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26548f0a805861520e4097b0f1fb278f

Among the anti-herpesvirus agents , aciclovir , valaciclovir , penciclovir , famciclovir , idoxuridine , trifluridine and brivudin are used in the treatment of herpes simplex virus and varicella-zoster virus infections , and ganciclovir , foscarnet , cidofovir , fomivirsen and maribavir ( the latter in the developmental stage ) are used in the treatment of cytomegalovirus infections .

Antiviral drugs: current state of the art. The chemotherapy of virus infections has definitely come of age. There are now 15 antiviral agents that have been formally licensed for the treatment of human immunodeficiency virus infections (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, nevirapine, delavirdine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir) and several others, such as tenofovir disoproxil, emtricitabine, capravirine, emivirine, T-20 (pentafuside) and AMD3100 (bicyclam) are under clinical development. Lamivudine has been approved, and several other compounds (such as adefovir dipivoxil, emtricitabine and entecavir) are under clinical development, for the treatment of hepatitis B virus infections. Among the anti-herpesvirus agents , aciclovir , valaciclovir , penciclovir , famciclovir , idoxuridine , trifluridine and brivudin are used in the treatment of herpes simplex virus and varicella-zoster virus infections , and ganciclovir , foscarnet , cidofovir , fomivirsen and maribavir ( the latter in the developmental stage ) are used in the treatment of cytomegalovirus infections . Following amantadine and rimantadine, the neuraminidase inhibitors, zanamivir and oseltamivir, have now become available for the therapy and prophylaxis of influenza virus infections, and so is ribavirin for the treatment of respiratory syncytial virus infections and the combination of ribavirin with interferon-alpha for the treatment of hepatitis C virus infections.

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The present study examined the efficacy of single and combined treatment with an anticholinesterase , tetrahydroaminoacridine ( i.p . ) , and a glycine-B site partial agonist , D-cycloserine ( i.p . ; a positive allosteric modulator of NMDA receptors ) , in alleviating the deficit in water maze spatial navigation induced by electrolytic lesion of the medial septum or lidocaine infusion into the dorsal hippocampi .

Tetrahydroaminoacridine and D-cycloserine fail to alleviate the water maze spatial navigation defect induced by hippocampal inactivation. The present study examined the efficacy of single and combined treatment with an anticholinesterase , tetrahydroaminoacridine ( i.p . ) , and a glycine-B site partial agonist , D-cycloserine ( i.p . ; a positive allosteric modulator of NMDA receptors ) , in alleviating the deficit in water maze spatial navigation induced by electrolytic lesion of the medial septum or lidocaine infusion into the dorsal hippocampi . In medial septum-lesioned rats, a combination of tetrahydroaminoacridine 3 mg kg(-1) and D-cycloserine 10 mg kg(-1) facilitated acquisition of the water maze test more effectively than either of the drugs alone. Single or combined treatment with tetrahydroaminoacridine 3 mg kg(-1) and D-cycloserine 10 mg kg(-1) had no effect on the water maze deficit induced by hippocampal lidocaine infusion. These results suggest that combined treatment with tetrahydroaminoacridine and D-cycloserine can effectively stimulate water maze spatial navigation, and that functioning of the hippocampus is a prerequisite for this effect.

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He was initially treated with combination chemotherapy regimen of vincristine , actinomycin-D and cyclophosphamide ( VAC therapy ) .

[Rhabdomyosarcoma of the bladder: a case report]. A 15-year-old man with the chief complaint of general fatigue was referred to our hospital on November 11, 1993. Bilateral percutaneous nephrostomy was performed for postrenal anuria. X-ray examinations revealed a huge intrapelvic tumor, and it was histopathologically diagnosed as rhabdomyosarcoma by transrectal needle biopsy. He was initially treated with combination chemotherapy regimen of vincristine , actinomycin-D and cyclophosphamide ( VAC therapy ) . Pelvic exenteration was performed on December 15, 1993. Histopathological findings were alveolar rhabdomyosarcoma with degenerative change and partial necrosis. After the operation, he was given two course of VAC therapy. In May, 1994, brain metastasis occurred, so 4 courses of VAC therapy were administered. For a very short period, neurological symptoms improved, but he died of pneumonia on November 15, 1994.

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However , when a lung mass was noted two months later , he started to receive combination chemotherapy consisting of cyclophosphamide , adriamycin , vincristine , and prednisolone every three months .

[Lymphomatoid granulomatosis (LYG) occurring in a patient with follicular lymphoma during remission]. A 49 years-old man presented with dry cough, low grade fever, and abnormal shadow on a chest X-ray. He had suffered from follicular lymphoma of the liver 5 years previously. He received irradiation therapy in combination with chemotherapy for approximately three years and had been in complete remission. Physical and radiological examination revealed pleural effusion and softly dense masses in the right lung. The laboratory data were within normal limits. He was diagnosed as having lymphomatoid granulomatosis (LYG) by open lung biopsy. The lung lesion was mainly infiltrated with T cells. The patient received prednisolone and the lung lesions disappeared. However , when a lung mass was noted two months later , he started to receive combination chemotherapy consisting of cyclophosphamide , adriamycin , vincristine , and prednisolone every three months . He has not shown relapse of LYG so far. To investigate the association between the preceding follicular lymphoma and subsequent LYG at this time, DNA analysis using the PCR technique was carried out. The LYG lesion did not show a rearranged band for the JH probe, while the paraffin-embedded specimen of the preceding follicular lymphoma had shown rearranged band for the JH band. Southern blot analysis of the LYG lesion, showed no rearrangement for TCR beta, gamma or JH probe. These findings indicate that the LYG was different from the preceding follicular lymphoma in terms of origin. LYG is considered to be induced in the immunosuppressive state due to lymphoma.

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Three patients treated initially with propranolol alone have required substitution of amiodarone due to refractory congestive heart failure .

The role of beta-blockade therapy for ventricular tachycardia induced with isoproterenol: a prospective analysis. Isoproterenol is sometimes required for ventricular tachycardia (VT) induction. However, the role of beta-blockade for treatment of such VT has not been critically assessed. The use of beta-blockade was evaluated prospectively in 14 consecutive patients who required isoproterenol 2.4 +/- 1.3 (+/- S.D.) micrograms/min to induce sustained monomorphic VT (greater than 30 seconds, or requiring termination due to hemodynamic collapse) after a negative baseline study. The VT mechanisms were enhanced automaticity (group A, six patients), triggered automaticity (group B, three patients), and reentry (group C, five patients). Groups A and B had serial intravenous electropharmacologic tests with propranolol alone (0.2 mg/kg), verapamil alone (0.15 mg/kg), and propranolol plus verapamil, and group C had serial tests with propranolol alone, procainamide or quinidine (class Ia drug) alone, and propranolol plus a class Ia drug until VT could no longer be induced. All six patients in group A responded to propranolol alone. In group B, one patient responded to verapamil alone, and two patients responded to propranolol plus verapamil. In group C, three patients responded to propranolol alone, one patient responded to a class Ia drug alone, and one patient responded to propranolol plus a class Ia drug. During a follow-up of 7 to 37 (17.9 +/- 10.7) (+/- S.D.) months, VT has not recurred in any patient. Three patients treated initially with propranolol alone have required substitution of amiodarone due to refractory congestive heart failure . In patients requiring isoproterenol for VT induction, beta-blockade alone appears to be effective in preventing reinduction of VT caused by enhanced automaticity. A heterogeneous response occurs when the VT mechanisms are triggered automaticity or reentry.

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We used MCF-7 and MDA-MB231 breast cancer cells incubated with Curcumin and Quercetin for 24h , in the absence and presence of Somatostatin , at their EC50 concentrations , to evaluate membrane fatty acid-based functional lipidomics together with the follow-up of EGFR and MAPK signaling pathways .

Effects of Somatostatin, Curcumin and Quercetin on the fatty acid profile of breast cancer cell membranes. We used MCF-7 and MDA-MB231 breast cancer cells incubated with Curcumin and Quercetin for 24h , in the absence and presence of Somatostatin , at their EC50 concentrations , to evaluate membrane fatty acid-based functional lipidomics together with the follow-up of EGFR and MAPK signaling pathways . The two cell lines gave different membrane free fatty acid reorganization: in MCF-7 cells, the following changes observed: increase of omega-6 linoleic acid in the cells incubated with Somatostatin+Quercetin and Quercetin and decrease of omega-3 acids in the cells incubated with Somatostatin+Curcumin compared to Somatostatin, and significant increases of monounsaturated fatty acid (MUFA), mono-trans arachidonic acid levels and docosapentaenoic acid for the cells incubated with Somatostatin+Quercetin compared to the control cells. In MDA-MB231 cells, incubations with Curcumin, Quercetin and Somatostatin+Quercetin induced the most significant membrane remodeling with the increase of stearic acid, diminution of omega-6 linoleic, arachidonic acids and omega-3 (docosapentaenoic and docosahexaenoic acids). Distinct signaling pathway changes were found for these cell lines. In MCF-7 cells, separate or combined incubations with Somatostatin and Quercetin, significantly decreased EGFR and incubation with Curcumin decreased MAPK signaling. In MDA-MB231 cells, incubation with Curcumin decreased AKT1 and p-AKT1(Thr308) levels. Incubation with Curcumin and Quercetin decreased the EGFR levels.

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Following corneal scrapings and culture , topical 0.5 % moxifloxacin and 0.5 % tobramycin were administered hourly .

A case of Stenotrophomonas maltophilia keratitis effectively treated with moxifloxacin. A 70-year-old man with a long history of diabetes mellitus presented to our hospital (Department of Ophthalmology, Sahm Yook Medical Center, Seoul, Korea) complaining of severe ocular pain and visual disturbance in his left eye that had started three days prior to admission. A round 3.7 × 5.0 mm dense central stromal infiltrate with an overlying epithelial defect was noted on slit-lamp examination. Following corneal scrapings and culture , topical 0.5 % moxifloxacin and 0.5 % tobramycin were administered hourly . A few days later, Stenotrophomonas maltophilia was isolated in a bacterial culture from a corneal specimen. According to the results of susceptibility tests, topical 0.5% moxifloxacin was given every hour and 0.5% tobramycin was stopped. The patient's clinical features improved steadily with treatment. The corneal epithelium healed rapidly, and the infiltrate resolved within four weeks of the initiation of treatment. The patient's best corrected visual acuity improved from hand motion to 20 / 25.

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Combination treatment with cetuximab and nystatin selectively increased cetuximab uptake by tumor tissues , translating into potentiated antitumor efficacy of cetuximab in vivo ( A431 and A549 tumors ) .

Enhancement of tumor uptake and therapeutic efficacy of EGFR-targeted antibody cetuximab and antibody-drug conjugates by cholesterol sequestration. Cetuximab, a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), has been intensively investigated as a promising cancer treatment strategy. The specific mechanism of cetuximab endocytosis and its influence on cetuximab uptake, biodistribution and efficacy still remain elusive. Recently, statins have been reported to synergize with EGFR-targeting agents. Our prior work established that nystatin, a cholesterol-sequestering antifungal drug, facilitates endocytosis via the clathrin-dependent pathway. This study aimed to investigate whether nystatin regulates the uptake and efficacy of cetuximab and cetuximab-based antibody-drug conjugates (cetuximab-ADCs). In vitro and in vivo efficacies of nystatin on the uptake and activity of cetuximab/cetuximab-ADCs were studied in multiple human carcinoma cell lines and xenograft models, respectively. We identified that cholesterol sequestration by nystatin enhanced cetuximab internalization in EGFR-positive carcinoma cells by regulating EGFR trafficking/turnover and facilitating a switch from lipid rafts to clathrin-mediated endocytosis. Combination treatment with cetuximab and nystatin selectively increased cetuximab uptake by tumor tissues , translating into potentiated antitumor efficacy of cetuximab in vivo ( A431 and A549 tumors ) . Nystatin-enhanced internalization of cetuximab further improved the uptake and potency of cetuximab-doxorubicin and cetuximab-methotrexate conjugates in EGFR-positive cetuximab-resistant tumors. Combination therapy with nystatin plus either cetuximab or cetuximab-ADC further prolonged animal survival and significantly suppressed tumor growth, as compared with single-agent cetuximab or cetuximab-ADC. In summary, our results identify a novel mechanism whereby cholesterol sequestration enhances the uptake of EGFR-targeting mAb and ADCs, therefore providing preclinical proof-of-concept that combination with nystatin can potentiate the delivery and efficacy of these EGFR-targeted agents.

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The effects of combination therapy with chenodeoxycholic acid ( CDCA ) and simvastatin on serum cholestanol , low-density lipoprotein ( LDL ) cholesterol , and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis ( CTX ) who were on long-term treatment with CDCA .

Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. The effects of combination therapy with chenodeoxycholic acid ( CDCA ) and simvastatin on serum cholestanol , low-density lipoprotein ( LDL ) cholesterol , and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis ( CTX ) who were on long-term treatment with CDCA . The patients were treated with a combination of CDCA 750 mg daily and an increasing dose of simvastatin from 10 mg to 40 mg daily for a period of 6 months. We found a significant effect of this combination therapy compared with CDCA alone in terms of decreasing the serum cholestanol and LDL cholesterol levels, particularly with a daily dose of 40 mg simvastatin. The mean cholestanol level decreased from 9.27 micromol/L (baseline) to 6.69 micromol/L (40 mg simvastatin), while the mean LDL cholesterol level decreased from 5.08 mmol/L (baseline) to 3.04 mmol/L (40 mg simvastatin). No side effects were reported, and there were no effects on the clinical condition, cerebral magnetic resonance imaging (MRI), visual evoked potentials, and electroencephalographic features. We conclude that a combination of 750 mg CDCA and 40 mg simvastatin daily is effective to further reduce serum cholestanol, LDL cholesterol, and lathosterol in adult CTX patients treated with long-term CDCA. Whether this combination treatment will be effective for the long-term prevention of neurological deterioration and atherosclerosis remains to be established.

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Paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) has been demonstrated to be highly effective in treating patients with advanced breast cancer , including those with anthracycline-resistant breast cancer , a fact that has led to efforts to combine paclitaxel and anthracyclines .

Paclitaxel and doxorubicin in metastatic breast cancer. For the past decades the anthracyclines have been regarded as among the most active drugs for the treatment of metastatic breast cancer. However, the 5-year survival rate in patients with stage IV breast cancer continues to be below 20%, and new active drugs and drug combinations clearly must be explored. Paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) has been demonstrated to be highly effective in treating patients with advanced breast cancer , including those with anthracycline-resistant breast cancer , a fact that has led to efforts to combine paclitaxel and anthracyclines . Several studies aiming to define the optimal dose and schedule of combination paclitaxel/doxorubicin have now been completed or are ongoing. Phase I/II studies have yielded encouraging preliminary response rates but quite variable toxicity profiles depending on the schedule used. These clinical trials involving combination paclitaxel/doxorubicin are reviewed, with special emphasis on the short-infusion trials.

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However , anastrozole , exemestane and letrozole are associated with significantly fewer endometrial cancers , as well as venous and arterial vascular events , when compared with tamoxifen [ 9 , 10 ] .

Erythema nodosum secondary to aromatase inhibitor use in breast cancer patients: case reports and review of the literature. Aromatase inhibitors (AI's) are increasingly being incorporated in the treatment strategy for hormone receptor positive breast cancer either alone or in combination with chemotherapy, biologics in both the adjuvant and metastatic setting [1]. They markedly suppress plasma estrogen levels by inhibiting or inactivating aromatase, the enzyme responsible for the synthesis of estrogens from androgenic substrates [1]. Currently, the three selective aromatase inhibitors that are available are anastrozole, letrozole and exemestane which reduce circulating estrogen to 1 to 10% of pretreatment levels [2]. For advanced breast cancer, aromatase inhibitors appear to be at a minimum, equivalent and perhaps even better than tamoxifen in the first line setting [3, 4]. In primary breast cancer, adjuvant therapy with anastrozole or letrozole appears to be superior to tamoxifen in reducing the risk of relapse [5, 6]. Common adverse effects associated with AI's include arthralgias (21%), myalgias (12%), other musculoskeletal disorders (28%) and an up to 60% increased risk of bone fracture [7, 8]. However , anastrozole , exemestane and letrozole are associated with significantly fewer endometrial cancers , as well as venous and arterial vascular events , when compared with tamoxifen [ 9 , 10 ] . Very rarely letrozole and anastrozole can cause a skin rash; the frequency of its occurrence has not been quantified(. )However, exemestane has not been reported to cause a skin rash [11]. To date, erythema nodosum (EN) has not been reported as a dermatologic side effect of AI's. Here, we report three cases of EN which developed in postmenopausal breast cancer patients on AI's.

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Additivity , synergy , or competition was observed with MIS and rapamycin , AzadC , doxorubicin , cisplatin , and paclitaxel , suggesting that MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone .

Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer. Mullerian Inhibiting Substance (MIS), a biological modifier that causes regression of Mullerian ducts in male embryos, is effective as a single agent in vitro and in vivo against human and mouse ovarian cancer cell lines expressing MIS type II receptor; however, little is known about how recombinant human MIS (rhMIS), now being scaled for preclinical trials, could be used in combination with cytotoxic or targeted chemotherapeutic agents. Mouse serous and endometrioid ovarian carcinoma cell lines were tested in vitro against rhMIS alone and with doxorubicin, paclitaxel, or cisplatin as agents in clinical use. Because MIS releases FK506 binding protein (FKBP12), which activates the mammalian target of rapamycin (mTOR) downstream of Akt, rhMIS and rapamycin combinations were tested. MIS increases p16 protein levels, and 5'-Aza-2'-deoxycytidine (AzadC) induces p16 mRNA; therefore, they were used in combination in vitro and in vivo with a human ovarian cancer cell line. A paclitaxel-resistant human ovarian cancer cell line and its parental line both respond to rhMIS in vitro. Additivity , synergy , or competition was observed with MIS and rapamycin , AzadC , doxorubicin , cisplatin , and paclitaxel , suggesting that MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone . These assays and statistical analyses could be useful in selecting rhMIS and chemotherapeutic agent combinations that enhance clinical efficacy and reduce toxicity.

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There was no cytotoxic effect of cisplatin , ifosfamide , and etoposide .

Overcoming Chemoresistance of Pediatric Ependymoma by Inhibition of STAT3 Signaling. The long-term clinical outcome of pediatric intracranial epepdymoma is poor with a high rate of recurrence. One of the main reasons for this poor outcome is the tumor's inherent resistance to chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is overactive in many human cancers, and inhibition of STAT3 signaling is an emerging area of interest in oncology. In this study, the possibility of STAT3 inhibition as a treatment was investigated in pediatric intracranial ependymoma tissues and cell lines. STAT3 activation status was checked in ependymoma tissues. The responses to conventional chemotherapeutic agents and a STAT3 inhibitor WP1066 in primarily cultured ependymoma cells were measured by cell viability assay. Apoptosis assays were conducted to reveal the cytotoxic mechanism of applied agents. Knockdown of STAT3 was tried to confirm the effects of STAT3 inhibition in ependymoma cells. High levels of phospho-STAT3 (p-STAT3) expression were observed in ependymoma tissue, especially in the anaplastic histology group. There was no cytotoxic effect of cisplatin , ifosfamide , and etoposide . Both brain tumor-initiating cells (BTICs) and bulk tumor cells (BCs) showed considerably decreased viability after WP1066 treatment. However, BTICs had fewer responses than BCs. No additive or synergistic effect was observed for combination therapy of WP1066 and cisplatin. WP1066 effectively abrogated p-STAT3 expression. An increased apoptosis and decreased Survivin expression were observed after WP1066 treatment. Knockdown of STAT3 also decreased cell survival, supporting the critical role of STAT3 in sustaining ependymoma cells. In this study, we observed a cytotoxic effect of STAT3 inhibitor on ependymoma BTICs and BCs. There is urgent need to develop new therapeutic agents for pediatric ependymoma. STAT3 inhibitors may be a new group of drugs for clinical application.

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Several first-line phase III trials , as well as ongoing trials for which only preliminary results have been published , have fueled debates on the optimal dose and schedule ; these have focused not only on weekly vs q3-weeks paclitaxel , but also on other modifications and the advisability of adding bevacizumab .

Carboplatin/Paclitaxel Induction in Ovarian Cancer: The Finer Points. The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer. This two-drug regimen, with carboplatin dosed using the Calvert formula, yielded convincing noninferior outcomes when compared with the prior, more toxic, regimen of cisplatin/paclitaxel. Carboplatin's dose-limiting toxicity is thrombocytopenia; however, when this drug is properly dosed and combined with paclitaxel, the doublet's cycle 1 dose in chemotherapy-naive women is generally safe. Carboplatin (unlike cisplatin) contributes minimally to the cumulative sensory neuropathy of paclitaxel, thus ensuring noticeable reversibility of neuropathy symptoms following completion of 6 cycles and only occasionally requiring cessation or substitution of the taxane. Paclitaxel is responsible for the hair loss associated with the carboplatin/paclitaxel doublet; preventive measures must be considered for patients who would otherwise refuse treatment. Several first-line phase III trials , as well as ongoing trials for which only preliminary results have been published , have fueled debates on the optimal dose and schedule ; these have focused not only on weekly vs q3-weeks paclitaxel , but also on other modifications and the advisability of adding bevacizumab . Our view is that results of this doublet in the first-line treatment of ovarian cancer are driven primarily by carboplatin, given that ovarian cancer is a platinum-sensitive disease. Consequently, the roles of the accompanying paclitaxel dose and schedule and the addition of bevacizumab are currently unsettled, and questions regarding these issues should be decided based on patient tolerance and comorbidities until additional data are available.

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The primary goal was achieve the correct estimation of the target plasma area against the topotecan concentration-time curve ( AUC ) in a 5 day course of cladribine followed by monitored topotecan in pediatric patients with recurrent/refractory AML .

Topotecan exposure estimation in pediatric acute myeloid leukemia supported by LC-MS-based drug monitoring and pharmacokinetic analysis. Individualization of the topotecan dosing can reduce inter-patient variability, toxicity, and at the same time increases chemotherapy efficacy. Topotecan dosing based on simultaneous drug monitoring and pharmacokinetic analysis can yield more accurate and precise estimation of the topotecan systemic exposure than that attainable with the fixed dosing approach. Therefore, a combined approach could provide a tool assisting the clinicians in individualization of the topotecan dosing. The aim of the study was to estimate the topotecan exposure in pediatric patients with acute myeloid leukemia (AML) based on the plasma concentration-time data and using the pharmacokinetic analysis. The primary goal was achieve the correct estimation of the target plasma area against the topotecan concentration-time curve ( AUC ) in a 5 day course of cladribine followed by monitored topotecan in pediatric patients with recurrent/refractory AML . A sensitive and selective reversed-phase liquid chromatographic-mass spectrometry (LC-MS) assay was developed to quantify total topotecan in the human plasma samples. This method, with its lower quantification limit of 1 ng/ml, was validated over a linear range of 1-150 ng/ml. Under the proposed approach, the topotecan dosing was selected so as to achieve the final AUC value of 140±20 ng/ml h. The presented analytical and pharmacokinetic data demonstrate that the proposed approach can be a practical, useful, efficient, and accurate tool for individualizing the topotecan dosing in children with AML.

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The management of EP is challenging : no standardized guidelines exist with literature suggesting cyclosporine or infliximab as first-line therapy .

Erythrodermic psoriasis successfully and rapidly treated with brodalumab: Report of two cases. Erythrodermic psoriasis (EP) is a rare form of the disease clinically characterized by a generalized erythema covering ≥90% of the body surface area (BSA). The management of EP is challenging : no standardized guidelines exist with literature suggesting cyclosporine or infliximab as first-line therapy . However, a recent systematic review showed a positive response in EP patients treated with biologic agents. The most common biologic used for EP up until now has been ustekinumab, whereas infliximab might represent a first-line option in case of complicated EP (acute, severe, or unstable). Up until now, no case of brodalumab (a monoclonal antibody blocking IL-17 receptor) treatment for EP in real-life has ever been described. Here, we report the first two cases of efficacy and safety of brodalumab in real-life cases of EP.

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As single agents , curcumin and metformin are reported to exhibit chemopreventive properties , in vitro as well as in patients with oral cancer .

Curcumin and metformin-mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells. Effective chemoprevention is critical for improving outcomes of oral cancer. As single agents , curcumin and metformin are reported to exhibit chemopreventive properties , in vitro as well as in patients with oral cancer . In this study, the chemopreventive efficacy of this drug combination was tested in a 4-nitro quinoline-1-oxide (4NQO) induced mice oral carcinogenesis model. Molecular analysis revealed a cancer stem cell (CSC)-driven oral carcinogenic progression in this model, wherein a progressive increase in the expression of CSC-specific markers (CD44 and CD133) was observed from 8th to 25th week, at transcript (40-100-fold) and protein levels (P ≤ 0.0001). Chemopreventive treatment of the animals at 17th week with curcumin and metformin indicated that the combination regimen decreased tumor volume when compared to the control arm (0.69+0.03 vs 6.66+2.4 mm

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Withdrawal rates were comparable to drug survival rates of other biological therapies and rates of adverse events were similar between brodalumab and ustekinumab .

Brodalumab for the Treatment of Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal. As part of the National Institute for Health and Care Excellence single technology appraisal process, brodalumab was assessed to determine the clinical and cost effectiveness of its use in the treatment of moderate-to-severe plaque psoriasis. The Centre for Reviews and Dissemination and the Centre for Health Economics Technology Assessment Group at the University of York were commissioned to act as the independent Evidence Review Group. This article provides a summary of the Evidence Review Group's review of the company's submission, the Evidence Review Group report and the National Institute for Health and Care Excellence Appraisal Committee's subsequent guidance issued in March 2018. The main clinical effectiveness data were derived from three well-conducted, multicentre, double-blind randomised controlled trials. The trials demonstrated that brodalumab statistically significantly reduced the severity of psoriasis and its impact on health-related quality of life, compared with placebo, at 12 weeks. In comparison with ustekinumab, statistically significantly more patients taking brodalumab had reduced psoriasis severity at 12 weeks. Psoriasis severity and quality of life also appeared improved at 52 weeks, although statistical significance was not assessed. Withdrawal rates were comparable to drug survival rates of other biological therapies and rates of adverse events were similar between brodalumab and ustekinumab . A network meta-analysis was presented, comparing brodalumab with other therapies available at the same point in the treatment pathway (i.e. in patients for whom standard systemic therapy or phototherapy is inadequately effective, not tolerated or contraindicated). The network meta-analysis ranked treatments in order of effectiveness, in terms of achieving different levels of Psoriasis Area and Severity Index response. The results indicated that brodalumab had a similar probability of response to ixekizumab, secukinumab and infliximab and a higher probability of response than ustekinumab, adalimumab, etanercept, apremilast, dimethyl fumarate and placebo. The company's economic model compared nine treatment sequences that included three lines of active therapy, consisting of brodalumab and other comparators recommended by the National Institute for Health and Care Excellence, followed by best supportive care. The sequence with brodalumab in the first-line position dominated sequences that started with adalimumab, infliximab, secukinumab and ustekinumab. The incremental cost-effectiveness ratio of the brodalumab sequence compared to less effective and non-dominated sequences ranged from £7145 (vs. the etanercept sequence) to £13,353 (vs. the dimethyl fumarate sequence) per quality-adjusted life-year gained. The incremental cost-effectiveness ratio for the more costly and effective ixekizumab sequence was £894,010 per quality-adjusted life-year gained compared to the brodalumab sequence. At a threshold of £20,000 per quality-adjusted life-year gained, the brodalumab sequence had the highest probability of being cost effective (96%). The main limitation of the company's economic model was the restrictive nature of the sequences compared. Twelve separate scenarios based on key uncertainties were explored by the Evidence Review Group. The only scenarios where brodalumab was ranked lower than first were not considered to be more appropriate or plausible than the assumptions or scenarios included in the company's base case. The treatment rankings identified in the Evidence Review Group's alternative base case were identical to those derived from the company's base case model. At the first National Institute for Health and Care Excellence Appraisal Committee meeting, the Committee concluded that brodalumab appears to be as effective as other anti-interleukin-17 agents and is cost effective, based on the discount agreed in the patient access scheme. Brodalumab is recommended as an option for treating adults with severe plaque psoriasis (defined by a total Psoriasis Area and Severity Index score of 10 or more and a Dermatology Life Quality Index score of more than 10) who have not responded to other systemic non-biological therapies. Brodalumab should be stopped at 12 weeks if the psoriasis has not responded adequately.

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In patients with NPSLE , the use of high-dose corticosteroids is recommended in combination with immunosuppressants , such as mycophenolate mofetil and intravenous cyclophosphamide pulse therapy .

[Neuropsychiatric Systemic Lupus Erythematosus]. Central nervous system damage, a major organ manifestation of systemic lupus erythematosus (SLE), causes significant morbidity and mortality. Designating this condition as neuropsychiatric SLE (NPSLE), the American College of Rheumatology defines it as involving the central and peripheral nervous systems and being characterized by various manifestations including stroke, seizures, and psychosis. NPSLE treatment mainly seeks to reduce damage accrual. In patients with NPSLE , the use of high-dose corticosteroids is recommended in combination with immunosuppressants , such as mycophenolate mofetil and intravenous cyclophosphamide pulse therapy . This can be accomplished by controlling the activity of the disease, minimizing the use of corticosteroids, and optimizing the management of comorbidities, including cardiovascular risk factors. An international task force analysis of a treat-to-target strategy for SLE (T2T/SLE) recommended targeting remission, preventing damage, and improving quality of life. Thus, more effective and less toxic treatments, such as those using biologics or kinase inhibitors, are still being developed for the treatment of SLE/NPSLE.

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Thirty-three women diagnosed with metastatic breast cancer participated in a phase 1 clinical trial of a new combination of cyclophosphamide ( CTX ) and mitoxantrone ( MXT ) , with dose escalation of paclitaxel .

Longitudinal effects of high-dose chemotherapy and autologous stem cell transplantation on quality of life in the treatment of metastatic breast cancer. This study determined the effects of high-dose chemotherapy (HDCT) with autologous blood stem cell transplantation (ASCT) on quality of life (QL) in women with metastatic breast cancer prior to, and during treatment, and up to 1-year post-ASCT. Thirty-three women diagnosed with metastatic breast cancer participated in a phase 1 clinical trial of a new combination of cyclophosphamide ( CTX ) and mitoxantrone ( MXT ) , with dose escalation of paclitaxel . Longitudinal QL data were collected using the functional living index-cancer (FLIC) and symptom scales at seven time periods: pre-induction chemotherapy (CT), post-induction CT, post-high dose CT (HDCT), and at 3, 6, 9 and 12 months post-ASCT. FLIC scores indicated that the worst problems for patients were feelings of hardship on themselves and their families, followed by psychological functioning and physical functioning problems. The time around diagnosis of the metastatic disease and following HDCT were the worst times for all levels of quality of life, but anxiety and depression symptoms continued to increase in severity across the entire follow-up period. The symptoms that were most problematic were worry about the future, loss of sexual interest, anxiety about the treatment, general worrying, and joint pain. These data highlight the problems that women with metastatic breast cancer encounter at different stages of the disease and treatment process, and can be used to tailor psychosocial interventions appropriate for treating the relevant issues at different points in time.

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These studies suggest a slight advantage to the combined approaches that contain flutamide and bicalutamide , but the lack of dramatic differences in outcome makes monotherapy reasonable , especially in patients with more indolent disease .

The selection of hormonal therapy in prostate cancer: who, when, and for how long? Androgen deprivation is the foundation for the systemic therapy of advanced prostate cancer. Multiple trials have tested combined androgen blockade versus androgen deprivation alone in patients with advanced disease. These studies suggest a slight advantage to the combined approaches that contain flutamide and bicalutamide , but the lack of dramatic differences in outcome makes monotherapy reasonable , especially in patients with more indolent disease . Intermittent androgen deprivation is an alternative that may allow patients to reduce the total time on androgen suppression as well as possibly delay the onset of androgen independence. A number of secondary hormonal therapies, including deferred and secondary antiandrogens, ketoconazole, and estrogens have shown modest response proportions. Patients with less advanced disease such as a rising prostate-specific antigen have varied outcomes, and no standard approach exists. In this group, noncastrating forms of hormonal therapy are being evaluated. Patients undergoing definitive local therapy who have high-risk features may benefit from early, as opposed to deferred, androgen deprivation. This review examines the evidence for the current state of the art in hormonal therapy in patients with prostate cancer and focuses, in particular, on treatment composition and timing as well as the rationale for the use of hormonal therapy in early stage disease.

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We examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy ( HDC ) with autologous hematopoietic stem cell transplantation ( AHST ) for patients with HER2-positive metastatic breast cancer .

Paclitaxel and Trastuzumab as Maintenance Therapy in Patients with HER2-Positive Metastatic Breast Cancer Who Underwent High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation. We examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy ( HDC ) with autologous hematopoietic stem cell transplantation ( AHST ) for patients with HER2-positive metastatic breast cancer . Ten patients (9 women and 1 man) were enrolled in the study. The median age was 46.5 years (range, 27-65 years). The median follow-up time was 1003 days (range, 216-2526 days). All patients had metastatic disease, but 2 had only bone metastasis. One patient had complete response, 6 had partial response and 3 had stable disease to the standard-dose chemotherapy prior to transplantation. The conditioning regimen consisted of cyclophosphamide, carmustine, and thiotepa. After AHST, patients received weekly paclitaxel for 12 doses and trastuzumab every 3 weeks for 1 year as maintenance therapy. All patients experienced successful engraftment. The only grade 4 toxic effects observed were leukopenia and thrombocytopenia. The most common grade 3 toxic effect was neutropenic fever. No treatment-related deaths were observed. The median progression-free survival time was 441 days, and the median overall survival time was 955 days. Two patients died in accidents while their disease remained in remission. Five patients died with disease progression. At the time of this report, 3 patients are alive with stable disease, 1 of whom has remained free of disease progression for 2526 days since transplantation. Our findings indicate that paclitaxel plus trastuzumab as maintenance therapy after HDC with AHST for patients with HER2-positive metastatic breast cancer not only is feasible and safe but also results in survival outcomes similar to historical results.

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Dual antiplatelet therapy with aspirin and clopidogrel ( the preferred thienopyridine because of its superior hematologic safety ) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents .

Long-term care after percutaneous coronary intervention: focus on the role of antiplatelet therapy. Arterial wall injury caused by percutaneous coronary intervention (PCI) triggers transient platelet activation and mural thrombosis; these effects are superimposed on the preexisting platelet hyperreactivity associated with underlying atherothrombosis. Platelet activation has been implicated in the major complications of PCI: acute and subacute thrombosis and restenosis. Antithrombotic and anticoagulant therapy minimizes thrombotic complications after PCI. Aspirin plus a thienopyridine (ticlopidine or clopidogrel) is more effective than aspirin plus heparin and extended warfarin therapy in preventing periprocedural ischemic events and subsequent stent thrombosis and results in less major and minor bleeding. Dual antiplatelet therapy with aspirin and clopidogrel ( the preferred thienopyridine because of its superior hematologic safety ) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents . Coronary atherothrombosis is a diffuse vascular disease, and reduction of the risk of future ischemic events requires strategies that extend beyond the focal treatment of stenotic lesions. Optimal long-term care after PCI requires aggressive systemic pharmacotherapy (antiplatelet agents, statins, beta-blockers, and angiotensin-converting enzyme Inhibitors) in conjunction with therapeutic lifestyle changes (smoking cessation, weight reduction, dietary measures, and exercise). In this context, dual antiplatelet therapy (aspirin plus clopidogrel) is recommended for at least 12 months after PCI for prophylaxis of future atherothrombotic events.

a66cb578b3228b7980765b70f98fe955

Furthermore , in non-metastatic castration-resistant prostate cancer ( M0 CRPC ) , two second-generation anti-androgens , apalutamide and enzalutamide , when used in combination with ADT , have demonstrated a significant benefit in metastasis-free survival .

Recent trends in the management of advanced prostate cancer. Advanced prostate cancer includes a wide spectrum of disease ranging from hormone naïve or hormone sensitive to castration resistant, both containing populations of men who have demonstrable metastatic and non-metastatic states. The mainstay of treatment for metastatic hormone-sensitive prostate cancer is androgen deprivation therapy (ADT). However, recent level 1 evidence demonstrates that the addition of chemotherapy or abiraterone acetate to ADT results in significant survival advantage as compared with ADT alone. Furthermore , in non-metastatic castration-resistant prostate cancer ( M0 CRPC ) , two second-generation anti-androgens , apalutamide and enzalutamide , when used in combination with ADT , have demonstrated a significant benefit in metastasis-free survival . Here, we review the most recent studies leading to these significant changes in the treatment of advanced prostate cancer.

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A screening method based on liquid chromatography-electrospray mass spectrometry for the simultaneous determination of six corticosteroids ( betamethasone 17-valerate BM 17-V , beclomethasone BC , beclomethasone dipropionate BCDP , methylprednisolone MP , budesonide BD , flunisolide FN ) was developed in order to control their illegal use in cosmetic and natural products .

LC-MS method for the simultaneous determination of six glucocorticoids in pharmaceutical formulations and counterfeit cosmetic products. A screening method based on liquid chromatography-electrospray mass spectrometry for the simultaneous determination of six corticosteroids ( betamethasone 17-valerate BM 17-V , beclomethasone BC , beclomethasone dipropionate BCDP , methylprednisolone MP , budesonide BD , flunisolide FN ) was developed in order to control their illegal use in cosmetic and natural products . Indeed, despite corticosteroids are banned in cosmetics, counterfeit products might be present on the market, representing a health hazard. Therefore, effective analytical methods are required to rapidly screen over the counter products in health care shops for counterfeit corticosteroids. The analytical method involves the employment of a Waters Synergy C18 column (150mm×2.0mm I.D.) by using the following mobile phase: A (0.1% formic acid in acetonitrile), B (0.1% formic acid in water) in a linear gradient (from A-B 25:75, v/v to A-B 95:5, v/v in 30min) at the flow rate of 0.3mL/min. The detection was performed with an ion trap (IT) mass spectrometer in positive polarity, total ion current (TIC) and tandem mass modalities for qualitative purpose; single ion monitoring (SIM) mode was used for quantitative analysis on the ESI generated most abundant ion for each steroid. The method was fully validated in terms of precision, detection and quantification limits, linearity, recovery, and it was applied to the identification and quantification of corticosteroids in pharmaceutical formulations and cosmetic products. The mean recovery of BM 17-V, BC, BCDP, MP, BD and FN were found to be 101.3, 101.5, 98.8, 98.9, 98.1, 99.0%, respectively. Limits of quantitation (LOQ) were comprised in the range 29-95ng/mL. To the best of our knowledge, for the first time this mix of glucocorticoids were simultaneously determined in cosmetic products by using a fully validated method. BMV, in its two isomeric forms BM 17-V and BM 21-V, was found to be illegally present in one cream sample (A) with the total concentration level of 0.036% (w/w).

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Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib ( MLN9708 ) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant .

Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib ( MLN9708 ) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant . fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. ### background fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. ### methods This is a single-center phase Ib study with a 3+3 design of fulvestrant and the proteasome inhibitor ixazomib (MLN9708) in patients with advanced ER+ breast cancer that was progressing on fulvestrant. A dose-escalation design allowed establishment of the ixazomib maximum tolerated dose (MTD). Secondary objectives included progression-free survival, pharmacokinetics, and tumor molecular analyses. ### results Among nine evaluable subjects, treatment was well-tolerated without dose-limiting toxicities The MTD of ixazomib was 4 mg in combination with fulvestrant. Plasma concentrations of the active form of ixazomib (MLN2238) in the 4-mg dose cohort had a median (range) Cmax of 155 (122-171) ng/mL; Tmax of 1 (1-1.5) h; terminal elimination half-life of 66.6 (57.3-102.6) hr after initial dose; AUC of 5,025 (4,160-5,345) ng*h/mL. One partial response was observed, and median progression-free survival was 51 days (range 47-137). ### conclusion This drug combination has a favorable safety profile and anti-tumor activity in patients with fulvestrant-resistant advanced ER+ breast cancer that justifies future testing.

1a7d989c08fa3795bc567e8ab0166a64

Second-Line Treatment of Her2-Positive Metastatic Breast Cancer : Trastuzumab beyond Progression or Lapatinib ? A Population Based Cohort Study .

Second-Line Treatment of Her2-Positive Metastatic Breast Cancer : Trastuzumab beyond Progression or Lapatinib ? A Population Based Cohort Study . The relative efficacy of lapatinib vs. continuing trastuzumab beyond progression (TBP) in HER2-positive metastatic breast cancer (MBC) patients, who progressed on first-line trastuzumab, is still unclear. The objective of this population based cohort study was to compare outcomes of lapatinib vs. TBP in daily practice. ### methods All HER2-positive MBC patients who began second-line anti HER2 therapy between 1st January 2010 and 30th August 2013 were selected from Clalit Health Services' (CHS) electronic database. Available data on patient and disease characteristics and treatments were analyzed. The primary endpoint was overall survival (OS). Outcomes were compared using the Kaplan-Meier (log-rank) method and Cox proportional hazards model. ### results 64 patients received second-line lapatinib and 93 TBP. The two treatment groups were similar in age and co-morbidity rates, but differed in proportion of prior adjuvant trastuzumab (lapatinib: 29.7%, TBP: 16.1%, P = 0.043) and rates of prior brain metastases (lapatinib: 32.8%, TBP: 10.8%, P = 0.01). lapatinib median OS was 13.0 months (95% CI: 9.5-16.5) vs. 31.0 for TBP (95% CI: 20.6-41.4), P<0.001. On multivariate analysis, longer OS was preserved for TBP, after controlling for differences in age, adjuvant trastuzumab, duration of first-line trastuzumab therapy, brain metastases, visceral metastases and hormonal treatment [Hazard Ratio (HR) = 0.63, 95% CI: 0.40-0.99, P = 0.045]. ### conclusion In this comparative cohort study, OS of HER2-positive MBC patients treated with TBP was significantly longer than with lapatinib. These results might be especially relevant in settings where ado-trastuzumab-emtansine (TDM-1), the current preferred agent in this setting, is not available yet for patients.

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Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80 % of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab , and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance .

A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m(2) and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80 % of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab , and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance . We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252).

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Furthermore , the overall response rate for docetaxel in the intent-to-treat population ( 42.5 % ) is superior to the response rate of either doxorubicin as second-line therapy ( 29.3 % ) or paclitaxel ( Taxol ; Bristol-Myers Squibb Oncology , Princeton , NJ ) when used as first- or second-line therapy ( 29 % ) in metastatic disease .

Docetaxel (Taxotere): an effective agent in the management of second-line breast cancer. Despite improvements in detection and management, metastatic breast cancer remains a leading cause of death among women in industrialized countries. Chemotherapy is the initial treatment of choice for patients with a negative estrogen receptor status, as well as for those with a positive estrogen receptor status who have failed to respond to endocrine treatment. Patients who fail on first-line chemotherapy become candidates for second-line salvage chemotherapy; the outlook for these patients is poor, and new active agents continue to be sought. docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is a semisynthetic taxoid that is an inhibitor of microtubule depolymerization. This new anticancer agent has been studied in an extensive phase II clinical trial program involving 162 patients with second-line metastatic breast cancer, 134 of whom were anthracycline resistant. Doses of 100 mg/m2 of docetaxel, administered over 1 hour every 3 weeks, produced an overall response rate of 50% (range, 41% to 58%) in 129 evaluable patients, with a median duration of 6 months (range, 2 to 17 months). The response rates achieved to date with docetaxel in anthracycline-resistant patients compare favorably with those produced by the best monotherapies currently available, and are equivalent to those achieved with current combination chemotherapy options. docetaxel also was found to be highly effective in patients with a poor prognosis, having metastases in three or more organs (53%), and/or visceral sites of disease (47%). Furthermore , the overall response rate for docetaxel in the intent-to-treat population ( 42.5 % ) is superior to the response rate of either doxorubicin as second-line therapy ( 29.3 % ) or paclitaxel ( Taxol ; Bristol-Myers Squibb Oncology , Princeton , NJ ) when used as first- or second-line therapy ( 29 % ) in metastatic disease . In conclusion, docetaxel appears to be a very effective therapeutic option for women with second-line metastatic breast cancer.

8b1bb23841ae2c6e696bac92e3c4182e

Correlation of lidocaine induced changes in bladder capacity , compliance and number of uninhibited contractions with improvement on oral oxybutynin was 70.6 % , 64.3 % and 66.7 % , respectively .

The effects of intravesical lidocaine on bladder dynamics of children with myelomeningocele. Other studies have suggested that intravesical lidocaine may temporarily improve bladder dynamics but details of these effects and their application to children have not been examined. We evaluated the effects of intravesical lidocaine on bladder urodynamics of children with myelomeningocele and tried to correlate these effects with subsequent clinical response to oral oxybutynin. ### Materials And Methods Charts of children with myelomeningocele who had undergone urodynamic examinations from 1992 to 1998 were reviewed retrospectively. In children with uninhibited contractions or poor compliance 150 to 300 mg. lidocaine were instilled for 8 minutes and cystometry was repeated. Changes in bladder capacity and compliance, number of uninhibited contractions and bladder volume at which pressure of 40 cm. H2O was reached were recorded before and after the lidocaine instillation. Clinical response to subsequent treatment with oral oxybutynin was assessed from chart review. ### results A total of 48 urodynamic studies in 22 girls and 20 boys with a mean age plus or minus standard deviation of 8.3 +/- 5.7 years and myelomeningocele were evaluable. After instillation of lidocaine, urodynamics showed increased bladder capacity in 70.8% of studies (34 of 48), with an average increase in volume of 66% (p <0.05). No change or decreased bladder capacity occurred in 29.2% of studies. Bladder compliance improved in 61.7% of the studies (29 of 47, p <0.05) and worsened in 38.3%. Bladder volume at which the pressure of 40 cm. H2O was reached increased in 77.8% of studies (14 of 18, p <0.05). After lidocaine the number of uninhibited contractions decreased by 3.2 in 56.8% of studies (21 of 37, p <0.05). Correlation of lidocaine induced changes in bladder capacity , compliance and number of uninhibited contractions with improvement on oral oxybutynin was 70.6 % , 64.3 % and 66.7 % , respectively . ### conclusions Intravesical lidocaine can improve bladder capacity and compliance and decrease the number of uninhibited contractions in many children with neurogenic bladder caused by myelomeningocele. These observations suggest that intravesical lidocaine has effects on the neurogenic bladder that improve bladder dynamics. Although intravesical lidocaine testing may not reliably predict clinical response to oral oxybutynin at the prescribed dosages, a possible therapeutic role for intravesical lidocaine or similar agents should be explored further.

25a7dedfa19e3aaf3f8c7c38492f1afa

Compared with risedronate alone , at 6 months , risedronate plus atorvastatin produced significantly greater increases in the bone mineral density of the lumbar spine ( 1.58 % versus 0.75 % , p < 0.05 ) .

Statins have additive effects to vertebral bone mineral density in combination with risedronate in hypercholesterolemic postmenopausal women. Recent data suggest that statins used in the treatment of hypercholesterolaemia decrease fracture risk. In this study, we aimed to investigate prospectively whether statins have an additive effect to bisphosphonates (risedronate) according to the primary hypothesis that the addition of atorvastatin to risedronate would produce an increase, from baseline, in lumbar vertebrae and total hip BMD that was greater than that observed with risedronate alone. ### methods A total of 120 hypercholesterolaemic postmenopausal women with osteoporosis or osteopenia were randomized to receive risedronate (5 mg/day) or risedronate (5 mg/day) plus atorvastatin (20 mg/day). Changes in bone mineral density in the lumbar spine and hip, and serum lipid and glucose metabolism changes were assessed. ### results Compared with risedronate alone , at 6 months , risedronate plus atorvastatin produced significantly greater increases in the bone mineral density of the lumbar spine ( 1.58 % versus 0.75 % , p < 0.05 ) . We found no difference after therapy in BMD of the total hip (1.2% versus 1.1%). risedronate plus atorvastatin therapy had favorable effects on the serum lipid profile: LDL and total cholesterol. Serum fasting glucose and HbA1c levels were not affected during the treatments. ### conclusion Statins have modest additive effects to bisphosphonates in improving lumbar spine bone mineral density in hypercholesterolaemic postmenopausal women with established osteoporosis-osteopenia. A long-term study with adequate sample size is necessary to assess the effects of statins -- in combination or alone -- on the bones and prevention of fractures.

04ad370c0e3ca668b9c417e2cfeafa8c

The anti-CD22 immunoconjugate , inotuzumab ozogamicin , and the anti-CD19 BiTE ( ® ) antibody , blinatumomab , have demonstrated impressive single agent activity in patients with relapsed or refractory B-ALL .

Novel targeted therapies in acute lymphoblastic leukemia. Chemotherapy alone cures only 25-45% of adult patients with acute lymphoblastic leukemia (ALL), making novel treatment agents and strategies desperately needed. The addition of monoclonal antibodies (rituximab, alemtuzumab, epratzumab) to chemotherapy has demonstrated encouraging results in patients with newly diagnosed and relapsed ALL. The anti-CD22 immunoconjugate , inotuzumab ozogamicin , and the anti-CD19 BiTE ( ® ) antibody , blinatumomab , have demonstrated impressive single agent activity in patients with relapsed or refractory B-ALL . Early reports of chimeric antigen receptor therapies have been promising in patients with relapsed ALL. Other agents targeting NOTCH1, FLT3, the proteasome and DNA methylation are early in development. These new agents hope to improve the outcome of ALL therapy with less toxicity. The challenge going forward will be to find safe and effective combinations and determine where in the treatment schema these agents will be most effective in ALL therapy.

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Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab ( 5 mg/kg body weight i.v . every 21 days ) and oral capecitabine ( 950 mg/m(2 ) twice daily for 14 days followed by 7 days of rest ) in 2006 - 2008 .

Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. No standard therapy for advanced adrenocortical carcinoma (ACC) is established by any randomized trial but a consensus conference 2003 recommended mitotane as monotherapy or combined with etoposide, doxorubicin and cisplatin or with streptozotocin as first-line systemic therapy. However, there is no evidence for any therapy beneficial in patients failing these therapies. Therefore, we evaluated the effects of the anti-VEGF antibody bevacizumab plus capecitabine as salvage therapy in ACC. ### methods Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab ( 5 mg/kg body weight i.v . every 21 days ) and oral capecitabine ( 950 mg/m(2 ) twice daily for 14 days followed by 7 days of rest ) in 2006 - 2008 . Evaluation of tumour response was performed by imaging according to response evaluation criteria in solid tumours every 12 weeks. ### results Ten patients were treated with bevacizumab plus capecitabine. None of them experienced any objective response or stable disease. Two patients had to stop therapy after few weeks due to hand-foot syndrome, and three patients died on progressive disease within 12 weeks. Other adverse events were mild (grade I-II). Median survival after treatment initiation was 124 days. ### conclusions bevacizumab plus capecitabine has no activity in patients with very advanced ACC. Hence, this regimen cannot be recommended as a salvage therapy.

7ebb3f2cc13e75ceaad2830378a07a9f

Patients who had pathologically been proven to have measurable lesions were treated with paclitaxel ( 200 mg/m(2 ) for 3 h ) and carboplatin [ area under the concentration-time curve ( AUC = 6 ) ] on day 1 and in 21 day cycles .

Phase II study of paclitaxel and carboplatin in advanced gastric cancer previously treated with 5-fluorouracil and platinum. The combination of paclitaxel and carboplatin has been used to treat patients with many types of tumor, including gastric cancer. We evaluated the efficacy and safety of this combination in advanced gastric cancer patients previously treated with 5-fluorouracil and platinum. ### methods Patients who had pathologically been proven to have measurable lesions were treated with paclitaxel ( 200 mg/m(2 ) for 3 h ) and carboplatin [ area under the concentration-time curve ( AUC = 6 ) ] on day 1 and in 21 day cycles . ### results A partial response was achieved in 10 of 45 patients [22%, 95% confidence interval (CI), 10-34]. Of the 32 patients previously treated with cisplatin, four (13%) achieved partial response, whereas, of the 13 patients previously treated with heptaplatin, six (46%) achieved partial response. In all patients, the median time to progression was 14 weeks (95% CI, 10-18), and the median overall survival was 32 weeks (95% CI, 26-38). The most common grade 3/4 adverse events were neutropenia (40% of patients) and neuropathy (2.2%). Two patients developed neutropenic fever. However, there were no treatment-related deaths. ### conclusions Combination chemotherapy with paclitaxel and carboplatin is feasible in patients with advanced gastric cancer who were previously treated with 5-fluorouracil and platinum.

e3807edae1596e1c8d9abf185e0a3c2b

With regard to efficacy in metastatic disease , exemestane is superior to megestrol acetate after progression on tamoxifen .

Long-term efficacy and safety of exemestane in the treatment of breast cancer. exemestane, a steroidal aromatase inhibitor, is licensed for postmenopausal patients with estrogen receptor (ER)-positive breast cancer as second-line therapy in metastatic disease following antiestrogen failure and as part of sequential adjuvant therapy following initial tamoxifen. This study is a systematic literature review, evaluating exemestane in different clinical settings. The Ovid Medline (1948-2012), Embase (1980-2012), and Web of Science (1899-2012) databases were searched. Forty-two relevant articles covering randomized controlled trials were reviewed for efficacy and safety, and three for adherence. With regard to efficacy in metastatic disease , exemestane is superior to megestrol acetate after progression on tamoxifen . There is evidence for noninferiority to fulvestrant (following a prior aromatase inhibitor) and to nonsteroidal aromatase inhibitors in the first-line setting. Combined use with everolimus is shown to be more efficacious than exemestane alone following previous aromatase inhibitor use. In the adjuvant setting, a switch to exemestane after 2-3 years of tamoxifen is superior to 5 years of tamoxifen. exemestane is noninferior to 5 years of tamoxifen as upfront therapy, and may have a role as an extended adjuvant therapy. Used as neoadjuvant therapy, increased breast conservation is achievable. As chemoprevention, exemestane significantly reduces the incidence of breast cancer in "at-risk" postmenopausal women. exemestane is associated with myalgias and arthralgias, as well as reduced bone mineral density and increased risk of fracture, which do not appear to persist at follow-up, with subsequent return to pretreatment values. Compared with tamoxifen, there is a reduced incidence of endometrial changes, thromboembolic events, and hot flashes. Limited evidence shows nonadherence in 23%-32% of patients. Evidence is growing in support of exemestane in all clinical settings. It is generally more efficacious and has a better safety profile than tamoxifen. How it compares with the nonsteroidal aromatase inhibitors remains to be established. Further studies are required on adherence to ensure that maximum benefit is obtained.

0c5e3efa2736c3c9b15160e5b87b1966

Aim of the study was to measure plasma levels of specific miRNAs ( miRNA-223 , -150 , -21 and -126 ) after physician-driven cessation of chronic P2Y12 inhibition and to study differences in the expression levels of these miRNAs between the different oral P2Y12 inhibitors clopidogrel , prasugrel and ticagrelor , respectively .

Course of platelet miRNAs after cessation of P2Y12 antagonists. Circulating platelet micro-RNAs (miRNAs) may be used to monitor platelet function during dual antiplatelet therapy (DAPT). Aim of the study was to measure plasma levels of specific miRNAs ( miRNA-223 , -150 , -21 and -126 ) after physician-driven cessation of chronic P2Y12 inhibition and to study differences in the expression levels of these miRNAs between the different oral P2Y12 inhibitors clopidogrel , prasugrel and ticagrelor , respectively . ### design Patients with coronary artery disease (CAD) on DAPT maintenance dose (including aspirin 100 mg OD, plus clopidogrel 75 mg OD, or prasugrel 10 mg OD, or ticagrelor 90 mg BID) were prospectively enrolled before cessation of the P2Y12-inhibitor therapy. MiRNA-223, -150, -21 and -126 were determined at baseline (=last day of P2Y12-inhibitor intake) and 10, 30 and 180 days thereafter. ### results Cessation of P2Y12-inhibitor therapy did not significantly change miRNA levels. However, in ticagrelor-treated patients, miRNA levels were significantly increased at baseline (miRNA-223 and -21), day 10 (miRNA-223, -150, -21, -126) and day 30 (miRNA-223, -150, -21, -126) as compared to prasugrel, and at day 10 (miRNA-150 and -21) and day 30 (miRNA-150) as compared to clopidogrel (all P < 0.05). At day 180, only miRNA-126 levels differed significantly with respect to the P2Y12 inhibitor used (P < 0.05). After adjustment for confounders, choice of P2Y12-inhibitor was the strongest predictor of miRNA levels (P < 0.001), while cessation of P2Y12-inhibitor therapy did not significantly impact miRNA levels. ### conclusion In patients with CAD, ticagrelor intake is associated with increased levels of platelet miRNAs as compared to clopidogrel and prasugrel. Platelet miRNAs are not useful to monitor platelet function after cessation of P2Y12 inhibitors.

186c1f47aa16e787370c97d07b302bc4

Eligible patients received ramucirumab ( 10mg/kg ) + dacarbazine ( 1000 mg/m(2 ) ) ( Arm A ) or ramucirumab only ( 10mg/kg ) ( Arm B ) every 3 weeks .

A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma. To evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-naïve patients with metastatic melanoma (MM). ### methods Eligible patients received ramucirumab ( 10mg/kg ) + dacarbazine ( 1000 mg/m(2 ) ) ( Arm A ) or ramucirumab only ( 10mg/kg ) ( Arm B ) every 3 weeks . The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), overall response and safety. ### findings Of 106 randomised patients, 102 received study treatment (Arm A, N=52; Arm B, N=50). Baseline characteristics were similar in both arms. Median PFS was 2.6 months (Arm A) and 1.7 months (Arm B); median 6-month PFS rates were 30.7% and 17.9% and 12-month PFS rates were 23.7% and 15.6%, respectively. In Arm A, 9 (17.3%) patients had partial response (PR) and 19 (36.5%), stable disease (SD); PR and SD in Arm B were 2 (4.0%) and 21 (42.0%), respectively. Median OS was 8.7 months in Arm A and 11.1 months in Arm B. Patients in both arms tolerated the treatment with limited Grade 3/4 toxicities. ### interpretation ramucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm.

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The aim of this study was to investigate the mutagenic and antigenotoxic effects of different doses of the flavonoid , apigenin , alone and in combination with the antitumor drugs , cyclophosphamide and doxorubicin , in vitro and in vivo .

The effect of apigenin on cyclophosphamide and doxorubicin genotoxicity in vitro and in vivo. The aim of this study was to investigate the mutagenic and antigenotoxic effects of different doses of the flavonoid , apigenin , alone and in combination with the antitumor drugs , cyclophosphamide and doxorubicin , in vitro and in vivo . Using bacterial reverse mutation inhibition in vitro, with and without metabolic activation, the effect of apigenin (10-400 μg/plate) was studied on genotoxicity induced by cyclophosphamide (800 μg/plate) and by doxorubicin (0.2 μg/plate). Subsequent to a dose-finding study in vivo, CD1 mice were treated with either cyclophosphamide (40 mg/kg, i.p.) or doxorubicin (5 mg/kg, i.p.) with or without co-administration of apigenin (1-100 mg/kg, p.o.). Micronuclei were determined microscopically in blood smears and glutathione peroxidase (GPX), superoxide dismutase (SOD) and total antioxidative status (TAS) in whole blood, erythrocytes and plasma, respectively. Apigenin decreased doxorubicin-induced, but not cyclophosphamide-induced mutagenicity in vitro. In vivo, apigenin caused a statistically significant decrease in micronucleus frequency in response to cyclophosphamide, possibly due to active flavonoid metabolite formation or inhibition of cyclophosphamide metabolic activation. In animals treated with apigenin and doxorubicin, a significant decrease in micronucleus frequency was not observed, probably due to interindividual variability. No changes in GPX, SOD or TAS were observed in response to either cytotoxic agents or the flavonoid, possibly due to limited metabolic transformation of the drugs at the doses used. The results of the present study provide further evidence for the chemo-preventative properties of apigenin.

29e6970b74408855d05ebb70363a839d

The novel agents , romidepsin , pralatrexate , and brentuximab vedotin , are currently approved in the relapsed/refractory setting .

Treatment of peripheral T-cell lymphoma: are we data driven or driving the data? Peripheral T-cell lymphomas (PTCL) are a group of uncommon and heterogeneous malignancies arising from a postthymic or mature T-lymphocyte. The treatment of PTCL remains a challenging endeavor. Compared with the more common aggressive B-cell lymphomas, more patients with PTCL will be refractory to initial therapy and those who achieve responses often will have shorter progression-free survival. Despite retrospective data that suggest that anthracycline-based multiagent chemotherapy regimens may not provide a benefit compared with nonanthracycline regimens, nonanthracycline-based regimens, with the notable exception of L-asparaginase regimens for extranodal NK/T-cell lymphoma, have been disappointing so far. Based on phase II evidence and subset analyses available, we believe that the addition of etoposide to standard regimens and consolidation of first remissions with autologous stem cell transplantation (autoSCT) provides the best outcome in patients with PTCL and currently use CHOEP followed by ASCT for eligible patients with the common PTCL subtype: PTCL-NOS, AITL, and ALK negative ALCL. For those with ALK-positive ALCL standard CHOP or CHOEP is appropriate with consideration of ASCT only for those with high-risk disease. Other strategies to incorporate additional agents, such as with dose-adjusted EPOCH or sequential CHOP-ICE regimens are logical options; however, they lack the supporting literature of CHOEP. Whereas the above recommendation is our current off-protocol approach, with the possible exception of low risk ALK positive ALCL, none of these choices is supported by strong enough data to supplant a well-conceived clinical trial as the truly preferred strategy in PTCL. The novel agents , romidepsin , pralatrexate , and brentuximab vedotin , are currently approved in the relapsed/refractory setting . These agents are being studied as additions or substitutions for other agents in up-front multiagent chemotherapy regimens. In the relapsed/refractory setting, both pralatrexate and romidepsin remain well-studied choices with some patients achieving a response with durability. Clinical trials of new agents in PTCL continue to be a valuable option and an important part of routine patient management as progressive disease often is seen. Lastly, we believe patients with relapsed/refractory PTCL should be considered for allogeneic stem cell transplantation if a suitable response is demonstrated and a willing donor is available.

aef93dee5953fbbbf30f53423ef2c08b

More effective regimens are urgently needed for squamous cell carcinoma of esophagus ( SCCE ) , therefore , we conducted a phase I/II trial of a combination of docetaxel , platinum , and fluorouracil ( TPF ) for treating metastatic SCCE .

Phase I/II study of docetaxel/cisplatin/fluorouracil combination chemotherapy against metastatic esophageal squamous cell carcinoma. More effective regimens are urgently needed for squamous cell carcinoma of esophagus ( SCCE ) , therefore , we conducted a phase I/II trial of a combination of docetaxel , platinum , and fluorouracil ( TPF ) for treating metastatic SCCE . ### methods This phase I/II trial (n = 12/39) was conducted in our institute from April 2005 to June 2008. Progression-free survival (PFS) and overall survival were analyzed by the Kaplan-Meier method. ### results The recommended dose of docetaxel was determined to be 50 mg/m in phase I. In phase II with a mean follow-up period of 13.3 months, the objective response rate was 66.6%, a median survival period of 13 months and PFS of 7 months was achieved, and the 1-year survival and PFS rates were 52.9% and 19.6%, respectively. Grade 3/4 toxicities of leukopenia, neutropenia, and anorexia were observed in 53.8%, 43.6%, and 25.6%, respectively. ### conclusions A TPF regimen against metastatic SCCE was well tolerated and achieved a favorable objective response rate and survival benefit compared with other recently reported regimens. Randomized phase III trials of the TPF regimen are warranted and urgently required.

9dc9c448c1cfe0ae6228e1de335aa21a

Gemcitabine with cyclosporine or with tacrolimus exerts a synergistic effect and induces tolerance in the rat .

Gemcitabine with cyclosporine or with tacrolimus exerts a synergistic effect and induces tolerance in the rat . This study investigated the effect of the antineoplastic agent gemcitabine (dFdC) in combination with cyclosporine (CsA) or with FK506 on acute heart allograft rejection in a rat model. ### methods Transplantations were performed in the fully allogeneic Lewis-to-Brown Norway strain combination. dFdC, CsA, and FK506 single-drug therapy and combinations of dFdC with CsA and FK506 were administered at various dosages starting on day 1 to prevent and on day 4 to treat acute rejection until day 20. Animals who did not reject their graft were intraperitoneally injected with 108 splenic donor-type lymphocytes. In addition, Lewis and third-party skin grafts were transplanted to these animals. ### results Mean graft survival times under CsA, FK506, and dFdC monotherapy were 18.3/63.7 days (1 mg/5 mg per kg), 41.7 days, and 24.7/38.7 days (100 microg/150 microg per kg), respectively. CsA and FK506 in combination with dFdC prolonged graft survival to more than 100 days (CsA) and more than 95.2 days (FK506). Graft survival after treatment of an ongoing rejection was 21.5/38.3 days for CsA (1 mg/5 mg per kg) and 17.7/59.2 days for dFdC (100 microg/150 microg per kg). The combination of CsA+dFdC prompted indefinite survival of five of six hearts. Lymphocyte inoculation did not induce graft rejection. Notably, none of the Lewis, but all third-party, skin grafts were rejected immediately. Histomorphologic analysis of grafted hearts, however, demonstrated typical features of chronic rejection. ### conclusions The combination of CsA and FK506 with low-dose dFdC exerts a synergistic effect in the prevention and treatment of acute allograft rejection in this model. Although chronic rejection could not be prevented, strain-specific tolerance was achieved. Therefore, combining standard immunosuppressants with dFdC is a novel, promising strategy for prevention and treatment of acute allograft rejection.

a44da7163dbe0769202832b6392742c8

Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells .

Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells . Resistance to trastuzumab is a major issue in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Several potential resistance mechanisms have been investigated, but the results are controversial and no conclusion has been reached. erythropoietin receptor (EPOR) may function in cell growth, and expressed in various cancer cells. Because the downstream signaling pathways for EPOR and HER2 partially overlapped, we hypothesized that EPOR may play a role in the inhibition effect of trastuzumab and resistance to trastuzumab. Here, we detected the expression of EPOR mRNA and protein in HER2-positive breast cancer cell lines and tissues. EPOR expressed in SKBR3, MDA-MB-453, and UACC-812 cell lines, but not in BT474. Of the 55 HER2-positive cancer tissues, EPOR was positive in 42 samples and highly expressed (H-score ≥ 25) in 24 by immunohistochemistry. The difference between EPOR expression and Ki67 index was significant (P = 0.033), and EPOR expression also positively correlated with higher pathological stage (Spearman correlation coefficient = 0.359; P = 0.007). Exogenous EPO antagonized trastuzumab-induced inhibition of cell proliferation in HER2/EPOR dual-positive breast cancer cells. We then exposed SKBR3 cells to trastuzumab for 4 months to obtain trastuzumab-resistant SKBR3 cell line, which demonstrated higher phosphorylated EPOR level, higher EPO expression and more extracellular secretion than non-resistant parental SKBR3 cells. Downregulation EPOR expression using short hairpin RNA resensitized trastuzumab-resistant cells to this drug, and SKBR3 cells with EPOR downregulation demonstrated attenuated trastuzumab resistance after the same resistance induction. EPOR downregulation plus trastuzumab produced a synergetic action in the inhibition of cell proliferation and invasion in SKBR3 and MDA-MB-453 cell lines. Therefore, EPOR expression may be involved in tumor progression and proliferation in HER2-positive breast cancer. EPO/EPOR contributes to the mechanism of trastuzumab resistance in SKBR3 cell lines, and EPOR downregulation can reverse the resistance to trastuzumab and increase the inhibition effect of this drug.

2f3b2589dc0ee0e5195219864acdb46e

Both paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) and ifosfamide have been demonstrated to be active agents in patients with clinically defined platinum-refractory ovarian cancer .

Rationale for examining the combination of paclitaxel and ifosfamide in the treatment of advanced ovarian cancer. Both paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) and ifosfamide have been demonstrated to be active agents in patients with clinically defined platinum-refractory ovarian cancer . While there might be interest in combining these two drugs as salvage therapy for this disease, the recent inclusion of paclitaxel as initial therapy for advanced ovarian cancer, along with a platinum agent (cisplatin or carboplatin), makes it unlikely that paclitaxel and ifosfamide will be used clinically in this malignancy. However, if alkylating agents are not to be used as part of the initial chemotherapy strategy for women with advanced ovarian cancer, it will be important to evaluate the activity of ifosfamide as salvage therapy in individuals treated only with, and demonstrated to be refractory to, a platinum agent and paclitaxel. If significant activity for ifosfamide is observed in this clinical setting, evaluation of the potential utility of a three-drug combination regimen comprising ifosfamide, paclitaxel, and cisplatin or carboplatin may be quite relevant.

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All M. simiae complex species proved susceptible to clarithromycin and , to a lesser extent , rifabutin , clofazimine , streptomycin and moxifloxacin .

Drug susceptibility testing and pharmacokinetics question current treatment regimens in Mycobacterium simiae complex disease. The Mycobacterium simiae complex bacteria can cause opportunistic infections in humans. In the case of definite disease, there are no evidence-based treatment regimens and outcomes are very disappointing. To increase the evidence base underpinning treatment regimens for M. simiae complex disease, drug susceptibility patterns and rifampicin/ethambutol synergy were assessed retrospectively in 69 clinical M. simiae complex isolates from 60 patients (22 patients with M. simiae, 24 with Mycobacterium lentiflavum, 8 with Mycobacterium triplex, 5 with Mycobacterium parascrofulaceum and 1 with Mycobacterium stomatepiae) submitted to the mycobacteriology laboratory at National Jewish Health (Denver, CO). Quantitative drug susceptibility testing (DST) was performed using the radiometric BacTec 460 macrodilution method. Results were related to pharmacokinetic (PK) measurements, where available. All M. simiae complex species proved susceptible to clarithromycin and , to a lesser extent , rifabutin , clofazimine , streptomycin and moxifloxacin . Synergy or additive action between rifampicin and ethambutol was observed for all species except M. simiae. Mycobacterium simiae is poorly susceptible in vitro to rifampicin and ethambutol alone as well as in combination; PK measurements support the limited efficacy of these drugs against M. simiae. The triple-drug regimen of a rifamycin, ethambutol and a macrolide may be advised to treat disease caused by M. lentiflavum, M. triplex, M. parascrofulaceum and M. stomatepiae; for M. simiae, this regimen appears less active. These findings may partly explain the limited treatment results in M. simiae disease. A treatment regimen including a macrolide, moxifloxacin and one or two additional drugs based on DST results may be advisable; clofazimine and amikacin or streptomycin are potential candidates.

78070d46a5752185cc2d9f118c577564

Drug exposure of mesenchymal HCC cells showed higher resistance to the targeted therapeutic agents sorafenib and erlotinib as compared to epithelial HCC cells , which were slightly more resistant to cytostatic drugs .

A human model of epithelial to mesenchymal transition to monitor drug efficacy in hepatocellular carcinoma progression. The epithelial to mesenchymal transition (EMT) of malignant hepatocytes is a crucial event in hepatocellular carcinoma (HCC) progression and recurrence. We aimed to establish a human model of EMT to examine drug efficacy and specificity in HCC progression. Human HCC cell populations were characterized by immunofluorescence analysis, migration and invasion assays, array comparative genomic hybridization, whole-genome expression profiling, and promoter methylation. Therapeutic agents clinically used against HCC were examined for efficacy by determination of IC(50) values. We show that liver cancer cell lines exhibited either an epithelial or mesenchymal phenotype of which the latter showed strong migratory and invasive abilities in vitro. The common cellular origin of both cell types indicated that mesenchymal HCC cells have been derived from epithelial hepatocytes through EMT in the HCC patient. Drug exposure of mesenchymal HCC cells showed higher resistance to the targeted therapeutic agents sorafenib and erlotinib as compared to epithelial HCC cells , which were slightly more resistant to cytostatic drugs . Most remarkably, combined treatment with doxorubicin and sorafenib caused increased susceptibility of both HCC cell types resulting in enhanced drug efficacy. Taken together, this EMT model of human HCC allows the identification of molecular mechanisms and the assessment of therapeutic drug efficacy during liver cancer progression in preclinical studies.

9d29356786d19764fd35e5c55994cb45

To compare the effectiveness and safety of adalimumab and infliximab in biologic-naïve patients with CD , in a nationwide register-based propensity score-matched cohort study in Denmark .

Comparison of infliximab with adalimumab in 827 biologic-naïve patients with Crohn's disease: a population-based Danish cohort study. There are conflicting data on comparative effectiveness of adalimumab and infliximab in patients with Crohn's disease (CD). ### aims To compare the effectiveness and safety of adalimumab and infliximab in biologic-naïve patients with CD , in a nationwide register-based propensity score-matched cohort study in Denmark . ### methods A total of 2908 Danish adults with CD had been treated with adalimumab or infliximab as their first biologic agent between 2005-2014. By Cox regression, we compared rates of all-cause hospitalisation, CD-related hospitalisation, major abdominal surgery and serious infections after variable 2:1 propensity score matching, accounting for baseline disease characteristics, healthcare utilisation and use of CD-related medications. ### results After propensity-score matching, we included 315 adalimumab- (34.9 ± 12.9 years, 41.9% males) and 512 infliximab-treated (33.6 ± 12.6 years, 40.8% males) patients, with median disease duration 4.0 years; 36.9% had prior abdominal surgery. Over a median follow-up 2.3 years after starting biological therapy, there were no significant differences in rate of CD-related hospitalisation (hazard ratio [HR], 0.81 [95% CI, 0.55-1.20]) or major abdominal surgery (HR, 1.24 [0.66-2.33]) between adalimumab- and infliximab-treated patients, though rate of all-cause hospitalisation was lower in adalimumab-treated patients (HR, 0.74 [0.56-0.97]). There was no significant difference in incidence of serious infections requiring hospitalisation (HR, 1.06 [0.26-4.21]). These results were stable in patients treated with biological monotherapy (all-cause hospitalisation: HR, 0.75 [0.53-1.05]; CD-related hospitalisation: HR, 0.82 [0.51-1.32], abdominal surgery: HR, 1.47 [0.63-3.47]) or in combination with immunomodulators (all-cause hospitalisation: HR, 0.70 [0.44-1.11]; CD-related hospitalisation: HR, 0.80 [0.42-1.52], abdominal surgery: HR, 1.02 [0.39-2.64]). ### conclusions In this population-based, propensity score matched, real-life cohort study using administrative claims, there was no significant difference in effectiveness and safety of adalimumab and infliximab in biologic-naïve patients with CD.

f9e6f79e5313dcceeafb28a5d3c04a7b

Hematologic National Cancer Institute Common Toxicity Criteria grade 3 to 4 adverse events were more common with bendamustine than with chlorambucil ( occurring in 40 % v 19 % of patients ) .

Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. This randomized, open-label, parallel-group, multicenter study was designed to compare the efficacy and safety of bendamustine and chlorambucil in previously untreated patients with advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL). ### Patients And Methods Patients (<or= 75 years of age) were randomly assigned to receive bendamustine 100 mg/m(2)/d intravenously on days 1 to 2, or chlorambucil 0.8 mg/kg (Broca's normal weight) orally on days 1 and 15; treatment cycles were repeated every 4 weeks for a maximum of six cycles. The response to treatment was assessed according to National Cancer Institute Working Group criteria, and the final determination of response was made by a blinded independent review committee. ### results A total of 319 patients were randomly assigned (162 bendamustine, 157 chlorambucil). Complete or partial responses were achieved in 110 (68%) of 162 bendamustine-treated and 48 (31%) of 157 chlorambucil-treated patients (P < .0001). More patients showed complete responses with bendamustine than with chlorambucil (31% v 2%). Median progression-free survival was 21.6 months with bendamustine and 8.3 months with chlorambucil (P < .0001). bendamustine was also associated with an improvement in duration of remission, compared with chlorambucil (median, 21.8 v 8.0 months). Hematologic National Cancer Institute Common Toxicity Criteria grade 3 to 4 adverse events were more common with bendamustine than with chlorambucil ( occurring in 40 % v 19 % of patients ) . Severe infections (grade 3 to 4) occurred in 8% of bendamustine-treated patients and 3% of chlorambucil-treated patients. ### conclusion bendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity profile, when used as first-line therapy in patients with advanced CLL.

9f41b57d1dbe5a07e388863d29a381a2

We determined the effects of diclofenac sodium , octreotide , and their combination on extrapancreatic organ injuries in caerulein-induced acute pancreatitis in mice .

Diclofenac Sodium Treatment Ameliorates Extrapancreatic Organ Injuries in a Murine Model of Acute Pancreatitis Induced by Caerulein. We determined the effects of diclofenac sodium , octreotide , and their combination on extrapancreatic organ injuries in caerulein-induced acute pancreatitis in mice . ### methods A total of 58 BALB-C male mice (25 g) were divided into seven groups and used to create a caerulein-induced acute pancreatitis model. diclofenac sodium, octreotide, and their combination were given for treatment of caerulin-induced acute pancreatitis in mice. At the end of the experiment, the lung, liver, kidney, and stomach were removed for histopathologic assessment. ### results Histopathologic investigation revealed a statistically significant difference between the groups in mean congestion, edema, tubular injury, perirenal fat tissue inflammation, and tubular stasis scores in kidney tissue ( ### conclusion diclofenac sodium alone ameliorates lung edema due to caerulin-induced acute pancreatitis.

5ad27773a3ec299ab3f8bcf2f358c135

Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models .

[Successful treatment of a persistent rhino-cerebral mucormycosis in a pediatric patient with a debut of acute lymphoblastic leukemia]. The fungi of the order Mucorales cause mucormycosis, which usually presents as an invasive fungal disease with rapid angioinvasion in immunocompromised patients. Rhinocerebral is the most common presentation. The lipid formulations of amphotericin B are used as primary treatment in invasive mucormycosis; the combined use of posaconazole could allow a reduction in the dose of amphotericin B improving tolerance and adherence to treatment. Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models . We present the case of a preschool patient that during the debut of acute lymphoblastic leukemia developed a rhinocerebral mucormycosis successfully responding to antifungal treatment with the combination of liposomal amphotericin and caspofungin.

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Canine leishmaniosis is most frequently treated with the drugs meglumine antimoniate , allopurinol , amphotericin B , or a combination of meglumine antimoniate and allopurinol .

Chemotherapy of canine leishmaniosis. Visceral leishmaniosis is a widespread and potentially fatal disease of dogs and humans common in the Mediterranean region, the Middle East, and South America. Canine leishmaniosis is most frequently treated with the drugs meglumine antimoniate , allopurinol , amphotericin B , or a combination of meglumine antimoniate and allopurinol . Therapy with the currently used drugs often achieves temporary clinical improvement and changes in immunologic parameters with restoration of the ability to mount parasite-specific cell mediated responses and decrease in anti-leishmanial antibody titers. However, treatment usually does not prevent relapse of disease or eliminate parasite carriage. Due to the current lack of an ultimate and effective therapy for canine leishmaniosis, new drugs, delivery systems and treatment strategies are necessary to achieve a consistent parasitological cure in infected dogs.

56d69e4f3b906e7c44c8241207cf7be6

Haloperidol , carbamazepine and levomepromazine were then discontinued .

Pituitary microadenoma treated with antipsychotic drug aripiprazole. Male patient 24 years old with a pituitary microadenoma and mental and behavioural disorders due to multiple drug use and use of other psychoactive substances (cocaine, cannabis and alcohol) were treated with haloperidol (dopamine receptor blocker) 10 mg daily. In the last control, the patient presented mammary hypertrophy; laboratory testing and brain magnetic resonance imaging (MRI) was performed, reporting the presence of a pituitary microadenoma syndrome with hormonal alteration (Prolactin levels 28.4 ng/ml). Haloperidol , carbamazepine and levomepromazine were then discontinued . He was started on aripiprazole 15 mg po daily for 4 days; the dosage was then increased to 30 mg po daily, with valproic Acid 500 mg po tid. After 3 weeks on aripiprazole, the mammary hypertrophy that had increased in the patient had resolved. After 10 weeks follow up of prolactin revealed a normal level, at 4.33 ng/ml. Insomnia, aggressiveness, irritability, visual, tactile and auditory hallucinations remained absent after treatment with aripiprazole which is not a first line drug in multiple drug use patient with psychosis. We also consider the correlation of drug use in patient with psychosis, haloperidol treatment, pituitary microadenoma syndrome, hyperprolactinemia, and dopamine D2- receptor partial agonist aripiprazole treatment. This article also summarizes some relevant patents.

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Recent clinical work has questioned the safety of a combined therapy of oral quinidine and intravenous verapamil , because some patients were reported to react with severe hypotension probably due to drug interactions with vascular alpha-adrenergic receptors .

Additive competitive interaction of verapamil and quinidine at alpha-adrenergic receptors of isolated cardiac guinea pig myocytes and human platelets. Recent clinical work has questioned the safety of a combined therapy of oral quinidine and intravenous verapamil , because some patients were reported to react with severe hypotension probably due to drug interactions with vascular alpha-adrenergic receptors . In order to obtain further quantitative information on the underlying mechanism, we used the radioligands (3H)-prazosin and (3H)-yohimbine to perform binding studies on intact cells, with predominantly alpha-1 (isolated myocytes) or alpha-2 subtypes (human platelets) of adrenergic receptors. Our studies confirm that both verapamil and quinidine possess a distinct alpha-adrenergic receptor blocking activity and do not discriminate between the alpha-1 and alpha-2 subtype (Ki-values were between 0.24-0.28 mumol/l for alpha-1 receptors and 0.49-0.50 mumol/l for alpha-2 receptors). Their interaction was competitive and in the presence of both drugs inhibition of radioligand binding was additive. The alpha-adrenergic blockade by verapamil was stereospecific as D-verapamil increased the dissociation constant of the radioligand to a much lesser degree than L-verapamil (Ki = 1.67 +/- 0.29 mumol/l for D-verapamil). The calcium channel blocker nitrendipine, a 1,4-dihydropyridine derivative, did not show any competition up to concentrations of 10 mumol/l. Our results thus give evidence that verapamil and quinidine have already at therapeutic blood levels significant alpha-adrenergic blocking activities which may be of clinical interest. In addition our results show that adult cardiac myocytes are very well suited for pharmacological adrenergic interaction studies.

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The mean duration of total ( i.v . and oral ) therapy was significantly shorter for the azithromycin group than for the cefuroxime group ( 6.2 days vs 10.1 days ) .

Clinical efficacy and safety of a short regimen of azithromycin sequential therapy vs standard cefuroxime sequential therapy in the treatment of community-acquired pneumonia: an international, randomized, open-label study. An international, randomized, open-label, comparative study was undertaken in order to assess the efficacy and safety of azithromycin and cefuroxime, short sequential vs standard sequential therapy, respectively, in the treatment of patients with community-acquired pneumonia (CAP). 180 adult patients were included in the study. 89 patients received azithromycin 500 mg intravenously (i.v.) once daily for 1-4 days followed by azithromycin 500 mg orally once daily for 3 days. 91 patients received cefuroxime 1.5 g i.v. three times daily for 1-4 days followed by cefuroxime axetil 500 mg orally twice daily for 7 days. Clinical efficacy was achieved in 67/82 (81.7%) patients treated with azithromycin, and in 73/89 (82.0%) patients treated with cefuroxime. The mean duration of total ( i.v . and oral ) therapy was significantly shorter for the azithromycin group than for the cefuroxime group ( 6.2 days vs 10.1 days ) . Adverse events were recorded in 38.2% of patients treated with azithromycin, and in 29.7% of patients treated with cefuroxime (p = 0.20). Shorter sequential i.v.-to-oral azithromycin therapy of patients with CAP was as effective as standard sequential i.v.-to-oral cefuroxime therapy.

7ab70148e0d2476ff23e259f31c9296e

To increase the dose-intensity of two drugs in metastatic breast cancer , we tested the feasibility , in phase I studies , of two schedules of epirubicin ( E ) and cyclophosphamide ( C ) - sequential ( E-- > C ) and alternating ( E/C ) - with respect to the standard combination ( EC ) .

The impact of schedule on acute toxicity and dose-intensity of high-dose chemotherapy with epirubicin and cyclophosphamide plus colony stimulating factors in advanced breast cancer. To increase the dose-intensity of two drugs in metastatic breast cancer , we tested the feasibility , in phase I studies , of two schedules of epirubicin ( E ) and cyclophosphamide ( C ) - sequential ( E-- > C ) and alternating ( E/C ) - with respect to the standard combination ( EC ) . Drugs were given at three planned-dose levels, plus either G-CSF or GM-CSF. Patients with metastatic (30), inoperable stage IIIb (2) or inflammatory (7) breast cancer were treated. The doses of EC, given every 21 days (4 cycles), were 75/1500, 82.5/2250, 90/3000 mg/m2. In the E/C schedule, epirubicin was given at cycles 1, 3 and 5, and cyclophosphamide at cycles 2, 4 and 6. In the E--> C schedule, three cycles of epirubicin then three cycles of cyclophosphamide were administered. In both experimental schedules, drugs were given every 14 days for 6 cycles at doses of 100, 110, 120 mg/m2 (E) and 2000, 3000, 4000 mg/m2 (C). The average relative dose-intensity was 1.2-fold and 2-fold greater with E/C and E--> C, respectively, than with EC. The third level dose was feasible with all schedules. Grade 4 leucopenia occurred in 77% of patients. Thrombocytopenia was absent in 6 cases and grade 4 in 12 (30.8%). Eighty-one percent of patients on experimental schedules required red blood cell support versus 44.4% of patients on EC. At the third level, platelet transfusions were more frequent among patients treated with EC (27. 8%). Non-haematological toxicity was mild: about 20% of patients experienced grade 3 vomiting, irrespective of schedule. Only 2 patients had grade 3 mucositis; no patient developed heart failure. Fever (61% of patients) and bone pain (55.5% of patients) were relevant in the GM-CSF treated groups and 12 patients shifted to G-CSF. The overall response rate was 84.6%: 5/39 (12.8%) complete response and 28/39 (71.8%) partial response. At 30/9/98, median survival was 29.5 months, with no difference between patients with metastatic and stage IIIb/inflammatory breast cancer. Median follow-up of surviving patients was 62 months (range 17-83). The 5-year estimated survival was 19% (95% confidence intervals = 7-31%). Rapidly alternating or sequential cycles of epirubicin and cyclophosphamide with CSF support is a feasible strategy that allows a higher increase of dose-intensity of the single drugs. Hospitalization and anemia were more frequent with the experimental schedules, and thrombocytopenia with the standard schedule. Overall, this intensified therapy was very active.

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On February 3 , 2015 , the FDA granted accelerated approval to palbociclib ( IBRANCE , Pfizer Inc. ) , an inhibitor of cyclin-dependent kinases 4 and 6 ( CDK4 and CDK6 ) , for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive , HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease .

FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. On February 3 , 2015 , the FDA granted accelerated approval to palbociclib ( IBRANCE , Pfizer Inc. ) , an inhibitor of cyclin-dependent kinases 4 and 6 ( CDK4 and CDK6 ) , for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive , HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease . The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2.

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a combination treatment : estramustine phosphate , cyproterone acetate or estrogens plus bromocriptine .

[Current aspects of hormonal therapy in prostate cancer]. The following endocrine treatment modalities have been used in advanced prostatic carcinoma: 1. orchiectomy plus estrogens; 2. primary orchiectomy with delayed estrogen employment; 3. initial estrogen therapy with delayed orchiectomy; 4. initial cyproterone acetate or medroxyprogesterone acetate; 5. a combination treatment : estramustine phosphate , cyproterone acetate or estrogens plus bromocriptine . The application of phase-III studies permits the subsequent conclusions: Simultaneous orchiectomy is to no advantage (exception: urinary stasis). cyproterone acetate does neither yield better nor worse results regarding survival than estrogen alone, but has fewer side effects. Estrogens and cyproterone acetate produce a rise of serum prolactin justifying the use of bromocriptine (or lisuride). estramustine phosphate should be reserved for relapsing prostatic cancer.

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Hormone induced elevations in temperature and possibly other unidentified factors during thyroid crisis may facilitate the triggering of MH following halothane and succinylcholine challenge .

Differential diagnosis of thyroid crisis and malignant hyperthermia in an anesthetized porcine model. The intra-operative differential diagnosis between thyroid crisis and malignant hyperthermia can be difficult. Also stress alone can trigger MH. The purposes of this study were: 1) to investigate the metabolic and hemodynamic differences between thyroid crisis and MH, 2) determine how thyroid crisis affects the development of MH, and 3) determine if the stress of thyroid crisis can trigger MH in susceptible individuals. We studied MH susceptible and normal swine. Two groups of animals (MH susceptible and normal) were induced into thyroid crisis (critical core hyperthermia, sustained tachycardia and increase in oxygen consumption) by pretreatment with intraperitoneal triiodothyronine (T3) followed by large hourly intravenous injections of T3. Two similar groups were given intravenous T3 but no pretreatment. These animals did not develop thyroid crisis and served as controls. Thyroid crisis did not result in metabolic changes or rigidity characteristic of an acute episode of MH. When the animals were subsequently challenged with MH triggering agents (halothane plus succinylcholine) dramatic manifestations of fulminant MH episodes (acute serious elevation in exhaled carbon dioxide, arterial CO2, rigidity and acidemia) were noted only in the MH susceptible animals. Although thyroid crisis did not trigger MH in the susceptible animals it did decrease the time to trigger MH (14.1 +/- 7.2 minutes versus 47.2 +/- 17.7 minutes, p < 0.01) in susceptible animals. Hormone induced elevations in temperature and possibly other unidentified factors during thyroid crisis may facilitate the triggering of MH following halothane and succinylcholine challenge .

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Mitomycin C plus vinblastine is an effective and well-tolerated regimen for anthracycline resistant cancer .

Mitomycin C and vinblastine in anthracycline-resistant metastatic breast cancer: a phase II study. The purpose of this phase II study was to evaluate the clinical efficacy of mitomycin C and vinblastine in patients with anthracycline-resistant metastatic breast cancer. This single-center, non-randomized trial enrolled 39 patients. Eligible patients must have received at least three chemotherapy regimens with epirubicin or CAF and had treatment failure while on chemotherapy or within 6 months of completing therapy. Treatment consisted of mitomycin C at a starting dose of 8 mg/m2 on day 1 and vinblastine (8 mg/m2, days 1 and 28). The regimen was repeated every 6 weeks with a 20% dose escalation of both drugs after the first cycle in the absence of grade III hematologic or other toxicity. On an intent-to-treat basis, 38 patients were eligible for assessment; 9 (23.7%, 95% confidence interval 1.92-2.45%) achieved a partial response and 13 (34.2%) had stable disease. The median time to disease progression was 6.21+/-4.26 months (range, 1-15; 95% confidence interval, 4.81-7.61), and the median survival was 10.76+/-7.6 (range, 1-29; 95% confidence interval 8.0-13.1%). Responsive patients had a significantly better survival than those with stable and progressive disease. Treatment was well tolerated. Anemia and neutropenia (grade I-III) developed in 28.9% and 26.3% of the patients, respectively. One patient with grade III granulocytopenia developed fever and infection that required hospitalization. Moderate neurotoxicity, myalgia, constipation, diarrhea and alopecia were observed. No toxic death occurred. Mitomycin C plus vinblastine is an effective and well-tolerated regimen for anthracycline resistant cancer .

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An angiotensin 2 type 1 receptor blocker , olmesartan , and a calcium channel blocker , azelnidipine , possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects .

Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke-prone spontaneously hypertensive rats. An angiotensin 2 type 1 receptor blocker , olmesartan , and a calcium channel blocker , azelnidipine , possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects . In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.

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Forty patients with metastatic breast cancer who had received no previous cytotoxic therapy were treated with a combination chemotherapy program CMF ( P ) , which included methotrexate , 60 mg/m2 , and 5-fluorouracil , 700 mg/m2 intravenously on the first and eighth days , in addition to cyclophosphamide , 100 mg/m2 , and prednisone , 40 mg/m2 , by mouth daily from the first to the fourteenth day of a 28-day cycle .

Combination chemotherapy for advanced breast cancer: response and effect on survival. Forty patients with metastatic breast cancer who had received no previous cytotoxic therapy were treated with a combination chemotherapy program CMF ( P ) , which included methotrexate , 60 mg/m2 , and 5-fluorouracil , 700 mg/m2 intravenously on the first and eighth days , in addition to cyclophosphamide , 100 mg/m2 , and prednisone , 40 mg/m2 , by mouth daily from the first to the fourteenth day of a 28-day cycle . Only 2 of 25 patients responded to hormonal therapy or endocrine ablation. Twenty-seven of the 40 patients (68%) had a complete response (8 patients) or partial response (19 patients). Lung, soft tissue, and nodal metastases were the most responsive sites. The median survival of 18 months for the responding group. The nonresponders had a median survival of 4 months. The toxicity was primarily hematologic and was especially severe in patients with functional liver impairment due to metastatic disease.

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At present , it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma , which , in a sense , have become a milestone as a second-line therapy for osteosarcoma .

Anti-angiogenesis target therapy for advanced osteosarcoma (Review). Osteosarcomas (OS), especially those with metastatic or unresectable disease, have limited treatment options. The greatest advancement in treatments occurred in the 1980s when multi-agent chemotherapy, including doxorubicin, cisplatin, high-dose methotrexate, and, in some regimens, ifosfamide, was demonstrated to improve overall survival compared with surgery alone. However, standard chemotherapeutic options have been limited by poor response rates in patients with relapsed or advanced cases. It has been reported that VEGFR expression correlates with the outcome of patients with osteosarcoma and circulating VEGF level has been associated with the development of lung metastasis. At present , it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma , which , in a sense , have become a milestone as a second-line therapy for osteosarcoma . Although the recognization of muramyltripepetide phosphatidyl-ethanolamine has made some progress based on its combination with standard chemotherapy, its effect on refractory cases is controversial. Personalized comprehensive molecular profiling of high-risk osteosarcoma up to now has not changed the therapeutic prospect of advanced osteosarcoma significantly. Thus, how far have we moved forward and what therapeutic strategy should we prefer for anti-angiogenesis therapy? This review provides an overview of the most updated anti-angiogenesis therapy in OS and discusses some clinical options in order to maintain or even improve progression-free survival.

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Failure to sedate patients who might be aware of paralysis occurred in three of 25 succinylcholine and eight of 94 pancuronium uses .

Neuromuscular blockade for critical patients in the emergency department. This retrospective study examines the indications and the effects of 119 doses of succinylcholine or pancuronium given in the emergency department during a 24-month period to patients considered to have immediately life-threatening emergencies. The most common indication for succinylcholine was to accomplish tracheal intubation (20 of 25 patients). Indications for pancuronium included computerized tomography of the head (60 of 94), control of agitation (40 of 94), facilitation of tracheal intubation (20 of 94), control of ventilation (12 of 94), and control of seizure unresponsive to anticonvulsants (4 of 94). Deterioration following succinylcholine occurred in three cases. These included two involving bradycardia and one involving ventricular tachycardia. Major complications following pancuronium included four incidences of ventricular arrhythmias. Intubation failure requiring surgical airway occurred in one patient given succinylcholine, two patients given pancuronium, and one patient who received both succinylcholine and pancuronium. Inadequate documentation of neurological examination prior to blockade was noted in six of 25 succinylcholine and nine of 94 pancuronium cases. Failure to sedate patients who might be aware of paralysis occurred in three of 25 succinylcholine and eight of 94 pancuronium uses . Neuromuscular blocking agents facilitate expeditious management of selected critical patients in the ED. Their prudent use requires anticipation of potential complications, preparation for surgical airway should intubation fail, documentation of physical examination before paralysis, and prior sedation when the patient responds to pain.

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Thirty-one isolates were classified as resistant to amprolium , 23 resistant to monensin , 10 resistant to diclazuril , and 6 resistant to clopidol .

Sensitivity of isolates of Eimeria from turkey flocks to the anticoccidial drugs amprolium, clopidol, diclazuril, and monensin. The sensitivity of field isolates of turkey coccidia from the United States to the anticoccidial drugs amprolium, clopidol, diclazuril, and monensin was investigated. clopidol and diclazuril were the most effective, followed by monensin and amprolium. Thirty-one isolates were classified as resistant to amprolium , 23 resistant to monensin , 10 resistant to diclazuril , and 6 resistant to clopidol . Six isolates were partially resistant to monensin, 10 partially resistant to clopidol, and 11 partially resistant to diclazuril. Four isolates were sensitive to monensin, 12 sensitive to diclazuril, and 17 sensitive to clopidol.

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Thirteen patients with interstitial cystitis diagnosed by the NIH criteria were treated with intravesical electromotive administration of lidocaine and dexamethasone followed by cystodistention .

Electromotive drug administration and hydrodistention for the treatment of interstitial cystitis. Thirteen patients with interstitial cystitis diagnosed by the NIH criteria were treated with intravesical electromotive administration of lidocaine and dexamethasone followed by cystodistention . After a mean follow-up of 10 (range 3-22) months, 8/13 (62%) of the patients reported complete resolution of bladder symptoms lasting an average 4.5 (range 0.75-17) months. Partial or short-term improvement of bladder symptoms was observed in three patients, while two patients reported aggravation of pain for several days after therapy. A significant increase in bladder capacity, to an average 166% of the pretreatment capacity, was observed in all patients. Whenever symptoms recurred after initially effective therapy, retreatments were performed with equal efficacy in 11 patients. This promising new therapeutic approach, performed on an outpatient basis, may become first-line treatment for patients with interstitial cystitis.

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Drug therapy included omega-3 fish oil , extended-release niacin , colesevelam hydrochloride , and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin .

Lipoprotein-associated phospholipase A2 mass is significantly reduced in dyslipidemic patients treated with lifestyle modification and combination lipid-modifying drug therapy. Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass is a novel inflammatory biomarker. In human blood, Lp-PLA(2) is predominately associated with low-density lipoprotein (LDL). This study examines the ability of lifestyle modification (diet and exercise) and combination lipid therapy to reduce Lp-PLA(2) levels while also determining the relationship between changes in LDL cholesterol and Lp-PLA(2). Thirty dyslipidemic patients who received lifestyle intervention and combination lipid therapy for an average of 6 months were included in these analyses (mean age, 60.9 years); 40% had stable angiographically established coronary artery disease, 40% had the metabolic syndrome, and 70% were men. Drug therapy included omega-3 fish oil , extended-release niacin , colesevelam hydrochloride , and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin . The study revealed a 33% reduction in mean Lp-PLA(2) values (baseline 224.9+/-47.5 vs posttreatment 149.5+/-35.5 ng/mL; P<.001). Significant changes in mean LDL cholesterol from baseline (127.9+/-49.3 vs posttreatment 65.2+/-32.1 mg/dL; P<.001) were also observed. However, regression analysis revealed only a weak positive relationship between changes in LDL cholesterol and Lp-PLA(2) mass (R(2)=0.29; P<.01). Thus, Lp-PLA(2) mass is significantly reduced with lifestyle and combination lipid therapy. Changes in Lp-PLA(2) were only partially explained by the changes observed for LDL cholesterol.

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Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI ( bolus irinotecan , folinic acid , and fluorouracil followed by 46-hour fluorouracil infusion ) followed by bevacizumab ( 5 mg/kg ) in Cycle 1 .

Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms. Previous reports of the influence of UGT1A1 gene polymorphisms on the pharmacokinetics of irinotecan metabolism have not assessed Asian patients treated with FOLFIRI plus bevacizumab for advanced and recurrent colorectal cancer. Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI ( bolus irinotecan , folinic acid , and fluorouracil followed by 46-hour fluorouracil infusion ) followed by bevacizumab ( 5 mg/kg ) in Cycle 1 . In Cycle 2, patients received bevacizumab followed by FOLFIRI. The regimen was in 2-week cycles. The area under-the-curves ratio (AUC0-last) (Cycle 2/Cycle 1) was determined from plasma concentrations of irinotecan and metabolites (SN-38, SN-38G). Safety, efficacy, and drug-drug interactions were analyzed. Median observation period was 7.8 months; median number of cycles 15. Drug-drug interactions were evaluated in eight patients without irinotecan dose reduction. Mean AUC0-last ratios (with/without bevacizumab) of irinotecan, SN-38, and SN-38G were 0.959, 0.927, and 0.931 respectively. Response rate was 65%; median progression-free survival 16.4 months. Response occurred in four patients with, and nine without, UGT1A1 polymorphism. No significant differences occurred between efficacy, safety, or polymorphism status. This cohort showed no differences in safety or efficacy compared to previous reports. bevacizumab did not affect the pharmacokinetics of irinotecan and its metabolites, irrespective of UGT1A1 polymorphism status.

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Patients received vinorelbine starting at 20 mg/m(2 ) ( to 25 mg/m(2 ) ) and carboplatin area under the curve ( AUC ) 2.5 in divided-doses , both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression .

Phase I/II trial of vinorelbine and divided-dose carboplatin in advanced non-small cell lung cancer. vinorelbine administered in a doublet with cisplatin has become a standard treatment in patients with advanced non-small cell lung cancer (NSCLC). However, carboplatin appears to provide comparable efficacy with a better nonhematologic safety profile than cisplatin. Herein we report the results of a phase I/II trial of weekly vinorelbine and divided-dose carboplatin in patients with stage IIIB/IV NSCLC, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow. Patients received vinorelbine starting at 20 mg/m(2 ) ( to 25 mg/m(2 ) ) and carboplatin area under the curve ( AUC ) 2.5 in divided-doses , both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression . Dose-limiting toxicity was defined for Cycles 1 and 2. Tumor response and toxicity were assessed using standard criteria. Twenty-one patients with a mean age of 67 years (range, 43-79) and stage IIIB/IV (8/13) disease were enrolled. All but 1 patient were chemotherapy-nai;ve; the majority (n = 20) had good performance status (< or = 1). Seventy-nine courses (median, 4) were administered. The vinorelbine/carboplatin doublet was well tolerated, with 7 courses interrupted or delayed because of toxicity. Toxicities were generally mild and evenly divided between hematologic (i.e., neutropenia) and nonhematologic (i.e., fatigue). No growth factor support was required for hematologic toxicity. There was only one case of grade 2 alopecia, and no cases of > or = grade 2 neurotoxicity. There were 5 (24%) partial responses, and 9 (43%) patients had stable disease. Weekly vinorelbine 25 mg/m(2) and divided-dose carboplatin AUC 2.5 is a well tolerated regimen with activity in advanced NSCLC patients. Further evaluation of this regimen in combination with novel targeted biologic therapy is warranted.

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Dexamethasone exhibited the highest effect on paclitaxel anti-tumor activity , in a dose-dependent fashion .

Efficacy of paclitaxel/dexamethasone intra-tumoral delivery in treating orthotopic mouse breast cancer. The effect of topical co-administration of promoter drugs with paclitaxel to increase anti-tumor effects of paclitaxel was investigated. Mice with orthotopic 4T1-Luc breast cancer received single intra-tumoral injection of a polymeric formulation with paclitaxel and a specific promoter drug. Several promoter drugs were evaluated, including: dexamethasone, losartan, nicotinamide, Azone, and oleic acid. Dexamethasone exhibited the highest effect on paclitaxel anti-tumor activity , in a dose-dependent fashion . However, this effect was accompanied by systemic effects of dexamethasone, and inability to prevent tumor metastasis to the lungs. Topical co-administration of promoter drugs with anti-cancer agents can enhance their anti-tumor effects. Further investigations are needed to identify the most efficient combinations of promoter and anti-cancer drugs, and their suitability for the clinical management of the breast cancer disease.

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The first available studies demonstrate the value of these compounds with an improved prognosis of metastatic patients in combination with endocrine therapy ( palbociclib , ribociclib ) or in monotherapy ( abemaciclib ) .

[Cell cycle inhibitors in endocrine receptor positive breast cancer]. Dysregulation of cellular cycle is a key component of carcinogenesis and its targeting represents an interesting approach. Recently, the development of selective inhibitors of the cycle targeting the cyclin-dependent kinases (CDK) 4 and 6 revived interest in this therapeutic class after the failure of pan-inhibitors. palbociclib, ribociclib, and abemaciclib are the 3 drugs with the most advanced development. They demonstrated preclinical activity in luminal breast cancer models and are under clinical evaluation. The first available studies demonstrate the value of these compounds with an improved prognosis of metastatic patients in combination with endocrine therapy ( palbociclib , ribociclib ) or in monotherapy ( abemaciclib ) . The results of ongoing studies will clarify the role of these agents in our new strategies and the individualisation of biomarkers will help to define patients who benefit most from this approach.

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Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective .

Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers. Recent studies suggest that calcium influx via L-type calcium channels is necessary for psychostimulant-induced behavioral sensitization. In addition, chronic amphetamine upregulates subtype Cav1.2-containing L-type calcium channels. In the present studies, we assessed the effect of calcium channel blockers (CCBs) on cocaine-induced behavioral sensitization and determined whether the functional activity of L-type calcium channels is altered after repeated cocaine administration. Rats were administered daily intraperitoneal injections of either flunarizine (40 mg/kg), diltiazem (40 mg/kg) or cocaine (20 mg/kg) and the combination of the CCBs and cocaine for 30 days. Motor activities were monitored on Day 1, and every 6th day during the 30-day treatment period. Daily cocaine administration produced increased locomotor activity. Maximal augmentation of behavioral response to repeated cocaine administration was observed on Day 18. Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective . Measurement of tissue monoamine levels on Day 18 revealed cocaine-induced increases in DA and 5-HT in the nucleus accumbens. By contrast to behavioral response, diltiazem was more effective in attenuating increases in monoamine levels than flunarizine. Cocaine administration for 18 days produced increases in calcium uptake in synaptosomes prepared from the nucleus accumbens and frontal cortex. Increases in calcium uptake were abolished by flunarizine and diltiazem pretreatment. Taken together, the augmented cocaine-induced behavioral response on Day 18 may be due to increased calcium uptake in the nucleus accumbens leading to increased dopamine (DA) and serotonin (5-HT) release. flunarizine and diltiazem attenuated the behavioral response by decreasing calcium uptake and decreasing neurochemical release.

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We therefore explored the in vitro combination of amphotericin B with itraconazole against 14 clinical Aspergillus fumigatus isolates ( 9 itraconazole susceptible and 5 itraconazole resistant ) with a colorimetric broth microdilution checkerboard technique using two drug interaction models able to explore complicated patterns of interactions : the response surface analysis of Bliss independence and the isobolographic analysis of Loewe additivity zero interaction theories .

The concentration-dependent nature of in vitro amphotericin B-itraconazole interaction against Aspergillus fumigatus: isobolographic and response surface analysis of complex pharmacodynamic interactions. The interaction between polyenes and azoles is not well understood. We therefore explored the in vitro combination of amphotericin B with itraconazole against 14 clinical Aspergillus fumigatus isolates ( 9 itraconazole susceptible and 5 itraconazole resistant ) with a colorimetric broth microdilution checkerboard technique using two drug interaction models able to explore complicated patterns of interactions : the response surface analysis of Bliss independence and the isobolographic analysis of Loewe additivity zero interaction theories . Synergy was found at combinations with low concentrations of amphotericin B (<0.125 mg/L), whereas antagonism was found at combinations with higher concentrations of amphotericin B. For itraconazole-resistant isolates, synergistic interactions were observed at high concentrations of itraconazole (>0.5 mg/L). Synergy was more frequently observed for the itraconazole-resistant isolates than for the itraconazole-susceptible isolates.

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This study evaluated the safety and efficacy of inotuzumab ozogamicin ( INO ) , a targeted humanized anti-CD22 antibody conjugated to calicheamicin , plus rituximab ( R-INO ) every 3 weeks , up to six cycles , followed by high dose therapy and autologous stem cell transplant ( HDT-aSCT ) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma ( DLBCL ) .

A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma. This study evaluated the safety and efficacy of inotuzumab ozogamicin ( INO ) , a targeted humanized anti-CD22 antibody conjugated to calicheamicin , plus rituximab ( R-INO ) every 3 weeks , up to six cycles , followed by high dose therapy and autologous stem cell transplant ( HDT-aSCT ) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma ( DLBCL ) . The primary endpoint was overall response (OR) rate after three cycles of R-INO. Sixty-three patients were enrolled. Common grade 3/4 adverse events during R-INO treatment were thrombocytopenia, lymphopenia and neutropenia. OR rate after three cycles of R-INO was 28.6% (95% confidence interval: 17.9-41.4). Eighteen patients underwent HDT-aSCT; 2-year progression-free survival (PFS) for these patients was 61.1%. Serious infections and hepatic toxicity following aSCT occurred in 33% and 22%, respectively. One- and 2-year PFS rates for all enrolled patients were 28.9% and 25.3%, respectively (median, 3.0 months). R-INO had lower than expected activity as a salvage regimen for transplant eligible patients with DLBCL.

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These are the first 2 reports of successful treatment of this condition by use of a combination of methylprednisolone and mycophenolate mofetil , and , in 1 of the cases , additional medication with intravenous immunoglobulin .

Severe Ocular Myositis After Ipilimumab Treatment for Melanoma: A Report of 2 Cases. ipilimumab binds and blocks cytotoxic T-lymphocyte-associated antigen-4, causing enhanced T-cell reaction, antitumor response, and significant improvement of the overall survival of patients with metastatic melanoma. Patients treated with ipilimumab can develop immune-related adverse effects, primarily dermatitis, colitis, hepatitis, and hypophysitis. Although, in phase I-III studies, 64.2% of all patients suffered from immune-related adverse effects, ocular adverse effects occurred in 1.3% only. In the cases reported below, 2 patients with metastatic melanoma developed severe ocular myositis after treatment with ipilimumab. These are the first 2 reports of successful treatment of this condition by use of a combination of methylprednisolone and mycophenolate mofetil , and , in 1 of the cases , additional medication with intravenous immunoglobulin .

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The introduction of the selective serotonin reuptake inhibitors , moclobemide and mianserin has been a major advance in the treatment of depression , and is already leading to major shifts in the pattern of antidepressants prescribing .

The management of depression. The place of the new antidepressants. Part 1. General overview. The introduction of the selective serotonin reuptake inhibitors , moclobemide and mianserin has been a major advance in the treatment of depression , and is already leading to major shifts in the pattern of antidepressants prescribing . These antidepressants are safe, well tolerated and effective, and in conjunction with older agents such as the tricyclics, provide the clinician with a broad range of treatments for this common and disabling disorder. This two-part review will focus on the management of depression in general practice.

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Four of these had equivocal plasma levels of both norepinephrine and epinephrine , suggesting that overnight clonidine suppression may be of particular value when tumor secretion is intermittent or low .

Overnight clonidine suppression test in the diagnosis and exclusion of pheochromocytoma. In a prospective study designed to differentiate pheochromocytoma from other forms of hypertension, urinary catecholamines were measured after sleep and clonidine administration in 12 patients with pheochromocytoma, 19 hypertensive patients in whom pheochromocytoma was suspected but later excluded, and 31 hypertensive patients in whom pheochromocytoma was never suspected. The test correctly identified all 12 patients in whom pheochromocytoma was present. Four of these had equivocal plasma levels of both norepinephrine and epinephrine , suggesting that overnight clonidine suppression may be of particular value when tumor secretion is intermittent or low . When pheochromocytoma was not present, urinary norepinephrine and epinephrine levels were suppressed below 60 and 20 nmol/mmol creatinine, respectively, after sleep and clonidine, the two in combination giving better suppression than sleep alone. Since urinary catecholamines can be determined relatively easily by high-pressure liquid chromatography with electrochemical detection, this test may be more widely applicable than suppression tests based on plasma measurements.

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In conclusion , concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine .

Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis. We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade IV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025--0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21--1081 d) with 35% of patients remaining alive. Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P < 0.001). In conclusion , concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine .

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Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel .

Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel. pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel . In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.

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This study was designed to test the hypothesis that positively charged dendrimers form a complex with enoxaparin , a low-molecular weight heparin ( LMWH ) , and that the resulting drug-dendrimer complex is effective in preventing deep vein thrombosis after pulmonary administration .

Dendrimers as a carrier for pulmonary delivery of enoxaparin, a low-molecular weight heparin. This study was designed to test the hypothesis that positively charged dendrimers form a complex with enoxaparin , a low-molecular weight heparin ( LMWH ) , and that the resulting drug-dendrimer complex is effective in preventing deep vein thrombosis after pulmonary administration . Fourier Transform Infrared (FTIR) spectroscopy and the azure A assay were used to evaluate interactions between dendrimers and enoxaparin. The efficacy of polyamidoamine (PAMAM) dendrimers in enhancing pulmonary absorption of enoxaparin was studied by administering enoxaparin-dendrimer formulations into the lungs of anesthetized rats and monitoring drug absorption by measuring plasma anti-factor Xa activity. The optimized formulations were evaluated for their efficacy in preventing deep vein thrombosis in a rodent model. The safety of the formulations was tested by studying their effects on mucociliary transport rate (MTR) in a frog palate model and by measuring injury markers in rat bronchoalveolar fluid. The FTIR data and azure A assay revealed ionic interactions between the amino groups of cationic dendrimers and the carboxylic and sulfate groups of enoxaparin. Positively charged dendrimers increased the relative bioavailability of enoxaparin by 40%, while a negatively charged dendrimer had no effect. Formulations containing 1% G2 or 0.5% G3 PAMAM dendrimer plus enoxaparin were as efficacious in preventing deep vein thrombosis in a rat model as subcutaneously administered enoxaparin. The formulations did not adversely affect the MTR or produce extensive damage to the lungs. Positively charged dendrimers are a suitable carrier for pulmonary delivery of enoxaparin. They enhance pulmonary absorption of LMWH probably by reducing negative surface charge density of the drug molecule.

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We proved experimentally the use of ECEEM for multiplex determination of kinetic parameters describing weak ( 3 mM > K(d ) > 80 μM ) and fast ( 0.25 s ≥ τ ≥ 0.9 ms ) noncovalent interactions between four small molecule drugs ( ibuprofen , S-flurbiprofen , salicylic acid and phenylbutazone ) and α- and β-cyclodextrins .

Revealing equilibrium and rate constants of weak and fast noncovalent interactions. Rate and equilibrium constants of weak noncovalent molecular interactions are extremely difficult to measure. Here, we introduced a homogeneous approach called equilibrium capillary electrophoresis of equilibrium mixtures (ECEEM) to determine k(on), k(off), and K(d) of weak (K(d) > 1 μM) and fast kinetics (relaxation time, τ < 0.1 s) in quasi-equilibrium for multiple unlabeled ligands simultaneously in one microreactor. Conceptually, an equilibrium mixture (EM) of a ligand (L), target (T), and a complex (C) is prepared. The mixture is introduced into the beginning of a capillary reactor with aspect ratio >1000 filled with T. Afterward, differential mobility of L, T, and C along the reactor is induced by an electric field. The combination of differential mobility of reactants and their interactions leads to a change of the EM peak shape. This change is a function of rate constants, so the rate and equilibrium constants can be directly determined from the analysis of the EM peak shape (width and symmetry) and propagation pattern along the reactor. We proved experimentally the use of ECEEM for multiplex determination of kinetic parameters describing weak ( 3 mM > K(d ) > 80 μM ) and fast ( 0.25 s ≥ τ ≥ 0.9 ms ) noncovalent interactions between four small molecule drugs ( ibuprofen , S-flurbiprofen , salicylic acid and phenylbutazone ) and α- and β-cyclodextrins . The affinity of the drugs was significantly higher for β-cyclodextrin than α-cyclodextrin and mostly determined by the rate constant of complex formation.

daefc547a89f7ce7f0dc7b13ae5937ef

We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer , who had a positive second-look laparatomy or recurrent disease .

High-dose ifosfamide and etoposide with filgrastim for stem cell mobilization in patients with advanced ovarian cancer. High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation has shown promise as treatment for recurrent or persistent epithelial ovarian cancer. We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer , who had a positive second-look laparatomy or recurrent disease . ifosfamide was given at 10 g/m2 by continuous i.v. from days 1 to 3. etoposide was given at 150 mg/m2 every 12 h for six doses on days 1-3. filgrastim was given at 10 microg/kg/d s.c. from day 5 until the completion of peripheral blood stem cell harvest. Fourteen of 32 patients had measurable or evaluable disease before mobilization therapy and were assessed for response. In nine (64%) of the 14 patients, treatment response was demonstrated, and these patients received a second cycle of mobilization therapy. The target CD34+ cell dose (>8 x 106 cells/kg) was achieved with a median of one apheresis (range 1-5). A median of 25.1 (range 8.0-122.5) x 106 CD34+ cells/kg body weight was collected. Non-hematologic toxicity was limited to grade 2 renal dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was well tolerated, lead to successful stem cell harvest and had antitumor activity.

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Esomeprazole , a proton-pump inhibitor ( PPI ) , is the S-isomer of omeprazole .

Esomeprazole: a clinical review. The pharmacology, pharmacodynamics, pharmacokinetics, clinical efficacy, and adverse effects of esomeprazole are reviewed. Esomeprazole , a proton-pump inhibitor ( PPI ) , is the S-isomer of omeprazole . esomeprazole has FDA-approved labeling for use in the treatment of symptomatic gastroesophageal reflux disease (GERD), including healing and maintenance of healing of erosive esophagitis and as part of a triple-drug regimen for Helicobocter pylori infection. esomeprazole is structurally similar to other PPIs but is the first PPI to include only the active isomer, which may lead to improved pharmacokinetic and pharmacodynamic characteristics. esomeprazole maintains intragastric pH at a higher level and above 4 for a longer period than other PPIs. Clinical studies have shown that esomeprazole is at least equivalent in safety and efficacy to other drugs in the class. esomeprazole has demonstrated efficacy in the treatment of erosive esophagitis, the maintenance of healing of erosive esophagitis, and the treatment of signs and symptoms of GERD. Effective dosages are 20 or 40 mg orally every day or as needed. esomeprazole magnesium 40 mg once daily in combination with amoxicillin and clarithromycin is effective in eradicating H. pylori infection. The potential for interacting with other drugs is limited and is similar to that of omeprazole. The most common adverse effects are headache, respiratory infection, and abdominal symptoms. esomeprazole has pharmacokinetic properties that may make it more effective than omeprazole in some patients.

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This increase in the number of vasopressin and oxytocin containing neurons in the pig hypothalamus is much later in development than has ever been reported so far .

A vasopressin and oxytocin containing nucleus in the pig hypothalamus that shows neuronal changes during puberty. A vasopressin and oxytocin containing nucleus is described for the first time in the pig hypothalamus. It is located near the third ventricle, just dorsal to the suprachiasmatic nucleus, and consists of magnocellular neurons, similar to those of the supraoptic nucleus and paraventricular nucleus. Morphometric analysis of neuronal number, size, density, and volume was performed at four different ages: 1 day, 7 weeks, 16 weeks, and 30 weeks postnatally. No sex difference in these parameters was observed. In this period the volume of the nucleus increased gradually from 6.6 x 10(-3) to 54.2 x 10(-3) mm3. One day after birth 1,215 +/- 191 (mean +/- SEM) neurons were present in the vasopressin and oxytocin containing nucleus, followed by a decrease to 771 +/- 80 neurons at 7 weeks and 697 +/- 116 at 16 weeks. Between 16 and 30 weeks (puberty) there was a dramatic increase in neuron number up to 1,765 +/- 214 neurons. This increase in the number of vasopressin and oxytocin containing neurons in the pig hypothalamus is much later in development than has ever been reported so far .

4d1c93db896cd77cb92357c8cd08b272

Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies , but at the cost of increased haematological toxicity .

Clinical pharmacokinetics of nucleoside analogues: focus on haematological malignancies. This review establishes the pharmacokinetic characteristics of the major nucleoside analogues with cytotoxic activity. cytarabine, pentostatin, fludarabine, cladribine and gemcitabine are all prodrugs whose plasma pharmacokinetics do not fully reflect their therapeutic activity; after cellular uptake, these compounds undergo phosphorylation by deoxycytidine kinase before their incorporation into DNA results in cell death. cytarabine is principally active in the S phase of the cell cycle and is most toxic to replicating cells, whereas pentostatin, fludarabine and cladribine are incorporated into DNA during the process in which strand breaks are repaired and are therefore cytotoxic to slowly replicating cells (although the action of pentostatin results from its inhibition of adenosine deaminase). gemcitabine is unusual in being highly metabolised in solid tumour cells. The cytotoxic activity of pentostatin, fludarabine and cladribine against the clonal cells of lymphoproliferative disorders is accompanied by damage to normal lymphoid cells, which results in significant and long-lasting immunosuppression. Useful interactions between nucleoside analogues have been defined. Cells that are primed by exposure to fludarabine or cladribine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine) and an improved therapeutic effect against acute myeloid leukaemia and chronic lymphocytic leukaemia can be achieved by clinical schedules that exploit this effect. Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies , but at the cost of increased haematological toxicity . Developments in the clinical administration of gemcitabine are concentrating on efforts to extend the duration of exposure to the drug as a means of counteracting its rapid catabolism in the circulation. Future developments with this group of agents will further explore the use of fludarabine-based combination therapies to produce a transient period of myelosuppression and immunosuppression that is sufficient to permit the engraftment of allogeneic haemopoietic stem cells and also exploit the immunological benefits of graft-versus-tumour reactions. In addition, the clinical spectrum of activity of gemcitabine is also being extended by combining the drug with other active chemotherapeutic agents, such as cisplatin, and by early studies of its role as a radiosensitiser.

44961781380ebcb4e76b2474630bdd4c

The pharmacodynamic effects of single doses of trazodone ( 100 mg ) , amitriptyline ( 50 mg ) or placebo either alone or with ethanol ( 0.5 ml/kg ) were investigated in 6 healthy volunteers in a double-blind crossover study .

Evaluation of possible interactions between ethanol and trazodone or amitriptyline. The pharmacodynamic effects of single doses of trazodone ( 100 mg ) , amitriptyline ( 50 mg ) or placebo either alone or with ethanol ( 0.5 ml/kg ) were investigated in 6 healthy volunteers in a double-blind crossover study . Plasma concentrations of the drugs and ethanol were also measured. Pharmacodynamic tests were critical flicker fusion frequency threshold (CFF), choice reaction time (CRT), manual dexterity, a digit span test and visual analogue scales. Blood ethanol concentrations were not influenced by the co-administration of either antidepressant. tmax for trazodone was prolonged by ethanol but the other pharmacokinetic parameters for trazodone and amitriptyline were not influenced by ethanol. trazodone and amitriptyline caused the expected profound depressant effects on CFF, CRT, manual dexterity and on the rating scales for drowsiness, 'clearheadedness', aggression and disinhibition. Ethanol alone impaired manual dexterity, increased drowsiness, reduced 'clearheadedness' and also tended to reduce feelings of aggression. In combination with either trazodone or amitriptyline, ethanol caused little additional effect except in the case of manual dexterity, which was further impaired. This result may reflect the profound effects of the antidepressants alone and does not suggest that it is safe for patients receiving antidepressant medication to take ethanolic drinks.

f6d6d6d6c7e5d3b223469c4647ae830c

A 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin , irinotecan , and bevacizumab therapy for rectal cancer with liver metastases .

Portal Vein Thrombosis in Metastatic Colorectal Cancer During FOLFIRI-bevacizumab Chemotherapy Successfully Treated with Apixaban. Portal vein thrombosis (PVT) while using an angiogenesis inhibitor is relatively rare. A 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin , irinotecan , and bevacizumab therapy for rectal cancer with liver metastases . Because the metastases were small and shrinking, we suspected that the thrombosis might have been caused by bevacizumab-containing chemotherapy. We stopped bevacizumab and started apixaban, a direct oral anticoagulant (DOAC). Eight months later, the complete dissolution of the thrombus and recanalization of the portal vein were attained. Our case suggests that PVT can occur during bevacizumab-containing chemotherapy, and DOAC therapy might be beneficial for treating PVT in patients with cancer.

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Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5‑Fu synergistically inhibited cell growth , compared with treatment with any of these drugs alone .

Imatinib‑induced apoptosis of gastric cancer cells is mediated by endoplasmic reticulum stress. imatinib is a powerful tyrosine kinase inhibitor that specifically targets BCR‑ABL, c‑KIT, and PDGFR kinases, and is used in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other types of cancers. However, the possible anticancer effects of imatinib in gastric cancer have not yet been explored. The present study evaluated the in vitro effects of imatinib on gastric cancer cells and determined the molecular mechanism underlying these effects. We determined that imatinib induced mitochondria‑mediated apoptosis of gastric cancer cells by involving endoplasmic reticulum (ER) stress‑associated activation of c‑Jun NH2‑terminal kinase (JNK). We also found that imatinib suppressed cell proliferation in a time‑ and dose‑dependent manner. Cell cycle analysis revealed that imatinib‑treated AGS cells were arrested in the G2/M phase of the cell cycle. Moreover, imatinib‑treated cells exhibited increased levels of phosphorylated JNK, and of the transcription factor C/EBP homologous protein, an ER stress‑associated apoptotic molecule. Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5‑Fu synergistically inhibited cell growth , compared with treatment with any of these drugs alone . These data indicated that imatinib exerted cytotoxic effects on gastric cancer cells by inducing apoptosis mediated by reactive oxygen species generation and ER stress‑associated JNK activation. Furthermore, we revealed that imatinib induced the apoptosis of gastric cancer cells by inhibiting platelet‑derived growth factor receptor signaling. Collectively, our results strongly support the use of imatinib in the treatment of treating gastric cancer.