-treated cohort (P = .01). MMF vs mTOR immunosuppression (hazard ratio 18.77, P = .001) and older recipient age (hazard ratio 1.13 per year, P = .006) were independent risk factors for CMV viremia. Mean estimated GFR and HgbA1c levels were equivalent between groups at 1, 2, and 3 years post-transplantation.\n\n\n\nConversion from TAC/MMF into TAC/mTOR immunosuppression after KP transplantation reduced the incidences of BK and CMV viremia with an equivalent risk of acute rejection and similar renal/pancreas function.", "affiliations": "Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.;Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA.;Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA.;Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA.;Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA.;Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA.;Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.", "authors": "Knight|Richard J|RJ|0000-0002-0870-629X;Graviss|Edward A|EA|;Nguyen|Duc T|DT|;Kuten|Samantha A|SA|;Patel|Samir J|SJ|;Gaber|Lillian|L|;Gaber|A Osama|AO|", "chemical_list": "D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D009173:Mycophenolic Acid; D016559:Tacrolimus", "country": "Denmark", "delete": false, "doi": "10.1111/ctr.13265", "fulltext": null, "fulltext_license": null, "issn_linking": "0902-0063", "issue": "32(6)", "journal": "Clinical transplantation", "keywords": "graft survival; immunosuppression; incidence; kidney; mycophenolic acid; pancreas transplantation; risk factors; tacrolimus; viremia", "medline_ta": "Clin Transplant", "mesh_terms": "D000328:Adult; D001739:BK Virus; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D016035:Pancreas Transplantation; D027601:Polyomavirus Infections; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus; D014412:Tumor Virus Infections; D014766:Viremia; D055815:Young Adult", "nlm_unique_id": "8710240", "other_id": null, "pages": "e13265", "pmc": null, "pmid": "29676018", "pubdate": "2018-06", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Conversion from tacrolimus-mycophenolate mofetil to tacrolimus-mTOR immunosuppression after kidney-pancreas transplantation reduces the incidence of both BK and CMV viremia.", "title_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia" }

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CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. 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CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. 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null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "BK virus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, PATEL SJ, GABER L, ET AL. CONVERSION FROM TACROLIMUS?MYCOPHENOLATE MOFETIL TO TACROLIMUS?MTOR IMMUNOSUPPRESSION AFTER KIDNEY?PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. CLIN?TRANSPLANT 2018?32(6):E13265.", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180821", "receivedate": "20180801", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15228267, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-05717", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", 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"actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203005", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, BID, ON THE DAY OF SURGERY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft loss", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, ET AL.. CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. CLINICAL TRANSPLANTATION. 2018?32(6):E13265", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190103", "receivedate": "20190103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15784699, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP006383", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL AND PANCREAS TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 7.5 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL AND PANCREAS TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANTITHYMOCYTE IMMUNOGLOBULIN (RABBIT)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL AND PANCREAS TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL AND PANCREAS TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG, UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL AND PANCREAS TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, PATEL SJ, GABER L ET AL.. CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA.. CLIN TRANSPLANT. 2018?32(6):E13265", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190729", "receivedate": "20190729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16640629, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-05725", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203005", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, BID, ON THE DAY OF SURGERY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", 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"drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TARGETED TO A TROUGH LEVEL OF 8-10 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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"reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, ET AL.. CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. CLINICAL TRANSPLANTATION. 2018?32(6):E13265", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190103", "receivedate": "20190103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15784702, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "PHHY2018US001032", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { 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"drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL AND PANCREAS TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL AND PANCREAS TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CUMULATIVE DOSE OF 7.5 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL AND PANCREAS TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANTITHYMOCYTE IMMUNOGLOBULIN (RABBIT)" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL AND PANCREAS TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANTITHYMOCYTE IMMUNOGLOBULIN (RABBIT)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal and pancreas transplant rejection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, PATEL SJ, GABER L ET AL.. CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. CLINICAL TRANSPLANTATION. 2018?1-10", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180518", "receivedate": "20180518", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14915312, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2018-06056", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203005", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.15 MG/KG, QD TROUGH LEVELS WERE MAINTAINED AT 8-10 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5-7 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, ET AL.. CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. CLIN TRANSPLANT.. 2018?32(6):E13265", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20190102", "receivedate": "20190102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15780082, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2018-06053", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5-7 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.15 MG/KG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203005", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, ET AL.. CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. CLIN TRANSPLANT.. 2018?32(6):E13265", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20190102", "receivedate": "20190102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15780090, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2018-06051", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.15 MG/KG, QD TROUGH LEVELS WERE MAINTAINED AT 8-10 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203005", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5-7 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft loss", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, ET AL.. CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. CLIN TRANSPLANT.. 2018?32(6):E13265", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20190102", "receivedate": "20190102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15780091, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2018-06055", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.15 MG/KG, QD TROUGH LEVELS WERE MAINTAINED AT 8-10 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203005", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5-7 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, ET AL.. CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. CLIN TRANSPLANT.. 2018?32(6):E13265", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20190102", "receivedate": "20190102", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15780083, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-05724", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LOWERED TO TROUGH LEVEL OF 6-8 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG, ON THE DAY OF TRANSPLANTATION", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "GRADUALLY TAPERED TO A MAINTENANCE DOSE OF 5-10 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203005", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID, DAY 6 POST TRANSPLANT", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG, QD, BY DAY 3 POST-TRANSPLANTATION", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TARGETED TO A TROUGH LEVEL OF 8-10 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { 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"reaction": [ { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KNIGHT RJ, GRAVISS EA, NGUYEN DT, KUTEN SA, ET AL.. CONVERSION FROM TACROLIMUS-MYCOPHENOLATE MOFETIL TO TACROLIMUS-MTOR IMMUNOSUPPRESSION AFTER KIDNEY-PANCREAS TRANSPLANTATION REDUCES THE INCIDENCE OF BOTH BK AND CMV VIREMIA. CLINICAL TRANSPLANTATION. 2018?32(6):E13265", "literaturereference_normalized": "conversion from tacrolimus mycophenolate mofetil to tacrolimus mtor immunosuppression after kidney pancreas transplantation reduces the incidence of both bk and cmv viremia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190103", "receivedate": "20190103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15784703, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]

{ "abstract": "Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).", "affiliations": "Drug Development Unit, Institute of Cancer Research/The Royal Marsden, Downs Road, Sutton, Surrey, SM2 5PT, UK.;Drug Development Unit, Institute of Cancer Research/The Royal Marsden, Downs Road, Sutton, Surrey, SM2 5PT, UK.;Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.;UCL Cancer Institute, University College London Hospital, Gower Street, London, WC1E 6BT, UK.;Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.;UCL Cancer Institute, University College London Hospital, Gower Street, London, WC1E 6BT, UK.;Drug Development Unit, Institute of Cancer Research/The Royal Marsden, Downs Road, Sutton, Surrey, SM2 5PT, UK.;John Theurer Cancer Center, Hackensack University Medical Center, 92 2nd St, Hackensack, NJ 07601, USA.;AbbVie, Inc, 1 North Waukegan Road, North Chicago, IL 60064, USA.;AbbVie, Inc, 1 North Waukegan Road, North Chicago, IL 60064, USA.;AbbVie, Inc, 1 North Waukegan Road, North Chicago, IL 60064, USA.;Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.", "authors": "Puglisi|Martina|M|;Molife|L Rhoda|LR|;de Jonge|Maja Ja|MJ|;Khan|Khurum H|KH|;Doorn|Leni van|LV|;Forster|Martin D|MD|;Blanco|Montserrat|M|;Gutierrez|Martin|M|;Franklin|Catherine|C|;Busman|Todd|T|;Yang|Jianning|J|;Eskens|Ferry Alm|FA|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.2217/fon-2021-0140", "fulltext": null, "fulltext_license": null, "issn_linking": "1479-6694", "issue": "17(21)", "journal": "Future oncology (London, England)", "keywords": "ABT-263; Phase I; apoptosis; docetaxel; navitoclax", "medline_ta": "Future Oncol", "mesh_terms": null, "nlm_unique_id": "101256629", "other_id": null, "pages": "2747-2758", "pmc": null, "pmid": "33849298", "pubdate": "2021-07", "publication_types": "D016428:Journal Article", "references": null, "title": "A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors.", "title_normalized": "a phase i study of the safety pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors" }

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A PHASE I STUDY OF THE SAFETY, PHARMACOKINETICS AND EFFICACY OF NAVITOCLAX PLUS DOCETAXEL IN PATIENTS WITH ADVANCED SOLID TUMORS. FUTURE ONCOLOGY. 2021?UNK:UNK", "literaturereference_normalized": "a phase i study of the safety pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19194585, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "GB-SA-2021SA140893", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "020449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2,OVER 1 H IMMEDIATELY FOLLOWING NAVITOCLAX ADMINISTRATION ON DAY 1.", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NAVITOCLAX" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG,ON DAYS 1?3, 8?10 AND 15?17 EVERY 28 DAYS,", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAVITOCLAX" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "020449", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG/M2,ON DAYS 1, 8 AND 15", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NAVITOCLAX" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, QD,AS A LIQUID FORMULATION VIA SYRINGE ON DAYS 1?5 OR 1?3 EVERY 21 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "NEOPLASM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAVITOCLAX" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Demyelination", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "PUGLISI M, MOLIFE LR, DE JMJ, KHAN KH, DOORN LV, FORSTER MD, ET AL. A PHASE I STUDY OF THE SAFETY, PHARMACOKINETICS AND EFFICACY OF NAVITOCLAX PLUS DOCETAXEL IN PATIENTS WITH ADVANCED SOLID TUMORS. FUTURE ONCOLOGY. 2021?UNK:UNK", "literaturereference_normalized": "a phase i study of the safety pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20210429", "receivedate": "20210429", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19194553, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Encephalitis associated with anti-N-Methyl-D-aspartate (NMDA) receptor is a rare form of autoimmune encephalitis. We report the first case of anti-NMDAR encephalitis in an unmarried 16-years old female who was admitted to the Neurology Emergency Unit Faculty of Medicine, Udayana University, Sanglah General Hospital Bali, Indonesia due to decreased consciousness, repetitive talking, headache, involuntary movements in the mouth and feet, and seizures. She was initially diagnosed with viral encephalitis and symptomatic epilepsy. After four weeks of treatment, she was referred to the Gynecology Department. Rectal ultrasound revealed a cystic lesion with a solid component measuring 3.6x2.64x3.18 cm from the left ovary. Laparotomy cystectomy was performed, and the histopathological examination revealed glial cells and mesoderm components in the form of cartilage tissue. Serum and cerebrospinal fluid were positive for anti-NMDA receptor antibodies. She was treated with human intravenous immunoglobulin and rituximab. Her condition was improved gradually. She recovered fully after almost six weeks of hospitalisation.", "affiliations": "General Hospital Bali, Udayana University, Faculty of Medicine, Department of Obstetrics and Gynecology, Gynecology Oncology Division, Sanglah Denpasar, Bali. bayu.mahendra.nyoman@gmail.com.;General Hospital Bali, Udayana University, Faculty of Medicine, Department of Obstetrics and Gynecology, Gynecology Oncology Division, Sanglah Denpasar, Bali.;General Hospital Bali, Udayana University, Faculty of Medicine, Department of Pathology Anatomy, Sanglah Denpasar, Bali.", "authors": "Mahendra|I N B|INB|;Saspriyana|K Y|KY|;Ekawati|N P|NP|", "chemical_list": "D001323:Autoantibodies; D016194:Receptors, N-Methyl-D-Aspartate", "country": "Malaysia", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0300-5283", "issue": "76(1)", "journal": "The Medical journal of Malaysia", "keywords": null, "medline_ta": "Med J Malaysia", "mesh_terms": "D000293:Adolescent; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D001323:Autoantibodies; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms; D016194:Receptors, N-Methyl-D-Aspartate; D013724:Teratoma", "nlm_unique_id": "0361547", "other_id": null, "pages": "110-113", "pmc": null, "pmid": "33510121", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Mature ovarian teratoma associated with anti-N-Methyl-D-aspartate receptor encephalitis: A case report.", "title_normalized": "mature ovarian teratoma associated with anti n methyl d aspartate receptor encephalitis a case report" }

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{ "abstract": "Tacrolimus is an immunosuppressant frequently used following solid organ transplantation, including renal transplantation. Peripheral neuropathy is an uncommon neurological side effect of tacrolimus and has rarely been reported in renal transplantation. We report a patient who received a living-related donor kidney transplant and presented with altered mental status and new-onset bilateral foot drop. Laboratory tests including cerebrospinal fluid tests excluded infection, and MRI of the brain showed chronic microvascular ischaemic changes. Electromyography and nerve conduction study confirmed bilateral common peroneal nerve demyelination. He was also found to have inadvertently overdosed on tacrolimus at home. After switching from tacrolimus to cyclosporine, the patient's symptoms improved within 5 months. His renal function was maintained with an immunosuppressant regimen of cyclosporine, prednisone and mycophenolic acid. The prompt recognition of tacrolimus as a potential neurotoxic drug in a patient with renal transplant and substituting tacrolimus with a different immunosuppressant may prevent permanent neurological damage.", "affiliations": "Department of Internal Medicine Residency Program, St. Barnabas Medical Center, Livingston, New Jersey, USA.", "authors": "Wu|Geru|G|;Weng|Francis L|FL|;Balaraman|Vasanthi|V|", "chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2013()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D001927:Brain Diseases; D003937:Diagnosis, Differential; D004576:Electromyography; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D009431:Neural Conduction; D011115:Polyneuropathies; D012307:Risk Factors; D016559:Tacrolimus", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "24311415", "pubdate": "2013-12-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "18503483;1721397;15919502;17234523;7511197;10653398;11052266;16573841;18089409;23841745;10708096;24034387;7512320;22107249;7512691;1721398;9855339;11699028", "title": "Tacrolimus-induced encephalopathy and polyneuropathy in a renal transplant recipient.", "title_normalized": "tacrolimus induced encephalopathy and polyneuropathy in a renal transplant recipient" }

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"drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, SINGLE (DAY 1)", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Accidental overdose", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyneuropathy", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WU G, WENG FL, BALARAMAN V. TACROLIMUS-INDUCED ENCEPHALOPATHY AND POLYNEUROPATHY IN A RENAL TRANSPLANT RECIPIENT. BMJ CASE REP. 2013", "literaturereference_normalized": "tacrolimus induced encephalopathy and polyneuropathy in a renal transplant recipient", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20140709", "receivedate": "20140709", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10287975, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "Clinical failure of Malarone™ chemoprophylaxis is extremely rare. We report a case of Plasmodium falciparum malaria in a returned traveler to Ghana who fully adhered to atovaquone-proguanil (Malarone™) chemoprophylaxis daily dosing, yet took the pills on an empty stomach. Screening of the P. falciparum isolate revealed triple codon mutation of Dhfr at positions 51, 59, and 108. Plasma drug levels of both atovaquone and proguanil revealed sub-therapeutic concentrations.", "affiliations": "Tropical Disease Unit, Division of Infectious Diseases, University Health Network-Toronto General Hospital, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada; Public Health Ontario Laboratories, Public Health Ontario, Toronto, Canada. Electronic address: andrea.boggild@utoronto.ca.;Public Health Ontario Laboratories, Public Health Ontario, Toronto, Canada.;The Centre for the Study of Complex Childhood Diseases, Hospital for Sick Children, Toronto, Ontario, Canada.;Tropical Disease Unit, Division of Infectious Diseases, University Health Network-Toronto General Hospital, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada; Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University of Toronto, Canada.;Humber River Hospital, North York, Canada.", "authors": "Boggild|Andrea K|AK|;Lau|Rachel|R|;Reynaud|Denis|D|;Kain|Kevin C|KC|;Gerson|Marvin|M|", "chemical_list": "D000962:Antimalarials; D003062:Codon; D004338:Drug Combinations; C109496:atovaquone, proguanil drug combination; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil; D053626:Atovaquone", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1477-8939", "issue": "13(1)", "journal": "Travel medicine and infectious disease", "keywords": "Drug resistance; Malabsorption; Malaria; Malarone; Plasmodium falciparum", "medline_ta": "Travel Med Infect Dis", "mesh_terms": "D000328:Adult; D000962:Antimalarials; D053626:Atovaquone; D003062:Codon; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005869:Ghana; D006801:Humans; D016778:Malaria, Falciparum; D009154:Mutation; D010963:Plasmodium falciparum; D020641:Polymorphism, Single Nucleotide; D002727:Proguanil; D017422:Sequence Analysis, DNA; D013762:Tetrahydrofolate Dehydrogenase; D014195:Travel; D017211:Treatment Failure", "nlm_unique_id": "101230758", "other_id": null, "pages": "89-93", "pmc": null, "pmid": "25582377", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Failure of atovaquone-proguanil malaria chemoprophylaxis in a traveler to Ghana.", "title_normalized": "failure of atovaquone proguanil malaria chemoprophylaxis in a traveler to ghana" }

[ { "companynumb": "CA-GLAXOSMITHKLINE-CA2015GSK015196", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ATOVAQUONE\\PROGUANIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "021078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALARIA PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MALARONE" } ], "patientagegroup": null, "patientonsetage": "28", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood bilirubin increased", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Parasite blood test positive", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Plasmodium falciparum infection", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "BOGGILD AK, LAU R, RAYNAUD D, KAIN KC, GERSON M. FAILURE OF ATOVAQUONE-PROGUANIL MALARIA CHEMOPROPHYLAXIS IN A TRAVELER TO GHANA. TRAVEL MEDICINE AND INFECTIOUS DISEASE. 2015;1-5", "literaturereference_normalized": "failure of atovaquone proguanil malaria chemoprophylaxis in a traveler to ghana", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20150206", "receivedate": "20150206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10771456, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "Narcolepsy is a sleep disorder that can manifest in childhood or adolescence by causing excessive sleepiness, hallucinations, sleep attacks, or cataplexy. There is often a significant delay in diagnosis with the mean time being 15 years from the onset of symptoms, which may lead to further exacerbations and a high comorbidity burden. Although narcolepsy is predominantly associated with loss of hypocretin (orexin), the role of genetics is poorly understood and, therefore, is complementary to the diagnosis but not confirmatory. We present the case of a child who was misdiagnosed as suffering from schizophrenia only to later uncover narcolepsy with cataplexy. Even though she did not meet strict criteria for narcolepsy type 1, her history and objective data were consistent enough to make an official diagnosis. In addition, her clinical response to treatment was very positive, further supporting narcolepsy as the most likely underlying condition. This presentation highlights the importance of continued education and research to reduce the risk of delay in diagnosis or misdiagnosis.", "affiliations": "Medicine, Jersey Shore University Medical Center, Neptune City, USA.;Medicine, Jersey Shore University Medical Center, Neptune City, USA.", "authors": "Miskoff|Jeffrey A|JA|;Chaudhri|Moiuz|M|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.2526", "fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.2526Family/General PracticeInternal MedicinePediatricsOff-label Sodium Oxybate in Childhood Narcolepsy: A Comprehensive Report Muacevic Alexander Adler John R Miskoff Jeffrey A 1Chaudhri Moiuz 1\n1 \nMedicine, Jersey Shore University Medical Center, Neptune City, USA \nJeffrey A. Miskoff jamiskoff@yahoo.com24 4 2018 4 2018 10 4 e25266 2 2018 24 4 2018 Copyright © 2018, Miskoff et al.2018Miskoff et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/10872-off-label-sodium-oxybate-in-childhood-narcolepsy-a-comprehensive-reportNarcolepsy is a sleep disorder that can manifest in childhood or adolescence by causing excessive sleepiness, hallucinations, sleep attacks, or cataplexy. There is often a significant delay in diagnosis with the mean time being 15 years from the onset of symptoms, which may lead to further exacerbations and a high comorbidity burden. Although narcolepsy is predominantly associated with loss of hypocretin (orexin), the role of genetics is poorly understood and, therefore, is complementary to the diagnosis but not confirmatory. We present the case of a child who was misdiagnosed as suffering from schizophrenia only to later uncover narcolepsy with cataplexy. Even though she did not meet strict criteria for narcolepsy type 1, her history and objective data were consistent enough to make an official diagnosis. In addition, her clinical response to treatment was very positive, further supporting narcolepsy as the most likely underlying condition. This presentation highlights the importance of continued education and research to reduce the risk of delay in diagnosis or misdiagnosis.\n\ncase reportnarcolepsycataplexyorexin/hypocretinsleep disordermultiple sleep latency testnocturnal polysomnogramsodium oxybateexcessive daytime sleepinessThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nNarcolepsy is a complex sleep disorder that impairs the regulation of the sleep-wake cycle. Most patients present with excessive daytime sleepiness (EDS) occurring in isolation or in combination with features of abnormal rapid eye movement (REM), such as cataplexy, hypnagogic hallucinations, and sleep paralysis [1]. Narcolepsy is one of the most common causes of EDS despite being underdiagnosed due to lack of clinical experience [2]. Some studies have estimated the prevalence and incidence of narcolepsy to be 25 to 50 per 100,000 and 0.74 per 100,000, respectively [1-2]. Although the mechanism and etiology of this condition are not clear, evidence points toward a low level of hypocretin as the main culprit of this chronic condition [2].\n\nCase presentation\nA six-year-old-African American female presented to our care in April 2010 for the evaluation of sleep attacks and apnea during sleep. According to her mother, the patient experienced cataplexy episodes with laughter. At that time, the patient underwent a nocturnal polysomnogram (NPSG) for further investigation. According to the results of the sleep study, patient slept 474.00 minutes out of 539.3 minutes in bed for a sleep efficiency of 87.9% (n=89%). Her sleep latency was decreased at 7.3 minutes and 68.1% of the total sleep time was spent in the supine position. In addition, rapid eye movement (REM) sleep and latency were logged at 17% and 68.5 minutes (n=136-156), respectively. Furthermore, the NPSG illustrated that the patient experienced five central apneas, one mixed apnea, five hypopneas, and an apnea-hypopnea index of 1.4 events/hour consistent with mild obstructive sleep apnea (OSA) by pediatric criteria [1].\n\nThe patient underwent another NPSG with a multiple sleep latency test (MSLT) in November 2010 for persistent symptoms. Results indicated that the patient slept for 395.50 minutes out of the 411.8 minutes in bed, which translated to a sleep efficiency of 96.0%. Similar to the previous study, the patient experienced decreased sleep latency at 3.3 minutes. In addition, REM sleep and latency were logged at 20.4% and 106.5 minutes, respectively. In contrast to the earlier NPSG study, this evaluation illustrated three central apneas, six mixed apneas, nine obstructive hypopneas, and an apnea-hypopnea index of 2.9 events/hour with <1 being normal.\n\nAn MSLT is the primary diagnostic tool for narcolepsy and is typically performed following an NPSG to measure sleep latency, which is the time it takes an individual to go from wakefulness to sleep. Additionally, it measures how quickly the patient enters REM sleep, known as sleep onset REM periods (SOREMPs). This test includes four or five nap periods of 20 minutes each [3]. The patient is instructed to lie in the darkroom and attempt to fall asleep. Sensors transmit data such as the amount of time needed to fall asleep and enter REM sleep. Once asleep, the patient will be woken up fifteen minutes later; if 20 minutes pass and the patient has not fallen asleep, the nap trial is terminated. Next, the patient is given a two-hour break before the second nap trial can begin. During this break, the patient must stay awake and this process is repeated four more times [3]. The results of the study include the mean sleep latency (MSL) and the number of SOREMPs recorded. The diagnostic criterion requires an MSL of ≤8 minutes and ≥2 SOREMPs on an MSLT [1]. Our patient underwent a series of five nap trials with a sleep latency of 3, 2, 3, 6, and 2 minutes, respectively, and a mean sleep latency of 3.2 minutes. However, the patient did not enter REM sleep during any nap trials, thus having 0 SOREMPS. Additionally, laboratory workup for HLA-DR15 and DQ0602 was positive, and the patient had documented cataplexy.\n\nDiscussion\nNarcolepsy is one of the most common causes of excessive daytime sleepiness whose etiology is multifactorial. Although the role of genetics and rare brain lesions cannot be minimized, the loss of hypocretin is highly associated with the development of this condition [4]. Evidence suggests that hypocretin (an endogenous ligand for a G protein-coupled receptor) is a neuropeptide found in perifornical, lateral, and posterior hypothalamus targets monoaminergic areas (i.e. locus coeruleus, raphe nuclei, and tuberomammillary nucleus) and cholinergic areas (i.e. basal forebrain and laterodorsal tegmental nuclei) to increase activity, promoting wakefulness, inhibiting REM sleep, and suppressing REM phenomena, such as cataplexy [4]. Research indicates that low levels of hypocretin in type I narcolepsy is primarily due to the destruction of hypocretin-producing neurons in the hypothalamus [4]. Additionally, an autoimmune phenomenon is thought to be the driving force behind the destruction of hypocretin neurons in the hypothalamus.\n\nNarcolepsy can be grouped into type 1 (narcolepsy with cataplexy) and type 2 (narcolepsy without cataplexy). Although excessive daytime sleepiness is always present in narcolepsy, this symptom does not differentiate between type 1 or type 2 narcolepsy [1]. However, a positive finding of cataplexy is considered pathognomonic for the diagnosis of narcolepsy because it is rarely found in any other disorder [1,3]. Although clinical manifestations may vary, the patient experiences the REM disorder. Patients often struggle with the ability to fall asleep at night while others fall asleep suddenly regardless of the situation. In contrast, some patients fall asleep suddenly even if they are engaged in activities such as talking and eating [3-4]. Narcolepsy usually presents between the ages of 10 to 20 years with the sudden onset of excessive daytime sleepiness. However, it can also present as early as the age of five years [1,4]. Early onset narcolepsy can present with prominent oculobuccofacial involvement, irritability, and hyperactivity [2].\n\nWe presented a six-year-old female who presented to our care in April 2010 for an evaluation of sleep attacks, snoring, and hypnopompic/hypnagogic hallucinations dating back approximately two years. Over the years, the patient experienced frequent cataplexy episodes triggered by laughter. Additionally, the child experienced the sensation of spiders crawling on her arms upon awakening and described additional visual hallucinations of people sitting on her bed upon falling asleep. These complaints led her to be diagnosed with schizophrenia. Additionally, per the patient's mother, other conditions, such as bipolar disorder and psychosis, were also considered.\n\nCurrent diagnostic criteria for type 1 narcolepsy require the patient to meet both of the following: (1) Excessive daytime sleepiness (EDS), occurring for at least three months; (2) One or both of the following: (a) Cataplexy, mean sleep latency of ≤8 minutes and ≥2 SOREMPs on an MSLT; a SOREMP on the preceding NPSG (REM onset within 15 minutes of sleep onset) may replace one of the SOREMPs on the MSLT; and (b) Cerebrospinal fluid (CSF) hypocretin-1 levels less than ≤110 pg./ml [1,3]. Guidelines state that the mean sleep latency of ≤8 minutes on an MSLT is abnormal and latencies <5 minutes indicate severe EDS [1]. Our patient exhibited excessive daytime sleepiness, cataplexy, and mean sleep latency of 3.2 minutes; however; no SOREMPs were noted on the MSLT. Despite falling short of satisfying the SOREMP component of the diagnostic criteria, her clinical picture, when viewed as a whole, was still found to be consistent with the diagnosis of narcolepsy.\n\nAlthough narcolepsy is predominantly associated with loss of hypocretin, the role of genetics is less well understood and, therefore, is complementary to the diagnosis but not confirmatory. Evidence suggests a strong association between narcolepsy and human leukocyte antigen (HLA) especially HLA-DQB1*0602 [5]. The positivity of DQB1*0602, a subtype of DR2, in African American patients has been linked with the earlier onset of narcolepsy [5]. Since the patient tested positive for this gene, this further supports the diagnosis.\n\nNarcolepsy is a lifelong condition managed with a combination of pharmacologic and non-pharmacological agents. Pharmacologic agents are tailored to the individual based on the symptoms and severity. Current agents, such as amphetamines, modafinil, and antidepressants focusing on inhibiting norepinephrine or serotonin reuptake, are effective in reducing sleepiness and cataplexy [1,5].\n\nSodium oxybate (Xyrem) is the sodium salt of a compound, γ-hydroxybutyric acid (GHB), which serves as a precursor of the neurotransmitter γ-aminobutyric acid (GABA) along with possessing neuromodulator properties, and is involved in sleep regulation [6]. Furthermore, clinical evidence suggests that this compound is highly effective and safe in the treatment of narcolepsy due to its natural properties [6]. A study conducted in 1997 focused on 48 narcoleptic patients who were administered 2.25 to 3 grams of GHB daily for nine years [7]. Results indicated that this treatment alleviated their symptoms significantly without developing tolerance or addiction. It has been proposed that GHB induces the hyperdopaminergic process by modifying acetylcholine release [7]. Moreover, the role of GHB in increasing stages 3 and 4 sleep along with decreasing stage 1 non-REM (NREM) sleep is supported by decades of clinical evidence [1,7].\n\nAlthough Xyrem was approved by the FDA for narcolepsy in patients 18 years of age and older, a decision by the treating clinician to start the therapy off-label at a reduced dose was made in attempts to control both the cataplexy and severe hypersomnia complaints despite the patient only being seven years of age. To date, the patient remains on a reduced dose of Xyrem at 2.5 g at bedtime and repeated three to four hours later. Typically, in adults, Xyrem is started at 2.25 g at bedtime and repeated three to four hours later due to a short half-life (two to three hours) [8]. Recommendations suggest the need to titrate to a max dose of 4.5 g over approximately four weeks if the symptoms persist.\n\nThe patient was ultimately started on 2.5 mg Adderall in the morning as her first dose. As the patient progressed, the morning dose was increased along with adding an additional dose in the afternoon to control the symptoms. Current recommendations favor 5 mg in the morning as being the starting dose of amphetamines in children [6,8]. Furthermore, recommendations suggest 10 to 40 mg per day divided into two doses as being effective for children [8]. As of October 2017, the patient is on 20 mg Adderall taken in the morning along with an additional dose of 20 mg to be taken in the afternoon as needed. According to her mother, the patients’ symptoms are well controlled, and she is excelling in school, indicated by her making the honor roll and earning all As.\n\nAlthough pharmacologic management is at the forefront, behavioral and lifestyle modifications play a crucial role in reducing the impact of the disease. Modifications such as scheduled naps, practicing good sleep hygiene, and regular exercise during the day to improve alertness, being cautious around moving equipment/machinery and heights are beneficial. Interestingly, studies indicate that regulation of body temperature can be an important tool in the management of this condition. Specifically, higher body temperature is associated with improved vigilance, which can be used by the patients to improve their condition [9].\n\nUndoubtedly, existing medications are effective for the symptomatic management of this condition; research has illustrated histamine agonist and hypocretin analogs, which show promise. Pitolisant, an inverse agonist of the histamine H3 receptor, has shown to decrease cataplexy and improve wakefulness in patients with type 1 narcolepsy [10]. It has been granted orphan drug status by FDA, but it is only available in Europe and not being sold in the United States [10].\n\nConclusions\nIn conclusion, there are cases of pediatric patients misdiagnosed as having psychiatric disorders that may actually represent narcolepsy with cataplexy as in our patient. Even though she did not meet strict criteria for narcolepsy type 1, her history and objective data were strong enough to make an official diagnosis. In addition, her clinical response to medications was excellent, further cementing her underlying condition. Finally, staying abreast of new Food and Drug Authority (FDA)-approved medications despite effective treatment options is critical to improving medical care.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality Curr Med Res Opin Ruoff C Rye D 1611 1622 32 2016 \n2 Narcolepsy N Engl J Med Scammell TE 2654 2562 373 2015 26716917 \n3 The utility of a 5(th) nap in multiple sleep latency test J Thorac Dis Muza R Lykouras D Rees K 282 286 8 2016 26904269 \n4 History of narcolepsy at Stanford University Immunol Res Mignot EJM 315 339 58 2014 24825774 \n5 Narcolepsy in African Americans Sleep Kawai M O'Hara R Einen M Lin L Mignot E 1673 1681 38 2015 26158891 \n6 Sodium oxybate for narcolepsy with cataplexy: systematic review and meta-analysis J Clin Sleep Med Alshaikh MK Tricco AC Tashkandi M Mamdani M Straus SE BaHammam AS 451 458 8 2012 22893778 \n7 The gamma-hydroxybutyrate signalling system in brain: organization and functional implications Prog Neurobiol Maitre M 337 361 51 1997 9089792 \n8 Time to response with sodium oxybate for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy J Clin Sleep Med Bogan RK Roth T Schwartz J Miloslavsky M 427 432 11 2015 25580605 \n9 Current and future treatment options for narcolepsy: a review Sleep Sci Bhattarai J Sumerall S 19 27 10 2017 28966734 \n10 Update on the treatment of narcolepsy: clinical efficacy of pitolisant Nat Sci Sleep Calik MW 127 133 9 2017 28490912\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "10(4)", "journal": "Cureus", "keywords": "case report; cataplexy; excessive daytime sleepiness; multiple sleep latency test; narcolepsy; nocturnal polysomnogram; orexin/hypocretin; sleep disorder; sodium oxybate", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e2526", "pmc": null, "pmid": "29942729", "pubdate": "2018-04-24", "publication_types": "D002363:Case Reports", "references": "26158891;24825774;28966734;27359185;28490912;26904269;26716917;25580605;9089792;22893778", "title": "Off-label Sodium Oxybate in Childhood Narcolepsy: A Comprehensive Report.", "title_normalized": "off label sodium oxybate in childhood narcolepsy a comprehensive report" }

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{ "abstract": "Neutropenic sepsis is a life-threatening condition with mortality rates reported to range between 2 and 21% in adults. It can occur following chemotherapy treatment, due to disease (such as haematological conditions affecting the bone marrow) and in patients on disease-modifying agents (such as patients receiving methotrexate for rheumatoid arthritis). Appropriate emergency treatment is essential and achieving intravenous antibiotic door-to-needle time of less than 1 hour is a key target. Shortfalls in the management of patients presenting to teams with limited expertise in this area were identified in the National Confidential Enquiry into Patient Outcome and Death report in 2008, leading to recommendations including the need for an acute oncology service (AOS) at all hospitals with either an emergency department or medical admissions unit. Practice at Weston General Hospital has been audited at three time points since 2008 (in 2008, 2011 and 2013-14) during which there have been several service developments relevant to the management of neutropenic sepsis, including the introduction of an AOS in June 2013. The percentage of patients in which intravenous antibiotic 1-hour door-to-needle time was achieved has improved from 14% (2008) to 31% (2011) to 79% (2013-14) and neutropenic sepsis mortality has decreased from 39% (2008) to 14% (2011) to 0% (2013-14).", "affiliations": "Weston General Hospital, Weston-super-Mare, UK thomas.wells@nhs.net.;Weston General Hospital, Weston-super-Mare, UK.;Weston General Hospital, Weston-super-Mare, UK.;Weston General Hospital, Weston-super-Mare, UK.;Weston General Hospital, Weston-super-Mare, UK.;Weston General Hospital, Weston-super-Mare, UK.", "authors": "Wells|Tom|T|;Thomas|Corrine|C|;Watt|Dawn|D|;Fountain|Vanessa|V|;Tomlinson|Marjorie|M|;Hilman|Serena|S|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "England", "delete": false, "doi": "10.7861/clinmedicine.15-6-526", "fulltext": null, "fulltext_license": null, "issn_linking": "1470-2118", "issue": "15(6)", "journal": "Clinical medicine (London, England)", "keywords": "Neutropenic; antibiotics; door-to-needle time; sepsis", "medline_ta": "Clin Med (Lond)", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D003695:Delivery of Health Care; D006767:Hospitals, District; D006769:Hospitals, General; D006801:Humans; D008485:Medical Audit; D008875:Middle Aged; D009503:Neutropenia; D012189:Retrospective Studies; D018805:Sepsis; D061665:Time-to-Treatment", "nlm_unique_id": "101092853", "other_id": null, "pages": "526-30", "pmc": null, "pmid": "26621939", "pubdate": "2015-12", "publication_types": "D016428:Journal Article", "references": "10944139;16625125", "title": "Improvements in the management of neutropenic sepsis: lessons learned from a district general hospital.", "title_normalized": "improvements in the management of neutropenic sepsis lessons learned from a district general hospital" }

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IMPROVEMENTS IN THE MANAGEMENT OF NEUTROPENIC SEPSIS: LESSONS LEARNED FROM A DISTRICT GENERAL HOSPITAL. CLINICAL MEDICINE (LONDON) 2015 DEC? 15(6):526-30.", "literaturereference_normalized": "improvements in the management of neutropenic sepsis lessons learned from a district general hospital", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151222", "receivedate": "20151222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11858657, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" }, { "companynumb": "GB-ACCORD-036415", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neutropenic sepsis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardio-respiratory arrest", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "WELLS T, THOMAS C, WATT D, FOUNTAIN V, TOMLINSON M, HILMAN S. IMPROVEMENTS IN THE MANAGEMENT OF NEUTROPENIC SEPSIS: LESSONS LEARNED FROM A DISTRICT GENERAL HOSPITAL. 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IMPROVEMENTS IN THE MANAGEMENT OF NEUTROPENIC SEPSIS: LESSONS LEARNED FROM A DISTRICT GENERAL HOSPITAL. CLINICAL MEDICINE (LONDON) 2015 DEC? 15(6):526-30.", "literaturereference_normalized": "improvements in the management of neutropenic sepsis lessons learned from a district general hospital", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151222", "receivedate": "20151222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11858643, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]

{ "abstract": "Dopamine agonists are effective and widely used treatments for Parkinson disease (PD). However, patients on dopamine agonists may experience significant side effects which necessitate dose tapering or discontinuation. Dopamine agonist withdrawal syndrome (DAWS) is a complication that affects up to 19% of PD patients who undergo a dopamine agonist taper. It was initially described in 2010 as a severe stereotypical cluster of psychiatric and physical symptoms occurring with dopamine agonist withdrawal. Identified risk factors for DAWS include impulse control behavior disorders (ICD) and higher dopamine agonist dosage. There are emerging data suggesting that the dopamine agonist withdrawal in the setting of history of deep brain stimulation may also be a risk factor. Currently there is no standard treatment for DAWS. Therefore early recognition of risk factors is crucial for prevention. It's important to closely monitor for withdrawal symptoms in high-risk patients undergoing a dopamine agonist taper.", "affiliations": "Center for Neurological Restoration, Cleveland Clinic, 9500 Euclid Ave U2, Cleveland, OH, USA. Electronic address: yux@ccf.org.;Center for Neurological Restoration, Cleveland Clinic, 9500 Euclid Ave U2, Cleveland, OH, USA.", "authors": "Yu|Xin Xin|XX|;Fernandez|Hubert H|HH|", "chemical_list": "D018491:Dopamine Agonists", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jns.2016.12.070", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-510X", "issue": "374()", "journal": "Journal of the neurological sciences", "keywords": "Dopamine agonist; Dopamine agonist withdrawal syndrome; Impulse control disorder; Parkinson disease", "medline_ta": "J Neurol Sci", "mesh_terms": "D046690:Deep Brain Stimulation; D007174:Disruptive, Impulse Control, and Conduct Disorders; D018491:Dopamine Agonists; D006801:Humans; D010300:Parkinson Disease; D013375:Substance Withdrawal Syndrome", "nlm_unique_id": "0375403", "other_id": null, "pages": "53-55", "pmc": null, "pmid": "28104232", "pubdate": "2017-03-15", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Dopamine agonist withdrawal syndrome: A comprehensive review.", "title_normalized": "dopamine agonist withdrawal syndrome a comprehensive review" }

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"activesubstancename": "LEVODOPA" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVODOPA" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PRAMIPEXOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020667", "drugbatchnumb": null, "drugcharacterization": "1", 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"drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVODOPA" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PRAMIPEXOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "020667", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRAMIPEXOLE." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anxiety", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impulse-control disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Compulsions", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Restless legs syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug withdrawal syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Compulsive shopping", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Depression", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Crying", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Impaired work ability", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Motor dysfunction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Orthostatic hypotension", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Eating disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "YU X, FERNANDEZ H. DOPAMINE AGONIST WITHDRAWAL SYNDROME: A COMPREHENSIVE REVIEW. JOURNAL OF THE NEUROLOGICAL SCIENCES. 2017;374:53-55.", "literaturereference_normalized": "dopamine agonist withdrawal syndrome a comprehensive review", "qualification": "5", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171117", "receivedate": "20100127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 7258213, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "A 57-year-old man who had recently undergone a transrectal prostate biopsy for a rising prostate-specific antigen level developed postbiopsy necrotizing epididymo-orchitis (requiring orchiectomy) and then Gram-negative meningitis, despite fluoroquinolone administration for periprocedural prophylaxis and subsequent therapy. The causative organism proved to be a fluoroquinolone-resistant Escherichia coli strain from sequence type ST131.", "affiliations": "Sunwest Infusion and Infectious Disease Specialists, Goodyear, Arizona, USA.", "authors": "Assimacopoulos|Aris|A|;Johnston|Brian|B|;Clabots|Connie|C|;Johnson|James R|JR|", "chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones", "country": "United States", "delete": false, "doi": "10.1128/JCM.02026-12", "fulltext": null, "fulltext_license": null, "issn_linking": "0095-1137", "issue": "50(12)", "journal": "Journal of clinical microbiology", "keywords": null, "medline_ta": "J Clin Microbiol", "mesh_terms": "D000900:Anti-Bacterial Agents; D001706:Biopsy; D016000:Cluster Analysis; D024881:Drug Resistance, Bacterial; D016521:Electrophoresis, Gel, Pulsed-Field; D004823:Epididymitis; D004926:Escherichia coli; D004927:Escherichia coli Infections; D024841:Fluoroquinolones; D005838:Genotype; D006801:Humans; D008297:Male; D016920:Meningitis, Bacterial; D008875:Middle Aged; D058889:Molecular Typing; D009920:Orchitis; D011471:Prostatic Neoplasms", "nlm_unique_id": "7505564", "other_id": null, "pages": "4157-9", "pmc": null, "pmid": "23015671", "pubdate": "2012-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.", "references": "20572763;21404207;20038242;19741070;22469129;21752984;22354301;21420152;22575912;22419681;19952857;21029317;19347074;22386395", "title": "Post-prostate biopsy infection with Escherichia coli ST131 leading to epididymo-orchitis and meningitis caused by Gram-negative bacilli.", "title_normalized": "post prostate biopsy infection with escherichia coli st131 leading to epididymo orchitis and meningitis caused by gram negative bacilli" }

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POST-PROSTATE BIOPSY INFECTION WITH ESCHERICHIA COLI ST131 LEADING TO EPIDIDYMO-ORCHITIS AND MENINGITIS CAUSED BY GRAM-NEGATIVE BACILLI.. 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POST-PROSTATE BIOPSY INFECTION WITH ESCHERICHIA COLI ST131 LEADING TO EPIDIDYMO-ORCHITIS AND MENINGITIS CAUSED BY GRAM-NEGATIVE BACILLI. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN + CLAVULANIC ACID" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JOHNSON J, JOHNSTON B, CLABOTS C, ASSIMACOPOULOS A. POST-PROSTATE BIOPSY INFECTION WITH ESCHERICHIA COLI ST131 LEADING TO EPIDIDYMO-ORCHITIS AND MENINGITIS CAUSED BY GRAM-NEGATIVE BACILLI. 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"AMOXICILLIN CLAVULANIC ACID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "075817", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DUTASTERIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DUTASTERIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "075817", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacteriuria", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Orchitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ASSIMACOPOULOS A, JOHNSTON B, CLABOTS C, JOHNSON JR. POST-PROSTATE BIOPSY INFECTION WITH ESCHERICHIA COLI ST131 LEADING TO EPIDIDYMO-ORCHITIS AND MENINGITIS CAUSED BY GRAM-NEGATIVE BACILLI. J-CLIN-MICROBIOL 2012; 50(12) 4157-9", "literaturereference_normalized": "post prostate biopsy infection with escherichia coli st131 leading to epididymo orchitis and meningitis caused by gram negative bacilli", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150128", "receivedate": "20150128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10745363, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" } ]

{ "abstract": "OBJECTIVE\nWe present a case of clozapine-related myocarditis, with a rising C-reactive protein as the only initial evidence supporting the diagnosis.\n\n\nMETHODS\nAn otherwise healthy young male presenting with treatment-resistant schizophrenia was started on clozapine. Monitoring was performed.\n\n\nRESULTS\nAt day 18 he developed fever, tachycardia and a raised C-reactive protein, while troponin levels and echocardiogram remained normal.\n\n\nCONCLUSIONS\nCurrent protocols monitoring for myocarditis have their limitations and can often only be used to support a presumptive diagnosis of myocarditis. In keeping with the current clozapine monitoring guidelines, we demonstrate that a rise in C-reactive protein levels can be a critical early sign of myocarditis warranting close monitoring and serious consideration for cessation of clozapine.", "affiliations": "Resident Medical Officer, Department of Psychiatry, Alfred Health, Melbourne, VIC, Australia S.Fehily@alfred.org.au.;Consultant Psychiatrist, Department of Psychiatry, Alfred Health, Melbourne, VIC, Australia.;Consultant Psychiatrist, Professor of Psychiatry and Deputy Director, Department of Psychiatry, Alfred Health, Melbourne, VIC, and; Monash Alfred Psychiatry Research Centre, The Alfred and Monash University Central Clinical School, Melbourne, VIC, Australia.", "authors": "Fehily|Sasha R|SR|;Forlano|Rosaria|R|;Fitzgerald|Paul B|PB|", "chemical_list": "D014150:Antipsychotic Agents; D014336:Troponin; D002097:C-Reactive Protein; D003024:Clozapine", "country": "England", "delete": false, "doi": "10.1177/1039856215604482", "fulltext": null, "fulltext_license": null, "issn_linking": "1039-8562", "issue": "24(2)", "journal": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists", "keywords": "C-reactive protein; cardiac magnetic resonance imaging; clozapine; myocarditis", "medline_ta": "Australas Psychiatry", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D002097:C-Reactive Protein; D003024:Clozapine; D042241:Early Diagnosis; D006801:Humans; D008297:Male; D009205:Myocarditis; D013997:Time Factors; D014336:Troponin", "nlm_unique_id": "9613603", "other_id": null, "pages": "181-4", "pmc": null, "pmid": "26400456", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "C-reactive protein: an early critical sign of clozapine-related myocarditis.", "title_normalized": "c reactive protein an early critical sign of clozapine related myocarditis" }

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{ "abstract": "A 20-year-old woman presented with acute exacerbation of ulcerative colitis. After treatment with infliximab, she developed a fulminant liver failure. Under supportive therapy and steroid medication, recovery of symptoms and transaminases occurred. A few case reports about hepatic side effects of anti-TNF-α antibodies in patients with inflammatory bowel disease have been published. These side effects ranged from asymptomatic increase of transaminases to fulminant liver failure necessitating transplantation. The pathomechanism is not fully understood; in some case reports autoimmune phenomena have been described.", "affiliations": "Gastroenterologie, Rems-Murr-Klinik-Schorndorf, Schlichtener Str. 105, 73614, Schorndorf, Deutschland. rica.forker@rems-murr-kliniken.de.;Gastroenterologische Schwerpunktpraxis, Leonberg, Deutschland.;Abteilung für Gastroenterologie, Hepatologie und Endokrinologie, Robert-Bosch-Krankenhaus Stuttgart, Stuttgart, Deutschland.", "authors": "Forker|R|R|;Escher|M|M|;Stange|E F|EF|", "chemical_list": "D011239:Prednisolone; D000069285:Infliximab; D006854:Hydrocortisone; D016559:Tacrolimus", "country": "Germany", "delete": false, "doi": "10.1007/s00108-017-0205-4", "fulltext": null, "fulltext_license": null, "issn_linking": "0020-9554", "issue": "58(9)", "journal": "Der Internist", "keywords": "Antibodies; Drug-induced liver injury; Hepatitis, autoimmune; Infliximab; Tumor necrosis factor-α", "medline_ta": "Internist (Berl)", "mesh_terms": "D003093:Colitis, Ulcerative; D003937:Diagnosis, Differential; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D000069285:Infliximab; D007262:Infusions, Intravenous; D017114:Liver Failure, Acute; D008111:Liver Function Tests; D011239:Prednisolone; D012812:Sigmoidoscopy; D016559:Tacrolimus; D014057:Tomography, X-Ray Computed; D055815:Young Adult", "nlm_unique_id": "0264620", "other_id": null, "pages": "982-989", "pmc": null, "pmid": "28271269", "pubdate": "2017-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "23333219;11155419;23463462;19524577;22535279;21396413;24707412;20107930;24420801;22398069;16547695", "title": "A 20-year-old woman with ulcerative colitis and acute liver failure.", "title_normalized": "a 20 year old woman with ulcerative colitis and acute liver failure" }

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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE FORM: LYOPHILIZED POWDER", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIARRHOEA INFECTIOUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." } ], "patientagegroup": null, "patientonsetage": "20", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "54", "reaction": [ { "reactionmeddrapt": "Acute hepatic failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Colitis ulcerative", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastritis erosive", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Depressed level of consciousness", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Back pain", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Catheter site pruritus", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Unresponsive to stimuli", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea infectious", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2012" } }, "primarysource": { "literaturereference": "FORKER R, ESCHER M, STANGE E. A 20?YEAR?OLD WOMAN WITH ULCERATIVE COLITIS AND ACUTE LIVER FAILURE. INTERNIST. 2017?58 (9)::982?989.", "literaturereference_normalized": "a 20 year old woman with ulcerative colitis and acute liver failure", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180810", "receivedate": "20180810", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15264966, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "The growing coronavirus disease 2019 (COVID-19) pandemic initially led to widespread use of hydroxychloroquine sulfate as an off-label experimental treatment of this disease.\n\n\n\nAcute hemolytic anemia developed in an African American man with COVID-19-related pneumonia and glucose-6-phosphate dehydrogenase (G6PD) deficiency who completed the standard 5-day experimental course of hydroxychloroquine. Although the trigger leading to our patient's hemolytic sequelae will never be known with certainty, his clinical course suggests that hydroxychloroquine use and/or COVID-19 infection may trigger hemolysis in susceptible patients with G6PD deficiency.\n\n\n\nThis case confirms recent findings that the potential risks of hydroxychloroquine therapy for COVID-19 may outweigh the benefits.", "affiliations": "Montefiore Medical Center, Bronx, New York.", "authors": "Aguilar|Jorge|J|;Averbukh|Yelena|Y|", "chemical_list": "D004791:Enzyme Inhibitors; D006886:Hydroxychloroquine", "country": "United States", "delete": false, "doi": "10.7812/TPP/20.158", "fulltext": null, "fulltext_license": null, "issn_linking": "1552-5767", "issue": "24()", "journal": "The Permanente journal", "keywords": null, "medline_ta": "Perm J", "mesh_terms": "D000743:Anemia, Hemolytic; D000086382:COVID-19; D004791:Enzyme Inhibitors; D017707:Erythrocyte Transfusion; D005955:Glucosephosphate Dehydrogenase Deficiency; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "9800474", "other_id": null, "pages": null, "pmc": null, "pmid": "33183501", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "19904460;20701405;26545825;15888079;28556555;8861278;13919680;25363455", "title": "Hemolytic Anemia in a Glucose-6-Phosphate Dehydrogenase-Deficient Patient Receiving Hydroxychloroquine for COVID-19: A Case Report.", "title_normalized": "hemolytic anemia in a glucose 6 phosphate dehydrogenase deficient patient receiving hydroxychloroquine for covid 19 a case report" }

[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-271403", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "201691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "(DAY 1)400 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "201691", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, QD (ON DAY 2-4)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "AGUILAR J, AVERBUKH Y. HEMOLYTIC ANEMIA IN A GLUCOSE-6-PHOSPHATE DEHYDROGENASE-DEFICIENT PATIENT RECEIVING HYDROXYCHLOROQUINE FOR COVID-19:A CASE REPORT. PERM J. 2020?24:NO PAGINATION", "literaturereference_normalized": "hemolytic anemia in a glucose 6 phosphate dehydrogenase deficient patient receiving hydroxychloroquine for covid 19 a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201216", "receivedate": "20201216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18622486, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "US-TEVA-2020-US-1860320", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40081", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MILLIGRAM DAILY; ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40081", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM DAILY; ON DAYS 2?4", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AGUILAR J, AVERBUKH Y. HEMOLYTIC ANEMIA IN A GLUCOSE?6?PHOSPHATE DEHYDROGENASE?DEFICIENT PATIENT RECEIVING HYDROXYCHLOROQUINE FOR COVID?19: A CASE REPORT. PERM?J 2020?24:NO PAGINATION.", "literaturereference_normalized": "hemolytic anemia in a glucose 6 phosphate dehydrogenase deficient patient receiving hydroxychloroquine for covid 19 a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210126", "receivedate": "20201224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18663279, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "NVSC2020US323397", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "400 MG, BID (DAY 1)", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE SULFATE TABLETS USP" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE SULFATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "40104", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "400 MG, QD (DAYS 2-4)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE SULFATE TABLETS USP" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "AGUILAR J, AVERBUKH Y. HEMOLYTIC ANEMIA IN A GLUCOSE-6-PHOSPHATE DEHYDROGENASE- DEFICIENT PATIENT RECEIVING HYDROXYCHLOROQUINE FOR COVID-19: A CASE REPORT. PERMANENTE JOURNAL. 2020?24(20):158", "literaturereference_normalized": "hemolytic anemia in a glucose 6 phosphate dehydrogenase deficient patient receiving hydroxychloroquine for covid 19 a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201204", "receivedate": "20201204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18580119, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "US-JNJFOC-20201202191", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAYS 2-4", "drugenddate": "20200406", "drugenddateformat": "102", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200402", "drugstartdateformat": "102", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020634", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": "202003", "drugenddateformat": "610", "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "202003", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVAQUIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAY 1", "drugenddate": "20200402", "drugenddateformat": "102", "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20200401", "drugstartdateformat": "102", "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" } ], "patientagegroup": "5", "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200407" } }, "primarysource": { "literaturereference": "AGUILAR J, AVERBUKH Y. HEMOLYTIC ANEMIA IN A GLUCOSE-6-PHOSPHATE DEHYDROGENASE-DEFICIENT PATIENT RECEIVING HYDROXYCHLOROQUINE FOR COVID-19: A CASE REPORT. THE PERMANENTE JOURNAL. 2020?24. DOI: 10.7812/TPP/20.15.", "literaturereference_normalized": "hemolytic anemia in a glucose 6 phosphate dehydrogenase deficient patient receiving hydroxychloroquine for covid 19 a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201209", "receivedate": "20201209", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18593320, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "US-MYLANLABS-2020M1101456", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040274", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, BID, 0.5 DAY, ON DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19 PNEUMONIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040274", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, QD, ON DAYS 2-4", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemolytic anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "AGUILAR J, AVERBUKH Y. HEMOLYTIC ANEMIA IN A GLUCOSE-6-PHOSPHATE DEHYDROGENASE-DEFICIENT PATIENT RECEIVING HYDROXYCHLOROQUINE FOR COVID-19: A CASE REPORT. PERM-J 2020?24:NO PAGINATION.", "literaturereference_normalized": "hemolytic anemia in a glucose 6 phosphate dehydrogenase deficient patient receiving hydroxychloroquine for covid 19 a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201210", "receivedate": "20201210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18601081, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]

{ "abstract": "BACKGROUND\nThe antiepileptic drug pregabalin is one of the best-selling pharmaceutical products worldwide. There are increasing concerns about its potential for misuse and dependence especially among patients with former or current substance use disorders (SUDs).\n\n\nOBJECTIVE\nOur objective was to clarify the extent and pattern of pregabalin use as well as motives and predictors in this population.\n\n\nMETHODS\nWe conducted a cross-sectional study with patients on a detoxification ward for illicit drugs at the Center for Psychiatry, Südwürttemberg, Ravensburg in southern Germany from August 2012 until July 2013. We used an extensive questionnaire, part of the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) Axis I Disorders (SCID-I) and urine samples.\n\n\nRESULTS\nOf the 253 participating patients, 56% had used pregabalin at least once. Of these, 92% had acquired it at least in part from illegal sources. The main motives for the use of pregabalin were the attenuation of opioid withdrawal symptoms, the augmentation of other psychotropic substances, and the psychotropic effects of pregabalin itself. Predictors for pregabalin use were opioid and sedative use as well as younger age. The criteria of dependency according to DSM-IV was met by 11% of pregabalin users and 13% of urine samples were positive for pregabalin.\n\n\nCONCLUSIONS\nUse of pregabalin is common among users of illicit drugs in large parts of southern Germany, with motives for use, acquisition, and mode of use suggesting misuse. The mode of use, especially intake of high doses and concomitant use of other drugs, poses a serious risk to this population, including the development of dependency.", "affiliations": "Centre for Psychiatry South-Wuerttemberg, Weingartshoferstr. 2, 88124, Ravensburg, Germany. brendan.snellgrove@zfp-zentrum.de.;Centre for Psychiatry South-Wuerttemberg, Weingartshoferstr. 2, 88124, Ravensburg, Germany.;Centre for Psychiatry South-Wuerttemberg, Weingartshoferstr. 2, 88124, Ravensburg, Germany.", "authors": "Snellgrove|Brendan J|BJ|;Steinert|Tilman|T|;Jaeger|Susanne|S|", "chemical_list": "D002121:Calcium Channel Blockers; D013287:Illicit Drugs; D000069583:Pregabalin", "country": "New Zealand", "delete": false, "doi": "10.1007/s40263-017-0467-3", "fulltext": null, "fulltext_license": null, "issn_linking": "1172-7047", "issue": "31(10)", "journal": "CNS drugs", "keywords": null, "medline_ta": "CNS Drugs", "mesh_terms": "D000328:Adult; D002121:Calcium Channel Blockers; D003430:Cross-Sectional Studies; D005260:Female; D005858:Germany; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D000069583:Pregabalin; D011569:Psychiatric Status Rating Scales; D019966:Substance-Related Disorders; D011795:Surveys and Questionnaires", "nlm_unique_id": "9431220", "other_id": null, "pages": "891-898", "pmc": null, "pmid": "28965335", "pubdate": "2017-10", "publication_types": "D016428:Journal Article", "references": "19630724;27780322;27848217;22689280;27177422;28315808;27721044;25220244;28741741;26767525;25864607;24835028;28144823;24192603;23989299;8869456;25083536;18042886;23292158;24663439;15762817;24760436;21212719", "title": "Pregabalin Use Among Users of Illicit Drugs: A Cross-Sectional Survey in Southern Germany.", "title_normalized": "pregabalin use among users of illicit drugs a cross sectional survey in southern germany" }

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PREGABALIN USE AMONG USERS OF ILLICIT DRUGS: A CROSS-SECTIONAL SURVEY IN SOUTHERN GERMANY. 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PREGABALIN USE AMONG USERS OF ILLICIT DRUGS: A CROSS-SECTIONAL SURVEY IN SOUTHERN GERMANY. 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PREGABALIN USE AMONG USERS OF ILLICIT DRUGS: A CROSS-SECTIONAL SURVEY IN SOUTHERN GERMANY. 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{ "abstract": "BACKGROUND\nMisoprostol has a wide range of applications in obstetrics and gynaecology. It is widely recommended by WHO, FIGO and ACOG for the treatment of postpartum haemorrhage due to it safety and cost-effectiveness. However, usage might be associated to hyperpyrexia and shivering.\n\n\nMETHODS\nWe present a 30 year old Cameroonian female gravida 1 para 1 who had a vaginal delivery at 40 weeks of gestation complicated by primary postpartum haemorrhage (PPH). PPH was managed by sublingual misoprostol that induced shivering and hyperpyrexia managed successfully with paracetamol and cooling.\n\n\nCONCLUSIONS\nThe occurrence of fever and shivering should be kept in mind when administering misoprostol for PPH.", "affiliations": "Douala General Hospital, Douala, Cameroon. ptolefac15@gmail.com.;Intern Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaounde, Cameroon.", "authors": "Tolefac|Paul Nkemtendong|PN|;Minkande|Jacqueline Ze|JZ|", "chemical_list": "D010120:Oxytocics; D016595:Misoprostol", "country": "England", "delete": false, "doi": "10.1186/s13104-017-2661-2", "fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 266110.1186/s13104-017-2661-2Case ReportSublingual misoprostol and hyperpyrexia: case report with temperature curve Tolefac Paul Nkemtendong +237694035019ptolefac15@gmail.com 12Minkande Jacqueline Ze pnt2016@yahoo.com 21 Douala General Hospital, Douala, Cameroon 2 0000 0001 2173 8504grid.412661.6Intern Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaounde, Cameroon 26 7 2017 26 7 2017 2017 10 3292 5 2017 21 7 2017 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nMisoprostol has a wide range of applications in obstetrics and gynaecology. It is widely recommended by WHO, FIGO and ACOG for the treatment of postpartum haemorrhage due to it safety and cost-effectiveness. However, usage might be associated to hyperpyrexia and shivering.\n\nCase presentation\nWe present a 30 year old Cameroonian female gravida 1 para 1 who had a vaginal delivery at 40 weeks of gestation complicated by primary postpartum haemorrhage (PPH). PPH was managed by sublingual misoprostol that induced shivering and hyperpyrexia managed successfully with paracetamol and cooling.\n\nConclusions\nThe occurrence of fever and shivering should be kept in mind when administering misoprostol for PPH.\n\nKeywords\nMisoprostolHyperpyrexiaTemperatureCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nPostpartum haemorrhage (PPH) remains the most common cause of maternal mortality with uterine atony being the commonest underling aetiology [1, 2]. It accounts for nearly one-quarter of all maternal deaths worldwide and an estimated 125,000 deaths occur each year [1]. About 50% of these deaths occur in sub-Sahara Africa alone [3]. Researchers have for decades searched the safest, fastest and most effective pharmacological agents to manage this dreaded complication [4]. Conventional uterotonics such as oxytocin have been the drug of choice in the first line management of PPH secondary to uterine atony. However, a major short coming has been its obligate parenteral route of administration [2, 5].\n\nMisoprostol is an attractive alternative because of its uterotonic potency, multiple convenient routes of administration and stability at ambient temperatures [6]. The most common side effects associated with the postpartum administration of misoprostol are shivering and pyrexia [7]. Studies show the rates of shivering and fever to be related to the dose and route of administration. Higher rates of shivering and elevated body temperature are associated with oral and sublingual routes of administration, which achieve a higher and faster maximum plasma concentration than vaginal and rectal routes [6–8]. We report the case of a 30 year old Cameroonian female gravida 1 para 1 who had a vaginal delivery at 40 weeks of gestation complicated by primary postpartum haemorrhage (PPH). PPH was managed by sublingual misoprostol that induced shivering and hyperpyrexia managed successfully with paracetamol and cooling.\n\nCase report\nA 30 year old female Cameroonian gravida 1 para 1 at 40 weeks of gestation with an uneventful antenatal consultation presented at the active phase of labour with a cervical dilatation of 4 cm and good uterine contractions. Labour progressed normally 5 h later to the vaginal delivery of a live female baby with weight 2820 g and Apgar 8/10 and 10/10 at the first and 5th min respectively. Blood loss after delivery was estimated at 350 cc. Whilst active management of the third stage of labour was done with injection of 10 IU of oxytocin, the placenta was delivered, examined and found to be complete. At the end of the third stage of labour, the uterus was well contracted and globular. Patient was then transferred to the ward in a haemodynamically stable condition following 2 h of monitoring. Ten hours later and after evaluation she complained of abundant lochia associated with vertigo and physical examination revealed blood pressure 102/77, heart rate of 104 beats/min and temperature of 37.6 °C. The uterus was tender and poorly contracted, other aspects of the examination were normal. We concluded on mild uterine atony and placed 600 µg of misoprostol sublingual. 20 min later we were called for sudden shivering and cold sensation. The temperature measured was 37.2 °C, an hour later the temperature rose to 38.6 °C and two hours later to 39.7 °C (Fig. 1 showed temperature variations over 18 h). There was no dyspnoea, no itching, no rashes, no convulsion and no angioedema. Vital signs were stable and there was no cardiopulmonary distress. We concluded on a working diagnosis of hyperpyrexia from misoprostol. Emergency full blood count and C-reactive protein (CRP) were normal. The management consisted of paracetamol 1 g 6 hourly and cooling the patient via tepid sponging. Paracetamol and cooling were started 1 and 3 h respectively after misoprostol administration. Twelve hours later the temperature dropped and remained less than 38 °C and she was monitored for another 24 h and discharged.Fig. 1 Temperature variation after sublingual misoprostol administration, paracetamol was started immediately and cooling by tepid sponging started 2 h later. The plot started 20 min after misoprostol administration. Paracetamol 1 g was administered 1 h after misoprostol administration and thereafter repeated every 6 h. Cooling was started 3 h after misoprostol administration\n\n\n\n\nDiscussion\nMisoprostol, a synthetic prostaglandin E1 analogue originally used for the treatment of NSAID induced peptic ulcer has been found to have a wider application in the field of obstetrics and gynaecology because of its uterotonic and cervical-maturation effects [6]. It has been recommended for the treatment and prevention of PPH by ACOG, FIGO and WHO [9–11]. Compared to other uterotonics, misoprostol is cheap, readily available, has a longer shelf life, stable at ambient temperature, and can be administered easily. It is a very safe drug associated with transient, mild side-effects like fever, chills, nausea, vomiting, diarrhoea and abdominal pain [6]. Collective total daily doses of 1600 Âµg have been tolerated with only mild gastrointestinal discomfort [6]. A study done in Ecuador in 2010 showed that there was a sharp increase in temperature within 1 h of treatment, a peak in temperature 1–2 h post-treatment, and a gradual decline in temperature over a period of 3 h. Average temperatures remained above 40.0 °C for less than 2 h, and measured below 38.0 °C approximately 6 h after receiving misoprostol. In our indexed case shivering started 20 min after administration and the temperature started rising 1 h later reaching a peak of 40.3 °C 4 h later and dropping to less than 38.0 °C 12 h later. This was consistent with results of recent studies [4, 12]. Temperature elevations associated with the use of misoprostol are compatible with the hypothalamic adjustment. Prostaglandins E2 (PGE2) have been involved in the pathophysiological mechanism of endogenous fever and identified as the major mediator for inducing fever because of its interaction with the Prostaglandin E3 (PGE3) receptor. Misoprostol-induced fever mimics the PGE2 endogenous thermoregulation patterns, changing the hypothalamic adjustment in its upper segment and stimulating temperature elevation [4]. In our patient the possibility of a postpartum infection was almost zero as our patient had no risk factor such as prolong labour, premature rupture of membranes, etc. and emergency CRP and FBC had values within normal ranges. The fever is usually treated with paracetamol, anti-inflammatory and cooling [4, 12]. In our indexed case we used paracetamol and cooling and there was a good clinical response with temperature remaining less than 38 °C after 12 h (see Fig. 1).\n\nConclusion\nHyperpyrexia associated with shivering may be associated with administration of misoprostol 600 µg, this is more common after sublingual administration. Treatment is with oral paracetamol and cooling. This common side effect should be kept in mind when administering misoprostol for postpartum haemorrhage.\n\nAuthors’ contributions\nPNT managed the case, PNT & JZM wrote the draft manuscript, PNT & JZM corrected the original manuscript. Both authors read and approved the final manuscript.\n\nAcknowledgements\nWe express our sincere gratitude to all doctors, nurses and medical students who took part in the management of the patient. We sincerely thank Dr. Calypse Ngwasiri for proof reading the manuscript for language and spelling checks.\n\nCompeting interests\nThe authors declare that they have no competing interests” in this section.\n\nAvailability of data and materials\nThe datasets (details of all results) are available from the corresponding author on reasonable request.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nEthical approval was obtained from Douala general hospital for publication of this case report.\n\nFunding\nNone.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Hogan MC Foreman KJ Naghavi M Ahn SY Wang M Makela SM Maternal mortality for 181 countries, 1980-2008: a systematic analysis of progress towards Millennium Development Goal 5 Lancet Lond Engl. 2010 375 9726 1609 1623 10.1016/S0140-6736(10)60518-1 \n2. Bonnet MP, Benhamou D. Management of postpartum haemorrhage. F1000Res. 2016. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926727/. Accessed 28 Apr 2017.\n3. Tebeu P-M, Halle-Ekane G, Da Itambi M, Mbu RE, Mawamba Y, Fomulu JN. Maternal mortality in Cameroon: a university teaching hospital report. Pan Afr Med J. 2015. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561158/. Accessed 28 Apr 2017.\n4. Durocher J Bynum J León W Barrera G Winikoff B High fever following postpartum administration of sublingual misoprostol BJOG 2010 117 7 845 852 10.1111/j.1471-0528.2010.02564.x 20406228 \n5. Mousa HA, Blum J, Abou El Senoun G, Shakur H, Alfirevic Z. Treatment for primary postpartum haemorrhage. Cochrane Database Syst Rev. 2014;(2):CD003249.\n6. Allen R O’Brien BM Uses of misoprostol in obstetrics and gynecology Rev Obstet Gynecol. 2009 2 3 159 168 19826573 \n7. Khan RU El-Refaey H Pharmacokinetics and adverse-effect profile of rectally administered misoprostol in the third stage of labor Obstet Gynecol 2003 101 5 Pt 1 968 974 12738159 \n8. Al-Harazi AH Frass KA Sublingual misoprostol for the prevention of postpartum hemorrhage Saudi Med J 2009 30 7 912 916 19618006 \n9. American College of Obstetricians and Gynecologists ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 76, October 2006: postpartum hemorrhage Obstet Gynecol 2006 108 4 1039 1047 10.1097/00006250-200610000-00046 17012482 \n10. FIGO guideline. Treatment of postpartum haemorrhage with misoprostol. 2012.\n11. Hofmeyr GJ Gülmezoglu AM Novikova N Linder V Ferreira S Piaggio G Misoprostol to prevent and treat postpartum haemorrhage: a systematic review and meta-analysis of maternal deaths and dose-related effects Bull World Health Organ 2009 87 9 666 667 10.2471/BLT.08.055715 19784446 \n12. León W Durocher J Barrera G Pinto E Winikoff B Dose and side effects of sublingual misoprostol for treatment of postpartum hemorrhage: what difference do they make? BMC Pregnancy Childbirth 2012 12 65 10.1186/1471-2393-12-65 22769055\n\n", "fulltext_license": "CC BY", "issn_linking": "1756-0500", "issue": "10(1)", "journal": "BMC research notes", "keywords": "Case report; Hyperpyrexia; Misoprostol; Temperature", "medline_ta": "BMC Res Notes", "mesh_terms": "D000286:Administration, Sublingual; D000328:Adult; D005260:Female; D005334:Fever; D006801:Humans; D016595:Misoprostol; D010120:Oxytocics; D006473:Postpartum Hemorrhage; D011247:Pregnancy", "nlm_unique_id": "101462768", "other_id": null, "pages": "329", "pmc": null, "pmid": "28747212", "pubdate": "2017-07-26", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "17012482;19618006;12738159;24523225;20382417;19784446;20406228;22769055;19826573", "title": "Sublingual misoprostol and hyperpyrexia: case report with temperature curve.", "title_normalized": "sublingual misoprostol and hyperpyrexia case report with temperature curve" }

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{ "abstract": "OBJECTIVE\nCangrelor is a P2Y12 inhibitor that presents the advantage of having a short half-life. Its use may be helpful in the management of antiplatelet therapy for patients with intracranial aneurysms treated by stent-assisted coiling or flow-diverter stents. The purpose of this study was to report early experiences in using cangrelor for such indications.\n\n\nMETHODS\nFrom October 2017 to November 2018, 7 consecutive patients (5 females, 2 males, mean age = 56 years) were managed with cangrelor as antiplatelet therapy, combined with aspirin, for stent-assisted coiling embolization and flow-diverter embolization of challenging intracranial aneurysms. Anti-aggregation protocols, including cangrelor, were systematically recorded. Treatment-related complications (minor/major hemorrhagic complications, ischemic complications) as well as clinical and angiographic outcomes (evaluated at 8.7 ± 4.2 and 8.75 ± 10 months, respectively) were retrospectively analyzed.\n\n\nRESULTS\nOf the aneurysms 71.4% (5 out of 7) were ruptured and treated in the acute phase. In one case cangrelor was used as an alternative to clopidogrel in an asymptomatic hemorrhagic complication after stent-assisted coiling for better control of a possible worsening of the intracranial bleeding. Of the patients, 1 (14%) with a complex ruptured MCA aneurysm treated with a flow-diverter stent experienced a severe intracranial hemorrhage, which occurred after switching the cangrelor to ticagrelor and eventually led to death. No hemorrhagic complications under cangrelor were recorded for the six remaining patients. No mRS worsening was observed at discharge, except for the patient who died and six out of the seven patients had a mRS ≤2 at follow-up.\n\n\nCONCLUSIONS\nCangrelor is a new antiplatelet therapy with a P2Y12 inhibiting effect, with a rapid onset and offset of action, owing to its short half-life. This cases series presents a pilot experience with promising results in terms of antiplatelet management for challenging intracranial aneurysms treated by stent assisted coiling or flow-diverter stents.", "affiliations": "Neuro-Intensive Care Unit, Pitié-Salpêtrière Hospital, Paris, France.;Department of Neuroradiology, Pitié-Salpêtrière Hospital, 47, Bd de l'Hôpital, 75013, Paris, France.;Neuro-Intensive Care Unit, Pitié-Salpêtrière Hospital, Paris, France.;Department of Neuroradiology, Pitié-Salpêtrière Hospital, 47, Bd de l'Hôpital, 75013, Paris, France.;Department of Neuroradiology, Pitié-Salpêtrière Hospital, 47, Bd de l'Hôpital, 75013, Paris, France.;Neuro-Intensive Care Unit, Fondation A. de Rothschild, Paris, France.;Department of Anesthesiology, Hôpital Européen Georges Pompidou, INSERM UMRS-1140, université Paris Descartes, Paris, France.;Neuro-Intensive Care Unit, Pitié-Salpêtrière Hospital, Paris, France.;Department of Neuroradiology, Pitié-Salpêtrière Hospital, 47, Bd de l'Hôpital, 75013, Paris, France.;Neuro-Intensive Care Unit, Pitié-Salpêtrière Hospital, Paris, France.;Sorbonne University, Paris, France.;Neuro-Intensive Care Unit, Pitié-Salpêtrière Hospital, Paris, France.;Department of Neuroradiology, Pitié-Salpêtrière Hospital, 47, Bd de l'Hôpital, 75013, Paris, France. frederic.clarencon@aphp.fr.", "authors": "Abdennour|Lamine|L|;Sourour|Nader|N|;Drir|Mehdi|M|;Premat|Kévin|K|;Shotar|Eimad|E|;Taylor|Guillaume|G|;Godier|Anne|A|;Mathout|Jugurtha|J|;Lenck|Stéphanie|S|;Bernard|Remy|R|;Carpentier|Alexandre|A|;Degos|Vincent|V|;Clarençon|Frédéric|F|", "chemical_list": "D058921:Purinergic P2Y Receptor Antagonists; D000249:Adenosine Monophosphate; C117446:cangrelor; D001241:Aspirin", "country": "Germany", "delete": false, "doi": "10.1007/s00062-019-00811-2", "fulltext": null, "fulltext_license": null, "issn_linking": "1869-1439", "issue": "30(3)", "journal": "Clinical neuroradiology", "keywords": "Antiaggregation platelet therapy; Cangrelor; Flow diversion; Hemorrhagic complication; Stent-assisted coiling", "medline_ta": "Clin Neuroradiol", "mesh_terms": "D000249:Adenosine Monophosphate; D017542:Aneurysm, Ruptured; D001241:Aspirin; D002533:Cerebral Angiography; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D058921:Purinergic P2Y Receptor Antagonists; D015607:Stents", "nlm_unique_id": "101526693", "other_id": null, "pages": "453-461", "pmc": null, "pmid": "31309241", "pubdate": "2020-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Preliminary Experience with Cangrelor for Endovascular Treatment of Challenging Intracranial Aneurysms.", "title_normalized": "preliminary experience with cangrelor for endovascular treatment of challenging intracranial aneurysms" }

[ { "companynumb": "FR-CHIESI USA, INC.-FR-2020CHI000336", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANGRELOR" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "204958", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OFF LABEL USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANGRELOR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANGRELOR" }, "drugadditional": "1", "drugadministrationroute": "040", "drugauthorizationnumb": "204958", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 ?G/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRACRANIAL ANEURYSM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANGRELOR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TICAGRELOR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "90 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRACRANIAL ANEURYSM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "90", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICAGRELOR." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "040", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG, UNK (30 MINUTES BEFORE THE STENT DEPLOYMENT)", "drugenddate": null, "drugenddateformat": null, "drugindication": "INTRACRANIAL ANEURYSM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN /00002701/" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "23.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ABDENNOUR L, SOUROUR N, DRIR M , PREMAT K, SHOTAR E, TAYLOR G ET AL.. PRELIMINARY EXPERIENCE WITH CANGRELOR FOR ENDOVASCULAR TREATMENT OF CHALLENGING INTRACRANIAL ANEURYSMS. CLIN NEURORADIOL. 2019", "literaturereference_normalized": "preliminary experience with cangrelor for endovascular treatment of challenging intracranial aneurysms", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20200527", "receivedate": "20200527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17830487, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200714" } ]

{ "abstract": "Multiple myeloma (MM) is a plasma cell malignancy leading to significant life-expectancy shortening. Although the incorporation of the novel agents thalidomide, bortezomib, and lenalidomide in the front-line therapy has resulted in significant improvement, almost all patients relapse, making the treatment of relapse a real challenge. In the present article, when and how to treat relapsed MM is discussed. Treatment can be safely delayed in a subset of patients with asymptomatic relapse, whereas those with symptomatic relapse, advanced disease at diagnosis, or significant paraproteinemic increase require prompt rescue therapy. The benefit of retreatment and the use of a sequential approach for successive relapses considering drug synergism are highlighted. For patients with aggressive relapses and for those who have exhausted all available options, continued therapy until disease progression is recommended, particularly when using regimens with a long-term safety profile. Patients with a duration response to a first autologous stem cell transplantation (ASCT) longer than 2 years may benefit from a second ASCT. Patients with aggressive disease and/or poor cytogenetics at diagnosis relapsing within the first 2 years from ASCT should be considered for an allogeneic transplantation. Finally, a number of newer promising drugs are being actively investigated and the enrolment of patients in clinical trials is encouraged.", "affiliations": "Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic, Barcelona, Spain; and Institut d'Investigacions Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic, Barcelona, Spain; and Institut d'Investigacions Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain.;Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic, Barcelona, Spain; and Institut d'Investigacions Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain.", "authors": "Bladé|Joan|J|;Rosiñol|Laura|L|;Fernández de Larrea|Carlos|C|", "chemical_list": "D018906:Antineoplastic Agents, Alkylating; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib", "country": "United States", "delete": false, "doi": "10.1182/blood-2014-10-551531", "fulltext": null, "fulltext_license": null, "issn_linking": "0006-4971", "issue": "125(10)", "journal": "Blood", "keywords": null, "medline_ta": "Blood", "mesh_terms": "D000328:Adult; D064591:Allografts; D018906:Antineoplastic Agents, Alkylating; D000971:Antineoplastic Combined Chemotherapy Protocols; D064592:Autografts; D001897:Boronic Acids; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D012008:Recurrence; D016879:Salvage Therapy; D033581:Stem Cell Transplantation", "nlm_unique_id": "7603509", "other_id": null, "pages": "1532-40", "pmc": null, "pmid": "25587037", "pubdate": "2015-03-05", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "How I treat relapsed myeloma.", "title_normalized": "how i treat relapsed myeloma" }

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