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[ { "id": "passage-0", "type": "abstract", "text": [ "Methotrexate and leucovorin double-modulated 5-fluorouracil combined with cisplatin (MPFL) in metastatic/recurrent head and neck cancer. BACKGROUND: To determine the efficacy and safety profile of the combination of cisplatin and 5-fluorouracil modulated both by methotrexate and leucovorin in metastatic/recurrent squamous cell carcinoma of the head and neck. METHODS: Twenty-eight patients were treated with cisplatin 40 mg/m2/day continuous infusion for 24 hours on day 1; high-dose 5-fluorouracil 2,000 mg/m2/day and leucovorin 100 mg/m2/day continuous infusion for 48 hours on days 1 and 2; methotrexate 40 mg/m2/day as a bolus infusion 4 hours before 5-fluorouracil and leucovorin on day 1. The treatment was repeated every 2 weeks in a cycle. RESULTS: The overall response rate was 25%, and 14% of the patients achieved stable disease status. Subgroup analysis demonstrated significantly improved overall survival in the disease-control group (12.0 months vs. 5.3 months, p<0.001). Only 3 (10.7%) patients developed grade 3-4 neutropenia, and none developed grade 3-4 non-hematologic toxicity. CONCLUSION: This multiagent-containing regimen has an excellent safety profile and improved survival in disease-control group of patients with metastatic/recurrent squamous cell carcinoma of the head and neck." ], "offsets": [ [ 0, 1311 ] ] } ]

[ { "id": "entity-0-0", "type": "DISEASE", "text": [ "metastatic/recurrent head and neck cancer" ], "offsets": [ [ 94, 135 ] ], "normalized": [] }, { "id": "entity-0-1", "type": "DISEASE", "text": [ "metastatic/recurrent squamous cell carcinoma of the head and neck" ], "offsets": [ [ 295, 360 ] ], "normalized": [] }, { "id": "entity-0-2", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1034, 1045 ] ], "normalized": [] }, { "id": "entity-0-3", "type": "ADVERSE", "text": [ "non-hematologic toxicity" ], "offsets": [ [ 1076, 1100 ] ], "normalized": [] }, { "id": "entity-0-4", "type": "DISEASE", "text": [ "metastatic/recurrent squamous cell carcinoma of the head and neck" ], "offsets": [ [ 1245, 1310 ] ], "normalized": [] } ]

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[ { "id": "passage-1", "type": "abstract", "text": [ "Dose escalation of gemcitabine is possible with concurrent chest three-dimensional rather than two-dimensional radiotherapy: a phase I trial in patients with stage III non-small-cell lung cancer. PURPOSE: To determine in a Phase I study the maximum tolerated dose of weekly gemcitabine concurrent with radiotherapy in locally advanced non-small-cell lung cancer (NSCLC), as well as the relationship between the volume of the esophagus irradiated and severe esophagitis. METHODS AND MATERIALS: Twenty-one patients with Stage III NSCLC received gemcitabine initially at 150 mg/m(2)/wk over 7 weeks concurrently with chest radiotherapy to 63 Gy in 34 fractions. The first 9 patients underwent treatment with two-dimensional (2D) radiotherapy; the remaining 12 patients, with three-dimensional conformal radiotherapy (3D-CRT) and target volume reduced to clinically apparent disease. Consolidation was 4 cycles of gemcitabine at 1000 mg/m(2)/wk and cisplatin 60 mg/m(2). RESULTS: In the 2D group, the dose-limiting toxicity, Grade 3 esophagitis, occurred in 3 of 6 patients in the 150-mg/m(2)/wk cohort and 2 of 3 patients in the 125-mg/m(2)/wk cohort. No cases of Grade 3 esophagitis occurred at these doses in the 3D group. At gemcitabine 190 mg/m(2)/wk, 2 of 6 patients in the 3D cohort had Grade 3 esophagitis. The mean percentages of esophagus irradiated to 60 Gy were 68% in the 2D cohort and 18% in the 3D cohort. CONCLUSIONS: We could not escalate the dose of gemcitabine with concurrent radiotherapy when using 2D planning because of severe acute esophagitis. However, we could escalate the dose of gemcitabine to 190 mg/m(2)/wk when using 3D planning. The Phase II dose is 150 mg/m(2)/wk. Three-dimensional CRT permitted the use of higher doses of gemcitabine." ], "offsets": [ [ 0, 1767 ] ] } ]

[ { "id": "entity-1-0", "type": "DISEASE", "text": [ "non-small-cell lung cancer" ], "offsets": [ [ 168, 194 ] ], "normalized": [] }, { "id": "entity-1-1", "type": "DISEASE", "text": [ "non-small-cell lung cancer" ], "offsets": [ [ 336, 362 ] ], "normalized": [] }, { "id": "entity-1-2", "type": "DISEASE", "text": [ "NSCLC" ], "offsets": [ [ 364, 369 ] ], "normalized": [] }, { "id": "entity-1-3", "type": "DISEASE", "text": [ "esophagitis" ], "offsets": [ [ 458, 469 ] ], "normalized": [] }, { "id": "entity-1-4", "type": "DISEASE", "text": [ "NSCLC" ], "offsets": [ [ 529, 534 ] ], "normalized": [] }, { "id": "entity-1-5", "type": "ADVERSE", "text": [ "dose-limiting toxicity" ], "offsets": [ [ 998, 1020 ] ], "normalized": [] }, { "id": "entity-1-6", "type": "ADVERSE", "text": [ "esophagitis" ], "offsets": [ [ 1030, 1041 ] ], "normalized": [] }, { "id": "entity-1-7", "type": "ADVERSE", "text": [ "esophagitis" ], "offsets": [ [ 1170, 1181 ] ], "normalized": [] }, { "id": "entity-1-8", "type": "ADVERSE", "text": [ "esophagitis" ], "offsets": [ [ 1299, 1310 ] ], "normalized": [] }, { "id": "entity-1-9", "type": "ADVERSE", "text": [ "acute esophagitis" ], "offsets": [ [ 1547, 1564 ] ], "normalized": [] } ]

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[ { "id": "passage-2", "type": "abstract", "text": [ "Morphine-6-glucuronide, an active morphine metabolite for the potential treatment of post-operative pain. Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is being developed by CeNeS Pharmaceuticals as an alternative to morphine (the most commonly used opioid) for the management of postoperative pain. M6G is currently undergoing phase III clinical trials in patients with postoperative pain." ], "offsets": [ [ 0, 415 ] ] } ]

[ { "id": "entity-2-0", "type": "DISEASE", "text": [ "post-operative pain" ], "offsets": [ [ 85, 104 ] ], "normalized": [] }, { "id": "entity-2-1", "type": "DISEASE", "text": [ "postoperative pain" ], "offsets": [ [ 305, 323 ] ], "normalized": [] }, { "id": "entity-2-2", "type": "DISEASE", "text": [ "postoperative pain" ], "offsets": [ [ 396, 414 ] ], "normalized": [] } ]

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[ { "id": "passage-3", "type": "abstract", "text": [ "La3+ binds to BiP/GRP78 and induces unfolded protein response in HepG2 cells. The effects of La3+ on the unfolded protein response signaling pathways were investigated in human hepatoblastoma HepG2 cells. Our data showed that La3+ could induce unfolded protein response in HepG2 cells, including a significant increase of BiP/GRP78 level, which is an important ER residential chaperone and an ER stress hallmark, in a concentration and time-dependent manner, UPR transducer IRE1 phosphorylation and splicing activation IRE1 downstream substrate XBP1 mRNA. By using La3+-affinity chromatography, the possible cellular target of La3+ leading to UPR events was shown to be the ER residential chaperone BiP/GRP78. BiP/GRP78 was shown to be a La3+ binding protein and the interaction of La3+ with BiP/GRP78 resulted in dissociation of BiP-IRE1 complexes. La3+ induced dissociation of the BiP/GRP78-IRE1 complex was in a time and concentration manner. The apparent dissociation constant was estimated to be 4 nM. In addition, La3+ was observed to slightly stimulate the production of cellular ROS and cause alteration of intracellular Ca2+, indicating the possible involvement of ROS and Ca2+ alteration in La3+ induced UPR. The present work provides a new perspective for understanding the biological and toxicological effects of La3+." ], "offsets": [ [ 0, 1331 ] ] } ]

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[ { "id": "passage-4", "type": "abstract", "text": [ "The effects of 1,4-benzoquinone on c-Myb and topoisomerase II in K-562 cells. Exposure to benzene, a ubiquitous environmental pollutant, has been linked to leukemia, although the mechanism of benzene-initiated leukemogenesis remains unclear. Benzene can be bioactivated to toxic metabolites such as 1,4 benzoquinone (BQ), which can alter signaling pathways and affect chromosomal integrity. BQ has been shown to increase the activity of c-Myb, which is an important transcription factor involved in hematopoiesis, cell proliferation, and cell differentiation. The c-Myb protein has also been shown to increase topoisomerase IIalpha (Topo IIalpha) promoter activity specifically in cell lines with hematopoietic origin. Topo IIalpha is a critical nuclear enzyme that removes torsional strain by cleaving, untangling and religating double-stranded DNA. Since Topo IIalpha mediates DNA strand breaks, aberrant Topo IIalpha activity or increased protein levels may increase the formation of DNA strand breaks, leaving the cell susceptible to mutational events. We hypothesized that BQ can increase c-Myb activity, which in turn increases Topo IIalpha promoter activity resulting in increased DNA strand breaks. Using luciferase reporter assays in K-562 cells we demonstrated that BQ (25 and 37microM) exposure caused an increase in c-Myb activity after 24h. Contradictory to previous findings, overexpression of exogenous c-Myb or a polypeptide consisting of c-Myb's DNA binding domain (DBD), which competitively inhibits the binding of endogenous c-Myb to DNA, did not affect Topo IIalpha promoter activity. However, BQ (37microM for 24h) exposure caused a significant increase in Topo IIalpha promoter activity, which could be blocked by the overexpression of the DBD polypeptide, suggesting that BQ exposure increases Topo IIalpha promoter activity through the c-Myb signaling pathway." ], "offsets": [ [ 0, 1885 ] ] } ]

[ { "id": "entity-4-0", "type": "ADVERSE", "text": [ "leukemia" ], "offsets": [ [ 157, 165 ] ], "normalized": [] } ]

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[ { "id": "passage-5", "type": "abstract", "text": [ "Fragrance material review on alpha-bisabolol. A toxicologic and dermatologic review of alpha-bisabolol when used as a fragrance ingredient is presented." ], "offsets": [ [ 0, 153 ] ] } ]

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[ { "id": "passage-6", "type": "abstract", "text": [ "Experimental models of sepsis and their clinical relevance. Sepsis remains a major cause of morbidity and mortality mainly because of sepsis-induced multiple organ dysfunction. In contrast to preclinical studies, most clinical trials of promising new treatment strategies for sepsis have failed to demonstrate efficacy. Although many reasons could account for this discrepancy, the misinterpretation of preclinical data obtained from experimental studies and especially the use of animal models that do not adequately mimic human sepsis may have been contributing factors. In this review, the potentials and limitations of various animal models of sepsis are discussed to clarify to which extent these findings are relevant to human sepsis. Such models include intravascular infusion of endotoxin or live bacteria, bacterial peritonitis, cecal ligation and perforation, soft tissue infection, pneumonia or meningitis models using different animal species including rats, mice, rabbits, dogs, pigs, sheep, and nonhuman primates. Despite several limitations, animal models remain essential in the development of all new therapies for sepsis and septic shock because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that cannot be replaced by other methods. New therapeutic agents should be studied in infection models, even after the initiation of the septic process. Furthermore, debility conditions need to be reproduced to avoid the exclusive use of healthy animals, which often do not represent the human septic patient." ], "offsets": [ [ 0, 1578 ] ] } ]

[ { "id": "entity-6-0", "type": "DISEASE", "text": [ "sepsis" ], "offsets": [ [ 23, 29 ] ], "normalized": [] }, { "id": "entity-6-1", "type": "DISEASE", "text": [ "Sepsis" ], "offsets": [ [ 61, 67 ] ], "normalized": [] }, { "id": "entity-6-2", "type": "DISEASE", "text": [ "sepsis" ], "offsets": [ [ 135, 141 ] ], "normalized": [] }, { "id": "entity-6-3", "type": "DISEASE", "text": [ "multiple organ dysfunction" ], "offsets": [ [ 150, 176 ] ], "normalized": [] }, { "id": "entity-6-4", "type": "DISEASE", "text": [ "sepsis" ], "offsets": [ [ 277, 283 ] ], "normalized": [] }, { "id": "entity-6-5", "type": "DISEASE", "text": [ "sepsis" ], "offsets": [ [ 531, 537 ] ], "normalized": [] }, { "id": "entity-6-6", "type": "DISEASE", "text": [ "sepsis" ], "offsets": [ [ 649, 655 ] ], "normalized": [] }, { "id": "entity-6-7", "type": "DISEASE", "text": [ "sepsis" ], "offsets": [ [ 734, 740 ] ], "normalized": [] }, { "id": "entity-6-8", "type": "DISEASE", "text": [ "bacterial peritonitis" ], "offsets": [ [ 816, 837 ] ], "normalized": [] }, { "id": "entity-6-9", "type": "DISEASE", "text": [ "soft tissue infection" ], "offsets": [ [ 871, 892 ] ], "normalized": [] }, { "id": "entity-6-10", "type": "DISEASE", "text": [ "pneumonia" ], "offsets": [ [ 894, 903 ] ], "normalized": [] }, { "id": "entity-6-11", "type": "DISEASE", "text": [ "meningitis" ], "offsets": [ [ 907, 917 ] ], "normalized": [] }, { "id": "entity-6-12", "type": "DISEASE", "text": [ "sepsis" ], "offsets": [ [ 1133, 1139 ] ], "normalized": [] }, { "id": "entity-6-13", "type": "DISEASE", "text": [ "septic shock" ], "offsets": [ [ 1144, 1156 ] ], "normalized": [] }, { "id": "entity-6-14", "type": "DISEASE", "text": [ "infection" ], "offsets": [ [ 1355, 1364 ] ], "normalized": [] } ]

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[ { "id": "passage-7", "type": "abstract", "text": [ "Efficient clearance of Aspergillus fumigatus in murine lungs by an ultrashort antimicrobial lipopeptide, palmitoyl-lys-ala-DAla-lys. Aspergillus fumigatus is an opportunistic fungal pathogen responsible for invasive aspergillosis in immunocompromised individuals. The inefficiency of antifungal agents and high mortality rate resulting from invasive aspergillosis remain major clinical concerns. Recently, we reported on a new family of ultrashort cationic lipopeptides active in vitro against fungi. Mode of action studies supported a membranolytic or a detergent-like effect. Here, we screened several lipopeptides in vitro for their anti-A. fumigatus activity. To investigate the therapeutic properties of the selected peptides in vivo, we challenged immunosuppressed C57BL/6 wild-type mice intranasally with DsRed-labeled A. fumigatus conidia and subsequently treated the animals locally with the lipopeptides. Confocal microscopic analysis revealed the degradation of DsRed-labeled hyphal forms and residual conidia in the lungs of the mice. The most efficient peptide was tested further using a survival assay and was found to significantly prolong the life of the treated animals, whereas no mice survived with the current standard antifungal treatment with amphotericin B. Moreover, as opposed to the drug-treated lungs, the peptide-treated lungs did not display any toxicity of the peptide. Our results highlight the potential of this family of lipopeptides for the treatment of pulmonary invasive aspergillosis." ], "offsets": [ [ 0, 1522 ] ] } ]

[ { "id": "entity-7-0", "type": "DISEASE", "text": [ "aspergillosis" ], "offsets": [ [ 217, 230 ] ], "normalized": [] }, { "id": "entity-7-1", "type": "DISEASE", "text": [ "aspergillosis" ], "offsets": [ [ 351, 364 ] ], "normalized": [] }, { "id": "entity-7-2", "type": "DISEASE", "text": [ "aspergillosis" ], "offsets": [ [ 1508, 1521 ] ], "normalized": [] } ]

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[ { "id": "passage-8", "type": "abstract", "text": [ "Allogeneic SCT in refractory or relapsed adult ALL is effective without prior reinduction chemotherapy. We present 60 patients with refractory (n=8) or relapsed (n=52) adult ALL who received allogeneic hematopoietic SCT (HSCT) with (n=41) or without (n=19) prior reinduction chemotherapy. In our center, omission of reinduction is recommended if a suitable donor is promptly available, tumor burden is moderate and disease features suggest a highly aggressive course. Overall survival (OS) of the whole cohort at 1, 2 and 5 years was 42, 33 and 28%, respectively. Leukemia-free survival at 1, 2 and 5 years was 37, 33 and 24%. Deaths were due to relapse (n=25), acute or chronic GVHD (n=7), infections (n=8) or toxicity (n=4). Interestingly, patients who did not receive reinduction before HSCT had better outcomes than patients who received reinduction with OS at 1, 2 and 5 years being 58 vs 34%, 47 vs 25% and 47 vs 18%, respectively (P=0.039). Importantly, even achievement of a second CR after reinduction was not associated with improved survival compared to patients directly proceeding to HSCT. We conclude that patients who undergo HSCT for refractory or relapsed ALL can achieve long-term survival. In selected patients, reinduction chemotherapy can be omitted if immediate HSCT is feasible." ], "offsets": [ [ 0, 1302 ] ] } ]

[ { "id": "entity-8-0", "type": "DISEASE", "text": [ "relapsed adult ALL" ], "offsets": [ [ 32, 50 ] ], "normalized": [] }, { "id": "entity-8-1", "type": "DISEASE", "text": [ "ALL" ], "offsets": [ [ 175, 178 ] ], "normalized": [] }, { "id": "entity-8-2", "type": "DISEASE", "text": [ "tumor" ], "offsets": [ [ 387, 392 ] ], "normalized": [] }, { "id": "entity-8-3", "type": "DISEASE", "text": [ "Leukemia" ], "offsets": [ [ 565, 573 ] ], "normalized": [] }, { "id": "entity-8-4", "type": "DISEASE", "text": [ "chronic GVHD" ], "offsets": [ [ 672, 684 ] ], "normalized": [] }, { "id": "entity-8-5", "type": "DISEASE", "text": [ "infections" ], "offsets": [ [ 692, 702 ] ], "normalized": [] }, { "id": "entity-8-6", "type": "DISEASE", "text": [ "relapsed ALL" ], "offsets": [ [ 1165, 1177 ] ], "normalized": [] } ]

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[ { "id": "passage-9", "type": "abstract", "text": [ "Perception of validity of clinical and preclinical methods for assessment of torsades de pointes liability. In 2007 a meeting on drug-induced torsades de pointes (TdP) was held in London, UK, under the auspices of the British Society for Cardiovascular Research (BSCR). One of the objectives was to explore the validity of available biomarkers, risk factors and preclinical investigational methods for the detection of drug-induced TdP liability - preclinical methods and clinical 'thorough QT' testing. The first symposium was entitled \"How validated are current models and biomarkers for testing drug-induced torsades de pointes liability?\" Validation, as far as the symposium was concerned, meant that the endpoints measured in the method predict TdP liability specifically, selectively and quantitatively. Topics (and the publications derived from the presentations) were: human volunteer phase 1 studies [Vik, T., Pollard, C., & Sager, P. (2008-this issue), the anaesthetized rabbit TDP model [Carlsson, L. (2008-this issue), the AV blocked canine preparation [Oros, A., Beekman, J. D. M., & Vos, M. A. (2008-this issue), QT interval and its corrections in the in vivo conscious canine [Fossa, A. A. (2008-this issue), the rabbit heart failure model [Hamlin, R. L., & Kijtawornrat, A. (2008-this issue), the rabbit Langendorff preparation and the Screenit approach [Dumotier, B. M., Deurinck, M., Yang, Y., Traebert, M., & Suter, W. (2008-this issue), the wedge preparation [Yan G.-X. (2008-this issue)] and hERG screens [Hancox, J. C., McPate, M. J., El Harchi, A., & Zhang, Y. h. (2008-this issue). Unbeknownst to the speakers before the start of the sessions, the audience were invited, during the session, to rate each approach on a 0 to 10 scale in terms of the extent to which each approach appeared to be validated. The outcome of this exercise forms the basis of this article. We invite you to evaluate for yourselves the accompanying reviews in this edition of Pharmacology and Therapeutics." ], "offsets": [ [ 0, 2006 ] ] } ]

[ { "id": "entity-9-0", "type": "DISEASE", "text": [ "torsades de pointes" ], "offsets": [ [ 77, 96 ] ], "normalized": [] }, { "id": "entity-9-1", "type": "ADVERSE", "text": [ "torsades de pointes" ], "offsets": [ [ 143, 162 ] ], "normalized": [] }, { "id": "entity-9-2", "type": "ADVERSE", "text": [ "TdP" ], "offsets": [ [ 164, 167 ] ], "normalized": [] }, { "id": "entity-9-3", "type": "ADVERSE", "text": [ "TdP" ], "offsets": [ [ 433, 436 ] ], "normalized": [] }, { "id": "entity-9-4", "type": "ADVERSE", "text": [ "torsades de pointes" ], "offsets": [ [ 612, 631 ] ], "normalized": [] }, { "id": "entity-9-5", "type": "ADVERSE", "text": [ "TdP" ], "offsets": [ [ 751, 754 ] ], "normalized": [] }, { "id": "entity-9-6", "type": "DISEASE", "text": [ "heart failure" ], "offsets": [ [ 1236, 1249 ] ], "normalized": [] } ]

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[ { "id": "passage-10", "type": "abstract", "text": [ "Patient willingness to undergo chemotherapy and thoracic radiotherapy for locally advanced non-small cell lung cancer. OBJECTIVES: To determine how Japanese patients with lung cancer weigh the chance of cure and potential survival against the potential toxicity of different treatment strategies for locally advanced non-small cell lung cancer (NSCLC). METHODS: We used a questionnaire describing a hypothetical situation involving locally advanced NSCLC. Seventy-three patients with lung cancer who had received chemotherapy and a control group of 120 patients without cancer were asked to state the minimal benefit that would make two hypothetical treatments acceptable. RESULTS: Patients with lung cancer were significantly more likely than were patients without cancer to accept either intensive or less-intensive chemoradiotherapy for a potentially small benefit for 'chance of cure' and 'response but not cure'. The percentages of patients who would accept intensive or less-intensive chemoradiotherapy to prolong survival did not differ significantly between the two groups. When the chance of cure was 20%, 56 and 64% of patients with lung cancer were willing to receive intensive and less-intensive chemoradiotherapy, respectively. If their lives were prolonged by 6 months, 20 and 30% of patients with lung cancer would choose to receive intensive and less-intensive chemoradiotherapy, respectively. The chance of cure and the survival advantage that patients require for accepting chemoradiotherapy varied widely. No factors were associated with the choice of chemoradiotherapy in patients with lung cancer. CONCLUSIONS: Physicians must consider the substantial range of attitudes to chemoradiotherapy among patients when selecting treatment and give patients opportunities to be included in the treatment-selection process." ], "offsets": [ [ 0, 1836 ] ] } ]

[ { "id": "entity-10-0", "type": "DISEASE", "text": [ "non-small cell lung cancer" ], "offsets": [ [ 91, 117 ] ], "normalized": [] }, { "id": "entity-10-1", "type": "DISEASE", "text": [ "lung cancer" ], "offsets": [ [ 172, 183 ] ], "normalized": [] }, { "id": "entity-10-2", "type": "DISEASE", "text": [ "non-small cell lung cancer" ], "offsets": [ [ 318, 344 ] ], "normalized": [] }, { "id": "entity-10-3", "type": "DISEASE", "text": [ "lung cancer" ], "offsets": [ [ 485, 496 ] ], "normalized": [] }, { "id": "entity-10-4", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 571, 577 ] ], "normalized": [] }, { "id": "entity-10-5", "type": "DISEASE", "text": [ "lung cancer" ], "offsets": [ [ 697, 708 ] ], "normalized": [] }, { "id": "entity-10-6", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 767, 773 ] ], "normalized": [] }, { "id": "entity-10-7", "type": "DISEASE", "text": [ "lung cancer" ], "offsets": [ [ 1144, 1155 ] ], "normalized": [] }, { "id": "entity-10-8", "type": "DISEASE", "text": [ "lung cancer" ], "offsets": [ [ 1313, 1324 ] ], "normalized": [] }, { "id": "entity-10-9", "type": "DISEASE", "text": [ "lung cancer" ], "offsets": [ [ 1607, 1618 ] ], "normalized": [] } ]

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[ { "id": "passage-11", "type": "abstract", "text": [ "Identification and characterization of thiosemicarbazones with antifungal and antitumor effects: cellular iron chelation mediating cytotoxic activity. Thiosemicarbazones derived from acetylpyrazines were prepared by condensing an acetylpyrazine or a ring-substituted acetylpyrazine with thiosemicarbazide. Using the same procedure, N, N-dimethylthiosemicarbazones were synthesized from acetylpyrazines and N, N-dimethylthiosemicarbazide. A total of 20 compounds (16 novel) were chemically characterized and then tested for antifungal effects on eight strains of fungi and also for antitumor activity against SK-N-MC neuroepithelioma cells. The most effective compound identified in terms of both antifungal and antitumor activity was N, N-dimethyl-2-(1-pyrazin-2-ylethylidene)hydrazinecarbothioamide (5a). The mechanism of action of this and its related thiosemicarbazones was due, at least in part, to its ability to act as a tridentate ligand that binds metal ions. This was deduced from preparation of the related thiosemicarbazones [acetophenone thiosemicarbazone (6) and acetophenone N, N-dimethylthiosemicarbazone (7)] that do not possess a coordinating ring-N, which plays a vital role in metal ion chelation. Furthermore, 5a and several other thiosemicarbazones that showed high antiproliferative activity were demonstrated to have marked iron (Fe) chelation efficacy. In fact, these agents were highly effective at mobilizing (59)Fe from prelabeled SK-N-MC cells and preventing (59)Fe uptake from the serum Fe transport protein, transferrin. In contrast, compounds 6 and 7 that do not possess a tridentate metal-binding site showed little activity. Further studies examining ascorbate oxidation demonstrated that the Fe complexes of the most effective compounds were redox-inactive. Thus, in contrast to other thiosemicarbazones with potent antiproliferative activity, Fe chelation and mobilization rather than free radical generation played a significant role in the cytotoxic effects of the current ligands." ], "offsets": [ [ 0, 2019 ] ] } ]

[ { "id": "entity-11-0", "type": "ADVERSE", "text": [ "cytotoxic activity" ], "offsets": [ [ 131, 149 ] ], "normalized": [] }, { "id": "entity-11-1", "type": "ADVERSE", "text": [ "cytotoxic effects" ], "offsets": [ [ 1978, 1995 ] ], "normalized": [] } ]

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[ { "id": "passage-12", "type": "abstract", "text": [ "Transcriptome analyses in normal prostate epithelial cells exposed to low-dose cadmium: oncogenic and immunomodulations involving the action of tumor necrosis factor. BACKGROUND: Cadmium is implicated in prostate carcinogenesis, but its oncogenic action remains unclear. OBJECTIVES: In this study we aimed to decipher changes in cell growth and the transcriptome in an immortalized human normal prostate epithelial cell line (NPrEC) following exposure to low-dose Cd. METHODS: Synchronized NPrEC cells were exposed to different doses of Cd and assayed for cell viability and cell-cycle progression. We investigated changes in transcriptome by global profiling and used Ingenuity Pathways Analysis software to develop propositions about functional connections among differentially expressed genes. A neutralizing antibody was used to negate the effect of Cd-induced up-regulation of tumor necrosis factor (TNF) in NPrEC cells. RESULTS: Exposure of NPrEC to 2.5 microM Cd enhanced cell viability and accelerated cell-cycle progression. Global expression profiling identified 48 genes that exhibited >or= 1.5-fold changes in expression after 4, 8, 16, and 32 hr of Cd treatment. Pathway analyses inferred a functional connection among 35 of these genes in one major network, with TNF as the most prominent node. Fourteen of the 35 genes are related to TNF, and 11 exhibited an average of >2-fold changes in gene expression. Real-time reverse transcriptase-polymerase chain reaction confirmed the up-regulation of 7 of the 11 genes (ADAM8, EDN1, IL8, IL24, IL13RA2, COX2/PTGS2, and SERPINB2) and uncovered a 28-fold transient increase in TNF expression in Cd-treated NPrEC cells. A TNF-neutralizing antibody effectively blocked Cd-induced elevations in the expression of these genes. CONCLUSIONS: Noncytotoxic, low-dose Cd has growth-promoting effects on NPrEC cells and induces transient overexpression of TNF, leading to up-regulation of genes with oncogenic and immunomodulation functions." ], "offsets": [ [ 0, 1989 ] ] } ]

[ { "id": "entity-12-0", "type": "ADVERSE", "text": [ "prostate carcinogenesis" ], "offsets": [ [ 205, 228 ] ], "normalized": [] } ]

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[ { "id": "passage-13", "type": "abstract", "text": [ "Methylated bismuth, but not bismuth citrate or bismuth glutathione, induces cyto- and genotoxic effects in human cells in vitro. Bismuth compounds are widely used in industrial processes and products. In medicine, bismuth salts have been applied in combination with antibiotics for the treatment of Helicobacter pylori infections, for the prevention of diarrhea, and in radioimmunotherapy. In the environment, bismuth ions can be biotransformed to the volatile bismuth compound trimethylbismuth (Me3Bi) by methanobacteria. Preliminary in-house studies have indicated that bismuth ions are methylated in the human colon by intestinal microflora following ingestion of bismuth-containing salts. Information concerning cyto- and genotoxicity of these biomethylated products is limited. In the present study, we investigated the cellular uptake of an organic bismuth compound [monomethylbismuth(III), MeBi(III)] and two other bismuth compounds [bismuth citrate (Bi-Cit) and bismuth glutathione (Bi-GS)] in human hepatocytes, lymphocytes, and erythrocytes using ICP-MS. We also analyzed the cyto- and genotoxic effects of these compounds to investigate their toxic potential. Our results show that the methylbismuth compound was better taken up by the cells than Bi-Cit and Bi-GS. All intracellularly detected bismuth compounds were located in the cytosol of the cells. MeBi(III) was best taken up by erythrocytes (36%), followed by lymphocytes (17%) and hepatocytes (0.04%). Erythrocytes and hepatocytes were more susceptible to MeBi(III) exposure than lymphocytes. Cytotoxic effects of MeBi(III) were detectable in erythrocytes at concentrations >4 microM, in hepatocytes at >130 microM, and in lymphocytes at >430 microM after 24 h of exposure. Cytotoxic effects for Bi-Cit and Bi-GS were much lower or not detectable in the used cell lines up to a tested concentration of 500 microM. Exposure of lymphocytes to MeBi(III) (250 microM for 1 h and 25 microM/50 microM for 24 h) resulted in significantly increased frequencies of chromosomal aberrations (CA) and sister chromatid exchanges (SCE), whereas Bi-Cit and Bi-GS induced neither CA nor SCE. Our study also showed an intracellular production of free radicals caused by MeBi(III) in hepatocytes but not in lymphocytes. These data suggest that biomethylation of bismuth ions by the intestinal microflora of the human colon leads to an increase in the toxicity of the primary bismuth salt." ], "offsets": [ [ 0, 2440 ] ] } ]

[ { "id": "entity-13-0", "type": "ADVERSE", "text": [ "genotoxic effects" ], "offsets": [ [ 86, 103 ] ], "normalized": [] }, { "id": "entity-13-1", "type": "DISEASE", "text": [ "Helicobacter pylori infections" ], "offsets": [ [ 300, 330 ] ], "normalized": [] }, { "id": "entity-13-2", "type": "DISEASE", "text": [ "diarrhea" ], "offsets": [ [ 354, 362 ] ], "normalized": [] }, { "id": "entity-13-3", "type": "ADVERSE", "text": [ "genotoxicity" ], "offsets": [ [ 727, 739 ] ], "normalized": [] }, { "id": "entity-13-4", "type": "ADVERSE", "text": [ "genotoxic effects" ], "offsets": [ [ 1097, 1114 ] ], "normalized": [] }, { "id": "entity-13-5", "type": "ADVERSE", "text": [ "Cytotoxic effects" ], "offsets": [ [ 1563, 1580 ] ], "normalized": [] }, { "id": "entity-13-6", "type": "ADVERSE", "text": [ "Cytotoxic effects" ], "offsets": [ [ 1744, 1761 ] ], "normalized": [] } ]

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[ { "id": "passage-14", "type": "abstract", "text": [ "Integrated disinfection by-products research: assessing reproductive and developmental risks posed by complex disinfection by-product mixtures. This article presents a toxicologically-based risk assessment strategy for identifying the individual components or fractions of a complex mixture that are associated with its toxicity. The strategy relies on conventional component-based mixtures risk approaches such as dose addition, response addition, and analyses of interactions. Developmental toxicity data from two drinking-water concentrates containing disinfection by-products (DBP) mixtures were used to illustrate the strategy. The results of this study showed that future studies of DBP concentrates using the Chernoff-Kavlock bioassay need to consider evaluating DBP that are concentrated more than 130-fold and using a rat strain that is more sensitive to chemically-induced pregnancy loss than Sprague-Dawley rats. The results support the planned experimental design of a multigeneration reproductive and developmental study of DBP concentrates. Finally, this article discusses the need for a systematic evaluation of DBP concentrates obtained from multiple source waters and treatment types. The development of such a database could be useful in evaluating whether a specific DBP concentrate is sufficiently similar to tested combinations of source waters and treatment alternatives so that health risks for the former may be estimated using data on the latter." ], "offsets": [ [ 0, 1472 ] ] } ]

[ { "id": "entity-14-0", "type": "ADVERSE", "text": [ "Developmental toxicity" ], "offsets": [ [ 480, 502 ] ], "normalized": [] } ]

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[ { "id": "passage-15", "type": "abstract", "text": [ "Chemoprevention in postmenopausal women. Several large, prospective trials have evaluated tamoxifen compared with placebo for breast cancer risk reduction in women at increased risk of breast cancer. Combined results from these trials demonstrate that tamoxifen at 20 mg/d reduced the incidence of breast cancer by 38%. The risk of developing breast cancer is the primary determinant of net benefit, with greater benefits accrued to women with the highest risk of breast cancer. Age and the presence of risk factors for increased toxicity also have an effect on the net benefit associated with tamoxifen. The greatest clinical benefit from tamoxifen is evident for younger women who are at lower risk of thromboembolic complications and uterine cancer, women without a uterus, and women with breast biopsy results indicative of atypical hyperplasia or lobular carcinoma in situ. Raloxifene has also been shown to reduce the risk of invasive breast cancer in women with osteoporosis and is as effective as tamoxifen for reducing the risk of invasive breast cancer in postmenopausal women at increased risk of breast cancer. In high-risk younger, postmenopausal women, raloxifene seems to offer a net benefit when comparing the reduction of risk of breast cancer and prevention of fractures with the risk of stroke, venous thromboembolic events, uterine events, and symptomatic side effects. Raloxifene offers an acceptable option for breast cancer risk reduction in postmenopausal women." ], "offsets": [ [ 0, 1487 ] ] } ]

[ { "id": "entity-15-0", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 127, 140 ] ], "normalized": [] }, { "id": "entity-15-1", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 186, 199 ] ], "normalized": [] }, { "id": "entity-15-2", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 299, 312 ] ], "normalized": [] }, { "id": "entity-15-3", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 344, 357 ] ], "normalized": [] }, { "id": "entity-15-4", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 465, 478 ] ], "normalized": [] }, { "id": "entity-15-5", "type": "DISEASE", "text": [ "thromboembolic complications" ], "offsets": [ [ 705, 733 ] ], "normalized": [] }, { "id": "entity-15-6", "type": "DISEASE", "text": [ "uterine cancer" ], "offsets": [ [ 738, 752 ] ], "normalized": [] }, { "id": "entity-15-7", "type": "DISEASE", "text": [ "atypical hyperplasia" ], "offsets": [ [ 829, 849 ] ], "normalized": [] }, { "id": "entity-15-8", "type": "DISEASE", "text": [ "lobular carcinoma" ], "offsets": [ [ 853, 870 ] ], "normalized": [] }, { "id": "entity-15-9", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 942, 955 ] ], "normalized": [] }, { "id": "entity-15-10", "type": "DISEASE", "text": [ "osteoporosis" ], "offsets": [ [ 970, 982 ] ], "normalized": [] }, { "id": "entity-15-11", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 1050, 1063 ] ], "normalized": [] }, { "id": "entity-15-12", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 1109, 1122 ] ], "normalized": [] }, { "id": "entity-15-13", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 1248, 1261 ] ], "normalized": [] }, { "id": "entity-15-14", "type": "ADVERSE", "text": [ "stroke" ], "offsets": [ [ 1307, 1313 ] ], "normalized": [] }, { "id": "entity-15-15", "type": "ADVERSE", "text": [ "venous thromboembolic events" ], "offsets": [ [ 1315, 1343 ] ], "normalized": [] }, { "id": "entity-15-16", "type": "ADVERSE", "text": [ "uterine events" ], "offsets": [ [ 1345, 1359 ] ], "normalized": [] }, { "id": "entity-15-17", "type": "ADVERSE", "text": [ "symptomatic side effects" ], "offsets": [ [ 1365, 1389 ] ], "normalized": [] }, { "id": "entity-15-18", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 1434, 1447 ] ], "normalized": [] } ]

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[ { "id": "passage-16", "type": "abstract", "text": [ "DNA damage and repair detected by the comet assay in lymphocytes of african petrol attendants: a pilot study. Petrol attendants are exposed to petrol volatile organic compounds (VOCs) which may have genotoxic and carcinogenic effects. The single-cell gel electrophoresis assay (comet assay) is a method highly sensitive to DNA damage induced by environmental and occupational exposure to carcinogenic and mutagenic agents. The aim of this study was to evaluate the level of exposure of petrol attendants to petrol VOCs and also to determine their effect on DNA damage and repair in lymphocytes of African petrol attendants. The exposed group consisted of 20 subjects, randomly selected from three petrol stations. A control group of 20 unexposed subjects was also chosen and matched for age and smoking habits with the exposed group. Sorbent tubes were used to assess personal exposure of petrol attendants. The comet assay was used to investigate the basal DNA damage and repair capacity in isolated lymphocytes of petrol attendants and unexposed subjects. Blood samples were taken from the petrol attendants at the end of their 8-h working shift and also from the unexposed subjects. The petrol attendants were found to be exposed to levels of petrol VOCs lower than the South African occupational exposure limit for constituent chemicals. A significant relationship was found between the volume of petrol sold during the shift and the average concentrations of benzene, toluene and the total VOCs measured. However, relative humidity had a negative correlation with the average concentrations of benzene, toluene, xylene and the total VOCs. Significantly higher basal DNA damage was observed with the exposed group compared to the unexposed group. The period of exposure influenced the level of DNA damage and the calculated repair capacity. Smoking and age had a significant influence on the level of DNA damage. DNA repair capacity was delayed in smokers of both exposed and unexposed group." ], "offsets": [ [ 0, 1997 ] ] } ]

[ { "id": "entity-16-0", "type": "ADVERSE", "text": [ "carcinogenic effects" ], "offsets": [ [ 214, 234 ] ], "normalized": [] } ]

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[ { "id": "passage-17", "type": "abstract", "text": [ "Menorrhagia and severe menstrual pain related to the use of adalimumab in a psoriatic. The case is reported of a 32-year-old morbidly obese white woman who used adalimumab 40 mg every other week for 4 months for psoriatic arthritis, psoriasis vulgaris and inverse psoriasis with total clearance of her psoriasis who developed menorrhagia (at least twice the number of pads used daily for 4-6 days as opposed to 3-5 days previously) and severe menstrual pain. Treatment with Aviane (ethinyl estradiol and levonorgestrel) abated some of these menstrual symptoms. The symptoms resolved altogether when the adalimumab was discontinued. Menstrual disorders are listed as possible side effects from the use of infliximab and adalimumab in their respective package inserts and also for adalimumab and etanercept in the United Kingdom's Medicines and Healthcare products Regulatory Agency's drug side-effect database, but few case reports of menstrual side effects exist from including tumor necrosis alpha (TNFalpha) blockers. Physicians should be aware of the menstrual side effects of adalimumab and the role of oral contraceptive pills in treating such menstrual side effects." ], "offsets": [ [ 0, 1173 ] ] } ]

[ { "id": "entity-17-0", "type": "ADVERSE", "text": [ "Menorrhagia" ], "offsets": [ [ 0, 11 ] ], "normalized": [] }, { "id": "entity-17-1", "type": "ADVERSE", "text": [ "menstrual pain" ], "offsets": [ [ 23, 37 ] ], "normalized": [] }, { "id": "entity-17-2", "type": "DISEASE", "text": [ "psoriatic arthritis" ], "offsets": [ [ 213, 232 ] ], "normalized": [] }, { "id": "entity-17-3", "type": "DISEASE", "text": [ "psoriasis vulgaris" ], "offsets": [ [ 234, 252 ] ], "normalized": [] }, { "id": "entity-17-4", "type": "DISEASE", "text": [ "inverse psoriasis" ], "offsets": [ [ 257, 274 ] ], "normalized": [] }, { "id": "entity-17-5", "type": "DISEASE", "text": [ "psoriasis" ], "offsets": [ [ 303, 312 ] ], "normalized": [] }, { "id": "entity-17-6", "type": "ADVERSE", "text": [ "menorrhagia" ], "offsets": [ [ 327, 338 ] ], "normalized": [] }, { "id": "entity-17-7", "type": "ADVERSE", "text": [ "menstrual pain" ], "offsets": [ [ 444, 458 ] ], "normalized": [] }, { "id": "entity-17-8", "type": "ADVERSE", "text": [ "menstrual symptoms" ], "offsets": [ [ 542, 560 ] ], "normalized": [] }, { "id": "entity-17-9", "type": "ADVERSE", "text": [ "menstrual side effects" ], "offsets": [ [ 935, 957 ] ], "normalized": [] }, { "id": "entity-17-10", "type": "ADVERSE", "text": [ "menstrual side effects" ], "offsets": [ [ 1055, 1077 ] ], "normalized": [] }, { "id": "entity-17-11", "type": "ADVERSE", "text": [ "menstrual side effects" ], "offsets": [ [ 1150, 1172 ] ], "normalized": [] } ]

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[ { "id": "passage-18", "type": "abstract", "text": [ "Effects of stratification on data mining in the US Vaccine Adverse Event Reporting System (VAERS). BACKGROUND: Vaccines are administered differentially according to age and sex, and disease patterns also vary among people of different age and sex groups. Estimates of disproportionality should be calculated based on comparisons of groups that have a similar likelihood of receiving similar vaccines and experiencing similar adverse events, to prevent false disproportionality from occurring. Stratified empirical Bayesian (EB) methods have been compared with crude, but not stratified, proportional reporting ratios (PRRs) in their performance on adverse event data. OBJECTIVES: (i) to implement stratification of PRR; (ii) to quantify and compare vaccine-event pairs that are highlighted by PRR and EB05 (the lower bound of the 90% CI of the EB geometric mean), for both crude and stratified; and (iii) to evaluate the effects of stratification by age and sex, in identifying adverse events that are accepted to be caused by vaccines. METHODS: We applied EB and PRR data mining methods to data from the US Vaccine Adverse Event Reporting System (VAERS). We stratified PRR and EB05 by age and sex. To study the effects of stratification, we compared the crude PRR and stratified PRR. We also assessed the crude EB05 and stratified EB05, and then compared the effects of stratification on EB05 and PRR. RESULTS: Stratification not only changed the number of vaccine-event pairs that were highlighted, but also changed which pairs were highlighted. There were 283 vaccine-event pairs that were highlighted by the crude EB05, but not the stratified; 12 that were highlighted by the stratified EB05, but not the crude; and 162 that were highlighted by both. Similarly, there were 701 vaccine-event pairs that were highlighted by the crude PRR, but not the stratified; 139 that were highlighted by the stratified PRR, but not the crude; and 895 that were highlighted by both. There were 1466 vaccine-event pairs in which the effect of stratification was different for EB05 and PRR. CONCLUSION: To our knowledge, this is the first published analysis using stratified PRRs. In this analysis of passive surveillance data, stratification revealed and reduced confounding in EB and PRR, and also unmasked some vaccine-event pairs that the crude values did not highlight. Stratification should be applied if confounding is suspected. By decreasing the total number of highlighted vaccine-event pairs, stratification is likely to increase efficiency and therefore might reduce workload." ], "offsets": [ [ 0, 2576 ] ] } ]

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[ { "id": "passage-19", "type": "abstract", "text": [ "Brain development: anatomy, connectivity, adaptive plasticity, and toxicity. The developing brain is inherently more vulnerable to injury than the adult brain because brain development is extraordinarily complex, with periods of unique susceptibility. When brain developmental processes are suspended or delayed by any external influence, virtually no potential exists for subsequent regeneration and repair. This inevitably leads to long-lasting or permanent consequences. Recent genetic studies have contributed to a better understanding of the dynamic adaptive changes that occur in the developing brain as a consequence of genetic and environmental processes. Many industrial and environmental chemicals such as lead, methyl-mercury, polychlorinated biphenyls, arsenic, and toluene are recognized causes of neurodevelopmental disorders that lead to clinical or subclinical brain dysfunction. A number of these developmental disabilities arise from interactions between environmental factors and individual gene susceptibility. In addition, neurodevelopmental disorders of unknown origin, such as mental retardation, attention deficit disorder, cerebral palsy, and autism are becoming increasingly prevalent, with costly consequences for the family and society. The aim of this review is examine brain developmental anatomy, connectivity, adaptive plasticity, and toxicity in the context of current knowledge and future trends." ], "offsets": [ [ 0, 1431 ] ] } ]

[ { "id": "entity-19-0", "type": "ADVERSE", "text": [ "neurodevelopmental disorders" ], "offsets": [ [ 812, 840 ] ], "normalized": [] }, { "id": "entity-19-1", "type": "ADVERSE", "text": [ "subclinical brain dysfunction" ], "offsets": [ [ 866, 895 ] ], "normalized": [] }, { "id": "entity-19-2", "type": "DISEASE", "text": [ "neurodevelopmental disorders" ], "offsets": [ [ 1045, 1073 ] ], "normalized": [] }, { "id": "entity-19-3", "type": "DISEASE", "text": [ "mental retardation" ], "offsets": [ [ 1101, 1119 ] ], "normalized": [] }, { "id": "entity-19-4", "type": "DISEASE", "text": [ "attention deficit disorder" ], "offsets": [ [ 1121, 1147 ] ], "normalized": [] }, { "id": "entity-19-5", "type": "DISEASE", "text": [ "cerebral palsy" ], "offsets": [ [ 1149, 1163 ] ], "normalized": [] }, { "id": "entity-19-6", "type": "DISEASE", "text": [ "autism" ], "offsets": [ [ 1169, 1175 ] ], "normalized": [] } ]

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[ { "id": "passage-20", "type": "abstract", "text": [ "Impact of different anticancer regimens on biomarkers of angiogenesis in patients with advanced hepatocellular cancer. OBJECTIVE: Advanced hepatocellular cancer (HCC) is a highly vascularised tumor with limited treatment options. We wanted to evaluate the impact of different treatments on systemic biomarkers linked to angiogenesis. METHODS: Two subsequent prospective, randomised, phase-I/II trials in patients with advanced HCC were performed. A total of 38 patients was randomised to a total of 4 regimens consisting of 3 cycles of 4 weeks each: Trial 1 included group 1 receiving octreotide 30 mg im on day 1, and group 2 octreotide 30 mg on day 1 plus Imatinib 400 mg po daily; Trial 2 included group 3 with oxaliplatin on day 1 (60 mg-90 mg/m(2)), and group 4 with oxaliplatin on day 1, 8, 15 (20 mg-30 mg/m(2)) in combination with octreotide 30 mg on day 1 plus imatinib 400 mg po daily. Primary outcome measure was the relative changes in plasma biomarkers over time. RESULTS: Time-to-progression and overall survival was not different between the the two study trials. Within group 1-4, the mean relative increase from baseline to week 12 of treatment was 17, 18, 37, and 2% for s-E-selectin; -1, 90, 10, and -9% for VEGF-A; 18, 84, 141, and 74% for PDGF-BB, and 111, 142, 30, and 7% for serum AFP, respectively. CONCLUSIONS: The increase of plasma levels for s-E-selectin and PDGF-BB seen in patients receiving chemotherapy alone may reflect activation of angiogenesis. In contrast, low-dose metronomic chemotherapy in combination with anti-angiogenic drugs seems to correlate with the least increase in biomarkers. Imatinib-octreotide temporarily leads to a decrease in PDGF-BB, whereas octreotide alone had no effect on PDGF-BB plasma levels." ], "offsets": [ [ 0, 1756 ] ] } ]

[ { "id": "entity-20-0", "type": "DISEASE", "text": [ "hepatocellular cancer" ], "offsets": [ [ 96, 117 ] ], "normalized": [] }, { "id": "entity-20-1", "type": "DISEASE", "text": [ "hepatocellular cancer" ], "offsets": [ [ 140, 161 ] ], "normalized": [] }, { "id": "entity-20-2", "type": "DISEASE", "text": [ "HCC" ], "offsets": [ [ 163, 166 ] ], "normalized": [] }, { "id": "entity-20-3", "type": "DISEASE", "text": [ "HCC" ], "offsets": [ [ 428, 431 ] ], "normalized": [] } ]

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[ { "id": "passage-21", "type": "abstract", "text": [ "In vitro investigation of oxide nanoparticle and carbon nanotube toxicity and intracellular accumulation in A549 human pneumocytes. If released in the environment, nanomaterials might be inhaled by populations and cause damage to the deepest regions of the respiratory tract, i.e., the alveolar compartment. To model this situation, we studied the response of A549 human pneumocytes after exposure to aluminium oxide or titanium oxide nanoparticles, and to multi-walled carbon nanotubes. The influence of size, crystalline structure and chemical composition was investigated. After a detailed identification of nanomaterial physico-chemical characteristics, cells were exposed in vitro and viability and intracellular accumulation were assessed. In our conditions, carbon nanotubes were more toxic than metal oxide nanoparticles. Our results confirmed that both nanotubes and nanoparticles are able to rapidly enter into cells, and distribute in the cytoplasm and intracellular vesicles. Among nanoparticles, we demonstrate significant difference in biological response as a function of size, crystalline phase and chemical composition. Their toxicity was globally lower than nanotubes toxicity. Among nanotubes, the length did not influence cytotoxicity, neither the presence of metal catalyst impurities." ], "offsets": [ [ 0, 1307 ] ] } ]

[ { "id": "entity-21-0", "type": "ADVERSE", "text": [ "nanotubes toxicity" ], "offsets": [ [ 1177, 1195 ] ], "normalized": [] }, { "id": "entity-21-1", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 1243, 1255 ] ], "normalized": [] } ]

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[ { "id": "passage-22", "type": "abstract", "text": [ "Points to consider on the non-clinical safety evaluation of anticancer drugs. Since malignant tumors are life-threatening, the death rate from these diseases is high, and existing therapies have limited effectiveness, it is desired to provide new effective anticancer drugs to tumor patients sooner. However, there is no guideline regarding non-clinical safety studies on the development of anticancer drugs required for the first in human clinical trials and for the approval applications in Japan. Then, the Ministry of Health, Labour and Welfare (MHLW) established the collaboration group including regulatory, academic and industrial scientists to prepare the guideline on the non-clinical safety evaluation of anticancer drugs in 2004. As a guide for basic concept of non-clinical safety studies on anticancer drugs, the \"Points to Consider\" document was prepared by this group in 2007." ], "offsets": [ [ 0, 892 ] ] } ]

[ { "id": "entity-22-0", "type": "DISEASE", "text": [ "malignant tumors" ], "offsets": [ [ 85, 101 ] ], "normalized": [] } ]

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[ { "id": "passage-23", "type": "abstract", "text": [ "Delivery of daunorubicin to cancer cells with decreased toxicity by association with a lipidic nanoemulsion that binds to LDL receptors. A lipidic nanoemulsion termed LDE concentrates in neoplastic cells after injection into the bloodstream and thus can be used as a drug carrier to tumour sites. The chemotherapeutic agent daunorubicin associates poorly with LDE; the aim of this study was to clarify whether the derivatization of daunorubicin by the attachment of an oleyl group increases the association with LDE, and to test the cytotoxicity and animal toxicity of the new preparation. The association of oleyl-daunorubicin (oDNR) to LDE showed high yield (93 +/- 2% and 84 +/- 4% at 1:10 and 1:5 drug:lipid mass, respectively) and was stable for at least 20 days. Association with oDNR increased the LDE particle diameter from 42 +/- 4 nm to 75 +/- 6 nm. Cytotoxicity of LDE-oDNR was reduced two-fold in HL-60 and K-562 cell lines, fourteen-fold in B16 cells and nine-fold in L1210 cells when compared with commercial daunorubicin. When tested in mice, LDE-oDNR showed remarkable reduced toxicity (maximum tolerated dose > 253 micromol kg(-1), compared with <3 micromol kg(-1) for commercial daunorubicin). At high doses, the cardiac tissue of LDE-oDNR-treated animals had much smaller structural lesions than with commercial daunorubicin. LDE-oDNR is therefore a promising new preparation that may offer superior tolerability compared with commercial daunorubicin." ], "offsets": [ [ 0, 1471 ] ] } ]

[ { "id": "entity-23-0", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 534, 546 ] ], "normalized": [] }, { "id": "entity-23-1", "type": "ADVERSE", "text": [ "animal toxicity" ], "offsets": [ [ 551, 566 ] ], "normalized": [] } ]

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[ { "id": "passage-24", "type": "abstract", "text": [ "The novel cholinesterase-monoamine oxidase inhibitor and antioxidant, ladostigil, confers neuroprotection in neuroblastoma cells and aged rats. The current therapeutic advance in which future drugs are designed to possess varied pharmacological properties and act on multiple targets has stimulated the development of the multimodal drug, ladostigil (TV3326; (N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase (MAO)-A and MAO-B and cholinesterase (ChE) inhibitory activities in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy body disease. In the present study, we demonstrate that ladostigil (10(-6)-10 muM) dose-dependently increased cell viability, associated with increased activity of catalase and glutathione reductase and decrease of intracellular reactive oxygen species production in a cytotoxic model of human SH-SY5Y neuroblastoma cells exposed to hydrogen peroxide (H(2)O(2)). In addition, ladostigil significantly upregulated mRNA levels of several antioxidant enzymes (catalase, NAD(P)H quinone oxidoreductase 1 and peroxiredoxin 1) in both H(2)O(2)-treated SH-SY5Y cells, as well as in the high-density human SK-N-SH neuroblastoma cultured apoptotic models. In vivo chronic treatment with ladostigil (1 mg/kg per os per day for 30 days) markedly upregulated mRNA expression levels of various enzymes involved in metabolism and oxidation processes in aged rat hippocampus. In addition to its unique combination of ChE and MAO enzyme inhibition, these results indicate that ladostigil displays neuroprotective activity against oxidative stress-induced cell apoptosis, which might be valuable for aging and age-associated neurodegenerative diseases." ], "offsets": [ [ 0, 1771 ] ] } ]

[ { "id": "entity-24-0", "type": "DISEASE", "text": [ "Alzheimer's disease" ], "offsets": [ [ 602, 621 ] ], "normalized": [] }, { "id": "entity-24-1", "type": "DISEASE", "text": [ "AD" ], "offsets": [ [ 623, 625 ] ], "normalized": [] }, { "id": "entity-24-2", "type": "DISEASE", "text": [ "Lewy body disease" ], "offsets": [ [ 631, 648 ] ], "normalized": [] }, { "id": "entity-24-3", "type": "DISEASE", "text": [ "neurodegenerative diseases" ], "offsets": [ [ 1744, 1770 ] ], "normalized": [] } ]

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[ { "id": "passage-25", "type": "abstract", "text": [ "High dose chemotherapy and autologous stem cell transplantation in patients with multiple myeloma: the experience of a single haematological unit. PURPOSE: To study the toxicity of high dose chemotherapy (HDCT) in multiple myeloma (MM) patients and its impact on event free survival (EFS) and overall survival (OS), and also the impact of thalidomide maintenance therapy on EFS and OS after HDCT. PATIENTS AND METHODS: From April 1999 to November 2006 37 patients (29 males, 8 females) out of a total of 38 scheduled were treated with HDCT and autologous peripheral stem cell transplantation (APSCT), as consolidation treatment after first- or second-line chemotherapy. Their median age was 55 years (range 38-71). HDCT regimen used was melphalan 200 mg/m(2). Following HDCT thalidomide 100 mg/day was administered as maintenance therapy to 28 patients in a random fashion. RESULTS: All patients tolerated well HDCT and APSCT. There was no treatment-related mortality. The median time interval for neutrophil recovery (>500/mm(3)) was 10 days (range 8-20), while the median time interval for platelets to recover to >20.000/mm(3) was 14 days (range 9-32). Twenty (54%) patients achieved complete response (CR), 15 (40%) partial response (PR), and 2 (6%) stable disease (SD). Before receiving thalidomide as maintenance treatment 12 (42%) patients were in CR, while all the others, except one who had progressive disease (PD), were in PR. CR correlated with better EFS and probably OS. Thalidomide maintenance treatment correlated with better EFS. CONCLUSION: In our series of patients HDCT appears to be a totally feasible, safe and without treatment-related mortality procedure, even in patients older than 60 years of age. It has a major impact in terms of CR achievement, which seems to strongly correlate with a prolonged EFS and OS. The use of thalidomide as a maintenance therapy induces a greater EFS which could possibly yield an improved OS." ], "offsets": [ [ 0, 1951 ] ] } ]

[ { "id": "entity-25-0", "type": "DISEASE", "text": [ "multiple myeloma" ], "offsets": [ [ 81, 97 ] ], "normalized": [] }, { "id": "entity-25-1", "type": "DISEASE", "text": [ "multiple myeloma" ], "offsets": [ [ 215, 231 ] ], "normalized": [] }, { "id": "entity-25-2", "type": "DISEASE", "text": [ "MM" ], "offsets": [ [ 233, 235 ] ], "normalized": [] } ]

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[ { "id": "passage-26", "type": "abstract", "text": [ "Clinical and radiological features of brain neurotoxicity caused by antitumor and immunosuppressant treatments. Antitumor and immunosuppressant treatment-related neurotoxicity can determine nonspecific clinical syndromes. Exclusion of other possible causes, among which tumor progression, appearance of paraneoplastic disease, renal or hepatic failure, diabetes or hypertension, is relevant. We report clinical and neuroradiological features in five patients with neurotoxic syndromes due to chemotherapy/radiotherapy or immunosuppression in the context of neoplastic disease/organ transplantation. Acute neurological syndrome developed in three patients after methotrexate (MTX), cyclosporine A, and L-asparaginase therapy, respectively. MRI showed posterior reversible encephalopathy in two cases and venous thrombosis with intraparenchymal hematoma in the third patient. Late onset clinical syndrome occurred in the last two patients, treated with MTX or radiation therapy for breast cancer metastasis and pituitary adenoma. Neuroimaging showed brain diffuse abnormalities. Patients affected by tumors suffer from increased risk for treatment-related toxicities. Appearance or worsening of neurological signs and symptoms challenge the clinician to discriminate between CNS involvement by the tumor, toxicity of drugs, parane-oplastic disease and infections. MRI has a key role in differential diagnosis. Close interaction between the neurologist, the oncologist and the neuroradiologist leads to the optimal management of patients." ], "offsets": [ [ 0, 1536 ] ] } ]

[ { "id": "entity-26-0", "type": "ADVERSE", "text": [ "brain neurotoxicity" ], "offsets": [ [ 38, 57 ] ], "normalized": [] }, { "id": "entity-26-1", "type": "ADVERSE", "text": [ "neurotoxicity" ], "offsets": [ [ 163, 176 ] ], "normalized": [] }, { "id": "entity-26-2", "type": "ADVERSE", "text": [ "tumor progression" ], "offsets": [ [ 271, 288 ] ], "normalized": [] }, { "id": "entity-26-3", "type": "ADVERSE", "text": [ "paraneoplastic disease" ], "offsets": [ [ 304, 326 ] ], "normalized": [] }, { "id": "entity-26-4", "type": "ADVERSE", "text": [ "hepatic failure" ], "offsets": [ [ 337, 352 ] ], "normalized": [] }, { "id": "entity-26-5", "type": "ADVERSE", "text": [ "diabetes" ], "offsets": [ [ 354, 362 ] ], "normalized": [] }, { "id": "entity-26-6", "type": "ADVERSE", "text": [ "hypertension" ], "offsets": [ [ 366, 378 ] ], "normalized": [] }, { "id": "entity-26-7", "type": "ADVERSE", "text": [ "neurotoxic syndromes" ], "offsets": [ [ 465, 485 ] ], "normalized": [] }, { "id": "entity-26-8", "type": "ADVERSE", "text": [ "Acute neurological syndrome" ], "offsets": [ [ 600, 627 ] ], "normalized": [] }, { "id": "entity-26-9", "type": "ADVERSE", "text": [ "posterior reversible encephalopathy" ], "offsets": [ [ 751, 786 ] ], "normalized": [] }, { "id": "entity-26-10", "type": "ADVERSE", "text": [ "venous thrombosis" ], "offsets": [ [ 804, 821 ] ], "normalized": [] }, { "id": "entity-26-11", "type": "ADVERSE", "text": [ "intraparenchymal hematoma" ], "offsets": [ [ 827, 852 ] ], "normalized": [] }, { "id": "entity-26-12", "type": "DISEASE", "text": [ "breast cancer metastasis" ], "offsets": [ [ 981, 1005 ] ], "normalized": [] }, { "id": "entity-26-13", "type": "DISEASE", "text": [ "pituitary adenoma" ], "offsets": [ [ 1010, 1027 ] ], "normalized": [] }, { "id": "entity-26-14", "type": "DISEASE", "text": [ "tumors" ], "offsets": [ [ 1099, 1105 ] ], "normalized": [] } ]

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[ { "id": "passage-27", "type": "abstract", "text": [ "Drotrecogin alfa (activated) in the treatment of severe sepsis. Severe sepsis and septic shock are common in the critically ill patient and account for considerable morbidity and mortality not to mention the high associated costs. Advances in our understanding of sepsis pathophysiology and in the important link between the inflammatory response to sepsis and activation of coagulation led to the development and licensing of the first ever, specific, immunomodulatory anti-sepsis drug. Drotrecogin alfa (activated), a recombinant version of activated protein C, was shown in a large randomized controlled clinical trial to reduce mortality rates from 30.8% in the placebo group to 24.7% in the treatment group, which equated to one additional life saved for every 16 patients treated. Vasopressor requirements and duration of mechanical ventilation were also reduced. Apart from an expected increased risk of severe bleeding, mostly associated with interventions, drotrecogin alfa (activated) was not associated with any other adverse reactions. In this article, I will briefly summarize the events leading to the development of drotrecogin alfa (activated) including aspects of sepsis epidemiology and pathophysiology and the results of early animal and clinical studies. The results of the large multicenter phase III PROWESS study will then be reviewed, along with results from subsequent open-label studies. Finally, I will focus on the key side effect issue with drotrecogin alfa (activated), that of increased bleeding, drawing data from the available clinical studies, and highlighting the contraindications and precautions when prescribing this drug." ], "offsets": [ [ 0, 1661 ] ] } ]

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[ { "id": "passage-28", "type": "abstract", "text": [ "Current regulatory toxicology perspectives on the development of herbal medicines to prescription drug products in the United States. Toxicological studies constitute an essential part of the effort in developing an herbal medicine into a drug product. The US food and drug administration (FDA) published a guidance to assist academic and industry sponsors in the development of this unique group of drug products, and has recently approved an new drug application (NDA) based on green tea extract (Veregen) for topical treatment of genital and perianal warts. In this article, current regulatory views on issues related to requirements and recommendations on various types of nonclinical toxicity studies in support of clinical trials and filing an NDA for a herbal medicine, including pharm/tox aspects of green tea extract (Veregen) NDA, are discussed. Topics include nonclinical pharmacology/toxicology perspectives on herbal nomenclature and its identification, previous human experience and initial clinical trial proposal, regulatory aspects of acute toxicity studies, chronic toxicity studies, mutagenicity studies, reproductive toxicity studies, and carcinogenicity studies on botanicals. Certain regulatory review-related issues are also presented. It is anticipated that through a proactive two-way communication between the Agency and the sponsor, toxicological development of botanical drug product can be significantly facilitated." ], "offsets": [ [ 0, 1446 ] ] } ]

[ { "id": "entity-28-0", "type": "DISEASE", "text": [ "perianal warts" ], "offsets": [ [ 546, 560 ] ], "normalized": [] }, { "id": "entity-28-1", "type": "ADVERSE", "text": [ "acute toxicity" ], "offsets": [ [ 1053, 1067 ] ], "normalized": [] }, { "id": "entity-28-2", "type": "ADVERSE", "text": [ "chronic toxicity" ], "offsets": [ [ 1077, 1093 ] ], "normalized": [] }, { "id": "entity-28-3", "type": "ADVERSE", "text": [ "mutagenicity" ], "offsets": [ [ 1103, 1115 ] ], "normalized": [] }, { "id": "entity-28-4", "type": "ADVERSE", "text": [ "reproductive toxicity" ], "offsets": [ [ 1125, 1146 ] ], "normalized": [] }, { "id": "entity-28-5", "type": "ADVERSE", "text": [ "carcinogenicity" ], "offsets": [ [ 1160, 1175 ] ], "normalized": [] } ]

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[ { "id": "passage-29", "type": "abstract", "text": [ "Genotoxicity of topoisomerase II inhibitors: an anti-infective perspective. At present, an inevitable consequence of a chemical's inhibitory activity on key regulators of DNA topology in bacteria, the type II topoisomerases, is a less pronounced effect on their eukaryotic counterparts. In the context of anti-infectives drug development, this may pose a risk to patient safety as inhibition of eukaryotic type II topoisomerases (TOPO II) can result in the generation of DNA double-strand breaks (DSBs), which have the potential to manifest as mutations, chromosome breakage or cell death. The biological effects of several TOPO II inhibitors in mammalian cells are described herein; their modulation of DSB damage response parameters is examined and evidence for the existence of a threshold concept for genotoxicity and its relevance in safety assessment is discussed. The potential utility of gammaH2AX, a promising and highly sensitive molecular marker for DSBs, in a novel genotoxicity 'pre-screen' to conventional assays is also highlighted." ], "offsets": [ [ 0, 1048 ] ] } ]

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[ { "id": "passage-30", "type": "abstract", "text": [ "Study of cytotoxic and apoptogenic properties of saffron extract in human cancer cell lines. Saffron (dried stigmas of Crocus sativus L.) has been used as a spice, food colorant and medicinal plant for millennia. In this study cytotoxic effect of saffron extract was evaluated in HepG2 and HeLa cell lines. Meanwhile role of apoptosis and ROS were explored. Malignant and non-malignant cells (L929) were cultured in DMEM medium and incubated with different concentrations of ethanolic saffron extract. Cell viability was quantitated by MTT assay. Apoptotic cells were determined using PI staining of DNA fragmentation by flow cytometry (sub-G1 peak). ROS was measured using DCF-DA by flow cytometry analysis. Saffron could decrease cell viability in malignant cells as a concentration and time-dependent manner. The IC50 values against HeLa and HepG2 were determined 800 and 950 microg/ml after 48 h, respectively. Saffron induced a sub-G1 peak in flow cytometry histogram of treated cells compared to control indicating apoptotic cell death is involved in saffron toxicity. This toxicity was also independent of ROS production. It might be concluded that saffron could cause cell death in HeLa and HepG2 cells, in which apoptosis or programmed cell death plays an important role. Saffron could be also considered as a promising chemotherapeutic agent in cancer treatment in future." ], "offsets": [ [ 0, 1383 ] ] } ]

[ { "id": "entity-30-0", "type": "ADVERSE", "text": [ "cytotoxic effect" ], "offsets": [ [ 228, 244 ] ], "normalized": [] }, { "id": "entity-30-1", "type": "ADVERSE", "text": [ "saffron toxicity" ], "offsets": [ [ 1058, 1074 ] ], "normalized": [] }, { "id": "entity-30-2", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 1356, 1362 ] ], "normalized": [] } ]

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[ { "id": "passage-31", "type": "abstract", "text": [ "Synthesis of some pyrazolyl benzenesulfonamide derivatives as dual anti-inflammatory antimicrobial agents. Four series of pyrazolylbenzenesulfonamide derivatives were synthesized and evaluated for their anti-inflammatory activity using cotton pellet induced granuloma and carrageenan-induced rat paw edema bioassays. Moreover, COX-1 and COX-2 inhibitory activity, ulcerogenic effect and acute toxicity were also determined. Furthermore, the target compounds were screened for their in-vitro antimicrobial activity against Eischerichia coli, Staphylococcus aureus and Candida albicans. Compounds 4-(3-Phenyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9a and 4-(3-Tolyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9b were not only found to be the most active dual anti-inflammatory antimicrobial agents in the present study with good safety margin and minimal ulcerogenic effect but also exhibited good selective inhibitory activity towards COX-2. A docking pose for 9a and 9b separately in the active site of the human COX-2 enzyme was also obtained. Therefore, these compounds would represent a fruitful matrix for the development of dual anti-inflammatory antimicrobial candidates with remarkable COX-2 selectivity." ], "offsets": [ [ 0, 1216 ] ] } ]

[ { "id": "entity-31-0", "type": "ADVERSE", "text": [ "granuloma" ], "offsets": [ [ 259, 268 ] ], "normalized": [] }, { "id": "entity-31-1", "type": "ADVERSE", "text": [ "edema" ], "offsets": [ [ 301, 306 ] ], "normalized": [] }, { "id": "entity-31-2", "type": "ADVERSE", "text": [ "ulcerogenic effect" ], "offsets": [ [ 365, 383 ] ], "normalized": [] }, { "id": "entity-31-3", "type": "ADVERSE", "text": [ "acute toxicity" ], "offsets": [ [ 388, 402 ] ], "normalized": [] } ]

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[ { "id": "passage-32", "type": "abstract", "text": [ "Multicenter phase II study of capecitabine plus oxaliplatin as a first-line therapy in Chinese patients with advanced gastric cancer. The efficacy of chemotherapy for advanced gastric cancer with palliative intent compared with supportive care alone is now widely accepted. However, the survival advantage is small, and no internationally accepted standard regimen has emerged. This study is performed to evaluate the response rate, time to progression, and safety of the combination of capecitabine (1000 mg/m twice daily, days 1-14) plus oxaliplatin (130 mg/m as a 2-h intravenous infusion on day 1) every 3 weeks, in previously untreated Chinese patients with advanced gastric cancer. Sixty-five (95.6%) of the 68 patients were assessable for response. Three cases of complete response and 34 cases of partial response were confirmed, giving an overall response rate of 54.4% [95% confidence interval (CI), 42.6-66.2%]. The median time to progression and overall survival for all patients were 5.7 months (95% CI, 2.0-8.8 months) and 10.5 months (95% CI, 5.0-15.1 months). The most severe hematologic adverse event was neutropenia, which occurred with grade 3 intensity in three (4.6%) patients and grade 4 in one (1.5%) patient. Thrombocytopenia and leukopenia occurred with grade 3 intensity in five (7.7%) and three (4.6%) patients, respectively. However, no grade 4 thrombocytopenia and leukopenia were observed. Grade 1/2 nausea/vomiting and diarrhea were observed in 33 (50.8%), 17 (26.2%), 26 (40%), 44 (67.7%), and 13 (20%) patients, respectively, and grade 3 nausea/vomiting and diarrhea were observed in one (1.5%) and four (6.2%) patients. Yet, no grade 4 nonhematologic toxicity was observed. Capecitabine/oxaliplatin combination chemotherapy is active in Chinese patients with previously untreated advanced gastric cancer." ], "offsets": [ [ 0, 1839 ] ] } ]

[ { "id": "entity-32-0", "type": "DISEASE", "text": [ "gastric cancer" ], "offsets": [ [ 118, 132 ] ], "normalized": [] }, { "id": "entity-32-1", "type": "DISEASE", "text": [ "gastric cancer" ], "offsets": [ [ 177, 191 ] ], "normalized": [] }, { "id": "entity-32-2", "type": "DISEASE", "text": [ "gastric cancer" ], "offsets": [ [ 673, 687 ] ], "normalized": [] }, { "id": "entity-32-3", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1123, 1134 ] ], "normalized": [] }, { "id": "entity-32-4", "type": "ADVERSE", "text": [ "Thrombocytopenia" ], "offsets": [ [ 1234, 1250 ] ], "normalized": [] }, { "id": "entity-32-5", "type": "ADVERSE", "text": [ "leukopenia" ], "offsets": [ [ 1255, 1265 ] ], "normalized": [] }, { "id": "entity-32-6", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1374, 1390 ] ], "normalized": [] }, { "id": "entity-32-7", "type": "ADVERSE", "text": [ "leukopenia" ], "offsets": [ [ 1395, 1405 ] ], "normalized": [] }, { "id": "entity-32-8", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 1431, 1437 ] ], "normalized": [] }, { "id": "entity-32-9", "type": "ADVERSE", "text": [ "vomiting" ], "offsets": [ [ 1438, 1446 ] ], "normalized": [] }, { "id": "entity-32-10", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 1451, 1459 ] ], "normalized": [] }, { "id": "entity-32-11", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 1572, 1578 ] ], "normalized": [] }, { "id": "entity-32-12", "type": "ADVERSE", "text": [ "vomiting" ], "offsets": [ [ 1579, 1587 ] ], "normalized": [] }, { "id": "entity-32-13", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 1592, 1600 ] ], "normalized": [] }, { "id": "entity-32-14", "type": "ADVERSE", "text": [ "nonhematologic toxicity" ], "offsets": [ [ 1671, 1694 ] ], "normalized": [] }, { "id": "entity-32-15", "type": "DISEASE", "text": [ "gastric cancer" ], "offsets": [ [ 1824, 1838 ] ], "normalized": [] } ]

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[ { "id": "passage-33", "type": "abstract", "text": [ "Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. CONTEXT: Aberrant histone deacetylase activity is seen in a variety of malignancies, and histone deacetylase inhibitors such as vorinostat have been shown to induce cell death and sensitize cells to cytotoxic chemotherapy in thyroid cancer cell lines. This phase II study was undertaken to assess objective response to vorinostat in patients with advanced thyroid cancer. EXPERIMENTAL DESIGN: A total of 19 patients with differentiated thyroid cancer (n = 16) and medullary thyroid cancer (n = 3) were enrolled in the study. Patients received oral vorinostat at a starting dose of 200 mg twice daily, with dose adjustments allowed as necessary for toxicity. Patients were treated for 2 wk, followed by 1 wk off therapy (3-wk cycle) until disease progression or study withdrawal. Responses were measured by Response Evaluation Criteria in Solid Tumors criteria and correlated with tumor markers. RESULTS: No patient achieved a partial or complete response. Median duration of therapy in patients with differentiated thyroid cancer was 17 wk, whereas in medullary thyroid cancer patients it was 25 wk. Reasons for termination included progression of disease by RECIST criteria (n = 7), clinical progression (n = 3), and adverse events (AEs) (n = 9). AEs were primarily grade 1-3; no clinical grade 4 or grade 5 events were observed. Clinical grade 3 AEs consisted of fatigue, dehydration, ataxia, pneumonia, bruises, and deep vein thrombosis. Severe thrombocytopenia was seen in seven patients (grade 3, n = 5; grade 4, n = 2) and was associated with minor bleeding or bruises. CONCLUSIONS: Vorinostat at this dose and schedule is not an effective treatment for advanced thyroid cancer." ], "offsets": [ [ 0, 1830 ] ] } ]

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[ { "id": "passage-34", "type": "abstract", "text": [ "Cyclin D1 in excitatory neurons of the adult brain enhances kainate-induced neurotoxicity. G1-phase cyclin D1 (cD1) expression has been documented in post-mitotic neurons undergoing apoptosis, leading others to propose that attempted cell cycle re-entry may induce cell death. Here, cD1 immunoreactivity was found in a subpopulation of healthy excitatory neurons throughout the brain. Most striking was the selective cD1 expression in hippocampal pyramidal neurons, an especially vulnerable cell group. Seizure threshold, cD1 induction and CA1 neuron death were examined following application of kainate (KA) or pentylenetetrazole (PTZ) in cD1 heterozygous (+/-) and wildtype mice to determine whether baseline cD1 correlates with pathology. cD1+/- mice displayed resistance to KA, but not PTZ-induced seizures and had reduced or equivalent cytotoxicity respectively, compared with wildtype. KA administration, but not PTZ, induced cD1 expression. These findings suggest that basal cD1 expression may render hippocampal circuits more susceptible to particular epileptogenic agents and excitotoxic cell death, though cD1 is not a direct precipitant in apoptosis." ], "offsets": [ [ 0, 1162 ] ] } ]

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[ { "id": "passage-35", "type": "abstract", "text": [ "Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging." ], "offsets": [ [ 0, 1289 ] ] } ]

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[ { "id": "passage-36", "type": "abstract", "text": [ "Adapalene 0.1% and benzoyl peroxide 2.5% as a fixed-dose combination gel is as well tolerated as the individual components alone in terms of cumulative irritancy. International guidelines recommend the combination of retinoids (e.g. adapalene, tazarotene) and benzoyl peroxide for treating acne because of their complementary mechanisms of action. A new fixed-dose combination gel of adapalene 0.1% and benzoyl peroxide (BPO) 2.5% (adapalene/BPO*) is an effective acne treatment and offers the advantage of a once daily application. This paper reports the results of a cumulative irritancy study in healthy volunteers comparing adapalene/BPO to adapalene 0.1% and BPO 2.5% applied separately, BPO 10% gel, tazarotene 0.1% gel and the gel vehicle as a control.There was no significant difference between the mean cumulative irritation index (MCII) for adapalene/BPO and any test product except tazarotene 0.1% gel, which had a significantly greater MCII than all other test products (p < 0.05). This study showed that adapalene/BPO as a fixed-dose combination is as well tolerated as BPO 2.5% gel alone or adapalene 0.1% gel alone in terms of cumulative irritancy.*Epiduo, Galderma S.A." ], "offsets": [ [ 0, 1186 ] ] } ]

[ { "id": "entity-36-0", "type": "DISEASE", "text": [ "acne" ], "offsets": [ [ 291, 295 ] ], "normalized": [] }, { "id": "entity-36-1", "type": "DISEASE", "text": [ "acne" ], "offsets": [ [ 465, 469 ] ], "normalized": [] } ]

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[ { "id": "passage-37", "type": "abstract", "text": [ "Gene expression profiles in the cerebellum and hippocampus following exposure to a neurotoxicant, Aroclor 1254: developmental effects. The developmental consequences of exposure to the polychlorinated biphenyls (PCBs) have been widely studied, making PCBs a unique model to understand issues related to environmental mixture of persistent chemicals. PCB exposure in humans adversely affects neurocognitive development, causes psychomotor difficulties, and contributes to attention deficits in children, all of which seem to be associated with altered patterns of neuronal connectivity. In the present study, we examined gene expression profiles in the rat nervous system following PCB developmental exposure. Pregnant rats (Long-Evans) were dosed perinatally with 0 or 6 mg/kg/day of Aroclor 1254 from gestation day 6 through postnatal day (PND) 21. Gene expression in cerebellum and hippocampus from PND7 and PND14 animals was analyzed with an emphasis on developmental aspects. Changes in gene expression (> or =1.5 fold) in control animals identified normal developmental changes. These basal levels of expression were compared to data from Aroclor 1254-treated animals to determine the impact of gestational PCB exposure on developmental parameters. The results indicate that the expression of a number of developmental genes related to cell cycle, synaptic function, cell maintenance, and neurogenesis is significantly altered from PND7 to PND14. Aroclor 1254 treatment appears to dampen the overall growth-related gene expression levels in both regions with the effect being more pronounced in the cerebellum. Functional analysis suggests that Aroclor 1254 delays maturation of the developing nervous system, with the consequences dependent on the ontological state of the brain area and the functional role of the individual gene. Such changes may underlie learning and memory deficits observed in PCB exposed animals and humans." ], "offsets": [ [ 0, 1937 ] ] } ]

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[ { "id": "passage-38", "type": "abstract", "text": [ "Cognitive effects of hormone therapy in men with prostate cancer: a review. BACKGROUND: Men who receive androgen-deprivation therapy (ADT) for prostate cancer experience several side effects from this treatment. A few recent studies have examined the cognitive implications of ADT and how they impact a patient's treatment decision-making, occupational pursuits, and quality of life. For this report, the authors explored possible mechanisms for this association, reviewed research in animal studies and aging men, and examined the growing literature focused on the relation between ADT and cognitive functioning in patients with prostate cancer. METHODS: A systematic literature search was conducted using the PubMed and Information Sciences Institute Web of Knowledge-Web of Science databases to identify relevant studies that investigated the relation between ADT in men with prostate cancer and its cognitive effects. RESULTS: Testosterone and its derivatives may have an impact on cognition through several mechanisms in the brain, as supported by studies of animals and in aging men. Studies that researched the impact of ADT on cognition in patients with prostate cancer patients were designed relatively well but suffered from small sample sizes. Between 47% and 69% of men on ADT declined in at least 1 cognitive area, most commonly in visuospatial abilities and executive functioning. Some studies reported contradictory results with increased functioning in verbal memory. CONCLUSIONS: There is a strong argument that androgen-ablation therapy is linked to subtle but significant cognitive declines in men with prostate cancer. The authors believe that clinicians should become aware of this correlation as the use of ADT increases and should inform and monitor patients for this possible side effect of treatment." ], "offsets": [ [ 0, 1826 ] ] } ]

[ { "id": "entity-38-0", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 49, 64 ] ], "normalized": [] }, { "id": "entity-38-1", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 144, 159 ] ], "normalized": [] }, { "id": "entity-38-2", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 631, 646 ] ], "normalized": [] }, { "id": "entity-38-3", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 880, 895 ] ], "normalized": [] }, { "id": "entity-38-4", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 1163, 1178 ] ], "normalized": [] }, { "id": "entity-38-5", "type": "DISEASE", "text": [ "prostate cancer" ], "offsets": [ [ 1623, 1638 ] ], "normalized": [] } ]

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[ { "id": "passage-39", "type": "abstract", "text": [ "Paclitaxel and pegylated liposomal doxorubicin in recurrent head and neck cancer: clinical and unexpected pharmacokinetic interactions. BACKGROUND: The combination of paclitaxel (PTX) with pegylated liposomal doxorubicin (PLD) is an interesting treatment for recurrent head and neck cancer. The pharmacokinetic behavior may depend on the interval between the intravenous administration of the two drugs. This study evaluates the clinical efficacy, toxicity and any possible interval-dependent pharmacokinetic interactions. PATIENTS AND METHODS: Thirty patients were randomized to receive 80 mg/m2 PTX weekly and 12.5 mg/m2 PLD every two weeks at administration intervals of 0, 1, 3, 12 or 24 hours. Blood sampling was performed at day 1 and 15 and pharmacokinetics of PTX, PLD and Cremophor EL were evaluated by non-compartmental analysis. RESULTS: Neutropenia was the most frequent side-effect (100% of patients; 30% grade 3-4). Hand-foot syndrome was severe in only 3% of patients. Overall response rate was 30%, with 3% complete responses and 27% partial responses. Stable disease and progression were 43% and 27%, respectively. Median response duration and overall median survival were 5.5 and 10 months respectively. Co-administration of PLD markedly reduced Cmax and the area under the curve (AUC), and increased PTX clearance. The differences in the PTX AUC and clearance between the 0 h and the 24 h experimental arms were statistically significant. CONCLUSION: The PTX/PLD combination plays a palliative role (clinical benefit in 73% of patients) and has good tolerability. The PTX pharmacokinetic profile was unexpectedly affected by different administration time intervals; in the 0 h arm the AUC was reduced to one fourth, therefore a schedule with PTX on day one, PLD on day two may be preferred." ], "offsets": [ [ 0, 1810 ] ] } ]

[ { "id": "entity-39-0", "type": "DISEASE", "text": [ "recurrent head and neck cancer" ], "offsets": [ [ 50, 80 ] ], "normalized": [] }, { "id": "entity-39-1", "type": "DISEASE", "text": [ "recurrent head and neck cancer" ], "offsets": [ [ 260, 290 ] ], "normalized": [] }, { "id": "entity-39-2", "type": "ADVERSE", "text": [ "Neutropenia" ], "offsets": [ [ 850, 861 ] ], "normalized": [] }, { "id": "entity-39-3", "type": "ADVERSE", "text": [ "Hand-foot syndrome" ], "offsets": [ [ 931, 949 ] ], "normalized": [] } ]

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[ { "id": "passage-40", "type": "abstract", "text": [ "Denbinobin induces apoptosis by apoptosis-inducing factor releasing and DNA damage in human colorectal cancer HCT-116 cells. Denbinobin is a phenanthraquinone derivative present in the stems of Ephemerantha lonchophylla. We showed that denbinobin induces apoptosis in human colorectal cancer cells (HCT-116) in a concentration-dependent manner. The addition of a pan-caspase inhibitor (zVAD-fmk) did not suppress the denbinobin-induced apoptotic effect, and denbinobin-induced apoptosis was not accompanied by processing of procaspase-3, -6, -7, -9, and -8. However, denbinobin triggered the translocation of the apoptosis-inducing factor (AIF) from the mitochondria into the nucleus. Small interfering RNA targeting of AIF effectively protected HCT-116 cells against denbinobin-induced apoptosis. Denbinobin treatment also caused DNA damage, activation of the p53 tumor suppressor gene, and upregulation of numerous downstream effectors (p21WAF1/CIP1, Bax, PUMA, and NOXA). A HCT-116 xenograft model demonstrated the in vivo efficacy and low toxicity of denbinobin. Taken together, our findings suggest that denbinobin induces apoptosis of human colorectal cancer HCT-116 cells via DNA damage and an AIF-mediated pathway. These results indicate that denbinobin has potential as a novel anticancer agent." ], "offsets": [ [ 0, 1305 ] ] } ]

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[ { "id": "passage-41", "type": "abstract", "text": [ "Effect of treatment with epoetin-beta on survival, tumour progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomised controlled studies including 2301 patients. Epoetin-beta is used to treat patients with metastatic cancer undergoing chemotherapy to alleviate the symptoms of anaemia, reduce the risk of blood transfusions and improve quality of life. This meta-analysis of 12 randomised, controlled studies evaluated the impact of epoetin-beta on overall survival, tumour progression and thromboembolic events (TEEs). A total of 2297 patients were included in the analysis (epoetin-beta, n=1244; control, n=1053; 65% solid and 35% nonmyeloid haematological malignancies). A prespecified subgroup analysis assessed the effects in patients with a baseline Hb<or=11 g dl(-1), corresponding to current European Organisation for Research and Treatment of Cancer (EORTC) guidelines. No statistically significant effect on mortality was observed with epoetin-beta vs control, both overall (hazard ratio (HR)=1.13; 95% CI: 0.87, 1.46; P=0.355) and in patients with baseline Hb<or=11 g dl(-1) (HR=1.09; 95% CI: 0.80, 1.47; P=0.579). A trend for a beneficial effect on tumour progression was seen overall (HR=0.85; 95% CI: 0.72, 1.01; P=0.072) and in patients with an Hb<or=11 g dl(-1) (HR=0.80; 95% CI: 0.65, 0.99; P=0.041). An increased frequency of TEEs was seen with epoetin-beta vs control (7 vs 4% of patients); however, TEEs-related mortality was similar in both groups (1% each). The results of this meta-analysis indicate that when used within current EORTC treatment guidelines, epoetin-beta has no negative impact on survival, tumour progression or TEEs-related mortality." ], "offsets": [ [ 0, 1721 ] ] } ]

[ { "id": "entity-41-0", "type": "DISEASE", "text": [ "tumour progression" ], "offsets": [ [ 51, 69 ] ], "normalized": [] }, { "id": "entity-41-1", "type": "DISEASE", "text": [ "thromboembolic events" ], "offsets": [ [ 74, 95 ] ], "normalized": [] }, { "id": "entity-41-2", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 113, 119 ] ], "normalized": [] }, { "id": "entity-41-3", "type": "DISEASE", "text": [ "metastatic cancer" ], "offsets": [ [ 252, 269 ] ], "normalized": [] }, { "id": "entity-41-4", "type": "DISEASE", "text": [ "anaemia" ], "offsets": [ [ 323, 330 ] ], "normalized": [] }, { "id": "entity-41-5", "type": "DISEASE", "text": [ "tumour progression" ], "offsets": [ [ 513, 531 ] ], "normalized": [] }, { "id": "entity-41-6", "type": "DISEASE", "text": [ "thromboembolic events" ], "offsets": [ [ 536, 557 ] ], "normalized": [] }, { "id": "entity-41-7", "type": "DISEASE", "text": [ "TEEs" ], "offsets": [ [ 559, 563 ] ], "normalized": [] }, { "id": "entity-41-8", "type": "DISEASE", "text": [ "nonmyeloid haematological malignancies" ], "offsets": [ [ 679, 717 ] ], "normalized": [] }, { "id": "entity-41-9", "type": "DISEASE", "text": [ "Cancer" ], "offsets": [ [ 898, 904 ] ], "normalized": [] }, { "id": "entity-41-10", "type": "DISEASE", "text": [ "tumour progression" ], "offsets": [ [ 1207, 1225 ] ], "normalized": [] }, { "id": "entity-41-11", "type": "DISEASE", "text": [ "TEEs" ], "offsets": [ [ 1390, 1394 ] ], "normalized": [] }, { "id": "entity-41-12", "type": "DISEASE", "text": [ "TEEs" ], "offsets": [ [ 1465, 1469 ] ], "normalized": [] }, { "id": "entity-41-13", "type": "DISEASE", "text": [ "tumour progression" ], "offsets": [ [ 1676, 1694 ] ], "normalized": [] }, { "id": "entity-41-14", "type": "DISEASE", "text": [ "TEEs" ], "offsets": [ [ 1698, 1702 ] ], "normalized": [] } ]

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[ { "id": "passage-42", "type": "abstract", "text": [ "Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. OBJECTIVES: COPD exacerbations are associated with significant morbidity and mortality. This randomized, double-blind, parallel-group, multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations. METHODS: Patients received standardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in, followed by randomization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months. Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids, antibiotics, or hospitalization. RESULTS: In 782 patients with COPD (mean FEV(1)=0.94+/-0.36 L, 33% predicted normal), treatment with fluticasone propionate/salmeterol 250/50 significantly reduced (1) the annual rate of moderate to severe exacerbations by 30.5% compared with salmeterol (1.06 and 1.53 per subject per year, respectively, p<0.001), (2) the risk of time to first exacerbation by 25% (hazard ratio=0.750, p=0.003) and (3) the annual rate of exacerbations requiring oral corticosteroids by 40% (p<0.001). Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol. Adverse events were reported for a similar percentage of subjects across groups. A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol (7% vs. 4%). CONCLUSIONS: We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year. The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered. This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD." ], "offsets": [ [ 0, 2093 ] ] } ]

[ { "id": "entity-42-0", "type": "DISEASE", "text": [ "COPD exacerbations" ], "offsets": [ [ 89, 107 ] ], "normalized": [] }, { "id": "entity-42-1", "type": "DISEASE", "text": [ "COPD exacerbations" ], "offsets": [ [ 122, 140 ] ], "normalized": [] }, { "id": "entity-42-2", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 693, 697 ] ], "normalized": [] }, { "id": "entity-42-3", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 808, 812 ] ], "normalized": [] }, { "id": "entity-42-4", "type": "ADVERSE", "text": [ "pneumonia" ], "offsets": [ [ 1568, 1577 ] ], "normalized": [] }, { "id": "entity-42-5", "type": "ADVERSE", "text": [ "pneumonia" ], "offsets": [ [ 1927, 1936 ] ], "normalized": [] }, { "id": "entity-42-6", "type": "DISEASE", "text": [ "COPD exacerbations" ], "offsets": [ [ 2052, 2070 ] ], "normalized": [] }, { "id": "entity-42-7", "type": "DISEASE", "text": [ "COPD" ], "offsets": [ [ 2088, 2092 ] ], "normalized": [] } ]

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[ { "id": "passage-43", "type": "abstract", "text": [ "Efficacy of fractionated gemtuzumab ozogamicin combined with cytarabine in advanced childhood myeloid leukaemia. Gemtuzumab ozogamicin (GO) monotherapy is reported to yield a 20-30% response rate in advanced acute myeloid leukaemia (AML). This study examined the efficacy and tolerability of GO combined with cytarabine (GOCYT) in children with refractory/relapsed CD33(+) AML. Seventeen children received GO 3 mg/m(2) on days 1, 4 and 7 plus cytarabine 100 mg/m(2)/d for 7 d on a compassionate-use basis. Seven patients then received GO-based consolidation. At the outset of GOCYT, two patients were refractory; eight patients were in refractory first relapse; six patients had relapsed after stem cell transplantation (SCT); and one patient [del(5q) therapy-related AML (t-AML)] had not yet been treated. Mean follow-up was 17 months (8-33 months). Ten responses were obtained after GOCYT induction, including complete remission (CR) or CR without complete recovery of platelets (CRp) in six patients (35%). The responses improved in three children who received GOCYT consolidation, increasing the CR + CRp rate to 53%. SCT was subsequently performed in eight responders. Grade 3-4 adverse events consisted of haematological disorders (n = 17, 100%) and documented infections (n = 5, 29%). No cases of sinusoidal obstructive syndrome occurred. Three patients were alive at the cut-off date for this analysis, all of whom had responded to GOCYT. GOCYT combination therapy yielded a high response rate (53%) and showed acceptable toxicity in heavily pretreated children with refractory/relapsed AML. These results warrant a larger prospective study." ], "offsets": [ [ 0, 1650 ] ] } ]

[ { "id": "entity-43-0", "type": "DISEASE", "text": [ "myeloid leukaemia" ], "offsets": [ [ 94, 111 ] ], "normalized": [] }, { "id": "entity-43-1", "type": "DISEASE", "text": [ "acute myeloid leukaemia" ], "offsets": [ [ 209, 232 ] ], "normalized": [] }, { "id": "entity-43-2", "type": "DISEASE", "text": [ "AML" ], "offsets": [ [ 234, 237 ] ], "normalized": [] }, { "id": "entity-43-3", "type": "DISEASE", "text": [ "AML" ], "offsets": [ [ 374, 377 ] ], "normalized": [] }, { "id": "entity-43-4", "type": "DISEASE", "text": [ "AML" ], "offsets": [ [ 769, 772 ] ], "normalized": [] }, { "id": "entity-43-5", "type": "ADVERSE", "text": [ "haematological disorders" ], "offsets": [ [ 1213, 1237 ] ], "normalized": [] }, { "id": "entity-43-6", "type": "ADVERSE", "text": [ "infections" ], "offsets": [ [ 1268, 1278 ] ], "normalized": [] }, { "id": "entity-43-7", "type": "DISEASE", "text": [ "sinusoidal obstructive syndrome" ], "offsets": [ [ 1305, 1336 ] ], "normalized": [] }, { "id": "entity-43-8", "type": "DISEASE", "text": [ "refractory/relapsed AML" ], "offsets": [ [ 1576, 1599 ] ], "normalized": [] } ]

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[ { "id": "passage-44", "type": "abstract", "text": [ "Effect of linezolid against postneurosurgical meningitis caused by methicillin-resistant Staphylococcus epidermidis: case report. A 67-year-old man who had twice previously undergone operations for a tuberculum sellae meningioma was admitted to hospital for further treatment. After the third surgical intervention, the patient developed persistent low-grade fever and impaired consciousness. Computed tomography, 1 week after surgery, showed postsurgical hydrocephalus. Cerebrospinal fluid (CSF) studies revealed high intracranial pressure (above 30 cm H2O), and increased cell count (1232/3). One week after the ventricular drainage, coagulase-negative Staphylococcus epidermidis was recovered from his CSF, and antimicrobial susceptibility results indicated that the organism was methicillin-resistant. After 14 days of intravenous vancomycin (VCM) administration failed, linezolid (LZD) was initialized intravenously, resulting in a resolution of the meningitis. After a ventriculoperitoneal shunt procedure was performed, LZD was continued orally, which resulted in a cure. CSF penetration by VCM is reported to be poor, i.e., approximately 10% of serum concentration, which may explain its lack of efficacy. In this case, the penetration of LZD into the CSF was 58.9% of the peak value and 133% of the trough value of serum concentrations. LZD must be considered one of the first-line treatments against surgical-site infection in neurosurgery caused by methicillin-resistant Staphylococci." ], "offsets": [ [ 0, 1497 ] ] } ]

[ { "id": "entity-44-0", "type": "ADVERSE", "text": [ "postneurosurgical meningitis" ], "offsets": [ [ 28, 56 ] ], "normalized": [] }, { "id": "entity-44-1", "type": "DISEASE", "text": [ "tuberculum sellae meningioma" ], "offsets": [ [ 201, 229 ] ], "normalized": [] }, { "id": "entity-44-2", "type": "ADVERSE", "text": [ "fever" ], "offsets": [ [ 360, 365 ] ], "normalized": [] }, { "id": "entity-44-3", "type": "ADVERSE", "text": [ "impaired consciousness" ], "offsets": [ [ 370, 392 ] ], "normalized": [] }, { "id": "entity-44-4", "type": "ADVERSE", "text": [ "postsurgical hydrocephalus" ], "offsets": [ [ 444, 470 ] ], "normalized": [] }, { "id": "entity-44-5", "type": "ADVERSE", "text": [ "meningitis" ], "offsets": [ [ 956, 966 ] ], "normalized": [] }, { "id": "entity-44-6", "type": "ADVERSE", "text": [ "surgical-site infection" ], "offsets": [ [ 1411, 1434 ] ], "normalized": [] } ]

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[ { "id": "passage-45", "type": "abstract", "text": [ "Angio-oedema as an unusual tolerable side effect of voriconazole therapy. Voriconazole (VRC) has not previously been reported to cause angio-oedema. Here, we report a case of angio-oedema associated with VRC therapy. A 37-year-old woman with relapsing invasive vertebral aspergillosis received intravenous VRC and developed angio-oedema 10 days after starting therapy. This condition rapidly diminished after administration of intravenous antihistaminics and did not necessitate cessation of VRC treatment. The treatment was continued for 6 months without recurrence of the symptoms. After 18 months, the patient was in good health. To our knowledge, this is the first report of an angio-oedema associated with VRC." ], "offsets": [ [ 0, 716 ] ] } ]

[ { "id": "entity-45-0", "type": "DISEASE", "text": [ "Angio-oedema" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "entity-45-1", "type": "DISEASE", "text": [ "angio-oedema" ], "offsets": [ [ 136, 148 ] ], "normalized": [] }, { "id": "entity-45-2", "type": "DISEASE", "text": [ "angio-oedema" ], "offsets": [ [ 176, 188 ] ], "normalized": [] }, { "id": "entity-45-3", "type": "DISEASE", "text": [ "aspergillosis" ], "offsets": [ [ 272, 285 ] ], "normalized": [] }, { "id": "entity-45-4", "type": "DISEASE", "text": [ "angio-oedema" ], "offsets": [ [ 683, 695 ] ], "normalized": [] } ]

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[ { "id": "passage-46", "type": "abstract", "text": [ "Extended- and continuous-cycle oral contraceptives. Five new oral contraceptives, classified as extended- or continuous-cycle oral contraceptives, have been approved by the United States Food and Drug Administration. These agents have various combinations of estrogen and progestin, and different effects on the length of women's menstrual cycles. Usually they shorten the duration of menses, decrease the frequency of menses to 4 times/year, or completely eliminate menses. These new oral contraceptives are given in the following regimens: 24 days followed by placebo for 4 days (24/4), 84 days followed by placebo for 7 days (84/7), or continuously (without placebo). These agents contain ethinyl estradiol 20 microg-drospirenone 3 mg (24/4); ethinyl estradiol 20 microg-norethindrone 1 mg (24/4); ethinyl estradiol 30 microg-levonorgestrel 150 microg (84/7); ethinyl estradiol 30 microg-levonorgestrel 150 microg (84/7) with very low-dose ethinyl estradiol (10 microg/day) for 7 days; and ethinyl estradiol 20 microg-levonorgestrel 90 microg continuously. Clinical trials have demonstrated that extended- and continuous-cycle oral contraceptives are as effective in preventing pregnancy as traditional oral contraceptives. These new agents also have similar adverse effects; however, the only significantly different adverse effect compared with traditional oral contraceptives in clinical trials was change in bleeding pattern. These oral contraceptives are associated with more breakthrough bleeding and spotting than the traditional pills. Long-term effects on efficacy and safety are not known, as these new products generally have been used for only 1-2 years. Extended- and continuous-cycle oral contraceptives are a new option for women desiring decreased menses or for whom decreased menses may alleviate symptoms of coexisting medical conditions." ], "offsets": [ [ 0, 1860 ] ] } ]

[ { "id": "entity-46-0", "type": "ADVERSE", "text": [ "change in bleeding pattern" ], "offsets": [ [ 1406, 1432 ] ], "normalized": [] }, { "id": "entity-46-1", "type": "ADVERSE", "text": [ "breakthrough bleeding" ], "offsets": [ [ 1485, 1506 ] ], "normalized": [] } ]

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[ { "id": "passage-47", "type": "abstract", "text": [ "Phase II trial of S-1 and concurrent radiotherapy in patients with locally advanced pancreatic cancer. PURPOSE: S-1 has a favorable effect in unresectable pancreatic cancer and a potential radiosensitizer. In addition, daily oral administration of S-1 is more convenient than continuous infusion of 5-fluorouracil. This study was designed to evaluate the efficacy and safety of S-1 and concurrent radiotherapy in patients with locally advanced pancreatic cancer. METHODS: Eligibility criteria were histologically proven pancreatic adenocarcinoma, locally advanced disease, and no previous treatment. S-1 was administered orally at a dose of 40 mg/m(2) twice daily from day 1 to 14 and from day 22 to 35, and concurrent radiotherapy (a total dose of 50.4 Gy) was delivered in 28 fractions. One month after treatment completion, tumor response was evaluated by computed tomography (CT). RESULTS: A total of 25 patients were evaluable for efficacy and toxicity on the basis of the intention-to-treat analysis. The response rate and disease control rate were 24.0 and 68.0%, respectively. There was no treatment-related death or grade 4 toxicity. The most common grade 3 hematologic and non-hematologic toxicities were thrombocytopenia (4.0%) and anorexia (20%), respectively. All toxicities were tolerable and transient. The median time-to-progression and median overall survival were 6.5 months (95% confidence interval, 4.1-9.0 months) and 12.9 months (95% confidence interval, 6.7-19.0 months), respectively, and the 1-year survival rate was estimated to be 43%. CONCLUSIONS: S-1 and concurrent radiotherapy shows favorable efficacy for disease control against locally advanced pancreatic cancer and was well tolerated with no severe toxicities." ], "offsets": [ [ 0, 1746 ] ] } ]

[ { "id": "entity-47-0", "type": "DISEASE", "text": [ "pancreatic cancer" ], "offsets": [ [ 84, 101 ] ], "normalized": [] }, { "id": "entity-47-1", "type": "DISEASE", "text": [ "pancreatic cancer" ], "offsets": [ [ 156, 173 ] ], "normalized": [] }, { "id": "entity-47-2", "type": "DISEASE", "text": [ "pancreatic cancer" ], "offsets": [ [ 445, 462 ] ], "normalized": [] }, { "id": "entity-47-3", "type": "DISEASE", "text": [ "pancreatic adenocarcinoma" ], "offsets": [ [ 521, 546 ] ], "normalized": [] }, { "id": "entity-47-4", "type": "ADVERSE", "text": [ "thrombocytopenia" ], "offsets": [ [ 1216, 1232 ] ], "normalized": [] }, { "id": "entity-47-5", "type": "ADVERSE", "text": [ "anorexia" ], "offsets": [ [ 1244, 1252 ] ], "normalized": [] }, { "id": "entity-47-6", "type": "DISEASE", "text": [ "pancreatic cancer" ], "offsets": [ [ 1679, 1696 ] ], "normalized": [] } ]

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[ { "id": "passage-48", "type": "abstract", "text": [ "Induction of mucosal tolerance in SLE: a sniff or a sip away from ameliorating lupus? Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by aberrant immune responses against intracellularly derived self antigens. Treatment for SLE relies on the use of aggressive immunosuppressants and steroids that are nonspecific and can cause serious adverse effects. The observation that a systemic immune tolerance to self antigens or generation of regulatory T cells may follow mucosal (nasal or oral) exposure to self proteins or monoclonal antibody against CD3 respectively suggests that induction of mucosal tolerance offers the basis of a side effect-free therapy that could re-establish the ability to distinguish self from non-self and restore peripheral tolerance in individuals susceptible to developing autoimmune diseases. Here I review studies on mucosal tolerance in autoimmune diseases and discuss the therapeutic potential of inducing tolerance for the treatment of SLE." ], "offsets": [ [ 0, 998 ] ] } ]

[ { "id": "entity-48-0", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 34, 37 ] ], "normalized": [] }, { "id": "entity-48-1", "type": "DISEASE", "text": [ "Systemic lupus erythematosus" ], "offsets": [ [ 87, 115 ] ], "normalized": [] }, { "id": "entity-48-2", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 117, 120 ] ], "normalized": [] }, { "id": "entity-48-3", "type": "DISEASE", "text": [ "autoimmune disease" ], "offsets": [ [ 128, 146 ] ], "normalized": [] }, { "id": "entity-48-4", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 251, 254 ] ], "normalized": [] }, { "id": "entity-48-5", "type": "DISEASE", "text": [ "autoimmune diseases" ], "offsets": [ [ 826, 845 ] ], "normalized": [] }, { "id": "entity-48-6", "type": "DISEASE", "text": [ "autoimmune diseases" ], "offsets": [ [ 893, 912 ] ], "normalized": [] }, { "id": "entity-48-7", "type": "DISEASE", "text": [ "SLE" ], "offsets": [ [ 994, 997 ] ], "normalized": [] } ]

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[ { "id": "passage-49", "type": "abstract", "text": [ "Biochemical mechanism of acetaminophen (APAP) induced toxicity in melanoma cell lines. In this work, we investigated the biochemical mechanism of acetaminophen (APAP) induced toxicity in SK-MEL-28 melanoma cells using tyrosinase enzyme as a molecular cancer therapeutic target. Our results showed that APAP was metabolized 87% by tyrosinase at 2 h incubation. AA and NADH, quinone reducing agents, were significantly depleted during APAP oxidation by tyrosinase. The IC(50) (48 h) of APAP towards SK-MEL-28, MeWo, SK-MEL-5, B16-F0, and B16-F10 melanoma cells was 100 microM whereas it showed no significant toxicity towards BJ, Saos-2, SW-620, and PC-3 nonmelanoma cells, demonstrating selective toxicity towards melanoma cells. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, enhanced APAP toxicity towards SK-MEL-28 cells. AA and GSH were effective in preventing APAP induced melanoma cell toxicity. Trifluoperazine and cyclosporin A, inhibitors of permeability transition pore in mitochondria, significantly prevented APAP melanoma cell toxicity. APAP caused time and dose-dependent decline in intracellular GSH content in SK-MEL-28, which preceded cell toxicity. APAP led to ROS formation in SK-MEL-28 cells which was exacerbated by dicoumarol and 1-bromoheptane whereas cyslosporin A and trifluoperazine prevented it. Our investigation suggests that APAP is a tyrosinase substrate, and that intracellular GSH depletion, ROS formation and induced mitochondrial toxicity contributed towards APAP's selective toxicity in SK-MEL-28 cells." ], "offsets": [ [ 0, 1571 ] ] } ]

[ { "id": "entity-49-0", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 252, 258 ] ], "normalized": [] }, { "id": "entity-49-1", "type": "ADVERSE", "text": [ "melanoma cell toxicity" ], "offsets": [ [ 910, 932 ] ], "normalized": [] }, { "id": "entity-49-2", "type": "ADVERSE", "text": [ "APAP melanoma cell toxicity" ], "offsets": [ [ 1053, 1080 ] ], "normalized": [] }, { "id": "entity-49-3", "type": "ADVERSE", "text": [ "cell toxicity" ], "offsets": [ [ 1184, 1197 ] ], "normalized": [] }, { "id": "entity-49-4", "type": "ADVERSE", "text": [ "mitochondrial toxicity" ], "offsets": [ [ 1483, 1505 ] ], "normalized": [] } ]

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[ { "id": "passage-50", "type": "abstract", "text": [ "Hepatic safety of tipranavir plus ritonavir (TPV/r)-based antiretroviral combinations: effect of hepatitis virus co-infection and pre-existing fibrosis. OBJECTIVES: The aim of this study was to evaluate the incidence and risk factors of severe liver events among HIV-infected patients treated with drug combinations including tipranavir boosted with ritonavir (TPV/r). METHODS: One hundred and fifty patients were selected because they started a regimen that included TPV/r (500/200 mg twice a day) and had clinical visits at least every 3 months. Patients who discontinued TPV/r before their first visit were included. RESULTS: Twelve (8%) individuals developed grade>or=3 transaminase elevation (G>or=3TE). Nine (6%) patients discontinued TPV/r due to liver events. Six (8.6%) of 70 hepatitis C virus (HCV) co-infected patients and 6 (7.5%) of 80 subjects without HCV co-infection developed G>or=3TE (P=1). Liver fibrosis was evaluable in 48 (63%) of 76 individuals with hepatitis B virus and/or HCV infection. Four (13%) of 30 subjects with moderate-to-severe fibrosis and none of 18 with mild fibrosis showed G>or=3TE (P=0.3). None of nine patients with cirrhosis showed G>or=3TE. CONCLUSIONS: Liver tolerability of TPV/r was generally good in a cohort of patients with a high proportion of HCV co-infection, including subjects with advanced fibrosis. The presence of HCV co-infection was not associated with an increased risk of severe transaminase elevations." ], "offsets": [ [ 0, 1466 ] ] } ]

[ { "id": "entity-50-0", "type": "DISEASE", "text": [ "hepatitis virus co-infection" ], "offsets": [ [ 97, 125 ] ], "normalized": [] }, { "id": "entity-50-1", "type": "DISEASE", "text": [ "fibrosis" ], "offsets": [ [ 143, 151 ] ], "normalized": [] }, { "id": "entity-50-2", "type": "DISEASE", "text": [ "Liver fibrosis" ], "offsets": [ [ 910, 924 ] ], "normalized": [] }, { "id": "entity-50-3", "type": "DISEASE", "text": [ "HCV infection" ], "offsets": [ [ 999, 1012 ] ], "normalized": [] }, { "id": "entity-50-4", "type": "ADVERSE", "text": [ "fibrosis" ], "offsets": [ [ 1064, 1072 ] ], "normalized": [] }, { "id": "entity-50-5", "type": "ADVERSE", "text": [ "fibrosis" ], "offsets": [ [ 1098, 1106 ] ], "normalized": [] }, { "id": "entity-50-6", "type": "DISEASE", "text": [ "cirrhosis" ], "offsets": [ [ 1159, 1168 ] ], "normalized": [] }, { "id": "entity-50-7", "type": "DISEASE", "text": [ "HCV co-infection" ], "offsets": [ [ 1296, 1312 ] ], "normalized": [] }, { "id": "entity-50-8", "type": "DISEASE", "text": [ "fibrosis" ], "offsets": [ [ 1347, 1355 ] ], "normalized": [] }, { "id": "entity-50-9", "type": "DISEASE", "text": [ "HCV co-infection" ], "offsets": [ [ 1373, 1389 ] ], "normalized": [] } ]

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[ { "id": "passage-51", "type": "abstract", "text": [ "18beta-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity. Defects in mitochondrial function have been shown to participate in the induction of cell death in cancer cells. The present study was designed to assess the toxic effect of 18beta-glycyrrhetinic acid against human cervix and uterus tumor cell line SiHa cells in relation to the mitochondria-mediated cell-death process and evaluate the combined toxic effect of 18beta-glycyrrhetinic acid and anti-cancer drugs. 18beta-Glycyrrhetinic acid induced the nuclear damage, changes in the mitochondrial membrane permeability, formation of reactive oxygen species and depletion of glutathione in SiHa cells. It caused cell death by inducing the increase in the pro-apoptotic Bax protein and cytochrome c levels, reduction in anti-apoptotic Bcl-2 level, subsequent caspase-3 activation and loss of the mitochondrial transmembrane potential. Unlike 18beta-glycyrrhetinic acid, a pro-compound glycyrrhizin up to 100 microM did not induce cell death and depletion of glutathione. Combined treatment of mitomycin c (or doxorubicin) and 18beta-glycyrrhetinic acid revealed a synergistic toxic effect. Meanwhile, combination of camptothecin and 18beta-glycyrrhetinic acid exhibited an additive cytotoxic effect. Results suggest that 18beta-glycyrrhetinic acid may cause cell death in SiHa cells by inducing the mitochondrial membrane permeability change, leading to cytochrome c release and caspase-3 activation. The effect may be associated with increased formation of reactive oxygen species and depletion of glutathione. Combined treatment of antibiotic anti-cancer drug and 18beta-glycyrrhetinic acid seems to exhibit a synergistic toxic effect." ], "offsets": [ [ 0, 1785 ] ] } ]

[ { "id": "entity-51-0", "type": "ADVERSE", "text": [ "drug toxicity" ], "offsets": [ [ 135, 148 ] ], "normalized": [] }, { "id": "entity-51-1", "type": "ADVERSE", "text": [ "synergistic toxic effect" ], "offsets": [ [ 1212, 1236 ] ], "normalized": [] }, { "id": "entity-51-2", "type": "ADVERSE", "text": [ "cytotoxic effect" ], "offsets": [ [ 1330, 1346 ] ], "normalized": [] }, { "id": "entity-51-3", "type": "ADVERSE", "text": [ "synergistic toxic effect" ], "offsets": [ [ 1760, 1784 ] ], "normalized": [] } ]

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[ { "id": "passage-52", "type": "abstract", "text": [ "Role of the nitro functionality in the DNA binding of 3-nitro-10-methylbenzothiazolo[3,2-a]quinolinium chloride. Interest in DNA binding drugs has increased in recent years due to their importance in the treatment of genome-related diseases, like cancer. A new family of water-soluble DNA binding compounds, the benzothiazolo[3,2- a]quinolinium chlorides (BQCls), is studied here as potential candidates for chemical treatment of solid tumor cells that may encounter low-oxygen environments, a condition known as hypoxia. These compounds are good DNA intercalators; however, no studies have been made of these compounds under hypoxic conditions. This work demonstrates the importance of the nitro-functionality in the DNA binding of 3-nitro-10-methylbenzothiazolo[3,2- a]quinolinium chloride (NBQ-91), which possesses nitro-functionality, and 10-methylbenzothiazolo[3,2- a]quinolinium chloride (BQ-106), which does not. Both NBQ-91 and BQ-106 have similar noncovalent binding affinity toward DNA. Dialysis experiments show that NBQ-91 binds DNA under N2-saturated conditions with increasing concentrations of reducing agent, presumably due to reduction of the nitro-functionality. Conversely, because of the lack of nitro-functionality, the presence of a reducing agent had no effect on BQ-106 binding to DNA under both aerobic and N2-saturated conditions. Clonogenic assays were performed to determine the quinolinium chloride cytotoxicities under both aerobic (95% air and 5% CO2) and hypoxic (80% N2 and 20% CO2) conditions. The calculated ratios of cellular toxicity under aerobic to hypoxic conditions caused by the same concentration of test agent (CTR values) show greater levels of cell death under hypoxia than under aerobic conditions for mitomycin C (MC) (CTR = 0.7 at 1 microM) and NBQ-91 (CTR = 0.4 at 200 microM) than for BQ-106 (CTR = 1.0 at 200 microM), which agreed with the previously reported data for MC and confirmed the importance of nitro-functionality for reactivity under hypoxic conditions. There was no correlation between noncovalent binding affinity constants and their cytotoxicity under hypoxic conditions. Adduct formation between the NBQ-91 and 2'-dG was also assessed by reacting 2'-dG or DNA with NBQ-91 and BQ-106 under N2-saturated conditions in the presence of hypoxanthine and xanthine oxidase (HX/XO). DNA covalent adduct formation was analyzed by two techniques: LC-ESI-MS and Sephadex size exclusion chromatography. LC-ESI-MS results clearly indicate the formation of a prominent molecular ion at masses of 266.0 and 530.58 Da, corresponding to the [M + H](+2) and [M](+) molecular ions of the monitored 2'-dG-NBQ-91 adduct. Results from the Sephadex size exclusion chromatography support these findings because the NBQ-91 elution percentage increases in the presence of HX/XO due to the reduction of the nitro-functionality, which results in covalent binding to DNA. This study reports evidence of the DNA binding capacity of this bioreductive drug. The preferential N2-saturated over aerobic conditions for DNA binding makes NBQ-91 a potential bioreductive compound for hypoxic cell killing." ], "offsets": [ [ 0, 3136 ] ] } ]

[ { "id": "entity-52-0", "type": "DISEASE", "text": [ "genome-related diseases" ], "offsets": [ [ 218, 241 ] ], "normalized": [] }, { "id": "entity-52-1", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 248, 254 ] ], "normalized": [] }, { "id": "entity-52-2", "type": "DISEASE", "text": [ "hypoxia" ], "offsets": [ [ 514, 521 ] ], "normalized": [] }, { "id": "entity-52-3", "type": "ADVERSE", "text": [ "cellular toxicity" ], "offsets": [ [ 1554, 1571 ] ], "normalized": [] }, { "id": "entity-52-4", "type": "DISEASE", "text": [ "hypoxia" ], "offsets": [ [ 1708, 1715 ] ], "normalized": [] }, { "id": "entity-52-5", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 2100, 2112 ] ], "normalized": [] } ]

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[ { "id": "passage-53", "type": "abstract", "text": [ "AcylMPAG plasma concentrations and mycophenolic acid-related side effects in patients undergoing renal transplantation are not related to the UGT2B7-840G>A gene polymorphism. Mycophenolic acid (MPA) is metabolized primarily by glucuronidation to form the biologically inactive 7-O-glucuronide conjugate (MPAG), which is the major urinary excretion product. MPA is also converted to acyl-glucuronide metabolite (AcylMPAG), which has been suggested to be involved in the generation of MPA-related adverse events such as diarrhea or leucopenia. This conversion of MPA to AcylMPAG is catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). We studied the impact of the -840G>A polymorphisms in the UGT2B7 gene on the pharmacokinetics of AcylMPAG. We also investigated whether the plasma concentrations of AcylMPAG are correlated with MPA-related toxicity to further evaluate its potential clinical significance. In a randomized, controlled trial, comparing fixed-dose mycophenolate mofetil (MMF) with concentration-controlled MMF therapy, patients undergoing renal transplantation were treated with a calcineurin inhibitor, MMF, and corticosteroids. Informed consent was obtained from 332 patients for genotyping. In all patients, blood samples were drawn (three samples within the first 2 hours after administration) on Day 3, Day 10, Week 4, and Months 3, 6, and 12 to measure MPA and AcylMPAG plasma concentrations. The pharmacokinetics of AcylMPAG were correlated with the -840G>A single nucleotide polymorphism (SNP) in the UGT2B7 gene. Heterozygosity for the -840G>A SNP in the UGT2B7 gene was found in 145 patients (145 of 332 [44%]) and 93 (93 of 332 [28%]) patients were homozygous for the -840G>A allele. No difference was found in the dose-normalized AcylMPAG trough (C0) levels and dose-normalized AcylMPAG areas under the concentration-time curve (AUCs) at each visit between carriers and noncarriers of the -840G>A SNP. Also, metabolic ratios, expressed as AcylMPAG/MPA and AcylMPAG/MPAG, were not related to UGT2B7 genotype. The dose-normalized AcylMPAG-C0 and AcylMPAG AUC were higher in the cyclosporine-treated group compared with the tacrolimus-treated patients at each visit. There was no difference in AcylMPAG concentrations (trough or AUC) or AcylMPAG/MPAG ratio between patients with compared with patients without diarrhea. None of the -840G>A UGT2B7 SNPs was disproportionately present among the patients with diarrhea. There was a higher incidence of diarrhea in tacrolimus-treated patients [26 of 163 (16.0%)] compared with cyclosporine-treated individuals [five of 51 (9.8%)], although AcylMPAG concentrations were lower in tacrolimus-treated patients. In this study, we have found no influence of the -840G>A UGT2B7 SNP on AcylMPAG exposure in patients undergoing renal transplantation. There also was no association between this variant genotype and the incidence of diarrhea or leucopenia, two adverse events for which a role for AcylMPAG has been suggested." ], "offsets": [ [ 0, 2986 ] ] } ]

[ { "id": "entity-53-0", "type": "ADVERSE", "text": [ "mycophenolic acid-related side effects" ], "offsets": [ [ 35, 73 ] ], "normalized": [] }, { "id": "entity-53-1", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 519, 527 ] ], "normalized": [] }, { "id": "entity-53-2", "type": "ADVERSE", "text": [ "leucopenia" ], "offsets": [ [ 531, 541 ] ], "normalized": [] }, { "id": "entity-53-3", "type": "ADVERSE", "text": [ "MPA-related toxicity" ], "offsets": [ [ 830, 850 ] ], "normalized": [] }, { "id": "entity-53-4", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 2335, 2343 ] ], "normalized": [] }, { "id": "entity-53-5", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 2432, 2440 ] ], "normalized": [] }, { "id": "entity-53-6", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 2474, 2482 ] ], "normalized": [] }, { "id": "entity-53-7", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 2894, 2902 ] ], "normalized": [] }, { "id": "entity-53-8", "type": "ADVERSE", "text": [ "leucopenia" ], "offsets": [ [ 2906, 2916 ] ], "normalized": [] } ]

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[ { "id": "passage-54", "type": "abstract", "text": [ "Relationship between airborne pollen count and treatment outcome in Japanese cedar pollinosis patients. In Japan, information on daily Japanese cedar pollen counts is made public during pollen season. If symptom severity and treatment outcome are predictable according to these pollen counts, management of seasonal allergic rhinitis may become more precise. The aims of the study were to evaluate the relationship between airborne pollen counts, symptom severity and treatment outcome in Japanese cedar pollinosis patients. In the randomized study, patients with moderate to most severe Japanese pollinosis were treated with fexofenadine (60 mg BD) or fexofenadine and nasal corticosteroids for 2 weeks. During the same period daily airborne pollen counts were measured. A total of 105 adult patients were enrolled. No difference of treatment efficacy was seen among groups. Detailed results of efficacy and safety were previously described elsewhere. In univariate analysis, the mean cumulative amount of airborne pollen exposure for 4 days prior to the study tended to affect symptom severity (P = 0.053) and the mean cumulative amount of airborne pollen during the treatment period tended to show difference among five treatment outcome categories (P = 0.066). In multivariate analysis, the mean cumulative amount of airborne pollen exposure for 4 days prior to the study was identified as the only significant factor of symptom severity (P = 0.0327) and cumulative amount of airborne pollen during the treatment period (P = 0.027) and allergic history (P = 0.027) were significant factors of treatment outcomes. No serious adverse effect was reported during the study. The amount of airborne pollen may be predictive of both symptom severity and treatment outcome." ], "offsets": [ [ 0, 1770 ] ] } ]

[ { "id": "entity-54-0", "type": "DISEASE", "text": [ "pollinosis" ], "offsets": [ [ 83, 93 ] ], "normalized": [] }, { "id": "entity-54-1", "type": "DISEASE", "text": [ "seasonal allergic rhinitis" ], "offsets": [ [ 308, 334 ] ], "normalized": [] }, { "id": "entity-54-2", "type": "DISEASE", "text": [ "pollinosis" ], "offsets": [ [ 505, 515 ] ], "normalized": [] }, { "id": "entity-54-3", "type": "DISEASE", "text": [ "pollinosis" ], "offsets": [ [ 598, 608 ] ], "normalized": [] } ]

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[ { "id": "passage-55", "type": "abstract", "text": [ "Clinical implications of clopidogrel resistance. The benefits of clopidogrel in the treatment and prevention of coronary artery disease are well established, however, not all individuals respond in the same way to clopidogrel; there are patients who suffer adverse events despite clopidogrel treatment. This review focuses on the definition, potential mechanisms for and clinical implications of clopidogrel resistance, as well as the strategies to improve the response to this antiplatelet drug. There is an inter-individual variability in response to clopidogrel therapy, and a sub-optimal response (clopidogrel resistance) has been associated with adverse cardiovascular events. Nevertheless, there is no clear and consensual definition of clopidogrel resistance. Response to clopidogrel therapy follows a normal, bell-shaped distribution, so a more appropriate description would be variable response rather than clopidogrel resistance. Independent of the term used, lower response to clopidogrel therapy seems to be associated with a higher probability of suffering thrombotic events. Due to the misleading definition of resistance and non-standardized method for assessing platelet inhibition, current guidelines do not recommend the use of platelet function assays to monitor the inhibitory effect of antiplatelet drugs. Current guidelines also do not recommend clopidogrel loading doses higher than 300 mg and daily maintenance doses higher than 75 mg, even though a regimen of 600 mg clopidogrel loading dose seems to be preferred for patients undergoing percutaneous coronary interventions." ], "offsets": [ [ 0, 1600 ] ] } ]

[ { "id": "entity-55-0", "type": "DISEASE", "text": [ "coronary artery disease" ], "offsets": [ [ 113, 136 ] ], "normalized": [] }, { "id": "entity-55-1", "type": "ADVERSE", "text": [ "adverse cardiovascular events" ], "offsets": [ [ 652, 681 ] ], "normalized": [] }, { "id": "entity-55-2", "type": "ADVERSE", "text": [ "thrombotic events" ], "offsets": [ [ 1071, 1088 ] ], "normalized": [] } ]

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[ { "id": "passage-56", "type": "abstract", "text": [ "Vitamin D: criteria for safety and efficacy. The functional status indicator for vitamin D, for both safety and efficacy, is serum 25-hydroxyvitamin D concentration. Efficacy for several health endpoints requires levels of 80 nmol/L or higher. Toxicity occurs at levels of 500 nmol/L or higher. The input needed for efficacy, in addition to typical food and cutaneous inputs, will usually be 1000-2000 IU/day of supplemental cholecalciferol. Toxicity is associated only with excessive supplemental intake (usually well above 20,000 IU/day)." ], "offsets": [ [ 0, 541 ] ] } ]

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[ { "id": "passage-57", "type": "abstract", "text": [ "Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancer cells under UV irradiation. Failure of chemotherapy to the malignant tumor is usually induced by multidrug resistance (MDR). The development of anti-MDR agents for efficient drug delivery is of great importance in cancer therapy. Recent reports have demonstrated that some anticancer drugs could be readily self-assembled on some biocompatible nanomaterials covalently or non-covalently, which could effectively afford the sustained drug delivery for the target cancer cells and reduce the relevant toxicity towards normal cells and tissues. Thus these biocompatible nanomaterials may play an important role in the relevant biological and biomedical system. In this paper, we have explored the cytotoxic effect of anticancer drug daunorubicin on leukemia cancer cells in the absence and presence of different sized ZnO nanoparticles via fluorescence microscopy, UV-Vis absorption spectroscopy, electrochemical analysis as well as MTT assay. Meanwhile, the cytotoxicity suppression of daunorubicin together with different sized ZnO nanoparticles in the absence and presence of UV irradiation on leukemia cancer cells were also investigated using MTT assay. The results indicate that the combination of the different sized ZnO nanoparticles and daunorubicin under UV irradiation could have synergistic cytotoxic effect on leukemia cancer cells, indicating the great potential of ZnO nanoparticles in relevant clinical and biomedical applications." ], "offsets": [ [ 0, 1552 ] ] } ]

[ { "id": "entity-57-0", "type": "ADVERSE", "text": [ "cytotoxic effect" ], "offsets": [ [ 12, 28 ] ], "normalized": [] }, { "id": "entity-57-1", "type": "DISEASE", "text": [ "malignant tumor" ], "offsets": [ [ 167, 182 ] ], "normalized": [] }, { "id": "entity-57-2", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 322, 328 ] ], "normalized": [] }, { "id": "entity-57-3", "type": "ADVERSE", "text": [ "cytotoxicity" ], "offsets": [ [ 1064, 1076 ] ], "normalized": [] }, { "id": "entity-57-4", "type": "ADVERSE", "text": [ "cytotoxic effect" ], "offsets": [ [ 1408, 1424 ] ], "normalized": [] } ]

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[ { "id": "passage-58", "type": "abstract", "text": [ "Partial peroxisome proliferator-activated receptor agonist angiotensin receptor blockers. Potential multipronged strategy in stroke prevention. BACKGROUND AND PURPOSE: Although their primary mechanism of action is blood pressure lowering, emerging data suggest that select angiotensin receptor blockers (ARBs), which partially activate the peroxisome proliferator-activated receptor gamma (PPAR-gamma), may effectively treat insulin resistance and dyslipidemia without the toxicity sometimes associated with full PPAR-gamma agonists. Since up to 50% of the patients with ischemic stroke and transient ischemic attack harbor insulin resistance, drugs that simultaneously control hypertension and insulin resistance could be particularly useful for stroke prevention. SUMMARY OF REVIEW: This review presents the experimental and preliminary clinical evidence supporting a promising role for partial PPAR-gamma agonist ARBs in treating insulin resistance and the metabolic syndrome in patients with ischemic cerebrovascular disease. CONCLUSION: Partial PPAR-gamma agonist ARBs by virtue of their multiple beneficial mechanisms of action could provide a single multipronged strategy for reducing future vascular events in persons with, or at risk for, stroke." ], "offsets": [ [ 0, 1256 ] ] } ]

[ { "id": "entity-58-0", "type": "DISEASE", "text": [ "stroke" ], "offsets": [ [ 125, 131 ] ], "normalized": [] }, { "id": "entity-58-1", "type": "DISEASE", "text": [ "insulin resistance" ], "offsets": [ [ 426, 444 ] ], "normalized": [] }, { "id": "entity-58-2", "type": "DISEASE", "text": [ "dyslipidemia" ], "offsets": [ [ 449, 461 ] ], "normalized": [] }, { "id": "entity-58-3", "type": "DISEASE", "text": [ "ischemic stroke" ], "offsets": [ [ 572, 587 ] ], "normalized": [] }, { "id": "entity-58-4", "type": "DISEASE", "text": [ "transient ischemic attack" ], "offsets": [ [ 592, 617 ] ], "normalized": [] }, { "id": "entity-58-5", "type": "DISEASE", "text": [ "insulin resistance" ], "offsets": [ [ 625, 643 ] ], "normalized": [] }, { "id": "entity-58-6", "type": "DISEASE", "text": [ "hypertension" ], "offsets": [ [ 679, 691 ] ], "normalized": [] }, { "id": "entity-58-7", "type": "DISEASE", "text": [ "insulin resistance" ], "offsets": [ [ 696, 714 ] ], "normalized": [] }, { "id": "entity-58-8", "type": "DISEASE", "text": [ "stroke" ], "offsets": [ [ 748, 754 ] ], "normalized": [] }, { "id": "entity-58-9", "type": "DISEASE", "text": [ "insulin resistance" ], "offsets": [ [ 934, 952 ] ], "normalized": [] }, { "id": "entity-58-10", "type": "DISEASE", "text": [ "metabolic syndrome" ], "offsets": [ [ 961, 979 ] ], "normalized": [] }, { "id": "entity-58-11", "type": "DISEASE", "text": [ "ischemic cerebrovascular disease" ], "offsets": [ [ 997, 1029 ] ], "normalized": [] }, { "id": "entity-58-12", "type": "DISEASE", "text": [ "stroke" ], "offsets": [ [ 1249, 1255 ] ], "normalized": [] } ]

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[ { "id": "passage-59", "type": "abstract", "text": [ "Nonclinical aspects of biopharmaceutical development: discussion of case studies at a PhRMA-FDA workshop. Robust assessments of the nonclinical safety profile of biopharmaceuticals are best developed on a scientifically justified, case-by-case basis, with consideration of the therapeutic molecule, molecular target, and differences/similarities between nonclinical species and humans (ICH S6). Significant experience has been gained in the 10 years ensuing since publication of the ICH S6 guidance. In a PhRMA-FDA-sponsored workshop, \"Nonclinical Aspects of Biopharmaceutical Development,\" industry and US regulatory representatives engaged in exploration of current scientific and regulatory issues relating to the nonclinical development of biopharmaceuticals in order to share scientific learning and experience and to work towards establishing consistency in application of general principles and approaches. The proceedings and discussions of this workshop confirm general alignment of strategy and tactics in development of biopharmaceuticals with regard to such areas as species selection, selection of high doses in toxicology studies, selection of clinical doses, the conduct of developmental and reproductive toxicity (DART) studies, and assessment of carcinogenic potential. However, several important aspects, including, for example, appropriate use of homologues, nonhuman primates, and/or in vitro models in the assessment of risk for potential developmental and carcinogenic effects, were identified as requiring further scientific exploration and discussion." ], "offsets": [ [ 0, 1576 ] ] } ]

[ { "id": "entity-59-0", "type": "ADVERSE", "text": [ "reproductive toxicity" ], "offsets": [ [ 1208, 1229 ] ], "normalized": [] } ]

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[ { "id": "passage-60", "type": "abstract", "text": [ "Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis. The objective of the study was to evaluate the clinical features, response to treatment, and long-term outcome of subglottic stenosis (SGS) in a series of patients diagnosed as having Wegener's granulomatosis (WG) at a single institution. Subglottic stenosis developed in 6 out of 51 (11.7%) patients, in four of them in the absence of other features of active disease, and was the symptom that leads to WG diagnosis in three cases. In two cases, SGS began while the patients were receiving systemic immunosuppressive therapy for disease activity involving other sites. PR3-ANCAs were positive in four cases. An urgent tracheostomy was needed in two patients. Four patients achieved SGS clinical remission on standard treatment with glucocorticoids and cyclophosphamide, but three of them experienced repeated local relapses and required additional immunosuppressive therapy and mechanical dilations. In one case, a local relapse was successfully managed with endotracheal dilation of the stenotic segment and intralesional injection of a long-acting corticosteroid plus mechanical dilation of the stenotic segment (ILCD) without adding supplemental immunosuppressant drugs. Two patients with isolated SGS were also successfully managed with ILCD alone and did not require the institution of systemic immunosuppressive therapy. One patient underwent open surgical repair when the disease was under control. Our data suggest that Subglottic stenosis often occurs or progresses independently of other features of active WG, and that ILCD may be a safe alternative to conventional immunosuppressive therapy in patients who develop SGS in the absence of other features of active disease, allowing reducing the treatment-related toxicity." ], "offsets": [ [ 0, 1845 ] ] } ]

[ { "id": "entity-60-0", "type": "DISEASE", "text": [ "subglottic stenosis" ], "offsets": [ [ 48, 67 ] ], "normalized": [] }, { "id": "entity-60-1", "type": "DISEASE", "text": [ "Wegener's granulomatosis" ], "offsets": [ [ 85, 109 ] ], "normalized": [] }, { "id": "entity-60-2", "type": "DISEASE", "text": [ "subglottic stenosis" ], "offsets": [ [ 226, 245 ] ], "normalized": [] }, { "id": "entity-60-3", "type": "DISEASE", "text": [ "SGS" ], "offsets": [ [ 247, 250 ] ], "normalized": [] }, { "id": "entity-60-4", "type": "DISEASE", "text": [ "Wegener's granulomatosis" ], "offsets": [ [ 296, 320 ] ], "normalized": [] }, { "id": "entity-60-5", "type": "DISEASE", "text": [ "WG" ], "offsets": [ [ 322, 324 ] ], "normalized": [] }, { "id": "entity-60-6", "type": "DISEASE", "text": [ "Subglottic stenosis" ], "offsets": [ [ 351, 370 ] ], "normalized": [] }, { "id": "entity-60-7", "type": "DISEASE", "text": [ "WG" ], "offsets": [ [ 516, 518 ] ], "normalized": [] }, { "id": "entity-60-8", "type": "DISEASE", "text": [ "SGS" ], "offsets": [ [ 559, 562 ] ], "normalized": [] }, { "id": "entity-60-9", "type": "DISEASE", "text": [ "SGS" ], "offsets": [ [ 795, 798 ] ], "normalized": [] }, { "id": "entity-60-10", "type": "DISEASE", "text": [ "SGS" ], "offsets": [ [ 1314, 1317 ] ], "normalized": [] }, { "id": "entity-60-11", "type": "DISEASE", "text": [ "Subglottic stenosis" ], "offsets": [ [ 1541, 1560 ] ], "normalized": [] }, { "id": "entity-60-12", "type": "DISEASE", "text": [ "WG" ], "offsets": [ [ 1630, 1632 ] ], "normalized": [] }, { "id": "entity-60-13", "type": "DISEASE", "text": [ "SGS" ], "offsets": [ [ 1740, 1743 ] ], "normalized": [] }, { "id": "entity-60-14", "type": "ADVERSE", "text": [ "treatment-related toxicity" ], "offsets": [ [ 1818, 1844 ] ], "normalized": [] } ]

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[ { "id": "passage-61", "type": "abstract", "text": [ "Recent developments in the treatment of aggressive non-Hodgkin lymphoma. SUMMARY: Options for treating aggressive non-Hodgkin lymphoma (NHL) have expanded in recent years. In phase 3 clinical trials, giving rituximab with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) every 3 weeks (R-CHOP-21) has been associated with improved survival, without increased toxicity, in all patient groups studied. Giving dose-dense CHOP--CHOP every 2 weeks (CHOP-14)--has also proved appropriate for all patients 18-75 years old. Studies combining these approaches--dose-dense CHOP with rituximab (R-CHOP-14)--have shown improved survival over CHOP-14 in patients 60-81 years old. These results also indicate the importance of delivering chemotherapy at full dose and on schedule, which can improve survival in aggressive NHL. Effective delivery of dose-dense regimens requires granulocyte colony-stimulating factor support, which should also be considered for standard CHOP. A key question for the future is whether R-CHOP-14 is superior to R-CHOP-21." ], "offsets": [ [ 0, 1056 ] ] } ]

[ { "id": "entity-61-0", "type": "DISEASE", "text": [ "non-Hodgkin lymphoma" ], "offsets": [ [ 51, 71 ] ], "normalized": [] }, { "id": "entity-61-1", "type": "DISEASE", "text": [ "non-Hodgkin lymphoma" ], "offsets": [ [ 115, 135 ] ], "normalized": [] }, { "id": "entity-61-2", "type": "DISEASE", "text": [ "NHL" ], "offsets": [ [ 137, 140 ] ], "normalized": [] }, { "id": "entity-61-3", "type": "DISEASE", "text": [ "NHL" ], "offsets": [ [ 826, 829 ] ], "normalized": [] } ]

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[ { "id": "passage-62", "type": "abstract", "text": [ "Factors affecting sensitivity of distortion-product otoacoustic emissions to ototoxic hearing loss. OBJECTIVES: (1) To determine the ototoxicity detection rate (sensitivity) for distortion-product otoacoustic emissions (DPOAEs) testing in adults who received ototoxic medications and experienced pure-tone threshold changes during the course of treatment; (2) to determine the extent to which DPOAE sensitivity to ototoxicity depends on the type of drug administered (platinum or antibiotic), magnitude of ototoxic threshold shifts, pre-exposure pure-tone threshold, and DPOAE data; and (3) to build a model to predict DPOAE sensitivity. DESIGN: DPOAE and audiometric data were obtained as part of a prospective Veterans Affairs study investigating methods of ototoxicity monitoring. Data were analyzed from 90 ears of 53 subjects receiving ototoxic medications and showing significant hearing changes in at least one ear. Pure-tone threshold data were obtained at frequencies from 0.5 to 20 kHz, using 1/6-octave precision near the upper frequency limit of hearing. DPOAE data are reported for f2's from 0.8 to 8.0 kHz in 1/6-octave increments using primary levels (L1/L2) of 65/59 dB SPL and a primary frequency ratio (f2/f1) of 1.2. Test results were evaluated at various times during drug treatment to determine whether DPOAE level changes were associated with behavioral hearing changes. Univariate and multivariate analysis techniques were used to determine factors that affected DPOAE sensitivity to ototoxic damage. RESULTS: Of the 90 ears examined, 82 (91%) had DPOAEs that could be monitored for changes. Sixty-four of these 82 ears (78%) had DPOAEs that were reduced or absent following drug treatment. DPOAE sensitivity to ototoxicity was unrelated to the type of ototoxic drug administered. Rather, DPOAE sensitivity depended on the magnitude of postexposure hearing changes and on variables related to pre-exposure audiogram and DPOAE measurements. Behavioral hearing changes not detected by DPOAEs were small on average (<7 dB). DPOAE sensitivity was reduced in ears with poorer pre-exposure hearing, and in ears with measurable DPOAE frequencies limited to f2's below 2.5 kHz or more than one octave from the frequency region where hearing change occurred. Results of logistic regression modeling showed that DPOAEs present at f2's greater than 2.5 kHz were associated with the eventual success of ototoxicity monitoring with DPOAEs. However, independent variables examined could not explain differences in the relative timing of behavioral and DPOAE changes. A roughly equivalent proportion of ears experienced DPOAE changes before, during, or after behavioral hearing changes. CONCLUSIONS: DPOAEs are a useful screening tool for ototoxicity in adults with pre-exposure hearing loss, but are less sensitive compared with a behavioral test method that targets thresholds near the upper limit of a subject's audible frequency range. Ears successfully monitored for ototoxicity with DPOAEs are those with better pre-exposure hearing, greater postexposure hearing changes, and baseline DPOAEs near the highest behavioral test frequencies and present at high f2's. Results suggest that successful monitoring of ototoxicity with DPOAEs may be predicted clinically by assessing the measurable DPOAE f2 frequency range and its relation to the highest behavioral test frequencies." ], "offsets": [ [ 0, 3389 ] ] } ]

[ { "id": "entity-62-0", "type": "ADVERSE", "text": [ "ototoxic hearing loss" ], "offsets": [ [ 77, 98 ] ], "normalized": [] }, { "id": "entity-62-1", "type": "ADVERSE", "text": [ "ototoxicity" ], "offsets": [ [ 134, 145 ] ], "normalized": [] }, { "id": "entity-62-2", "type": "ADVERSE", "text": [ "ototoxicity" ], "offsets": [ [ 415, 426 ] ], "normalized": [] }, { "id": "entity-62-3", "type": "ADVERSE", "text": [ "ototoxicity" ], "offsets": [ [ 761, 772 ] ], "normalized": [] }, { "id": "entity-62-4", "type": "ADVERSE", "text": [ "ototoxic damage" ], "offsets": [ [ 1508, 1523 ] ], "normalized": [] }, { "id": "entity-62-5", "type": "ADVERSE", "text": [ "ototoxicity" ], "offsets": [ [ 1736, 1747 ] ], "normalized": [] }, { "id": "entity-62-6", "type": "ADVERSE", "text": [ "ototoxicity" ], "offsets": [ [ 2415, 2426 ] ], "normalized": [] }, { "id": "entity-62-7", "type": "DISEASE", "text": [ "ototoxicity" ], "offsets": [ [ 2748, 2759 ] ], "normalized": [] }, { "id": "entity-62-8", "type": "ADVERSE", "text": [ "hearing loss" ], "offsets": [ [ 2788, 2800 ] ], "normalized": [] }, { "id": "entity-62-9", "type": "ADVERSE", "text": [ "ototoxicity" ], "offsets": [ [ 2981, 2992 ] ], "normalized": [] }, { "id": "entity-62-10", "type": "ADVERSE", "text": [ "ototoxicity" ], "offsets": [ [ 3224, 3235 ] ], "normalized": [] } ]

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[ { "id": "passage-63", "type": "abstract", "text": [ "A new lipoglycopeptide: telavancin. The increase in infections caused by resistant Gram-positive organisms has led to an urgent need for new antibiotics. Telavancin is a rapidly bactericidal lipoglycopeptide with multiple mechanisms of action, including concentration-dependent inhibition of bacterial cell wall synthesis and disruption of the functional integrity of the cell membrane. Telavancin is active against a wide variety of Gram-positive organisms including Staphylococcus aureus with resistance to methicillin, reduced susceptibility to vancomycin, and full resistance to vancomycin. Telavacin is approximately 90% protein bound; it has a serum half-life of around 8 h and a prolonged postantibiotic effect, allowing once daily administration. Telavancin is eliminated principally through the urine, requiring dose adjustment in patients with renal impairment. The efficacy and safety of telavancin was demonstrated in a large program of patients with complicated skin and skin structure infections. Development of resistance has not been detected in clinical strains. Adverse events include taste disturbance, nausea and vomiting; a small proportion of patients experienced reversible increase in serum creatinine. Two large Phase III studies in patients with healthcare associated pneumonia were recently completed. Telavancin has the potential to become an important therapeutic option to treat serious infections produced by resistant Gram-positive cocci, particularly those caused by methicillin-resistant S. aureus." ], "offsets": [ [ 0, 1533 ] ] } ]

[ { "id": "entity-63-0", "type": "DISEASE", "text": [ "renal impairment" ], "offsets": [ [ 855, 871 ] ], "normalized": [] }, { "id": "entity-63-1", "type": "ADVERSE", "text": [ "taste disturbance" ], "offsets": [ [ 1104, 1121 ] ], "normalized": [] }, { "id": "entity-63-2", "type": "ADVERSE", "text": [ "nausea" ], "offsets": [ [ 1123, 1129 ] ], "normalized": [] }, { "id": "entity-63-3", "type": "ADVERSE", "text": [ "vomiting" ], "offsets": [ [ 1134, 1142 ] ], "normalized": [] }, { "id": "entity-63-4", "type": "DISEASE", "text": [ "pneumonia" ], "offsets": [ [ 1295, 1304 ] ], "normalized": [] }, { "id": "entity-63-5", "type": "DISEASE", "text": [ "infections" ], "offsets": [ [ 1418, 1428 ] ], "normalized": [] } ]

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[ { "id": "passage-64", "type": "abstract", "text": [ "Acute generalised exanthematous pustulosis and toxic epidermal necrolysis induced by carbamazepine. Acute generalised exanthematous pustulosis and Stevens-Johnson syndrome (toxic epidermal necrolysis spectrum of severe cutaneous drug reactions) are believed to have distinct underlying pathophysiologies. Our patient, a 28-year-old Chinese woman, represents the first known reported case of clinically-consistent and histologically-proven acute generalised exanthematous pustulosis and toxic epidermal necrolysis overlap induced by carbamazepine in the English literature." ], "offsets": [ [ 0, 573 ] ] } ]

[ { "id": "entity-64-0", "type": "ADVERSE", "text": [ "Acute generalised exanthematous pustulosis" ], "offsets": [ [ 0, 42 ] ], "normalized": [] }, { "id": "entity-64-1", "type": "ADVERSE", "text": [ "toxic epidermal necrolysis" ], "offsets": [ [ 47, 73 ] ], "normalized": [] }, { "id": "entity-64-2", "type": "ADVERSE", "text": [ "Acute generalised exanthematous pustulosis" ], "offsets": [ [ 101, 143 ] ], "normalized": [] }, { "id": "entity-64-3", "type": "ADVERSE", "text": [ "Stevens-Johnson syndrome" ], "offsets": [ [ 148, 172 ] ], "normalized": [] }, { "id": "entity-64-4", "type": "ADVERSE", "text": [ "toxic epidermal necrolysis" ], "offsets": [ [ 174, 200 ] ], "normalized": [] }, { "id": "entity-64-5", "type": "ADVERSE", "text": [ "acute generalised exanthematous pustulosis" ], "offsets": [ [ 440, 482 ] ], "normalized": [] }, { "id": "entity-64-6", "type": "ADVERSE", "text": [ "toxic epidermal necrolysis" ], "offsets": [ [ 487, 513 ] ], "normalized": [] } ]

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[ { "id": "passage-65", "type": "abstract", "text": [ "Proteasome activation by hepatitis C core protein is reversed by ethanol-induced oxidative stress. BACKGROUND & AIMS: The proteasome is a major cellular proteinase. Its activity is modulated by cellular oxidants. Hepatitis C core protein and ethanol exposure both cause enhanced oxidant generation. The aim was to investigate whether core protein, by its ability to generate oxidants, alters proteasome activity and whether these alterations are further affected by ethanol exposure. METHODS: These interactions were examined in Huh-7 cell lines that expressed inducible HCV core protein and/or constitutive cytochrome P450 2E1 (CYP2E1) and as purified components in a cell-free system. Chymotrypsin-like proteasome activity was measured fluorometrically. RESULTS: Proteasome activity in core-positive 191-20 cells was 20% higher than that in core-negative cells and was enhanced 3-fold in CYP2E1-expressing L14 cells. Exposure of core-positive cells to glutathione ethyl ester, catalase, or the CYP2E1 inhibitor diallyl sulfide partially reversed the elevation of proteasome activity in core-positive cells, whereas ethanol exposure suppressed proteasome activity. The results indicate that proteasome activity was up-regulated by low levels of core-induced oxidative stress but down-regulated by high levels of ethanol-elicited stress. These findings were partially mimicked in a cell-free system. Addition of core protein enhanced the peptidase activity of purified 20S proteasome containing the proteasome activator PA28 and was further potentiated by addition of liver mitochondrial and/or microsome fractions. However, proteasome activation was significantly attenuated when fractions were obtained from ethanol-fed animals. CONCLUSIONS: HCV core protein interacts with PA28, mitochondrial, and endoplasmic reticulum proteins to cause low levels of oxidant stress and proteasome activation, which is dampened during ethanol metabolism when oxidant generation is higher." ], "offsets": [ [ 0, 1976 ] ] } ]

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[ { "id": "passage-66", "type": "abstract", "text": [ "Evolving concepts in liver tissue modeling and implications for in vitro toxicology. The development of human cell models stably expressing functional properties of the in vivo cells they are derived from for predicting toxicity of chemicals is a major challenge. For mimicking the liver, a major target of toxic chemicals, primary hepatocytes represent the most pertinent model. Their use is limited by interdonor functional variability and early phenotypic changes although their lifespan can be extended not only by culturing in a 2D dimension under sophisticated conditions but also by the use of synthetic and natural scaffolds as 3D supporting templates that allow cells to have a more stable microenvironment. Hepatocytes derived from stem cells could be the most appropriate alternative but up to now only liver progenitors/hepatoblasts are obtained in vitro. A few hepatocyte cell lines have retained a variable set of liver-specific functions. Among them are the human hepatoma HepaRG cells that express drug metabolism capacity at levels close to those found in primary hepatocytes making them a suitable model for both acute and chronic toxicity studies. New screening strategies are now proposed based on miniaturized and automated systems; they include the use of microfluidic chips and cell chips coupled with high content imaging analysis. Toxicogenomics technologies (particularly toxicotranscriptomics) have emerged as promising in vitro approaches for better identification and discrimination of cellular responses to chemicals. They should allow to discriminate compounds on the basis of the identification of a set of markers and/specific signaling pathways." ], "offsets": [ [ 0, 1680 ] ] } ]

[ { "id": "entity-66-0", "type": "ADVERSE", "text": [ "chronic toxicity" ], "offsets": [ [ 1142, 1158 ] ], "normalized": [] } ]

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[ { "id": "passage-67", "type": "abstract", "text": [ "Mycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-versus-host disease-like changes. Mycophenolate mofetil (MMF) is a commonly used immunosuppressive drug used in the management of transplant recipients. Although gastrointestinal (GI) toxicity is a known complication of MMF, the literature characterizing the pathologic features of MMF in the GI tract is sparse. This study characterizes the pathologic features of MMF toxicity in both the upper and lower GI tract, correlating it with clinical and endoscopic findings. Seventy-five GI biopsies (9 esophageal, 15 gastric, 16 duodenal, 5 ileal, 30 colonic) from 46 transplant recipients from 2002 to 2006 were obtained and assessed for multiple histologic features. Clinical features were recorded for all cases and endoscopic findings. Only MMF patients showed ulcerative esophagitis (5/7 cases) and reactive gastropathy (4/10 cases). Only MMF patients showed graft-versus-host disease (GVHD)-like features in duodenal (4/12 cases) and ileal (1/5 cases) biopsies. GVHD-like changes were seen more frequently among patients on MMF compared with those not on MMF [9 (56%) vs. 2 (14%); P=0.017]. Crypt architectural disarray [12 (75%) vs. 2 (14%); P=0.001], lamina propria edema [9 (56%) vs. 2 (14%); P=0.017], increased lamina propria inflammation [13 (81%) vs. 3 (21%); P=0.001], dilated damaged crypts [7 (44%) vs. 1 (7%); P=0.024], and increased crypt epithelial apoptosis [9 (56%) vs. 2 (14%); P=0.017] were more common with MMF patients compared with non-MMF patients. In conclusion, pathologists should be aware of the potential manifestations of MMF toxicity throughout the GI tract, including ulcerative esophagitis, reactive gastropathy, and GVHD-like features in intestinal biopsies." ], "offsets": [ [ 0, 1797 ] ] } ]

[ { "id": "entity-67-0", "type": "ADVERSE", "text": [ "gastrointestinal mucosal injury" ], "offsets": [ [ 30, 61 ] ], "normalized": [] }, { "id": "entity-67-1", "type": "ADVERSE", "text": [ "graft-versus-host disease" ], "offsets": [ [ 99, 124 ] ], "normalized": [] }, { "id": "entity-67-2", "type": "ADVERSE", "text": [ "gastrointestinal (GI) toxicity" ], "offsets": [ [ 268, 298 ] ], "normalized": [] }, { "id": "entity-67-3", "type": "ADVERSE", "text": [ "MMF toxicity" ], "offsets": [ [ 471, 483 ] ], "normalized": [] }, { "id": "entity-67-4", "type": "ADVERSE", "text": [ "ulcerative esophagitis" ], "offsets": [ [ 867, 889 ] ], "normalized": [] }, { "id": "entity-67-5", "type": "ADVERSE", "text": [ "reactive gastropathy" ], "offsets": [ [ 906, 926 ] ], "normalized": [] }, { "id": "entity-67-6", "type": "ADVERSE", "text": [ "graft-versus-host disease" ], "offsets": [ [ 966, 991 ] ], "normalized": [] }, { "id": "entity-67-7", "type": "ADVERSE", "text": [ "GVHD" ], "offsets": [ [ 993, 997 ] ], "normalized": [] }, { "id": "entity-67-8", "type": "ADVERSE", "text": [ "GVHD" ], "offsets": [ [ 1070, 1074 ] ], "normalized": [] }, { "id": "entity-67-9", "type": "ADVERSE", "text": [ "Crypt architectural disarray" ], "offsets": [ [ 1199, 1227 ] ], "normalized": [] }, { "id": "entity-67-10", "type": "ADVERSE", "text": [ "lamina propria edema" ], "offsets": [ [ 1261, 1281 ] ], "normalized": [] }, { "id": "entity-67-11", "type": "ADVERSE", "text": [ "lamina propria inflammation" ], "offsets": [ [ 1324, 1351 ] ], "normalized": [] }, { "id": "entity-67-12", "type": "ADVERSE", "text": [ "dilated damaged crypts" ], "offsets": [ [ 1385, 1407 ] ], "normalized": [] }, { "id": "entity-67-13", "type": "ADVERSE", "text": [ "MMF toxicity" ], "offsets": [ [ 1657, 1669 ] ], "normalized": [] }, { "id": "entity-67-14", "type": "ADVERSE", "text": [ "ulcerative esophagitis" ], "offsets": [ [ 1705, 1727 ] ], "normalized": [] }, { "id": "entity-67-15", "type": "ADVERSE", "text": [ "reactive gastropathy" ], "offsets": [ [ 1729, 1749 ] ], "normalized": [] }, { "id": "entity-67-16", "type": "ADVERSE", "text": [ "GVHD" ], "offsets": [ [ 1755, 1759 ] ], "normalized": [] } ]

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[ { "id": "passage-68", "type": "abstract", "text": [ "Broccoli flower head extract reduces mitomycin-C induced sister chromatid exchange in cultured human lymphocytes. This study is a continuation of our previous work [Murugan, S.S., Balakrishnamurthy, P., Mathew, Y.J., 2007. Antimutagenic effect of broccoli flower head by the Ames Salmonella reverse mutation assay. Phytother. Res. 21, 545-547], in search of possible antimutagenic properties in broccoli flower head extracts. In the present investigation, the effect of addition of ethanol extract of broccoli flower head on mitomycin-C (MMC) induced sister chromatid exchange (SCE) in cultured human peripheral blood lymphocytes was investigated. Broccoli flower head was extracted in ethanol using either acetone or ethanol as solvents. The extract was tested at final concentrations of 200 and 400 microg/ml culture and set for SCE assay. MMC at a concentration of 1 microg/ml and the test concentrations of broccoli flower head were added to the culture following 48 h from the initiation of culture. Enumeration of SCE in second division mitotic cells indicated that broccoli flower head extract significantly reduced MMC induced SCEs at both the concentrations tested. This observation is in line with our earlier finding and confirms to the presence of antimutagenic principles in broccoli flower head extract." ], "offsets": [ [ 0, 1318 ] ] } ]

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[ { "id": "passage-69", "type": "abstract", "text": [ "Establishing causality in the assessment of safety of medicines for children. BACKGROUND: Data on safety of medicines in children typically arises from various sources, rendering assessment of causality challenging. METHODS: We outline these sources, together with their strengths and weaknesses. Bradford Hill proposed criteria for assessment of causality of observed associations; we explore their utility in this context. CONCLUSION: Collaborations between clinicians, epidemiologists and clinical pharmacologists, making intelligent use of both older and newer methodologies, can help make the use of medicines in children safer." ], "offsets": [ [ 0, 634 ] ] } ]

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[ { "id": "passage-70", "type": "abstract", "text": [ "The effect of thiazolidinediones on BMD and osteoporosis. Thiazolidinediones, also known as glitazones, are insulin-sensitizing medications that account for approximately 21% of oral antihyperglycemic drugs used in the US. Although the main therapeutic effects occur in adipose tissue, muscles and the liver, studies suggest effects in bone as well. Currently, two thiazolidinediones are marketed in the US-rosiglitazone and pioglitazone-and several others are under investigation. This Review examines the evidence regarding the effects of thiazolidinediones on skeletal health. These drugs appear to trigger preferential differentiation of mesenchymal stem cells into adipocytes rather than osteoblasts, leading to decreased bone formation and increased adipogenesis. Although only a few small, randomized studies have examined the effects of thiazolidinediones on bone in humans, the available data suggest that these agents contribute to bone loss in postmenopausal women; the relationship is less clear in men. On the basis of this limited evidence, the absolute increase in fracture risk associated with thiazolidinediones seems to be small. Pending data from future randomized, controlled trials of the association between thiazolidinediones and low bone mass, prescribers should consider use of these drugs as a risk factor for the development of osteoporosis in postmenopausal women." ], "offsets": [ [ 0, 1393 ] ] } ]

[ { "id": "entity-70-0", "type": "DISEASE", "text": [ "BMD" ], "offsets": [ [ 36, 39 ] ], "normalized": [] }, { "id": "entity-70-1", "type": "DISEASE", "text": [ "osteoporosis" ], "offsets": [ [ 44, 56 ] ], "normalized": [] }, { "id": "entity-70-2", "type": "ADVERSE", "text": [ "bone loss" ], "offsets": [ [ 943, 952 ] ], "normalized": [] }, { "id": "entity-70-3", "type": "ADVERSE", "text": [ "fracture" ], "offsets": [ [ 1081, 1089 ] ], "normalized": [] }, { "id": "entity-70-4", "type": "ADVERSE", "text": [ "osteoporosis" ], "offsets": [ [ 1356, 1368 ] ], "normalized": [] } ]

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[ { "id": "passage-71", "type": "abstract", "text": [ "Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). OBJECTIVES: PETACC-1 assessed if raltitrexed is non-inferior to 5-fluorouracil and leucovorin for relapse-free survival (RFS) and overall survival (OS) in adjuvant stage III colon cancer. METHODS: Non-inferiority required both HR for RFS and OS<1.25 at 1-sided alpha=0.05. Patients (1921) were randomised to six cycles of 5-FU/LV (n=969) or eight cycles of raltitrexed (n=952). We report the final results in 993 eligible patients who started and completed the allocated treatment (489 5-FU/LV and n=504 Raltitrexed) of whom respectively 146 and 148 died, respectively. RESULTS: The trial closed prematurely when 17 (1.9%) raltitrexed-related deaths were reported. Haematological and gastrointestinal toxicities were more frequent with 5-FU/LV, liver toxicities with raltitrexed. Raltitrexed was stopped for toxicity in 13.2% and 5-FU/LV in 8.5%. Sixty-day mortality was 9% versus 7%. With 4.1 years median follow-up, the HR for RFS was 1.16 (90% CI 0.99-1.37) and that for OS was 1.01 (90% CI 0.84-1.23). CONCLUSION: The trial failed to demonstrate non-inferiority of raltitrexed. FUNDING: Free drugs and financial support from AstraZeneca." ], "offsets": [ [ 0, 1320 ] ] } ]

[ { "id": "entity-71-0", "type": "DISEASE", "text": [ "Colon Cancer" ], "offsets": [ [ 150, 162 ] ], "normalized": [] }, { "id": "entity-71-1", "type": "DISEASE", "text": [ "colon cancer" ], "offsets": [ [ 353, 365 ] ], "normalized": [] }, { "id": "entity-71-2", "type": "ADVERSE", "text": [ "gastrointestinal toxicities" ], "offsets": [ [ 863, 890 ] ], "normalized": [] }, { "id": "entity-71-3", "type": "ADVERSE", "text": [ "liver toxicities" ], "offsets": [ [ 924, 940 ] ], "normalized": [] } ]

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[ { "id": "passage-72", "type": "abstract", "text": [ "Identifying patterns of adverse event reporting for four members of the angiotensin II receptor blockers class of drugs: revisiting the Weber effect. PURPOSE: To evaluate the evidence for temporal reporting patterns, such as the Weber effect, in spontaneous post-marketing adverse event (AE) reports submitted to the Food and Drug Administration (FDA), for four members of the angiotensin II receptor blockers drug class (ARBs). METHODS: For losartan, valsartan, irbesartan, and candesartan, we evaluated temporal trends in reporting for the total number of AE reports, serious AE reports, and direct reports from consumers or health care providers (direct reports) to FDA. Reporting patterns were considered consistent with the Weber effect when the peak occurred 2 years after US marketing and the number of reports declined thereafter. We tabulated the number of reports by year since the first report. We adjusted the total number of reports, number of serious AE reports, and number of direct reports by the number of US dispensed prescriptions. RESULTS: There were no clear temporal reporting patterns for the total number of reports, direct reports, or serious AE reports. We observed a consistent trend for the adjusted number of direct and serious AE reports. The adjusted number was highest in the first year and continually decreased over time for all four ARBs. For the adjusted total number of reports, the decline was not constant over time. CONCLUSION: A characteristic temporal pattern in the adjusted number of reports, in which the adjusted number was highest in the first year and declined thereafter, was identified. However, we did not observe a pattern consistent with the Weber effect for these four ARBs." ], "offsets": [ [ 0, 1729 ] ] } ]

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[ { "id": "passage-73", "type": "abstract", "text": [ "Pharmacogenetics of Crohn's disease. The considerable interindividual differences in efficacy and side effects of commonly used medications in Crohn's disease are partly owing to genetic polymorphisms. Many genetic variants have been studied in genes possibly involved in the metabolism or mechanism of action of therapeutic agents such as glucocorticosteroids, azathioprine/6-mercaptopurine, methotrexate, calcineurin inhibitors or anti-TNF agents. However, the only test translated into clinical practice is thiopurine S-methyltransferase (TPMT) genotyping for hematological toxicity of thiopurine treatment. To date, there are no other meaningful applications for pharmacogenomics in clinical practice of Crohn's disease. In the future, designed therapeutic trials should possibly permit the development of predictive models including genotypic markers, such as that proposed for the clinical outcome after infliximab therapy, which includes an apoptotic pharmacogenetic index. The recent identification of new susceptibility genes provides additional candidate markers that have possible effects on the outcomes of therapies, and prioritizes new therapeutic targets, such as the IL-23 pathway. Further innovative approaches might be relevant for the pharmacogenetic investigation of gene variants implied in innate immune pattern recognition and autophagy." ], "offsets": [ [ 0, 1361 ] ] } ]

[ { "id": "entity-73-0", "type": "DISEASE", "text": [ "Crohn's disease" ], "offsets": [ [ 20, 35 ] ], "normalized": [] }, { "id": "entity-73-1", "type": "DISEASE", "text": [ "Crohn's disease" ], "offsets": [ [ 144, 159 ] ], "normalized": [] }, { "id": "entity-73-2", "type": "ADVERSE", "text": [ "hematological toxicity" ], "offsets": [ [ 564, 586 ] ], "normalized": [] }, { "id": "entity-73-3", "type": "DISEASE", "text": [ "Crohn's disease" ], "offsets": [ [ 709, 724 ] ], "normalized": [] } ]

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[ { "id": "passage-74", "type": "abstract", "text": [ "Pharmacokinetic and safety profile of rupatadine when coadministered with azithromycin at steady-state levels: a randomized, open-label, two-way, crossover, Phase I study. BACKGROUND: Rupatadine is an oral active antihistamine and platelet-activating factor antagonist indicated for the management of allergic rhinitis and chronic urticaria in Europe. OBJECTIVE: The purpose of this study was to describe the effect of the concomitant administration of azithromycin and rupatadine on the pharmacokinetics of rupatadine and its metabolites after repeated doses. METHODS: This was a multiple-dose, randomized, open-label, 2-way, crossover, Phase I study in which healthy male and female volunteers received rupatadine 10 mg once a day for 6 days either alone or with azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6. Treatments were administered after a fasting period of 10 hours with 240 mL of water, and fasting conditions were kept until 3 hours postmedication. A washout period of at least 21 days between the 2 active periods was observed. Blood samples were collected and plasma concentrations of rupatadine and its metabolites desloratadine and 3-hydroxydesloratadine were determined by liquid chromatography tandem mass spectrometry. Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiograms, and laboratory screen controls at baseline and the final study visit. RESULTS: Twenty-four healthy volunteers (15 males, 9 females; mean [SD] age, 25.67 [5.58] years; weight, 65.96 [8.57] kg) completed the study. Except for maximum observed concentration during a dosing interval (Cmax,ss) of 3-hydroxydesloratadine, on average, there were no statistically significant differences in mean plasma concentrations in any of the main pharmacokinetic parameters of rupatadine, desloratadine, and 3-hydroxydesloratadine when administered in combination with azithromycin or alone. The Cmax,ss ratio was 111 (90% CI, 91-136) and area under the plasma concentration-time curve during a dosing interval (AUC0-tau) ratio had a value of 103 (90% CI, 91-117). The corresponding ratios for the rupatadine metabolites were 109 (90% CI, 100-120) for Cmax,ss and 103 (90% CI, 96-110) for AUC0-tau for desloratadine and 109 (90% CI, 103-115) for Cmax,ss and 104 (90% CI, 100-108) for AUC0-tau for 3-hydroxydesloratadine. Point estimates for Cmax,ss ratios using paired data were 111% for rupatadine, 109% for desloratadine, and 109% for 3-hydroxydesloratadine. The 90% CIs were included in the interval 80% to 125% for desloratadine and 3-hydroxydesloratadine, whereas 90% CI for rupatadine was shifted to the right of the interval used for comparing bioavailability of the drugs. A total of 5 subjects reported 9 AEs; 5 of these were thought to be related to the drug administration and all were categorized as mild or moderate. The reported AEs were somnolence (1/24 in the rupatadine group and 1/24 in the rupatadine plus azithromycin group), diarrhea (1/24 in the rupatadine plus azithromycin group), and gastric discomfort (2/24 in the rupatadine plus azithromycin group). Four AEs were considered not to be related (2 episodes of headache, 1 anemia, 1 cheilitis). All were resolved spontaneously. No serious AEs were reported. CONCLUSIONS: The results of this study in these healthy volunteers found no significant differences in pharmacokinetic parameters other than Cmax,ss of 3-hydroxydesloratadine between rupatadine 10 mg administered alone or with azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6. The administration of rupatadine compared with rupatadine plus azithromycin met the regulatory definition of bioequivalence in terms of exposure and rate parameters; however, Cmax,ss of rupatadine was outside the conventional confidence interval." ], "offsets": [ [ 0, 3810 ] ] } ]

[ { "id": "entity-74-0", "type": "DISEASE", "text": [ "allergic rhinitis" ], "offsets": [ [ 302, 319 ] ], "normalized": [] }, { "id": "entity-74-1", "type": "DISEASE", "text": [ "chronic urticaria" ], "offsets": [ [ 324, 341 ] ], "normalized": [] }, { "id": "entity-74-2", "type": "ADVERSE", "text": [ "somnolence" ], "offsets": [ [ 2895, 2905 ] ], "normalized": [] }, { "id": "entity-74-3", "type": "ADVERSE", "text": [ "diarrhea" ], "offsets": [ [ 2989, 2997 ] ], "normalized": [] }, { "id": "entity-74-4", "type": "ADVERSE", "text": [ "gastric discomfort" ], "offsets": [ [ 3052, 3070 ] ], "normalized": [] }, { "id": "entity-74-5", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 3179, 3187 ] ], "normalized": [] }, { "id": "entity-74-6", "type": "ADVERSE", "text": [ "anemia" ], "offsets": [ [ 3191, 3197 ] ], "normalized": [] }, { "id": "entity-74-7", "type": "ADVERSE", "text": [ "cheilitis" ], "offsets": [ [ 3201, 3210 ] ], "normalized": [] } ]

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[ { "id": "passage-75", "type": "abstract", "text": [ "Pluripotent stem cell lines. The derivation of human embryonic stem cells 10 years ago ignited an explosion of public interest in stem cells, yet this achievement depended on prior decades of research on mouse embryonic carcinoma cells and embryonic stem cells. In turn, the recent derivation of mouse and human induced pluripotent stem cells depended on the prior studies on mouse and human embryonic stem cells. Both human embryonic stem cells and induced pluripotent stem cells can self-renew indefinitely in vitro while maintaining the ability to differentiate into advanced derivatives of all three germ layers, features very useful for understanding the differentiation and function of human tissues, for drug screen and toxicity testing, and for cellular transplantation therapies. Here we review the family of pluripotent cell lines derived from early embryos and from germ cells, and compare them with the more recently described induced pluripotent stem cells." ], "offsets": [ [ 0, 971 ] ] } ]

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[ { "id": "passage-76", "type": "abstract", "text": [ "Advances in plasma skin regeneration. Plasma skin regeneration (PSR) is a novel method of resurfacing that uses plasma energy to create a thermal effect on the skin. PSR is different from lasers, light sources, and ablative lasers in that it is not chromophore dependent and does not vaporize tissue, but leaves a layer of intact, desiccated epidermis that acts as a natural biologic dressing and promotes wound healing and rapid recovery. Histological studies performed on plasma resurfacing patients have confirmed continued collagen production, reduction of elastosis, and progressive skin rejuvenation beyond 1 year after treatment. PSR has received US Food and Drug Administration 510 (k) clearance for treatment of rhytides of the body, superficial skin lesions, actinic keratoses, viral papillomata, and seborrheic keratoses. PSR also has beneficial effects in the treatment of other conditions including dyschromias, photoaging, skin laxity, and acne scars. The safety profile of PSR is excellent, and there have been no reports of demarcation lines in perioral, periorbital, or jawline areas, as can sometimes be observed following CO2 resurfacing. PSR is effective in improving facial and periorbital rhytides and can be used on nonfacial sites, including the hands, neck, and chest. Numerous treatment protocols with variable energy settings allow for individualized treatments and provide the operator with fine control over the degree of injury and length of subsequent recovery time." ], "offsets": [ [ 0, 1498 ] ] } ]

[ { "id": "entity-76-0", "type": "DISEASE", "text": [ "wound" ], "offsets": [ [ 407, 412 ] ], "normalized": [] }, { "id": "entity-76-1", "type": "DISEASE", "text": [ "rhytides of the body" ], "offsets": [ [ 722, 742 ] ], "normalized": [] }, { "id": "entity-76-2", "type": "DISEASE", "text": [ "superficial skin lesions" ], "offsets": [ [ 744, 768 ] ], "normalized": [] }, { "id": "entity-76-3", "type": "DISEASE", "text": [ "actinic keratoses" ], "offsets": [ [ 770, 787 ] ], "normalized": [] }, { "id": "entity-76-4", "type": "DISEASE", "text": [ "viral papillomata" ], "offsets": [ [ 789, 806 ] ], "normalized": [] }, { "id": "entity-76-5", "type": "DISEASE", "text": [ "seborrheic keratoses" ], "offsets": [ [ 812, 832 ] ], "normalized": [] }, { "id": "entity-76-6", "type": "DISEASE", "text": [ "dyschromias" ], "offsets": [ [ 913, 924 ] ], "normalized": [] }, { "id": "entity-76-7", "type": "DISEASE", "text": [ "photoaging" ], "offsets": [ [ 926, 936 ] ], "normalized": [] }, { "id": "entity-76-8", "type": "DISEASE", "text": [ "skin laxity" ], "offsets": [ [ 938, 949 ] ], "normalized": [] }, { "id": "entity-76-9", "type": "DISEASE", "text": [ "acne scars" ], "offsets": [ [ 955, 965 ] ], "normalized": [] } ]

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[ { "id": "passage-77", "type": "abstract", "text": [ "Hydrogen peroxide induces heme oxygenase-1 and dentin sialophosphoprotein mRNA in human pulp cells. Although the induction of heme oxygenase-1 (HO-1) by hydrogen peroxide (H2O2) has been reported, the HO-1 and odontoblastic differentiation-inducing effects against H2O2 have not been clarified in human pulp cells. In this study, we investigated whether HO-1 is involved in the protective mechanisms against the cytotoxic effects of H2O2 by using a cell viability assay, and we examined the production of dentin sialophosphoprotein (DSPP) and other mineralization markers by using reverse transcriptase-polymerase chain reaction in human pulp cells. H2O2 decreased cell viability but increased HO-1 and DSPP expression in a concentration- and time-dependent manner. Antioxidants and inhibitors of HO-1, phosphatidylinositol-3'-kinase, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase blocked H2O2-induced cytotoxicity and the expression of HO-1 and DSPP mRNA in pulp cells. These data suggest that the induction of HO-1 by H2O2 in pulp cells plays a protective role against the cytotoxic effects of H2O2 and stimulates DSPP expression, resulting in premature odontoblast differentiation through pathways that involve phosphatidylinositol-3'-kinase, p38, and extracellular signal-regulated kinase." ], "offsets": [ [ 0, 1328 ] ] } ]

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[ { "id": "passage-78", "type": "abstract", "text": [ "Pharmacokinetics of levobupivacaine 0.5% after superficial or combined (deep and superficial) cervical plexus block in patients undergoing minimally invasive parathyroidectomy. STUDY OBJECTIVE: To evaluate the pharmacokinetic profile of 0.35 mL/kg of 0.5% levobupivacaine during superficial and combined (deep and superficial) cervical plexus block (CPB) in patients undergoing minimally invasive parathyroidectomy. DESIGN: Prospective randomized study. SETTING: Operating theater of a university hospital. PATIENTS: 12 ASA physical status II and III patients (11 women and 1 man), scheduled for minimally invasive parathyroidectomy. INTERVENTIONS: Seven and 5 patients were randomly assigned to receive either superficial or combined CPB, respectively. The superficial CPB was performed with an injection of 0.35 mL/kg of 0.5% levobupivacaine subcutaneously along the posterior border of the sternocleidomastoid muscle and deeper on its medial surface. The combined CPB was initiated by the deep block at the C3 level vertebra by injecting 0.2 mL/kg of 0.5% levobupivacaine, followed by the superficial block with an injection of the remaining 0.15 mL/kg. After completion of the block, venous blood was sampled at the intervals of 5, 10, 15, 20, 30, 45, and 60 minutes. MEASUREMENTS AND MAIN RESULTS: Venous plasma concentrations were measured using gas chromatography-mass spectroscopy. Mean +/- SD of maximal concentrations of levobupivacaine was 0.58 +/- 0.41 mg/L in group superficial and 0.52 +/- 0.28 mg/L in group combined (P = 0.71). The median (range) time required to reach the maximal concentrations was 30 minutes (20-30 min) in group superficial and 20 minutes (15-30 min) in group combined (P = 0.45). The areas under the drug concentration/time curve (AUC(10-60)) were also similar in both groups. No signs of central nervous system or cardiovascular toxicity or other untoward events were observed in any patient. CONCLUSION: With the given dose regimen, levobupivacaine plasma concentrations were within safe ranges." ], "offsets": [ [ 0, 2036 ] ] } ]

[ { "id": "entity-78-0", "type": "ADVERSE", "text": [ "cardiovascular toxicity" ], "offsets": [ [ 1854, 1877 ] ], "normalized": [] } ]

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[ { "id": "passage-79", "type": "abstract", "text": [ "Genotoxicity evaluation of drinking water sources in human peripheral blood lymphocytes using the comet assay. The potential harm of organic pollutants in drinking water to human health is widely focused on in the world; more and more pollutants with genotoxic substances are released into the aquatic environment. Water source samples were collected from 7 different localities of Nanjing City. The potential genotoxicity of organic extracts from drinking water sources were investigated by means of the comet assay in human peripheral lymphocytes. The results showed that all the organic extracts from all the water source samples could induce DNA damages of human peripheral blood lymphocytes at different levels. A significant difference (P < 0.01) was observed when compared with the solvent control. The DNA damage increased with the increase of the dosage of the original water source. Significant differences of DNA damage were observed in different drinking water sources, as shown by the multiple comparisons analysis at the dosage of 100x; the degree of DNA damage treated by Hushu waterworks (at town level) was the most serious, the arbitrary units (AU) was 141.62 +/- 6.96, however, that of Shangyuanmen waterworks (at city level) was only 109.64 +/- 2.97. The analysis also revealed that the genotoxicity of town's water sources was higher than that of the city. The results demonstrated that the comet assay can be successfully applied to the genotoxicity monitoring programs of drinking water sources." ], "offsets": [ [ 0, 1519 ] ] } ]

[ { "id": "entity-79-0", "type": "ADVERSE", "text": [ "Genotoxicity" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "entity-79-1", "type": "ADVERSE", "text": [ "genotoxicity" ], "offsets": [ [ 411, 423 ] ], "normalized": [] }, { "id": "entity-79-2", "type": "ADVERSE", "text": [ "genotoxicity" ], "offsets": [ [ 1308, 1320 ] ], "normalized": [] }, { "id": "entity-79-3", "type": "ADVERSE", "text": [ "genotoxicity" ], "offsets": [ [ 1460, 1472 ] ], "normalized": [] } ]

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[ { "id": "passage-80", "type": "abstract", "text": [ "WITHDRAWN: Multi-agent chemotherapy for early breast cancer. BACKGROUND: There have been many randomised trials of adjuvant prolonged polychemotherapy among women with early breast cancer, and an updated overview of their results is presented. OBJECTIVES: In this report, the Early Breast Cancer Trialists' Collaborative Group present their updated systematic overview (meta-analysis) of treatment with polychemotherapy. SEARCH STRATEGY: Trial identification procedures for the EBCTCG overviews have been described elsewhere. See under \"EBCTCG\" in the Breast Cancer Collaborative Review Group module. SELECTION CRITERIA: All randomised trials that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens that were being compared. DATA COLLECTION AND ANALYSIS: In 1995, information was sought on each woman in any randomised trial that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens that were being compared. Analyses involved about 18,000 women in 47 trials of prolonged polychemotherapy versus no chemotherapy, about 6000 in 11 trials of longer versus shorter polychemotherapy, and about 6000 in 11 trials of anthracycline-containing regimens versus CMF (cyclophosphamide, methotrexate, and fluorouracil). MAIN RESULTS: For recurrence, polychemotherapy produced substantial and highly significant proportional reductions both among women aged under 50 at randomisation (35% [SD 4] reduction; 2p<0.00001) and among those aged 50-69 (20% [SD 3] reduction; 2p<0.00001); few women aged 70 or over had been studied. For mortality, the reductions were also significant both among women aged under 50 (27% [SD 5] reduction; 2p<0.00001) and among those aged 50-69 (11% [SD 3] reduction; 2p=0.0001). The recurrence reductions emerged chiefly during the first 5 years of follow-up, whereas the difference in survival grew throughout the first 10 years. After standardisation for age and time since randomisation, the proportional reductions in risk were similar for women with node-negative and node-positive disease. Applying the proportional mortality reduction observed in all women aged under 50 at randomisation would typically change a 10-year survival of 71% for those with node-negative disease to 78% (an absolute benefit of 7%), and of 42% for those with node-positive disease to 53% (an absolute benefit of 11%). The smaller proportional mortality reduction observed in all women aged 50-69 at randomisation would translate into smaller absolute benefits, changing a 10-year survival of 67% for those with node-negative disease to 69% (an absolute gain of 2%) and of 46% for those with node-positive disease to 49% (an absolute gain of 3%). The age-specific benefits of polychemotherapy appeared to be largely irrespective of menopausal status at presentation, oestrogen receptor status of the primary tumour, and of whether adjuvant tamoxifen had been given. In terms of other outcomes, there was a reduction of about one-fifth (2p=0.05) in contralateral breast cancer, which has already been included in the analyses of recurrence, and no apparent adverse effect on deaths from causes other than breast cancer (death rate ratio 0.89 [SD 0.09]). The directly randomised comparisons of longer versus shorter durations of polychemotherapy did not indicate any survival advantage with the use of more than about 3-6 months of polychemotherapy. By contrast, directly randomised comparisons did suggest that, compared with CMF alone, the anthracycline-containing regimens studied produced somewhat greater effects on recurrence (2p=0.006) and mortality (69% vs 72% 5-year survival; log-rank 2p=0.02). But this comparison is one of many that could have been selected for emphasis, the 99% CI reaches zero, and the results of several of the relevant trials are not yet available. AUTHORS' CONCLUSIONS: Some months of adjuvant polychemotherapy (eg, with CMF or an anthracycline-containing regimen) typically produces an absolute improvement of about 7-11% in 10-year survival for women aged under 50 at presentation with early breast cancer, and of about 2-3% for those aged 50-69 (unless their prognosis is likely to be extremely good even without such treatment). Treatment decisions involve consideration not only of improvements in cancer recurrence and survival but also of adverse side-effects of treatment, and this report makes no recommendations as to who should or should not be treated." ], "offsets": [ [ 0, 4508 ] ] } ]

[ { "id": "entity-80-0", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 46, 59 ] ], "normalized": [] }, { "id": "entity-80-1", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 175, 188 ] ], "normalized": [] }, { "id": "entity-80-2", "type": "DISEASE", "text": [ "Breast Cancer" ], "offsets": [ [ 283, 296 ] ], "normalized": [] }, { "id": "entity-80-3", "type": "DISEASE", "text": [ "Breast Cancer" ], "offsets": [ [ 553, 566 ] ], "normalized": [] }, { "id": "entity-80-4", "type": "DISEASE", "text": [ "contralateral breast cancer" ], "offsets": [ [ 3060, 3087 ] ], "normalized": [] }, { "id": "entity-80-5", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 3216, 3229 ] ], "normalized": [] }, { "id": "entity-80-6", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 4138, 4151 ] ], "normalized": [] }, { "id": "entity-80-7", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 4347, 4353 ] ], "normalized": [] } ]

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[ { "id": "passage-81", "type": "abstract", "text": [ "Changes in retinal sensitivity from retained subretinal perfluorocarbon liquid. PURPOSE: To study the effect of retained subretinal perfluorocarbon liquid (PFCL) on retinal function. METHODS: Scanning laser ophthalmoscope microperimetry was performed on four eyes with retained subretinal PFCL after vitreoretinal surgery for complicated retinal detachments with and without proliferative vitreoretinopathy. RESULTS: Scotomas to the highest intensity stimulus were noted in the area of the subretinal PFCL in all four eyes. All scotomas encompassed approximately the same area as the retained PFCL droplets. In the area vacated by a migrating PFCL droplet in one eye, the highest intensity stimulus could be perceived, but a relative scotoma (to a lower intensity stimulus) was present. CONCLUSIONS: There is a local reduction in retinal function in the area of retained subretinal PFCL. There may be partial recovery of retinal function in an area vacated by the subretinal PFCL. Subretinal PFCL beneath the fovea or at risk for migration beneath the fovea should be considered for removal." ], "offsets": [ [ 0, 1092 ] ] } ]

[ { "id": "entity-81-0", "type": "DISEASE", "text": [ "proliferative vitreoretinopathy" ], "offsets": [ [ 376, 407 ] ], "normalized": [] }, { "id": "entity-81-1", "type": "DISEASE", "text": [ "scotoma" ], "offsets": [ [ 735, 742 ] ], "normalized": [] } ]

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[ { "id": "passage-82", "type": "abstract", "text": [ "Dose intensive melphalan and cyclophosphamide with autologous hematopoietic stem cells for recurrent medulloblastoma or germinoma. PURPOSE: To determine the response, toxicity, and survival for children with progressive or recurrent medulloblastoma and germinoma using a single myeloablative course of chemotherapy supported by autologous hematopoietic stem cells. PATIENTS AND METHODS: Subjects were in second remission or had minimal residual disease at the time of study entry. The conditioning regimen consisted of cyclophosphamide 6,000 mg/m(2) plus melphalan 180 mg/m(2). RESULTS: Twenty-nine evaluable pediatric patients were accrued. The most frequent major toxicities were myelosuppression, infections, and stomatitis, but no toxic deaths were recorded. Best responses were: CR = 6, CCR = 13, PR = 6, SD = 2, and PD = 2. There were 6 medulloblastoma and 3 germinoma survivors with a median follow-up of 7.5 years (range = 2.8-10). Two germinoma survivors received radiotherapy after autografting for presumptive progressive disease. CONCLUSION: Myeloablative chemotherapy consisting of cyclophosphamide and melphalan was tolerable in the relapsed brain tumor setting with 19/29 cases achieving CR or CCR status and 9/29 becoming long-term survivors." ], "offsets": [ [ 0, 1259 ] ] } ]

[ { "id": "entity-82-0", "type": "DISEASE", "text": [ "recurrent medulloblastoma" ], "offsets": [ [ 91, 116 ] ], "normalized": [] }, { "id": "entity-82-1", "type": "DISEASE", "text": [ "germinoma" ], "offsets": [ [ 120, 129 ] ], "normalized": [] }, { "id": "entity-82-2", "type": "DISEASE", "text": [ "recurrent medulloblastoma" ], "offsets": [ [ 224, 249 ] ], "normalized": [] }, { "id": "entity-82-3", "type": "DISEASE", "text": [ "germinoma" ], "offsets": [ [ 254, 263 ] ], "normalized": [] }, { "id": "entity-82-4", "type": "ADVERSE", "text": [ "myelosuppression" ], "offsets": [ [ 683, 699 ] ], "normalized": [] }, { "id": "entity-82-5", "type": "ADVERSE", "text": [ "infections" ], "offsets": [ [ 701, 711 ] ], "normalized": [] }, { "id": "entity-82-6", "type": "ADVERSE", "text": [ "stomatitis" ], "offsets": [ [ 717, 727 ] ], "normalized": [] }, { "id": "entity-82-7", "type": "DISEASE", "text": [ "medulloblastoma" ], "offsets": [ [ 844, 859 ] ], "normalized": [] }, { "id": "entity-82-8", "type": "DISEASE", "text": [ "germinoma" ], "offsets": [ [ 866, 875 ] ], "normalized": [] }, { "id": "entity-82-9", "type": "DISEASE", "text": [ "germinoma" ], "offsets": [ [ 945, 954 ] ], "normalized": [] }, { "id": "entity-82-10", "type": "DISEASE", "text": [ "relapsed brain tumor" ], "offsets": [ [ 1148, 1168 ] ], "normalized": [] } ]

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[ { "id": "passage-83", "type": "abstract", "text": [ "Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5. Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd may induce neuronal apoptosis in part through activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (Erk1/2) pathways. However, the underlying mechanism remains enigmatic. Here we show that Cd induced generation of reactive oxygen species (ROS), leading to apoptosis of PC12 and SH-SY5Y cells. Pretreatment with N-acetyl-L-cysteine (NAC) scavenged Cd-induced ROS, and prevented cell death, suggesting that Cd-induced apoptosis is attributed to its induction of ROS. Furthermore, we found that Cd-induced ROS inhibited serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5), leading to activation of Erk1/2 and JNK, which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented Cd-induced activation of Erk1/2 and JNK, as well as cell death. Cd-induced ROS was also linked to the activation of caspase-3. Pretreatment with inhibitors of JNK (SP600125) and Erk1/2 (U0126) partially blocked Cd-induced cleavage of caspase-3 and prevented cell death. However, zVAD-fmk, a pan caspase inhibitor, only partially prevented Cd-induced apoptosis. The results indicate that Cd induction of ROS inhibits PP2A and PP5, leading to activation of JNK and Erk1/2 pathways, and consequently resulting in caspase-dependent and -independent apoptosis of neuronal cells. The findings strongly suggest that the inhibitors of JNK, Erk1/2, or antioxidants may be exploited for prevention of Cd-induced neurodegenerative diseases." ], "offsets": [ [ 0, 1752 ] ] } ]

[ { "id": "entity-83-0", "type": "ADVERSE", "text": [ "neurodegenerative diseases" ], "offsets": [ [ 223, 249 ] ], "normalized": [] }, { "id": "entity-83-1", "type": "ADVERSE", "text": [ "neurodegenerative diseases" ], "offsets": [ [ 1725, 1751 ] ], "normalized": [] } ]

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[ { "id": "passage-84", "type": "abstract", "text": [ "Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel dysfunction. Cocaine use is common in many areas of the world, particularly the United States and Western Europe. Toxicity following the use of cocaine is associated with a wide range of clinical features. In this review, we will focus on the cocaine-associated cardiac arrhythmias and, in particular, some of the controversies in their etiology and management. Cocaine can produce arrhythmias either through the production of myocardial ischemia or as a direct result of ion channel alterations. Excessive catecholamines, combined with sodium and potassium channel blockades, give rise to a wide variety of supra-ventricular and ventricular rhythms. The animal and human evidence for ion channel dysfunction is reviewed, and the effects of catecholamines are followed from the cardiac action potential to the development of arrhythmias. Finally, theoretical constructs are combined with existing evidence to develop a rational treatment strategy for patients with cocaine-induced cardiac arrhythmias. In particular, we review the evidence concerning the controversies relating to the use of lidocaine in comparison with sodium bicarbonate, in terms of QRS prolongation secondary to sodium channel blockade." ], "offsets": [ [ 0, 1285 ] ] } ]

[ { "id": "entity-84-0", "type": "ADVERSE", "text": [ "cardiac arrhythmias" ], "offsets": [ [ 30, 49 ] ], "normalized": [] }, { "id": "entity-84-1", "type": "ADVERSE", "text": [ "cardiac ion channel dysfunction" ], "offsets": [ [ 57, 88 ] ], "normalized": [] }, { "id": "entity-84-2", "type": "ADVERSE", "text": [ "cardiac arrhythmias" ], "offsets": [ [ 340, 359 ] ], "normalized": [] }, { "id": "entity-84-3", "type": "ADVERSE", "text": [ "arrhythmias" ], "offsets": [ [ 460, 471 ] ], "normalized": [] }, { "id": "entity-84-4", "type": "ADVERSE", "text": [ "myocardial ischemia" ], "offsets": [ [ 505, 524 ] ], "normalized": [] }, { "id": "entity-84-5", "type": "ADVERSE", "text": [ "ion channel dysfunction" ], "offsets": [ [ 763, 786 ] ], "normalized": [] }, { "id": "entity-84-6", "type": "ADVERSE", "text": [ "arrhythmias" ], "offsets": [ [ 903, 914 ] ], "normalized": [] }, { "id": "entity-84-7", "type": "ADVERSE", "text": [ "cardiac arrhythmias" ], "offsets": [ [ 1059, 1078 ] ], "normalized": [] } ]

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[ { "id": "passage-85", "type": "abstract", "text": [ "Venlafaxine versus clonidine for the treatment of hot flashes in breast cancer patients: a double-blind, randomized cross-over study. PURPOSE: Breast cancer patients with treatment-induced menopause experience frequent and severe hot flashes (HF). We compared venlafaxine and clonidine for the treatment of HF with regard to side effects, efficacy, quality of life and sexual functioning. METHODS: In a double-blind, cross-over study, 60 breast cancer patients experiencing HF were randomized to 8 weeks venlafaxine followed by 2 weeks wash-out, and 8 weeks clonidine or vice versa. HF frequency and severity, side effects, quality of life and sexuality were assessed. RESULTS: Thirty patients started with venlafaxine and 30 with clonidine. Premature discontinuation for toxicity occurred in 14/59 during venlafaxine and 5/53 during clonidine (P = .038). Venlafaxine induced more side effects. Median reduction in HF score was 49% for venlafaxine and 55% for clonidine (ns). CONCLUSION: Venlafaxine and clonidine are equally, but moderately effective in HF reduction. Side effects are the main reason for drug discontinuation, occurring more often with venlafaxine." ], "offsets": [ [ 0, 1167 ] ] } ]

[ { "id": "entity-85-0", "type": "DISEASE", "text": [ "hot flashes" ], "offsets": [ [ 50, 61 ] ], "normalized": [] }, { "id": "entity-85-1", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 65, 78 ] ], "normalized": [] }, { "id": "entity-85-2", "type": "DISEASE", "text": [ "Breast cancer" ], "offsets": [ [ 144, 157 ] ], "normalized": [] }, { "id": "entity-85-3", "type": "DISEASE", "text": [ "hot flashes" ], "offsets": [ [ 231, 242 ] ], "normalized": [] }, { "id": "entity-85-4", "type": "DISEASE", "text": [ "HF" ], "offsets": [ [ 244, 246 ] ], "normalized": [] }, { "id": "entity-85-5", "type": "DISEASE", "text": [ "breast cancer" ], "offsets": [ [ 439, 452 ] ], "normalized": [] }, { "id": "entity-85-6", "type": "DISEASE", "text": [ "HF" ], "offsets": [ [ 475, 477 ] ], "normalized": [] }, { "id": "entity-85-7", "type": "DISEASE", "text": [ "HF" ], "offsets": [ [ 584, 586 ] ], "normalized": [] }, { "id": "entity-85-8", "type": "DISEASE", "text": [ "HF" ], "offsets": [ [ 916, 918 ] ], "normalized": [] }, { "id": "entity-85-9", "type": "DISEASE", "text": [ "HF" ], "offsets": [ [ 1056, 1058 ] ], "normalized": [] } ]

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[ { "id": "passage-86", "type": "abstract", "text": [ "Increased circulating pro-inflammatory cytokines and imbalanced regulatory T-cell cytokines production in chronic idiopathic urticaria. The immunologic characterization of chronic idiopathic urticaria (CIU), mainly regarding cytokine profile needs more investigation. We examined circulating inflammatory cytokine levels, T-cell induced secretion, and cytokine mRNA expression in patients with CIU subjected to the intradermal autologous serum skin test (ASST). Increased levels of circulating pro-inflammatory cytokines, such as TNF-alpha, IL-1beta, IL-12p70, and IL-6 have been observed in most of patients with CIU, together with an enhancement of IL-2 secretion following T-cell stimulation. Highlighting the inflammatory profile in CIU found in ASST positive, is the enhanced B-cell proliferative responsiveness and increased IL-17 secretion levels. ASST-positive patients also exhibited impaired IL-4 secretion associated with increased IL-10 production. Altered cytokine expression in patients with ASST-negative, was the down-modulation of spontaneous IL-10 mRNA expression levels in peripheral blood mononuclear cells. Our findings support the concept of immunologic dysregulation in CIU, revealing a systemic inflammatory profile associated with disturbed cytokine production by T cells, mainly related to IL-17 and IL-10 production." ], "offsets": [ [ 0, 1344 ] ] } ]

[ { "id": "entity-86-0", "type": "DISEASE", "text": [ "chronic idiopathic urticaria" ], "offsets": [ [ 106, 134 ] ], "normalized": [] }, { "id": "entity-86-1", "type": "DISEASE", "text": [ "chronic idiopathic urticaria" ], "offsets": [ [ 173, 201 ] ], "normalized": [] }, { "id": "entity-86-2", "type": "DISEASE", "text": [ "CIU" ], "offsets": [ [ 203, 206 ] ], "normalized": [] }, { "id": "entity-86-3", "type": "DISEASE", "text": [ "CIU" ], "offsets": [ [ 395, 398 ] ], "normalized": [] }, { "id": "entity-86-4", "type": "DISEASE", "text": [ "CIU" ], "offsets": [ [ 615, 618 ] ], "normalized": [] }, { "id": "entity-86-5", "type": "DISEASE", "text": [ "CIU" ], "offsets": [ [ 738, 741 ] ], "normalized": [] }, { "id": "entity-86-6", "type": "DISEASE", "text": [ "CIU" ], "offsets": [ [ 1194, 1197 ] ], "normalized": [] } ]

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[ { "id": "passage-87", "type": "abstract", "text": [ "Target-controlled infusion versus manually-controlled infusion of propofol for general anaesthesia or sedation in adults. BACKGROUND: Continuous infusions of the intravenous anaesthetic propofol are commonly used to induce and maintain sedation and general anaesthesia. Infusion devices can be manually controlled (MCI) where the anaesthetist makes each change to the infusion rate or target-controlled (TCI) where the anaesthetist sets a target blood or effect-site concentration and the computerised infusion device makes the necessary changes to the infusion rate. Randomized trials have explored the differences in quality of anaesthesia, adverse event rate and cost between TCI and MCI but the effectiveness of TCI compared with MCI remains controversial. As TCI is in widespread international use, and potentially may be more expensive without added benefit, a systematic review of randomized controlled trials comparing TCI and MCI is warranted. OBJECTIVES: To assess whether TCI of propofol is as effective as MCI of propofol with respect to quality of anaesthesia or sedation, adverse events and propofol drug cost. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 3); PubMED (1950 to July week 2 2007); and EMBASE via OVID (1980 to week 28 2007). We also searched LILACS, CINAHL, ISI Web Knowledge, Panteleimon, KoreaMed and IndMed. We searched for ongoing trials via the National Research Register and metaRegister of Controlled Trials. SELECTION CRITERIA: We planned to include all published and unpublished randomized controlled trials that compared TCI of propofol with MCI of propofol for general anaesthesia or sedation in adult surgical patients. Only published studies were included as no unpublished studies were identified. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted outcome data. We contacted study authors and the pharmaceutical industry for additional information. MAIN RESULTS: Twenty trials of poor quality that involved 1759 patients were included. Heterogeneity was high (that is the trials were not comparing the same things). TCI was associated with higher total doses of propofol than was MCI resulting in marginally higher propofol drug costs. However, fewer interventions were required by the anaesthetist during the use of TCI compared with MCI. No clinically significant differences were demonstrated in terms of quality of anaesthesia or adverse events. AUTHORS' CONCLUSIONS: This systematic review does not provide sufficient evidence for us to make firm recommendations about the use of TCI versus MCI in clinical anaesthetic practice." ], "offsets": [ [ 0, 2698 ] ] } ]

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[ { "id": "passage-88", "type": "abstract", "text": [ "Kinetic analysis of superoxide anion radical-scavenging and hydroxyl radical-scavenging activities of platinum nanoparticles. There are few reports on the physiological effects of metal nanoparticles (nps), especially with respect to their functions as scavengers for superoxide anion radical (O2(.-)) and hydroxyl radical (.OH). We tried to detect the scavenging activity of Pt nps using a hypoxanthine-xanthine oxidase system for O2(.-) and using a Fenton and a UV/H2O2 system for .OH. Electron spin resonance analysis revealed that 2 nm particle size Pt nps have the ability to scavenge O2(.-) and .OH. The calculated rate constant for the O2(.-)-scavenging reaction was 5.03 +/- 0.03 x 10(7) M (-1) s (-1). However, the analysis of the Fenton and UV/H 2O 2 system in the presence of Pt nps suggested that the .OH-scavenging reaction cannot be determined in both systems. Among particle sizes tested from 1 to 5 nm, 1 nm Pt nps showed the highest O2(.-)-scavenging ability. Almost no cytotoxicity was observed even after adherent cells (TIG-1, HeLa, HepG2, WI-38, and MRC-5) were exposed to Pt nps at concentrations as high as 50 mg/L. Pt nps scavenged intrinsically generated reactive oxygen species (ROS) in HeLa cells. Additionally, Pt nps significantly reduced the levels of intracellular O2(.-) generated by UVA irradiation and subsequently protected HeLa cells from ROS damage-induced cell death. These findings suggest that Pt nps may be a new type of antioxidant capable of circumventing the paradoxical effects of conventional antioxidants." ], "offsets": [ [ 0, 1553 ] ] } ]

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[ { "id": "passage-89", "type": "abstract", "text": [ "Association between serious ischemic cardiac outcomes and medications used to treat diabetes. PURPOSE: Data on cardiovascular outcomes among treated diabetics have been inconsistent. Our goal was to compare cardiovascular outcomes associated with different treatments for diabetes. METHODS: This is a retrospective cohort study of diabetic patients at least 40 years of age treated in general practices participating in The Health Information Network (THIN) data system between 2002 and 2006. Our primary outcome was serious atherosclerotic vascular disease of the heart. RESULTS: Among all diabetics (N = 63 579), the fully adjusted hazard ratios of association with our outcome were 1.2 (1.1, 1.3) for insulin, 1.03 (0.97, 1.09) for sulfonylureas, 0.8 (0.7, 0.8) for biguanide, 1.2 (0.99, 1.5) for meglitinide, 0.5 (0.5, 0.6) for thiazolidinediones, and individually 0.6 (0.5, 0.6) for rosiglitazone, and 0.5 (0.4, 0.7) for pioglitazone. Among those individuals newly diagnosed and treated for diabetes after 2002 (N = 13 576), the adjusted hazard ratios of association with our outcome were 2.4 (2.0, 2.9) for insulin, 1.4 (1.2, 1.7) for sulfonylureas, 0.5 (0.4, 0.5) for biguanide, 0.9 (0.4, 2.1) for meglitinide, 0.8 (0.7, 1.0) for thiazolidinediones, and individually 0.8 (0.6, 1.0) for rosiglitazone, and 0.9 (0.6, 1.4) for pioglitazone. Risk increased as total duration of therapy increased for insulin, sulfonylureas, and biguanide, but decreased with duration for rosiglitazone and pioglitazone. CONCLUSIONS: Overall, insulin was associated with an increased risk of myocardial infarction. Its risk increased with longer use, and risk emerged with longer use of sulfonylureas and biguanide. Conversely, a protective effect emerged with longer use of rosiglitazone or pioglitazone." ], "offsets": [ [ 0, 1791 ] ] } ]

[ { "id": "entity-89-0", "type": "DISEASE", "text": [ "diabetes" ], "offsets": [ [ 84, 92 ] ], "normalized": [] }, { "id": "entity-89-1", "type": "DISEASE", "text": [ "diabetes" ], "offsets": [ [ 273, 281 ] ], "normalized": [] }, { "id": "entity-89-2", "type": "DISEASE", "text": [ "atherosclerotic vascular disease" ], "offsets": [ [ 526, 558 ] ], "normalized": [] }, { "id": "entity-89-3", "type": "DISEASE", "text": [ "diabetes" ], "offsets": [ [ 997, 1005 ] ], "normalized": [] }, { "id": "entity-89-4", "type": "ADVERSE", "text": [ "myocardial infarction" ], "offsets": [ [ 1578, 1599 ] ], "normalized": [] } ]

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[ { "id": "passage-90", "type": "abstract", "text": [ "Serotonin-dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesias. Appearance of dyskinesia is a common problem of long-term Levodopa (L-DOPA) treatment in Parkinson's disease (PD) patients and represents a major limitation for the pharmacological management of the motor symptoms in the advanced stages of disease. An increasing body of evidence points to dopamine released as a false neurotransmitter from the striatal serotonin terminals as the main pre-synaptic determinant of L-DOPA-induced dyskinesia. Here we review the animal experimental and human clinical data in support of this view, which point to the serotonin system as a promising target for anti-dyskinetic therapy in PD patients under L-DOPA medication." ], "offsets": [ [ 0, 750 ] ] } ]

[ { "id": "entity-90-0", "type": "ADVERSE", "text": [ "dyskinesias" ], "offsets": [ [ 82, 93 ] ], "normalized": [] }, { "id": "entity-90-1", "type": "ADVERSE", "text": [ "dyskinesia" ], "offsets": [ [ 110, 120 ] ], "normalized": [] }, { "id": "entity-90-2", "type": "DISEASE", "text": [ "Parkinson's disease" ], "offsets": [ [ 185, 204 ] ], "normalized": [] }, { "id": "entity-90-3", "type": "DISEASE", "text": [ "PD" ], "offsets": [ [ 206, 208 ] ], "normalized": [] }, { "id": "entity-90-4", "type": "ADVERSE", "text": [ "dyskinesia" ], "offsets": [ [ 525, 535 ] ], "normalized": [] }, { "id": "entity-90-5", "type": "DISEASE", "text": [ "PD" ], "offsets": [ [ 714, 716 ] ], "normalized": [] } ]

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[ { "id": "passage-91", "type": "abstract", "text": [ "Somatic pharmacogenomics in cancer. Many of the initial examples of the clinical utility of pharmacogenetics were elucidated in the field of oncology. Those examples were largely based on the existence of germline genetic variation that influences the metabolism of cytotoxic drugs. However, with the development of kinase inhibitors, drugs designed to preferentially target altered proteins driving oncogenesis, pharmacogenetics in cancer has shifted to understanding the somatic differences that determine response to these targeted agents. It is becoming increasingly clear that understanding the molecular genetics of cancer will lead to the further development of targeted therapeutics. Therefore, it is imperative that pharmacogenomics researchers understand the motivations and challenges of developing targeted therapies to treat cancer as a paradigm for personalized medicine. However, much of the discussion in the pharmacogenomics community in cancer is still largely focused on the germline variants as predictors of drug toxicity. In light of that fact, this review presents a detailed discussion of the development of commonly used targeted therapies for the treatment of hematological and solid tumors, the somatic mutations that determine response to those therapies, and the mechanisms of drug resistance." ], "offsets": [ [ 0, 1323 ] ] } ]

[ { "id": "entity-91-0", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 28, 34 ] ], "normalized": [] }, { "id": "entity-91-1", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 434, 440 ] ], "normalized": [] }, { "id": "entity-91-2", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 623, 629 ] ], "normalized": [] }, { "id": "entity-91-3", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 839, 845 ] ], "normalized": [] }, { "id": "entity-91-4", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 956, 962 ] ], "normalized": [] }, { "id": "entity-91-5", "type": "ADVERSE", "text": [ "drug toxicity" ], "offsets": [ [ 1030, 1043 ] ], "normalized": [] } ]

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[ { "id": "passage-92", "type": "abstract", "text": [ "Weekly irinotecan plus protracted venous fluorouracil infusion (WI-FI) in advanced colorectal cancer: a phase II study. BACKGROUND: Irinotecan (IRI) is a topoisomerase I inhibitor active as first- or second-line chemotherapy in advanced colorectal cancer (ACRC). Its combination with fluorouracil (FU) increases the response rate and prolongs survival. In order to identify a new effective and less toxic schedule of administration, we planned this phase II study with weekly IRI and protracted venous infusion of FU (WI-FI regimen). The primary endpoint was the objective response rate. Secondary aims were to detect toxicity, progression-free survival (PFS) and overall survival (OS) of patients (pts). MATERIALS AND METHODS: On May 2000, a monoinstitutional study commenced with the following schedule of administration: IRI 80 mg/m2 on days 1, 8, 15, 22, 29 plus a 28-day protracted venous infusion of FU 200 mg/m2/day. The treatment was repeated every 35 days. Cycles were administered until a maximum of 6 courses, disease progression or unacceptable toxicity. RESULTS: By March 2005, 52 patients (30 males and 22 females) had entered the study. Their median age was 61.5 years and the median ECOG PS was 1. In total, 223 courses were administered (median 5 cycles/patient). Toxicity was low: neutropenia G3 and asthenia G3 were the most observed toxicities (5 pts each). No other grade 3-4 toxic side-effects were seen. Weekly IRI was interrupted in 11 pts, mostly related to problems with the central venous catheter. Following RECIST criteria, we observed 5 complete responses, 15 partial responses, 17 pts had stable disease, while in 15 disease progressed. The overall response rate was 38.5% and the disease control rate was 71.2%. Thirteen pts underwent surgical resection of their relapsing disease. The median PFS was 8.2 months and the median OS was 16.3 months. CONCLUSION: The WI-FI regimen is an active treatment with a good safety profile in patients with CRC. The low incidence of grade 3-4 toxicities justifies further evaluation of this combination." ], "offsets": [ [ 0, 2073 ] ] } ]

[ { "id": "entity-92-0", "type": "DISEASE", "text": [ "colorectal cancer" ], "offsets": [ [ 83, 100 ] ], "normalized": [] }, { "id": "entity-92-1", "type": "DISEASE", "text": [ "colorectal cancer" ], "offsets": [ [ 238, 255 ] ], "normalized": [] }, { "id": "entity-92-2", "type": "DISEASE", "text": [ "ACRC" ], "offsets": [ [ 257, 261 ] ], "normalized": [] }, { "id": "entity-92-3", "type": "ADVERSE", "text": [ "neutropenia" ], "offsets": [ [ 1300, 1311 ] ], "normalized": [] }, { "id": "entity-92-4", "type": "ADVERSE", "text": [ "asthenia" ], "offsets": [ [ 1319, 1327 ] ], "normalized": [] }, { "id": "entity-92-5", "type": "DISEASE", "text": [ "CRC" ], "offsets": [ [ 1977, 1980 ] ], "normalized": [] } ]

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[ { "id": "passage-93", "type": "abstract", "text": [ "Selectins ligand decorated drug carriers for activated endothelial cell targeting. New active particulate polymeric vectors based on branched polyester copolymers of hydroxy-acid and allyl glycidyl ether were developed to target drugs to the inflammatory endothelial cell surface. The hydroxyl and carboxyl derivatives of these polymers allow grafting of ligand molecules on the polyester backbones at different densities. A known potent nonselective selectin ligand was selected and synthesized using a new scheme. This synthesis allowed the grafting of the ligand to the polyester polymers, preserving its binding activity as assessed by docking simulations. Selectin expression on human umbilical cord vascular endothelial cells (HUVEC) was induced with the pro-inflammatory bacterial lipopolysaccharide (LPS) or with the nonselective inhibitor of nitric oxide synthase L-NAME. Strong adhesion of the ligand decorated nanoparticles was evidenced in vitro on activated HUVEC. Binding of nanoparticles bearing ligand molecules could be efficiently inhibited by prior incubation of cells with free ligand, demonstrating that adhesion of the nanoparticles is mediated by specific interaction between the ligand and the selectin receptors. These nanoparticles could be used for specific drug delivery to the activated vascular endothelium, suggesting their application in the treatment of diseases with an inflammatory component such as rheumatoid arthritis and cancer." ], "offsets": [ [ 0, 1468 ] ] } ]

[ { "id": "entity-93-0", "type": "DISEASE", "text": [ "rheumatoid arthritis" ], "offsets": [ [ 1436, 1456 ] ], "normalized": [] }, { "id": "entity-93-1", "type": "DISEASE", "text": [ "cancer" ], "offsets": [ [ 1461, 1467 ] ], "normalized": [] } ]

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[ { "id": "passage-94", "type": "abstract", "text": [ "Radiation-induced bystander effects enhanced by elevated sodium chloride through sensitizing cells to bystander factors. Radiation-induced bystander effects (RIBE) have been demonstrated to occur widely in various cell lines. However, very little data is available on the genotoxic effects of RIBE combined with other factor(s). We reported previously that with a low dose of alpha-particle irradiation, the fraction of gamma-H2AX foci-positive cells in non-irradiated bystander cells was significantly increased under elevated NaCl culture conditions. In this study, we further investigated the functional role of NaCl in the enhancement of RIBE using a specially designed co-culture system and micronucleus (MN) test. It was shown that the MN frequency was not increased significantly by elevated NaCl (9.0 g/L) alone or by medium exposure. However, with 1.0 cGy alpha-particle irradiation, the induced MN frequency increased significantly in both irradiated and non-irradiated bystander regions. Additional studies showed that elevated NaCl made the non-irradiated bystander cells more vulnerable to bystander factors. Furthermore, it was found that the induced MN frequency in cells both in irradiated and non-irradiated bystander regions was weakened when the hypertonic medium was changed to normotonic medium for 2h before irradiation. Such observations were quite similar to the co-effect of NaCl and hydrogen peroxide (H(2)O(2)), indicating that elevated NaCl might sensitize non-irradiated cells to bystander factors-induced oxidative stress." ], "offsets": [ [ 0, 1553 ] ] } ]

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[ { "id": "passage-95", "type": "abstract", "text": [ "Cabergoline-induced psychotic exacerbation in schizophrenic patients. INTRODUCTION: Hyperprolactinemia is a well-recognized side effect of antipsychotic treatment. Cabergoline, a dopamine agonist, has been introduced on the market to treat hyperprolactinemia, even secondary to antipsychotic use. CASE REPORT: In this article, we described two schizophrenic patients who received cabergoline to treat their antipsychotic-induced hyperprolactinemia and developed a subsequent psychotic exacerbation. The first patient received amisulpride as antipsychotic medication, and the second one took risperidone and fluoxetine for her psychotic and depressive symptoms, respectively. Both patients improved significantly their psychotic symptoms in 1 week without changing their former antipsychotic regimens. DISCUSSION: To the best of our knowledge, we found no previous report of cabergoline-induced psychotic exacerbation in schizophrenic patients who received antipsychotics. We brought up questions whether schizophrenic patients on amisulpride or with the addition of fluoxetine may have higher risk to experience psychotic worsening. We also highlighted the possible role of dose-dependent nature in cabergoline-induced psychotic exacerbation, suggesting that the single starting dose of 0.5 mg or higher might be unsafe in schizophrenic patients. CONCLUSION: These cases suggest that cabergoline, like other dopaminergic agents, should be used with caution in psychotic patients and the dose should be as low as possible." ], "offsets": [ [ 0, 1522 ] ] } ]

[ { "id": "entity-95-0", "type": "ADVERSE", "text": [ "psychotic exacerbation" ], "offsets": [ [ 20, 42 ] ], "normalized": [] }, { "id": "entity-95-1", "type": "ADVERSE", "text": [ "Hyperprolactinemia" ], "offsets": [ [ 85, 103 ] ], "normalized": [] }, { "id": "entity-95-2", "type": "ADVERSE", "text": [ "hyperprolactinemia" ], "offsets": [ [ 241, 259 ] ], "normalized": [] }, { "id": "entity-95-3", "type": "ADVERSE", "text": [ "hyperprolactinemia" ], "offsets": [ [ 430, 448 ] ], "normalized": [] }, { "id": "entity-95-4", "type": "ADVERSE", "text": [ "psychotic exacerbation" ], "offsets": [ [ 476, 498 ] ], "normalized": [] }, { "id": "entity-95-5", "type": "ADVERSE", "text": [ "depressive symptoms" ], "offsets": [ [ 641, 660 ] ], "normalized": [] }, { "id": "entity-95-6", "type": "ADVERSE", "text": [ "psychotic symptoms" ], "offsets": [ [ 719, 737 ] ], "normalized": [] }, { "id": "entity-95-7", "type": "ADVERSE", "text": [ "psychotic exacerbation" ], "offsets": [ [ 895, 917 ] ], "normalized": [] }, { "id": "entity-95-8", "type": "ADVERSE", "text": [ "psychotic worsening" ], "offsets": [ [ 1113, 1132 ] ], "normalized": [] }, { "id": "entity-95-9", "type": "ADVERSE", "text": [ "psychotic exacerbation" ], "offsets": [ [ 1220, 1242 ] ], "normalized": [] } ]

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[ { "id": "passage-96", "type": "abstract", "text": [ "Bioequivalence and pharmacokinetic comparison of a single 200-mg dose of meclofenoxate hydrochloride capsule and tablet formulations in healthy Chinese adult male volunteers: a randomized sequence, open-label, two-period crossover study. BACKGROUND: Meclofenoxate hydrochloride is a psychostimulant in the nootropic agent group available in capsule and tablet formulations approved for traumatic cataphora, alcoholic poisoning, anoxia neonatorum, and children's enuresis in China. Although these 2 generic formulations are marketed in China, information regarding their pharmacokinetics and bioequivalence in humans has not been published. OBJECTIVE: The aim of this study was to compare the pharmacokinetic properties and bioequivalence of the capsule (test) and tablet (reference) formulations of meclofenoxate hydrochloride 200 mg in healthy Chinese volunteers. METHODS: This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 200-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. As a prodrug, meclofenoxate is hydrolyzed into 4-chlorophenoxyacetic acid and is not detected in plasma. The active metabolite of meclofenoxate, chlorophenoxyacetic acid, was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity, blood samples were obtained at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 14, and 24 hours after administration. The formulations were considered bioequivalent if the log-transformed ratios of Cmax and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Subjects were interviewed concerning the occurrence of adverse events including excitement, insomnia, lassitude, and headache. Tolerability was assessed at baseline (before administration) and at 1, 2, 6, and 12 hours after administration by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis). RESULTS: Twenty-four Chinese male subjects (mean [range]age,23.5[22-30]years;weight,63.3[56-68]kg; height, 171 [165-184] cm) were enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of chlorophenoxyacetic acid Cmax, AUC0-24, and AUC0-infinity were 95.7 to 122.9, 97.6 to 111.9, and 97.8 to 111.7, respectively (all, P>0.05). Similar results were found for the data without log-transformation. No adverse events were reported or observed during this single-dose study. CONCLUSIONS: In this small study in healthy Chinese adult male volunteers, a single 200-mg dose of the capsule formulation was found to be bioequivalent to a single 200-mg dose of the tablet formulation based on the US FDA's regulatory definition (rate and extent of absorption). Both formulations were well tolerated." ], "offsets": [ [ 0, 3214 ] ] } ]

[ { "id": "entity-96-0", "type": "DISEASE", "text": [ "traumatic cataphora" ], "offsets": [ [ 387, 406 ] ], "normalized": [] }, { "id": "entity-96-1", "type": "DISEASE", "text": [ "alcoholic poisoning" ], "offsets": [ [ 408, 427 ] ], "normalized": [] }, { "id": "entity-96-2", "type": "DISEASE", "text": [ "anoxia neonatorum" ], "offsets": [ [ 429, 446 ] ], "normalized": [] }, { "id": "entity-96-3", "type": "DISEASE", "text": [ "enuresis" ], "offsets": [ [ 463, 471 ] ], "normalized": [] }, { "id": "entity-96-4", "type": "ADVERSE", "text": [ "excitement" ], "offsets": [ [ 2085, 2095 ] ], "normalized": [] }, { "id": "entity-96-5", "type": "ADVERSE", "text": [ "insomnia" ], "offsets": [ [ 2097, 2105 ] ], "normalized": [] }, { "id": "entity-96-6", "type": "ADVERSE", "text": [ "lassitude" ], "offsets": [ [ 2107, 2116 ] ], "normalized": [] }, { "id": "entity-96-7", "type": "ADVERSE", "text": [ "headache" ], "offsets": [ [ 2122, 2130 ] ], "normalized": [] } ]

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[ { "id": "passage-97", "type": "abstract", "text": [ "Cumulative risk assessment of the exposure to organophosphorus and carbamate insecticides in the Dutch diet. We report the acute cumulative exposure to organophosphorus insecticides (OPs) and carbamates in the Dutch population and young children (1-6 years) via the diet. Residue data were derived from Dutch monitoring programmes performed during 2003-2005, and food consumption levels from the Dutch National Food Consumption Survey 1997/1998. The relative potency factor (RPF) approach was used to cumulate the exposure to OPs and carbamates using acephate and oxamyl as index compound respectively. The exposure was estimated using the probabilistic approach, including unit variability and processing effects. We demonstrate that about 3% of the composite samples analysed for OPs and 0.2% for carbamates contain combinations of these pesticides. The P99.9 of exposure to OPs and carbamates in the total Dutch population equals 23 and 0.64microg/kg BW/d respectively. For young children the corresponding exposure levels are 57 and 1.47microg/kg BW/d. When comparing the P99.9 of exposure with the ARfD, 50 and 9microg/kg BW/d for acephate and oxamyl respectively, there is only a possible health risk for young children. Spinach contributed most to the exposure to OPs in both age groups, followed by orange and mandarin. For carbamates apple (sauce) was the main product determining the exposure." ], "offsets": [ [ 0, 1404 ] ] } ]

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[ { "id": "passage-98", "type": "abstract", "text": [ "Hg2+ and Cd2+ interact differently with biomimetic erythrocyte membranes. In order to characterize the potentially deleterious effects of toxic Hg(2+) and Cd(2+) on lipid membranes, we have studied their binding to liposomes whose composition mimicked erythrocyte membranes. Fluorescence spectroscopy utilizing the concentration dependent quenching of Phen Green SK by Hg(2+) and Cd(2+) was found to be a sensitive tool to probe these interactions at metal concentrations < or =1 microM. We have systematically developed a metal binding affinity assay to screen for the interactions of Hg(2+) or Cd(2+) with certain lipid classes. A biomimetic liposome system was developed that contained four major lipid classes of erythrocyte membranes (zwitterionic lipids: phosphatidylcholine and phosphatidylethanolamine; negatively charged: phosphatidylserine and neutral: cholesterol). In contrast to Hg(2+), which preferentially bound to the negatively charged phosphatidylserine compared to the zwitterionic components, Cd(2+) bound stronger to the two zwitterionic lipids. Thus, the observed distinct differences in the binding affinity of Hg(2+) and Cd(2+) for certain lipid classes together with their known effects on membrane properties represent an important first step toward a better understanding the role of these interactions in the chronic toxicity of these metals." ], "offsets": [ [ 0, 1371 ] ] } ]

[ { "id": "entity-98-0", "type": "ADVERSE", "text": [ "chronic toxicity" ], "offsets": [ [ 1338, 1354 ] ], "normalized": [] } ]

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[ { "id": "passage-99", "type": "abstract", "text": [ "Efavirenz replacement by immediate full-dose nevirapine is safe in HIV-1-infected patients in Cambodia. BACKGROUND: Efavirenz is used for the antiretroviral treatment of HIV/tuberculosis-coinfected patients in developing countries. A switch to nevirapine is regularly carried out because of the cost and side effects of efavirenz. Pharmacokinetic studies suggested that nevirapine should be initiated at full dose when used as a substitute for efavirenz. OBJECTIVES: The aim of this study was to measure the cumulative incidence of adverse events (AEs) related to nevirapine in patients switched from efavirenz to immediate full-dose nevirapine (FDN). METHODS: In 2001 an antiretroviral treatment programme was initiated with the first-line regimen stavudine, lamivudine and efavirenz. In 2003, the fixed-dose combination of stavudine, lamivudine and nevirapine was recommended. Thus, first-line therapy was changed and FDN was initiated when patients were switched from efavirenz to nevirapine. RESULTS: Between April and December 2004, 394 patients were switched from efavirenz to FDN. The cumulative incidence of AEs related to nevirapine was 13.2% [95% confidence interval (CI) 10.2-16.7] and that of severe AEs was 8.9% (95% CI 6.5-11.9). In women the incidence of AEs was 17.6% (95% CI 12.1-24.3) and that of severe AEs was 12.2% (95% CI 7.7-18.2). CONCLUSIONS: Our results indicate that an FDN switch from efavirenz does not appear to result in more AEs than when nevirapine is initiated with escalating doses. These data are particularly relevant in resource-limited settings." ], "offsets": [ [ 0, 1585 ] ] } ]

[ { "id": "entity-99-0", "type": "DISEASE", "text": [ "HIV" ], "offsets": [ [ 171, 174 ] ], "normalized": [] }, { "id": "entity-99-1", "type": "DISEASE", "text": [ "tuberculosis" ], "offsets": [ [ 175, 187 ] ], "normalized": [] } ]

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