ximelagatran and Chemical-and-Drug-Induced-Liver-Injury

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings.

Topics: Alleles; Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Azetidines; Benzylamines; Carbamazepine; Chemical and Drug Induced Liver Injury; Diclofenac; Dideoxynucleosides; Drug Hypersensitivity; Floxacillin; Genetic Markers; HLA Antigens; HLA-A Antigens; HLA-B Antigens; HLA-DQ alpha-Chains; Humans; Lapatinib; Pharmacogenetics; Quinazolines; Skin; Stevens-Johnson Syndrome; Ticlopidine

The quest for a biomarker that would reliably identify patients at risk of developing acute drug-induced liver injury (DILI) to a specific agent or class of agents before it occurs, has been underway for years. Historical host factors for DILI, such as older age and female gender, are not considered sufficient to truly predict an individual's inherent risk of DILI. In vitro and animal-based biomarker discoveries, in many instances, have not been considered accurate enough for drug development in human subjects nor for use in clinical practice.. In order to assess the current state of biomarkers to predict idiosyncratic human DILI, the authors utilized the PubMed literature search tool to identify research reports dealing with clinical DILI biomarkers covering the period of 2010 through to June 2012. Studies involving pharmacogenetic, proteomic and toxicogenomic analyses are preferentially reviewed.. Although acute DILI has been linked to specific genetic associations (e.g., flucloxacillin and HLA-B*5701; and certain polymorphisms seen with anti-TB agent DILI), such predictors have been able to identify only some patients at risk for only a limited number of drugs. Proteomic-based biomarkers from stored sera in the US DILI Network, such as apolipoprotein E, have been identified as potential candidates, but require further study. As it currently stands, the quest for a widely applicable, validated DILI biomarker remains an ongoing clinical challenge.

Topics: Antitubercular Agents; Apolipoproteins E; Arylamine N-Acetyltransferase; Azetidines; Benzylamines; Biomarkers; Chemical and Drug Induced Liver Injury; Diclofenac; Floxacillin; HLA-B Antigens; Humans; Liver; Metabolomics; Pharmacogenetics; Polymorphism, Genetic; Proteomics; Risk Factors

The low incidence of idiosyncratic drug-induced liver injury (DILI), together with the lack of a reliable diagnostic biomarker and robust preclinical and in vitro toxicology test systems for the condition have limited our ability to define the mechanisms of DILI. A notable exception is acetaminophen hepatotoxicity, which is associated with the formation of a well-characterized and highly reactive intermediate metabolite, N-acetyl-p-benzoquinone imine. However, studies have also suggested a role for the host immune response and variation in the expression of the lymphocyte CD44 gene in the pathogenesis of acetaminophen hepatotoxicity. A careful review of the laboratory, clinical and histological phenotype of patients with DILI can provide potential clues to the mechanisms of disease pathogenesis, as observed with fialuridine and valproate hepatotoxicity. In addition, the use of transcriptomic and genomic approaches in patients with well-characterized DILI has provided important insights into the involvement of the host immune response in the pathogenesis of hepatotoxicity associated with the administration of flucloxacillin, lumiracoxib or ximelagatran. This Review highlights new developments regarding the potential role of reactive metabolites, mitochondrial toxicity, host immune-response pathways and biliary transporters in the etiopathogenesis of DILI. Going forward, a bedside-to-bench approach could improve our understanding of the mechanisms and risk factors for DILI.

Topics: Acetaminophen; Animals; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Diclofenac; Floxacillin; Humans; Inactivation, Metabolic; Mice; Mitochondria, Liver; Models, Animal

Ximelagatran was the first orally available direct thrombin inhibitor under clinical development that also reached the market. Ximelagatran was tested in an extensive clinical programme. Short-term use (<12 days) in humans including the phase III clinical trials did not indicate any hepatotoxic potential. Increased hepatic enzyme levels were first observed at a higher frequency when evaluating the long-term (>35 days) use of ximelagatran (incidence of >3x upper limit of normal (ULN) plasma ALT was 7.9%). The frequency of elevated total bilirubin levels was similar in the ximelagatran and the comparator groups. However, the combination of ALT > 3x ULN and total bilirubin > 2xULN was 0.5% among patients treated with ximelagatran and 0.1% among patients in the comparator group. Symptoms such as fever and rash potentially indicating hypersensitivity (immunologic type of reaction) were low and did not differ between ximelagatran and the comparators. The withdrawal of ximelagatran from the market and termination of the ximelagatran development program was triggered by safety data from a 35-day study, indicating that severe hepatic injury in a patient could develop after exposure to the drug has been completed and that regular liver function monitoring may not mitigate the possible risk of severe hepatic injury. As for many drugs causing liver injury, the standard preclinical toxicological studies provided no indication that ximelagatran affected hepatic functions. In addition, extensive investigations using human-based in vitro models have not been able to define mechanisms explaining the pattern of hepatic injury observed in long-term clinical trials. A pharmacogenomic study provided evidence that the ALT increases were associated with major histocompatibility complex (MHC) alleles DRB1'07 and DQA1*02 suggesting a possible immunogenic pathogenesis. This example provides important clues to the mechanism of idiosyncratic drug-induced liver toxicity.

Topics: Animals; Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Drug Evaluation, Preclinical; Genetic Predisposition to Disease; Humans; Liver; Pharmacogenetics; Risk Assessment; Risk Factors; Safety-Based Drug Withdrawals; Severity of Illness Index; Toxicity Tests

The occurrence of drug-induced liver injury (DILI) presents a significant safety issue for patients and represents a major cause of regulatory action. The methods that are in current use for early detection and prediction of DILI in patients are not adequate. The liver is the major site of synthesis of endogenous metabolites, and data suggest that alterations in the profiles of endogenous metabolites ("the metabolome") may precede development of clinically overt DILI. Metabonomics involves the application of analytical technologies such as nuclear magnetic resonance and mass spectrometry to detect changes in the metabolome. In this review, we describe the emerging role of metabonomics in predicting and understanding the mechanisms underlying DILI. Recent human clinical trials of drugs, including acetaminophen (APAP) and ximelagatran, have shown that the metabonomics of biofluids (plasma and urine) collected before and immediately after dosing can identify individual patients who are likely to develop DILI. These studies support the need to include metabonomic investigations in clinical trials of potentially hepatotoxic medications.

Topics: Acetaminophen; Animals; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Metabolomics

Ximelagatran is a new oral anticoagulant that acts by direct and reversible inhibition of thrombin and has the potential to replace warfarin. In 2004, the FDA Cardiovascular and Renal drug Advisory Committee (CRAC) reviewed the ximelagatran clinical program. Three indications were proposed: the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement surgery (TKR), the prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF), and the long-term secondary prevention of VTE after standard treatment of an episode of acute VTE. The database consisted of a total of 30,698 subjects and included five phase III pivotal studies. During the advisory panel debate, widely divergent analyses of the benefits and risks of ximelagatran were presented. Ximelagatran hepatic toxicity was a key feature leading the CRAC to conclude that the benefit risk ratio of ximelagtran was unfavorable for the three proposed indications. Some design issues also undermined the strength of efficacy data. This paper reviews the benefits and risks of ximelagatran and analyzes the reasons leading to conflicting conclusions among various experts. The aim of this review is to facilitate the interpretation of benefits and risks associated with a new drug product and to improve future clinical drug developments.

Topics: Advisory Committees; Alanine Transaminase; Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Drug Approval; Humans; Liver; Risk Assessment; Thromboembolism; United States; United States Food and Drug Administration; Warfarin

Antithrombotic agents have verified efficacy in reducing the thromboembolic risk associated with atrial fibrillation. This article focuses on the emergence of a new oral direct thrombin inhibitor, ximelagatran, into the arena of atrial fibrillation thromboprophylaxis. This review does not cover atrial fibrillation in the context of valvular heart disease. The efficacy of aspirin and warfarin will be discussed briefly.

Topics: Administration, Oral; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase III as Topic; Humans; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Thrombin; Thromboembolism; Warfarin

Nonvalvular atrial fibrillation (AF) is an independent risk factor for stroke that becomes increasingly prevalent as populations age. More than half a dozen clinical trials have demonstrated that anticoagulation with the vitamin K antagonist warfarin is the most effective therapy for stroke prophylaxis in AF. The narrow therapeutic index of warfarin requires that the intensity of anticoagulation be maintained within the international normalized ratio (INR) range of 2.0 to 3.0 to optimize efficacy while minimizing bleeding risk. The pharmacokinetics of warfarin are subject to variability due to interactions with multiple drugs and foods, making maintenance of the INR within this range difficult to achieve in clinical practice without close coagulation monitoring and frequent dose adjustments. Current guidelines recommend oral anticoagulation for high-risk individuals with AF but these inherent limitations lead to substantial underprescribing, particularly in elderly patients at greatest risk. This has stimulated the development of new agents with improved benefit-risk profiles, such as ximelagatran, the first of the oral direct thrombin inhibitors, which has a wider therapeutic margin and low potential for drug interactions, allowing fixed dosing without anticoagulation monitoring. Ximelagatran has been evaluated for stroke prevention in AF in the Stroke Prevention using an Oral Direct Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) program, the largest clinical trials of antithrombotic therapy for stroke prevention in AF to date. The phase III trials of ximelagatran in AF, SPORTIF III and V, found a fixed oral dose of ximelagatran (36 mg twice daily) comparable to dose-adjusted warfarin (INR 2.0 to 3.0) in preventing stroke and systemic thromboembolic complications among high-risk patients with AF. Results from the population of over 7000 patients in SPORTIF III and V demonstrate noninferiority of ximelagatran compared with warfarin. Data from SPORTIF III show an absolute reduction in stroke and systemic embolic events with ximelagatran compared with warfarin of 1.6% per year versus 2.3% per year, respectively ( P = 0.10). SPORTIF V further supports noninferiority between the two agents with an absolute risk reduction of 0.45%, well within the predefined noninferiority margin (95% confidence interval -0.13, 1.03; P = 0.13). Although event rates for major bleeding did not differ significantly with ximelagatran versus warfarin in either study, combined

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Hemorrhage; Humans; Risk Assessment; Stroke; Thrombin; Vitamin K; Warfarin

The risk of stroke is greater among women with atrial fibrillation (AF) than men. Warfarin protects against stroke, but treatment-related bleeding occurs more often in women than in men.. SPORTIF III (open label, n=3410) and V (double-blind, n=3922) included 2257 women with AF and one or more stroke risk factors randomized to warfarin [target international normalized ratio (INR) 2.0-3.0] or ximelagatran (36 mg twice daily). Primary outcomes were all stroke (ischaemic/haemorrhagic) and systemic embolic event. Women were older, on average, than men, 73.4+/-8.0 vs. 69.8+/-9.0 years (P<0.0001). More women were >75-years old and women had more risk factors than men had (P<0.0001). The INR on warfarin (mean 2.5+/-0.7) was within target range for 67% of follow-up regardless of gender. Women more often developed primary events [2.08%/year, 95% confidence interval (CI) 1.60-2.56%/year vs. 1.44%/year, 95% CI 1.18-1.71%/year in men; P=0.016). Major bleeding rates were similar (P=0.766) but women experienced more overall (major/minor) bleeding (P<0.001). Warfarin was associated with more overall bleeding in both genders and more major bleeding in women than in men (P=0.001).. When compared with men with AF, women in these studies were older and had more stroke risk factors. Women were more prone to anticoagulant-related bleeding; the higher rate of thrombo-embolism among women was related to more frequent interruption of anticoagulant therapy.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Double-Blind Method; Estrogen Replacement Therapy; Female; Hemorrhage; Humans; Male; Risk Factors; Sex Characteristics; Sex Factors; Stroke; Thromboembolism; Warfarin

The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immune-mediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting "altered repertoire" as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202,-DQA1*0201) were created. These two lines were crossed with a human (h)CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a pre-clinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.

Topics: Animals; Azetidines; Benzylamines; Cell Line; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Female; HLA-DQ Antigens; HLA-DR7 Antigen; Humans; Lymphocytes; Male; Mice, Inbred C57BL; Mice, Transgenic; Molecular Docking Simulation; Phenotype

Ximelagatran was denied marketing approval in the USA and was withdrawn from those markets in which it had been approved, because of concerns over potential liver toxicity. A retrospective analysis of phase 2 data relating to liver toxicity is performed using the methods of extreme value modelling. The analysis reveals that the phase 2 data were predictive of the phase 3 results and, had the methods been available at the time, such analysis would have provided valuable information relating to the decision to proceed with further development of the compound.

Topics: Alanine Transaminase; Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase II as Topic; Humans; Models, Statistical; Predictive Value of Tests; Retrospective Studies

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to results for internal validation. The Bayesian model with extended connectivity functional class fingerprints of maximum diameter 6 (ECFC_6) and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g., ketones, diols, and α-methyl styrene type structures. Using Smiles Arbitrary Target Specification (SMARTS) filters published by several pharmaceutical companies, we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, such as the Abbott alerts, which captures thiol traps and other compounds, may be of use in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies. These computational models may represent cost-effective selection criteria before in vitro or in vivo experimental studies.

Topics: Bayes Theorem; Chemical and Drug Induced Liver Injury; Humans; Ligands

Ximelagatran was developed for the prevention and treatment of thromboembolic conditions. However, in long-term clinical trials with ximelagatran, the liver injury marker, alanine aminotransferase (ALT) increased in some patients. Analysis of plasma samples from 134 patients was carried out using proteomic and metabolomic platforms, with the aim of finding predictive biomarkers to explain the ALT elevation. Analytes that were changed after ximelagatran treatment included 3-hydroxybutyrate, pyruvic acid, CSF1R, Gc-globulin, L-glutamine, protein S and alanine, etc. Two of these analytes (pyruvic acid and CSF1R) were studied further in human cell cultures in vitro with ximelagatran. A systems biology approach applied in this study proved to be successful in generating new hypotheses for an unknown mechanism of toxicity.

Topics: Adenosine Triphosphate; Alanine Transaminase; Azetidines; Benzylamines; Biomarkers; Blood Proteins; Cells, Cultured; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Complement C4b-Binding Protein; Female; Hepatocytes; Histocompatibility Antigens; Humans; Macrophages; Male; Metabolomics; Protein S; Proteomics; Pyruvic Acid; Receptor, Macrophage Colony-Stimulating Factor; Systems Biology; Tumor Cells, Cultured; Vitamin D-Binding Protein

To investigate the possible mechanisms underlying the liver enzyme elevations seen during clinical studies of long-term treatment (>35 days) with ximelagatran, and investigate the usefulness of pre-clinical in vitro systems to predict drug-induced liver effects.. Ximelagatran and its metabolites were tested for effects on cell viability, mitochondrial function, formation of reactive metabolites and reactive oxygen species, protein binding, and induction of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) gene expression or nuclear orphan receptors. Experimental systems included fresh and cryopreserved hepatocytes, human hepatoma cell lines (HepG2 and HuH-7) and subcellular human liver fractions.. Loss of cell viability was only seen in HepG2 cells at ximelagatran concentrations 100 microM and in cryopreserved human hepatocytes at 300 microM, while HuH-7 cells were not affected by 24 h exposure at up to 300 microM ximelagatran. Calcium homeostasis was not affected in HepG2 cells exposed to ximelagatran up to 300 microM for 15 min. There was no evidence for the formation of reactive metabolites when cell systems were exposed to ximelagatran. ALT and AST expression in human hepatoma cell lines were also unchanged by ximelagatran. Mitochondrial functions such as respiration, opening of the transition pore, mitochondrial membrane depolarization and beta-oxidation were not affected by ximelagatran or its metabolites.. Ximelagatran at concentrations considerably higher than that found in plasma following therapeutic dosing had little or no effect on cellular functions studied in vitro. The in vitro studies therefore did not elucidate the mechanism by which ximelagatran induces liver effects in humans, possibly because of limitations in the experimental systems not reflecting characteristics of the human hepatocyte, restricted exposure time, or because the primary mechanism for the observed clinical liver effects is not on the parenchymal liver cell.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Apoptosis; Azetidines; Benzylamines; Calcium; Carcinoma, Hepatocellular; Cell Line; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Cryopreservation; Fibrinolytic Agents; Flow Cytometry; Hepatocytes; Humans; In Vitro Techniques; Mass Spectrometry; Mitochondria, Liver; Necrosis; Permeability; Predictive Value of Tests; Rats; Reactive Oxygen Species; Subcellular Fractions; Thrombin

Topics: Alanine Transaminase; Anticoagulants; Azetidines; Benzylamines; Bilirubin; Biomarkers; Chemical and Drug Induced Liver Injury; Chromans; Drug Approval; Humans; Hypoglycemic Agents; Jaundice; Liver; Liver Failure, Acute; Pharmacoepidemiology; Predictive Value of Tests; Risk Assessment; Thiazolidinediones; Troglitazone; United States; United States Food and Drug Administration

Topics: Adverse Drug Reaction Reporting Systems; Alanine Transaminase; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Azetidines; Benzophenones; Benzylamines; Bilirubin; Biomarkers; Bromobenzenes; Chemical and Drug Induced Liver Injury; Chromans; Drug Approval; Humans; Hypoglycemic Agents; Liver; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Assessment; Thiazolidinediones; Troglitazone; United States; United States Food and Drug Administration

Topics: Adverse Drug Reaction Reporting Systems; Alanine Transaminase; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Azetidines; Benzophenones; Benzylamines; Bilirubin; Biomarkers; Bromobenzenes; Chemical and Drug Induced Liver Injury; Chromans; Drug Approval; Humans; Hypoglycemic Agents; Liver; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Assessment; Thiazolidinediones; Troglitazone; United States; United States Food and Drug Administration

Topics: Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Drug Approval; Humans; Liver; Risk Assessment; Thromboembolism; United States; United States Food and Drug Administration

Topics: Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Humans; Myocardial Infarction; Thrombin; Thrombosis; Vitamin K; Warfarin

Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a

Topics: Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Myocardial Ischemia; Oligosaccharides; Polysaccharides; Recurrence; Thrombin; Time Factors; Venous Thrombosis; Warfarin

Topics: Advisory Committees; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Drug Approval; Embolism; Humans; Randomized Controlled Trials as Topic; Stroke; United States; United States Food and Drug Administration; Venous Thrombosis