warfarin and Chemical-and-Drug-Induced-Liver-Injury

Except for bleeding complications, vitamin K antagonists (VKAs) are known to have few undesirable side effects. Herein is presented the case of a 45-year-old woman in whom liver damage was induced by fluindione and warfarin after mitral valve replacement. Hepatotoxicity is a rare complication of VKAs, both in the French National and Drug Safety registry and the medical literature. A diagnosis of VKA-induced drug damage was confirmed by the absence of other etiologies, the chronological sequence, recurrence after re-exposure to VKA, and rapid improvements after discontinuation of the drug. Despite possible cross-reactions between VKAs, the re-introduction of acenocoumarol was successfully achieved, with no recurrence of biological disturbances.

Topics: Anticoagulants; Chemical and Drug Induced Liver Injury; Drug Substitution; Female; Fibrinolytic Agents; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Heparin, Low-Molecular-Weight; Humans; Liver Function Tests; Middle Aged; Mitral Valve; Phenindione; Risk Factors; Treatment Outcome; Vitamin K; Warfarin

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

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

We report on a case of massive bleeding into the liver parenchyma during treatment with a combination of warfarin sodium and trimethoprim-sulfamethoxazole. A fifty-five-year-old woman was put on long-term anticoagulant therapy with warfarin sodium. Two years later a course of trimethoprim-sulfamethoxazole was given to treat bronchitis. Following a bout of severe epigastric pain, ultrasonography and computed tomography (CT) then showed an enlarged liver containing several large hematomas. Subsequent CT scans, after tentative treatment only, showed regression of the liver hematomas, with almost complete disappearance after eight months. Bleeding complications and drug interactions related to this case are discussed, together with a review of the only six previous reports in the world literature of liver hematomas following anticoagulant therapy. Also mentioned are five patients in whom thrombolytic therapy gave rise to the same adverse reaction.

Topics: Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Therapy, Combination; Female; Hematoma; Humans; Liver; Liver Diseases; Middle Aged; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination; Warfarin

Topics: Adult; Aged; Ajmaline; Anti-Arrhythmia Agents; Antihypertensive Agents; Cardiovascular Agents; Chemical and Drug Induced Liver Injury; Diuretics; Humans; Male; Methyldopa; Procaine; Quinidine; Warfarin

Topics: Anesthetics; Animals; Barbiturates; Biotransformation; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Endoplasmic Reticulum; Enzyme Induction; Ethers, Cyclic; Genetic Variation; Humans; Hydrocarbons, Halogenated; Microsomes, Liver; Oxidation-Reduction; Pharmaceutical Preparations; Toxicology; 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

Since its introduction in the United States in 1974, ibuprofen (Motrin, Upjohn) has been shown to be safe and effective for the treatment of pain, dysmenorrhea, inflammation, and fever. A careful review of pre-registration and postmarketing data from both patients and normal subjects clearly indicates ibuprofen's remarkable safety profile compared with that of aspirin and other commonly prescribed nonsteroidal anti-inflammatory agents. Continued safety can be anticipated on the basis of the past 15 years of review experience.

Topics: Anti-Inflammatory Agents; Aspirin; Blood Cell Count; Blood Coagulation Tests; Blood Proteins; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Eruptions; Drug Interactions; Drug Tolerance; Gastrointestinal Diseases; Humans; Ibuprofen; Kidney Diseases; Liver Function Tests; Warfarin

Topics: Anticoagulants; Chemical and Drug Induced Liver Injury; Cohort Studies; Humans; Warfarin

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening mucocutaneous disease that is predominantly drug-induced. Warfarin is the most commonly used drug for long-term anti-coagulant therapy; however, warfarin-induced SJS/TEN is seldom reported. In this study, we presented the case of a 61-year-old man who developed SJS after receiving multiple-drug therapy following aortic valve replacement surgery. The patient was diagnosed with drug-induced liver injury (DILI) based on significantly abnormal liver function test results. Warfarin was identified as the culprit drug using the algorithm of drug causality for epidermal necrolysis (ALDEN) score, enzyme-linked immunospot (ELISPOT) assay, and Roussel Uclaf Causality Assessment Method (RUCAM). After warfarin discontinuation and corticosteroid therapy, the lesions and liver function test findings improved. Human leukocyte antigen typing was conducted to detect the risk allele. To our knowledge, this is the first reported case of warfarin-induced SJS/TEN with DILI. This case suggests that commonly used and safe pharmaceutical agents such as warfarin can potentially cause serious adverse events, including SJS/TEN and DILI. The application of ALDEN, the ELISPOT assay, and RUCAM could be useful in identifying culprit drugs.

Topics: Algorithms; Chemical and Drug Induced Liver Injury; Humans; Male; Middle Aged; Stevens-Johnson Syndrome; Warfarin

The risk of liver injury in patients with atrial fibrillation (AF) using nonvitamin K antagonist oral anticoagulants (NOACs) has not been previously examined using liver function tests as the primary outcome in the real-world setting. This study assessed the association between NOACs (dabigatran, rivaroxaban, and apixaban) and warfarin and the risk of liver injury, as defined by laboratory tests.. Patients newly diagnosed with AF and prescribed NOACs or warfarin between 2010 and 2016, identified using the Hong Kong Clinical Database and Reporting System, were matched on age, sex, health status scores, comorbidities, and medications by propensity score on a 1:1 ratio. Risk of liver injury, defined as laboratory test values >3 times the upper limit of normal of alanine aminotransferase or aspartate aminotransferase and >2 times the upper limit of normal of total bilirubin, was compared between NOAC and warfarin users using Cox proportional hazards regression.. After propensity score matching, 13,698 patients were included, of which 141 (2.1%) NOAC users and 232 (3.4%) warfarin users developed liver injury. The hazard ratio (HR) for NOAC vs warfarin users was 0.71 (95% confidence interval: 0.58-0.89). When comparing individual NOACs, only dabigatran (hazard ratio: 0.63; 95% confidence interval: 0.48-0.82) was associated with a lower risk of liver injury.. Among patients with AF, NOACs as a group, and dabigatran alone were associated with a significantly lower risk of laboratory-based liver injury when compared with warfarin. However, liver injury occurs more frequently in real-world practice than in NOAC randomized controlled trials.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Chemical and Drug Induced Liver Injury; Cohort Studies; Dabigatran; Databases, Factual; Female; Humans; Male; Middle Aged; Propensity Score; Pyrazoles; Pyridones; Risk; Rivaroxaban; Warfarin

Topics: Anticoagulants; Chemical and Drug Induced Liver Injury; Humans; Warfarin

A 20-year-old male affected by transfusion-dependent β-thalassemia (β-thal), was prescribed intensive chelation therapy with deferoxamine (DFO) and deferiprone (DFP) because of severe hepatic and cardiac iron overload and β-blocker and warfarin to manage a previous event of atrial fibrillation (AFib) and heart failure. After a few months, he developed critical liver failure, renal tubulopathy and severe electrolyte imbalance. Laboratory and instrumental evaluations were performed to carry out differential diagnosis of acute liver failure and an exclusion diagnosis of drug induced liver injury (DILI) was made. The cholestatic pattern suggested warfarin as the main causative agent and polypharmacy, liver iron overload and heart failure as aggravating factors. Warfarin is a drug commonly prescribed in thalassemia patients who often need polypharmacy for the management of anemia- and iron-related complications. Strict monitoring and multidisciplinary approaches are mandatory to avoid preventable mortality in this fragile population.

Topics: Adrenergic beta-Antagonists; beta-Thalassemia; Chelation Therapy; Chemical and Drug Induced Liver Injury; Critical Illness; Deferiprone; Heart Failure; Humans; Iron Overload; Male; Warfarin; Young Adult

Topics: Anticoagulants; Atrial Fibrillation; Chemical and Drug Induced Liver Injury; Factor Xa Inhibitors; Hemorrhage; Humans; International Normalized Ratio; Pulmonary Embolism; Pyridines; Stroke; Thiazoles; Venous Thrombosis; Warfarin

Here we reported a patient with warfarin-induced autoimmune hepatitis (AIH), and explored new concerns for the pharmaceutical care of warfarin. A 57- year-old woman was admitted to hospital for repeated anorexia, abdominal pain and abnormal liver function. She received prosthetic heart valve replacement because of rheumatic heart disease, and had started warfarin medication since 2 years before. Her liver function was elevated with highest alanine aminotransferase 861 U/L, aspertate aminotransferase 604 U/L, and total bilirubin 106.7 μmol/L. Her anticoagulant therapy was switched to low molecular weight heparin and the liver function returned to normal. The liver function was elevated when she started to take warfarin again. The patient was then on liver protection therapy, and warfarin was stopped again for the liver biopsy for diagnosis reason. Through medication consultation and evaluation, pharmacists were invited to work together with the physicians and helped to differentiate the reason for abnormal liver function, and provided therapeutic suggestions. Also the pharmacists gained experiences in the treatment of AIH, and discovered a new and severe adverse drug reaction for warfarin. In treating this case, the pharmacists'active involvement into the treatment and evaluation of the effect on the patient reflected the advantage and importance of the multidisciplinary cooperation for pharmacists and physicians when complex diseases are faced.

Topics: Alanine Transaminase; Anticoagulants; Biopsy; Chemical and Drug Induced Liver Injury; Female; Heparin, Low-Molecular-Weight; Hepatitis, Autoimmune; Humans; Warfarin

Topics: Chemical and Drug Induced Liver Injury; Hepatitis, Autoimmune; Humans; Warfarin

Drug-induced hepatotoxicity is potentially lethal. Liver transplant patients receive a large number of medications and adverse drug reactions, and drug-drug interactions must be closely monitored.. We report a case of a 29-year-old liver transplant patient who suffered liver injury most likely induced by drug interaction between capecitabine and warfarin. Vitamin K1 caused skin rash possibly because of the distribution and metabolism characteristic of the drug in this patient.. Close monitoring and prompt discontinuation of the drugs with high volume of distribution and metabolized through the liver are necessary to avoid drug-drug interaction in liver transplant patients.

Topics: Adult; Anticoagulants; Antimetabolites, Antineoplastic; Capecitabine; Chemical and Drug Induced Liver Injury; Deoxycytidine; Drug Eruptions; Drug Interactions; Drug Monitoring; Fluorouracil; Follow-Up Studies; Humans; Liver Transplantation; Male; Tissue Distribution; Vitamin K 1; Warfarin

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy = 0.87, κ = 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Humans; Quantitative Structure-Activity Relationship

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 is a major issue of concern and has led to the withdrawal of a significant number of marketed drugs. An understanding of structure-activity relationships (SARs) of chemicals can make a significant contribution to the identification of potential toxic effects early in the drug development process and aid in avoiding such problems. This process can be supported by the use of existing toxicity data and mechanistic understanding of the biological processes for related compounds. In the published literature, this information is often spread across diverse sources and can be varied and unstructured in quality and content. The current work has explored whether it is feasible to collect and use such data for the development of new SARs for the hepatotoxicity endpoint and expand upon the limited information currently available in this area. Reviews of hepatotoxicity data were used to build a structure-searchable database, which was analyzed to identify chemical classes associated with an adverse effect on the liver. Searches of the published literature were then undertaken to identify additional supporting evidence, and the resulting information was incorporated into the database. This collated information was evaluated and used to determine the scope of the SARs for each class identified. Data for over 1266 chemicals were collected, and SARs for 38 classes were developed. The SARs have been implemented as structural alerts using Derek for Windows (DfW), a knowledge-based expert system, to allow clearly supported and transparent predictions. An evaluation exercise performed using a customized DfW version 10 knowledge base demonstrated an overall concordance of 56% and specificity and sensitivity values of 73% and 46%, respectively. The approach taken demonstrates that SARs for complex endpoints can be derived from the published data for use in the in silico toxicity assessment of new compounds.

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Humans; Structure-Activity Relationship; Tetracyclines; Thiophenes

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

2-acetylbenzothiophene-S-oxide (2-ABT-S-oxide or M1) is a reactive metabolite of zileuton, a drug used in the treatment of asthma and is capable of conjugating with glutathione in vitro. Human serum albumin (HSA) is the most abundant protein in plasma and plays a critical role in detoxifying reactive oxygen species. The current research is focused on understanding the interaction between M1 and HSA. The stability studies revealed the half-life of M1 to be about 0.85 h in HSA, 1.82 h in human plasma, and 4.48 h in phosphate-buffered saline (PBS) as determined by first-order approximation. The alkylation rate constant k for HSA was 20 M(-1) min(-1). After quenching with acetonitrile, the half-life of M1 did not change significantly, indicating that M1 is covalently bound to HSA. LC-MS and LC-MS/MS analysis of human plasma revealed the M1 alkylated peptide P (m/z 870) formed by HSA conjugation and concomitant water elimination. The specific amino acid on HSA bound to M1 was identified as Cys-34. This alkylation is observed to be concentration- and incubation-time-dependent in human plasma. HSA oxidized by N, N'-diacetyl-L-cystine exhibits a compromised ability of HSA to react with M1. The alkylated HSA diminished the binding affinity for warfarin. Furthermore, the alkylation was found to be irreversible in the dialysis experiment. In addition, M1 decomposes to 2-ABT in the presence of HSA, presumably acting as an oxidant. The formation of 2-ABT in the incubation and the self-condensation of M1 in PBS indicate that the alkylation of Cys-34 is only one of a number of reactions that occur in the presence of HSA. Irreversible protein modification may potentially lead to a loss of its function. HSA irreversible alkylation represents a model for other proteins to be potentially toxic and thus may help explain zileuton hepatotoxicity.

Topics: Alkylation; Anti-Asthmatic Agents; Binding, Competitive; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Half-Life; Humans; Hydroxyurea; Ibuprofen; Models, Biological; Serum Albumin; Tandem Mass Spectrometry; Thiophenes; Warfarin

Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin that produces hepatotoxicity in humans and animals. Administration of MCT to rats causes rapid sinusoidal endothelial cell (SEC) injury, hemorrhage, pooling of blood and fibrin deposition in centrilobular regions of liver. These events precede hepatic parenchymal cell (HPC) injury and produce marked changes in the microvasculature of the liver, which could interrupt blood flow and produce hypoxia in affected regions. To test the hypothesis that hypoxia occurs in liver after MCT exposure, rats were treated with 300mgMCT/kg, and hypoxia was detected immunohistochemically. MCT produced significant hypoxia in centrilobular regions of livers by 8h after treatment. Inasmuch as fibrin deposition can impair oxygen delivery by reducing blood flow, the effect of anticoagulant treatment on MCT-induced hypoxia was determined. Administration of warfarin to MCT-treated rats reduced hypoxia in the liver by approximately 70%, suggesting that fibrin deposition plays a causal role in the development of hypoxia in the liver. Conversely, administration of l-NAME, a nonspecific inhibitor of nitric oxide synthases (NOSs), enhanced MCT-induced hypoxia and HPC injury. l-NAME did not, however, affect SEC injury or coagulation system activation. Results from these studies show that hypoxia occurs in the liver after MCT exposure. Furthermore, hypoxia precedes HPC injury, and manipulations that modify hypoxia also modulate HPC injury.

Topics: Animals; Anticoagulants; Cell Hypoxia; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Fibrinogen; Hyaluronic Acid; Liver; Male; Monocrotaline; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Warfarin

Although there are many reports describing spontaneous rupture of either the spleen or the liver, the simultaneous rupture of both organs is a rare event, especially during anticoagulant therapy. We report a case of spontaneous rupture of the spleen and liver in a patient on warfarin therapy for deep venous thrombosis.

Topics: Adult; Chemical and Drug Induced Liver Injury; Follow-Up Studies; Hepatectomy; Humans; Liver Diseases; Male; Risk Assessment; Rupture, Spontaneous; Splenectomy; Splenic Rupture; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography, Doppler; Venous Thrombosis; Warfarin

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

Coexposure to a noninjurious dose of bacterial lipopolysaccharide (LPS; 7.4 x 106 EU/kg) and a nontoxic dose of the food-borne toxin monocrotaline (MCT; 100 mg/kg) leads to synergistic hepatotoxicity in Sprague-Dawley rats. Inflammatory factors, such as Kupffer cells (KCs), tumor necrosis factor-alpha (TNF)-alpha, and neutrophils (polymorphonuclear leukocytes; PMNs), are critical to the pathogenesis. Inasmuch as activation of the coagulation system and sinusoidal endothelial cell (SEC) injury precede hepatic parenchymal cell (HPC) injury, and since fibrin deposition occurs within liver lesions, the coagulation system might be a critical component of injury. In this study, this hypothesis is tested, and the interdependence of the coagulation system and inflammatory factors is explored. Administration of the anticoagulants heparin or warfarin to MCT/LPS-cotreated animals attenuated HPC and SEC injury. Morphometric analysis revealed that anticoagulant treatment significantly reduced the area of centrilobular and midzonal lesions. Heparin treatment also reduced fibrin deposition in these regions. Furthermore, anticoagulant treatment decreased hepatic PMN accumulation but did not affect plasma TNF-alpha concentration. Neither KC inactivation nor TNF-alpha depletion prevented activation of the coagulation system. PMN depletion, however, prevented coagulation system activation, suggesting that PMNs are needed for this response. These results provide evidence that the coagulation system and its interplay with PMNs are important in the pathogenesis of MCT/LPS-induced liver injury.

Topics: Animals; Anticoagulants; Blood Coagulation; Chemical and Drug Induced Liver Injury; Drug Antagonism; Drug Synergism; Escherichia coli; Heparin; Lipopolysaccharides; Male; Monocrotaline; Neutropenia; Neutrophils; Rats; Rats, Sprague-Dawley; Warfarin

Topics: Aged; Anticoagulants; Chemical and Drug Induced Liver Injury; Hepatitis B; Humans; Hypoalbuminemia; Liver Function Tests; Male; Warfarin

Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin that produces hepatotoxicity in humans and animals. Human exposure to MCT occurs through consumption of contaminated grains and herbal medicines. Administration of MCT to rats stimulates activation of the coagulation system and fibrin deposition in the liver. Fibrin deposition occurs simultaneously with endothelial cell damage and prior to hepatic parenchymal cell injury. Accordingly, the hypothesis that activation of the coagulation system is required for MCT-induced liver injury was tested. Treatment of rats with either heparin or warfarin significantly reduced MCT-induced activation of the coagulation system and the increase in alanine aminotransferase activity in the plasma, a biomarker of hepatic parenchymal cell injury. Histopathological examination of liver sections revealed that heparin decreased parenchymal cell necrosis but did not affect central venular endothelial cell damage, congestion and dilation of the sinusoids, or hemorrhage in the liver. Morphometric analysis revealed that 28% of the area of livers from MCT-treated rats contained regions of coagulative necrosis, whereas less than 5% of the area of livers from rats treated with MCT and heparin contained these regions. By contrast, neither heparin nor warfarin prevented MCT-induced damage to endothelial cells in the liver as estimated by increased plasma hyaluronic acid concentration. These results suggest that activation of the coagulation system is required for MCT-induced parenchymal cell injury but not endothelial cell injury in the liver.

Topics: Analysis of Variance; Animals; Anticoagulants; Chemical and Drug Induced Liver Injury; Endothelium; Fibrin; Heparin; Male; Monocrotaline; Rats; Rats, Sprague-Dawley; Warfarin

Except for bleeding complications, relevant adverse effects of coumarin anticoagulants are comparatively rare considering the widespread use of these substances. Here we present the case of a 56-year-old woman who developed recurrent episodes of severe hepatitis following repeated exposure to phenprocoumon (Marcumar; Roche, Grenzach-Wyhlen, Germany) and warfarin (Coumadin; DuPont Pharma, Bad Homburg, Germany) after replacement of the mitral valve with a mechanical prosthesis. The diagnosis of "coumarin-induced hepatitis" is compatible with the time relationship between start of the drug and the onset of hepatopathy (first episode 8 months, second episode 4 weeks, and third episode 7 days), the rapid improvement following discontinuation of the drug, recurrence of liver dysfunction after re-exposure to the drug, and liver histology. After anticoagulant therapy was changed to heparin and acenocoumarol (Sintrom; Ciba-Geigy, Basel, Switzerland), the patient's general state was markedly improved and her liver values became almost normal. This case will be discussed and compared with other reports of coumarin-induced hepatic lesions. Although liver damage induced by coumarin derivates is rare, it is important to be aware of the hepatotoxic potential of these drugs, which, in most cases, mimics the clinical presentation of viral hepatitis.

Topics: Anticoagulants; Bioprosthesis; Chemical and Drug Induced Liver Injury; Female; Humans; Middle Aged; Mitral Valve; Phenprocoumon; Postoperative Complications; Thrombosis; Warfarin

J.M., a healthy, 25-year-old male, volunteered for a study involving warfarin and acetaminophen. Acetaminophen 1 g four times a day was started for 21 days. Liver function tests taken at regular intervals for the first 12 days were unremarkable. On day 18, however, aspartate aminotransferase (AST) was 527 IU/liter and alanine aminotransferase (ALT) was 166 IU/liter. Acetaminophen was discontinued and serum transaminase levels returned to baseline levels two weeks later (AST = 26, ALT = 20). Analysis of J.M.'s urine samples over the first 18 days showed excretion patterns of glucuronide, sulfate, and glutathione derived cysteine and mercapturic acid conjugates were similar to the other subjects in the study. Acetaminophen causes hepatotoxicity in overdose or malnourished or alcoholic patients, none of which applied to our subject. Differences in metabolic activation and capacity for glutathione synthesis can predispose individuals given therapeutic doses of acetaminophen to adverse effects. Failure to detoxify a highly reactive metabolite, formed by P-450 metabolism, via glutathione conjugation is responsible for the development of acute hepatic necrosis. Accumulation of the toxic metabolite due to depleted glutathione stores may have occurred with prolonged high dosing in our subject and been responsible for his abnormal rise in liver enzymes.

Topics: Acetaminophen; Adult; Alanine Transaminase; Analgesics, Non-Narcotic; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Humans; Liver Function Tests; Male; Risk Factors; Time Factors; Warfarin

Evidence suggests that components of the coagulation system contribute to the pathogenesis of liver injury after exposure to lipopolysaccharide (LPS) from gram-negative bacteria. Although the mechanism by which the coagulation system mediates liver injury remains unknown, it has been proposed that the conversion of fibrinogen to insoluble fibrin and consequent deposition in liver microvasculature may contribute to the development of liver injury. The purpose of this study was to test the hypothesis that the coagulation system contributes to LPS hepatotoxicity by a mechanism which is dependent on circulating fibrinogen. A marked reduction in plasma fibrinogen concentration occurred in rats after LPS exposure. The decrease in circulating fibrinogen, which marked activation of the coagulation cascade: 1) occurred at doses of LPS that caused liver injury; 2) was temporally associated with the onset of liver injury; and 3) was attenuated by pretreatment with heparin or warfarin under conditions which afforded protection against liver injury. Pretreatment with either pentoxifylline or antiserum to tumor necrosis factor-alpha, both of which protect against LPS hepatotoxicity, also attenuated the LPS-induced decrease in circulating fibrinogen. Polymorphonuclear leukocyte (neutrophil) depletion protected against liver injury after administration of either a small (2 mg/kg) or a large (8 mg/kg) dose of LPS and attenuated the decrease in circulating fibrinogen albeit to a lesser degree after the larger LPS dose. Depletion of circulating fibrinogen with ancrod did not afford protection against LPS hepatotoxicity. These results suggest that the coagulation system contributes to the pathogenesis of LPS-induced liver injury, but it does so by a mechanism which is independent of circulating fibrinogen.

Topics: Ancrod; Animals; Blood Coagulation; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Fibrinogen; Heparin; Lipopolysaccharides; Neutrophils; Pentoxifylline; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Warfarin

Hepatotoxicity is a rare complication of coumarin anticoagulants. We present the case of a 56-year-old woman who developed a viral-hepatitis-like picture 8 months after mitral valve replacement and oral anticoagulation. Phenprocoumon-induced hepatitis was diagnosed after positive reexposure and improvement following withdrawal of the drug. There appeared to be cross-reactivity to warfarin since this drug led to a similar increase in alkaline phosphatase and gamma-glutamyl transferase after a few days of administration. Liver biopsy showed an acute viral-hepatitis-like picture. Anticoagulation was changed to a subcutaneous low molecular weight heparin and low-dose aspirin. Because of the widespread use of coumarin anticoagulants, physicians should be aware of the hepatotoxic potential of these drugs, which most frequently mimics the clinical presentation of viral hepatitis.

Topics: Administration, Oral; Alkaline Phosphatase; Biopsy; Chemical and Drug Induced Liver Injury; Female; gamma-Glutamyltransferase; Humans; Incidence; Liver; Middle Aged; Phenprocoumon; Warfarin

A case was presented of a 51-year-old woman who underwent aortic valve replacement with a St. Jude Medical prosthesis two and a half years before. The patient was initially placed on Warfarin potassium after the surgery. However she gradually developed jaundice during the period of two months Warfarin was replaced with ticlopidine hydrochloride as it was thought to be the most probable cause of jaundice. The prosthesis was subsequently thrombosed and had to be replaced with a Carpentier bovine pericardial valve. Warfarin potassium rarely induces the hepatic dysfunction as a result of drug allergy. However, the prompt diagnosis and adequate management are essential if it should occur.

Topics: Aortic Valve; Chemical and Drug Induced Liver Injury; Female; Heart Valve Prosthesis; Humans; Middle Aged; Reoperation; Thrombosis; Warfarin

Guidelines for the management of patients receiving chronic anticoagulation therapy who require liver biopsy are not clearly defined. In patients with normal coagulation, liver biopsy is a relatively safe procedure with a morbidity of less than 0.1% and a mortality of less than 0.01%. We report a patient with a prosthetic aortic valve who developed a large subcapsular hematoma 12 days after a percutaneous liver biopsy as a consequence of warfarin toxicity. Based on the experience with this patient, reinstitution of anticoagulant therapy should be avoided for at least 72 h after a percutaneous liver biopsy. Intravenous heparin should be resumed first, and warfarin added if no bleeding has occurred after an additional 48-72 h. The prothrombin time should be maintained at 1.5 times the baseline.

Topics: Biopsy, Needle; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Hematoma; Humans; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Prothrombin Time; Time Factors; Warfarin

The purpose of this experiment was to compare the toxic effects of aflatoxin B1 (AFB1) and warfarin in pigs and to determine whether these have an additive effect in these pigs fed dietary Cd. Cadmium was provided daily through the diets of 2 concentrations (0 or control, and 83 micrograms/g of diet) during the 40 days of the experiment. At the start of the 5th week, AFB1 and warfarin were given in 5 daily doses (each dose 0.2 mg/kg of body weight) and the effects were determined for 10 days (starting with the 1st treatment day). Aflatoxin B1 given to the pigs fed the control diet (0 Cd) was toxic, inducing significantly increased alkaline phosphatase, sorbitol dehydrogenase, and aspartate aminotransferase activities and the prothrombin time (PT) and activated partial thromboplastin time (APTT) and significantly decreased values in serum total protein, alpha-globulin, beta-globulin, gamma-globulin, and fibrinogen. There was no effect on blood urea nitrogen. The treatment with warfarin was more effective in producing earlier and significantly longer PT and APTT. In the pigs fed the diet with the added Cd, differences in activity of alkaline phosphatase, sorbitol dehydrogenase, aspartate aminotransferase values, but not blood urea nitrogen, as well as differences in intensity and duration of response in PT and APTT occurred when pigs were dosed daily for 5 days after AFB1 or warfarin. It is concluded that dietary Cd (83 micrograms/g of diet) in young pigs has an inhibitory effect on AFB1 toxicity and an enhancing synergistic effect with warfarin.

Topics: Aflatoxin B1; Aflatoxins; Animal Feed; Animals; Blood Proteins; Blood Urea Nitrogen; Cadmium; Cadmium Poisoning; Carcinogens; Chemical and Drug Induced Liver Injury; Liver Diseases; Male; Swine; Swine Diseases; Warfarin

To examine the ticrynafen-warfarin interaction, normal subjects received large single doses of 1.5 mg/kg racemic warfarin with and without daily oral doses of 250 mg ticrynafen beginning 3 days before warfarin and continuing for the duration of hypoprothrombinemia. Daily blood samples were analyzed for one-stage prothrombin time (Quick method) and warfarin concentrations (high-pressure liquid chromatography). Ticrynafen induced augmentations of both prothrombin time and warfarin concentration (P less than 0.001). The interaction was evaluated further with separated warfarin enantiomorphs. Ticrynafen induced augmentation of prothrombin times and warfarin concentrations of S-warfarin, but had little effect on R-warfarin. Thus, ticrynafen probably augments the hypoprothrombinemia of racemic warfarin by reducing metabolic clearance of S-warfarin. The lack of effect of ticrynafen on R-warfarin suggest that the interaction is stereoselective rather than hepatotoxic.

Topics: Adult; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Drug Interactions; Glycolates; Humans; Hypoprothrombinemias; Male; Prothrombin Time; Stereoisomerism; Ticrynafen; Warfarin

Topics: Animals; Antipyrine; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Half-Life; Liver; Male; Rabbits; Warfarin

Topics: Chemical and Drug Induced Liver Injury; Cholestasis; Female; Humans; Liver; Male; Middle Aged; Warfarin

Topics: Aged; Angina Pectoris; Chemical and Drug Induced Liver Injury; Erythrityl Tetranitrate; Female; Humans; Liver Diseases; Nitroglycerin; Prothrombin Time; Rupture; Warfarin

Topics: Animals; Chemical and Drug Induced Liver Injury; Dog Diseases; Dogs; Liver; Warfarin

Topics: Anticoagulants; Biopsy; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Guanethidine; Hepatitis; Humans; Hydrochlorothiazide; Hypertension; Methylprednisolone; Polyarteritis Nodosa; Thrombophlebitis; Warfarin