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Hepatic Toxicity (hepatic + toxicity)
Selected AbstractsGemcitabine plus epirubicin in patients with advanced urothelial carcinoma who are not eligible for platinum-based regimensCANCER, Issue 7 2002Sergio Ricci M.D. Abstract BACKGROUND The objective of this study was to evaluate the efficacy and toxicity of gemcitabine plus epirubicin in previously untreated patients with advanced urothelial carcinoma who were not eligible for cisplatin-based regimens. METHODS Patients with advanced urothelial carcinoma and at least one of the following characteristics were eligible: impaired renal function (creatinine clearance < 60 mL per minute), an Eastern Cooperative Oncology Group performance status (PS) , 2, and age , 75 years. The treatment included epirubicin 70 mg/m2 as an intravenous bolus on Day 1 and gemcitabine 1000 mg/m2 over 30 minutes on Days 1 and 8 of a 21-day cycle. RESULTS Thirty-eight patients entered the study, and a total of 152 cycles were administered, with a median of 4 cycles per patient (range, 1,6 cycles per patient). The following Grade 3,4 hematologic toxicities were reported (percent of cycles): neutropenia, 22.4%; anemia, 11.2%; and thrombocytopenia, 6.5%. No cardiac, renal, or hepatic toxicities were observed. Dose intensities of epirubicin and gemcitabine were 19.6 mg/m2 per week (84%) and 532.2 mg/m2 per week (80%), respectively. There were 2 complete responses (5.3%), 13 partial responses (34.2%), 11 patients with stable disease (28.9%), and 12 patients with progressive disease (31.6%), for an overall response rate of 39.5% (95% confidence interval, 25.1,55.1). The median progression free survival (PFS) and overall survival (OS) rates were 4.8 months and 8.0 months, respectively. The 1-year survival rate was 38%, and the median PFS and OS were 6.4 months and 16.4 months, respectively, in patients with PS 0,1. Thirty patients were symptomatic: Seventeen patients (56.7%) achieved a complete response, and 5 patients (16.7%) achieved a partial symptomatic response. CONCLUSIONS At the doses given in this study, gemcitabine and epirubicin had a good tolerability profile with interesting activity in patients with advanced urothelial carcinoma who were not fit for cisplatin-based regimens. Cancer 2002;95:1444,50. © 2002 American Cancer Society. DOI 10.1002/cncr.10860 [source] Telithromycin-associated hepatotoxicity: Clinical spectrum and causality assessment of 42 cases,HEPATOLOGY, Issue 1 2009Allen D. Brinker Telithromycin is the first of a new class of ketolide antibiotics with increased activity against penicillin-resistant and erythromycin-resistant pneumococci. This agent received approval by the United States Food and Drug Administration (FDA) in 2004 for treatment of upper and lower respiratory infections. Following market introduction, spontaneous reports of telithromycin-associated hepatotoxicity, including frank liver failure, were received. To address these reports, an ad hoc group with expertise in spontaneous adverse events reporting and experience in evaluating drug-induced liver injury was formed, including members of the FDA, other federal agencies, and academia. The primary objective of this group was to adjudicate case reports of hepatic toxicity for causal attribution to telithromycin. After an initial screening of all cases of liver injury associated with telithromycin reported to FDA as of April 2006 by one of the authors, 42 cases were comprehensively reviewed and adjudicated. Five cases included a severe outcome of either death (n = 4) or liver transplantation (n = 1); more than half were considered highly likely or probable in their causal association with telithromycin. Typical clinical features were: short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice, sometimes with the presence of ascites even in cases that resolved. Concurrence in assignment of causality increased after agreement on definitions of categories and interactive discussions. Conclusion: Telithromycin is a rare cause of drug-induced liver injury that may have a distinctive clinical signature and associated high mortality rate. Consensus for attribution of liver injury to a selected drug exposure by individual experts can be aided by careful definition of terminology and discussion. (HEPATOLOGY 2009;49:250-257.) [source] Assessing the antifungal activity and toxicity profile of amphotericin B lipid complex (ABLC; Abelcet®) in combination with caspofungin in experimental systemic aspergillosisJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2004Olena Sivak Abstract The purpose of this study was to assess the antifungal activity and renal and hepatic toxicity of amphotericin B lipid complex (ABLC; Abelcet®) following co-administration of Caspofungin to rats infected with Aspergillus fumigatus. Aspergillus fumigatus inoculum (1.3,2.3,×,107 colony forming units [CFU]) was injected via the jugular vein; 48 h later male albino Sprague,Dawley rats (350,400 g) were administered either a single intravenous (IV) dose of Fungizone® (1 mg AmpB/kg), ABLC (1 or 5 mg AmpB/kg), or an equivalent volume of normal saline (NS) (vehicle control) once daily for 4 days. Rats were further randomized into groups to receive 3 mg/kg Caspofungin or physiologic saline IV once daily for 4 days. To assess antifungal activity, brain, lung, heart, liver, spleen, and kidney sections were homogenized with NS (2 mL; 1 g of each tissue/mL) and a 0.1-mL aliquot was spread plated onto a Sabouraud dextrose agar plate. The plates were incubated for 48 h at 37°C, at which time the numbers of CFU were determined and corrected for tissue weight. To assess renal and hepatic toxicity, serum creatinine and aspartate aminotransferase levels were determined. Fungizone and ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days and Caspofungin at a dosing regimen of 3 mg/kg i.v. once daily for four consecutive days had similar effectiveness in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to non-treated controls. A combination of ABLC (1 mg/kg i.v.,×,4 days) and Caspofungin (3 mg/kg i.v.,×,4 days) significantly decreased the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Caspofungin alone and non-treated controls. ABLC at a dosing regiment of 5 mg/kg i.v. once daily for four consecutive days was more effective in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Fungizone or ABLC alone at 1 mg/kg and Caspofungin alone at 3 mg/kg. However, a combination of ABLC (5 mg/kg i.v.,×,4 days) and Caspofungin (3 mg/kg i.v.,×,4 days) was not more effective than ABLC at 5 mg/kg or the combination of ABLC at 1 mg/kg and Caspofungin 3 mg/kg in reducing the total number of Aspergillus fumigatus CFUs compared to controls. Except for non-treated infected control rats, none of the treatment groups tested displayed a greater than 50% increase in serum creatinine concentrations from baseline. In addition, only ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days displayed a greater than 50% increase in AST concentration from baseline. Taken together, these findings suggest that ABLC at 5 mg/kg once daily,×,4 days appears to be the best therapeutic choice in this animal model. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1382,1389, 2004 [source] The Coxib NSAIDs: Potential Clinical and Pharmacologic Importance in Veterinary MedicineJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2005Mary Sarah Bergh Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to control acute and chronic pain as well as to manage oncologic and neurologic diseases in human and veterinary patients. Despite ongoing research and efforts to improve the safety and efficacy of existing drugs, adverse effects such as gastrointestinal irritation, renal and hepatic toxicity, interference with hemostasis, and reproductive problems persist. The true incidence of NSAID-induced adverse effects in animals is unknown, but is likely underestimated, because cats and dogs may be more sensitive than humans to NSAIDs due to alterations in drug metabolism, absorption, and enterohepatic recirculation. NSAIDs produce both analgesia and toxic adverse effects primarily by inhibiting cyclooxygenase (COX), thereby decreasing the production of prostaglandins that signal inflammation and pain as well as mediate physiologic functions such as platelet aggregation, gastric protection, and electrolyte balance in the kidney. The presence of at least 2 COX isoforms may account for variability in NSAID efficacy and toxicity both within and among species. This paper reviews and evaluates the published literature on the safety, pharmacology, uses, and complications of a subclass of COX-1,sparing drugs, the coxibs, in veterinary medicine. Coxibs and other COX-1,sparing drugs provide a clinically useful improvement over traditional NSAIDs, but data are incomplete and more in vivo species-specific, target-tissue, and clinical studies are needed. [source] Review of comparative studies between conventional and liposomal amphotericin B (Ambisome®) in neutropenic patients with fever of unknown origin and patients with systemic mycosisMYCOSES, Issue 9-10 2000I. W. Blau Summary Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Treatment with amphotericin B is the main therapeutic approach. However, this treatment is limited by the substantial toxicity. We present the data of the first randomized prospective comparative trial in adults (134 patients with fever of unknown origin) with conventional amphotericin B and a liposomal formulation of amphotericin B (AmBisome®, published in 1997 by Prentice et al. (Br. J. Haematol. 98, 711,718) and the data of adults with documented fungal infections (59 patients), treated in this trial. Patients received either conventional amphotericin B 1 mg kg,1 per day, liposomal amphotericin B 1 mg kg,1 per day or liposomal amphotericin B 3 mg kg,1 per day. Patients were entered if they had fever of unknown origin (FUO), defined as temperature of 38 °C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (<0.5×109 l,1). Efficacy of treatment was assessed, with success defined as resolution of fever for three consecutive days (<38 °C) in the group of patients with FUO and the freedom of clinical signs and/or the elimination of fungus in the group of patients with documented fungal infections. The safety of treatment and renal and hepatic toxicity of liposomal and conventional amphotericin B were compared. No statistically significant difference was found in the treatment efficacy in the three study arms. However, there is a tendency of better treatment results in the two groups of patients, who received liposomal amphotericin B. Thirty-five per cent of patients with documented fungal infections and 46% of patients with FUO responded to amphotericin B. In the patients group, that received 1 mg kg,1 liposomal amphotericin B it was 63 and 49%, in the group of patients that received 3 mg kg,1 liposomal amphotericin B it was 47 and 64%. Evidence of toxicity due to amphotericin B was seen in 50 patients (83%), toxicity due to liposomal amphotericin B, 1 mg kg,1, was seen in 35 patients (50%), and due to liposomal amphotericin B 3 mg kg,1 in 34 patients (54%). This was a statistically significant difference (P=0.001). It was concluded that liposomal amphotericin B was safer than conventional amphotericin B, but both formulations are equivalent in treatment efficacy. The prophylactic use of amphotericin B in these immunocompromised patients is discussed. [source] Quantitative analysis of 2,3,7,8-tetrachlorodibenzo- p -dioxin-induced proteome alterations in 5L rat hepatoma cells using isotope-coded protein labelsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 8 2006Hakan Sarioglu Abstract In an effort to contribute to a better understanding of the hepatic toxicity of the ubiquitous environmental pollutant and hepatocarcinogen 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), a comprehensive quantitative proteome analysis was performed on 5L rat hepatoma cells exposed to 1,nM TCDD for 8,h. Changes in the abundances of individual protein species in TCDD-treated cells as compared to untreated cells were analysed using the nongel-based isotope-coded protein label (ICPL) method [Schmidt,,A., Kellermann,,J., Lottspeich,,F., Proteomics 2005, 5, 4,15]. 89 proteins were identified as up- or down-regulated by TCDD. For the majority of the altered proteins, an impact of TCDD on their abundance had not been known before. Due to the physicochemical properties or the translational regulation of a large number of the affected proteins, their alteration would have escaped detection by gel-based methods for proteome analysis and by standard mRNA expression profiling, respectively. The identified proteins with TCDD-altered abundance include several proteins implicated in cell cycle regulation, growth factor signalling and the control of apoptosis. The results thus provide new starting-points for the investigation of specific aspects of the toxicity and carcinogenicity of dioxin in liver. [source] | |||||||||||||