minocycline and Chemical-and-Drug-Induced-Liver-Injury

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

Drug-induced liver injury (DILI) with features of autoimmunity (AI) represents an important category of hepatotoxicity due to medication exposure. Drugs repeatedly associated with AI-DILI include diclofenac, α-methyl DOPA, hydralazine, nitrofurantoin, minocycline, and more recently statins and anti-TNF-α agents. Usually, symptoms of acute liver injury occur within a few months after initiation of a culprit medication, but a longer latency period is possible. Like idiopathic autoimmune hepatitis, circulating autoantibodies and a hypergammaglobulinemia are frequently present in sera from patients with AI-DILI. If performed, a liver biopsy should demonstrate interface hepatitis with a prominent plasma cell infiltrate. The severity of AI-DILI is variable, but a complete resolution after withdrawal of the offending medication is the expectation. A response to corticosteroid therapy supports the diagnosis, whereas a lack of recurrence of symptoms or signs following corticosteroid cessation distinguishes AI-DILI from idiopathic autoimmune hepatitis.

Topics: Adult; Anti-Bacterial Agents; Anti-Infective Agents, Urinary; Antihypertensive Agents; Autoantibodies; Autoimmunity; Chemical and Drug Induced Liver Injury; Cytokines; Diagnosis, Differential; Drug Hypersensitivity; Female; Hepatitis, Autoimmune; HLA Antigens; Humans; Hydralazine; Hypergammaglobulinemia; Liver; Liver Function Tests; Male; Methyldopa; Minocycline; Nitrofurantoin; Time Factors; Young Adult

The clinical phenotype of classical autoimmune hepatitis can be mimicked by idiosyncratic drug-induced liver injury, and differentiation can be difficult. The goals of this review are to enumerate the major agents of drug-induced autoimmune-like hepatitis, describe the clinical findings and risk factors associated with it, detail the clinical tools by which to assess causality, discuss putative pathogenic mechanisms, and describe treatment and outcome. The frequency of drug-induced autoimmune-like hepatitis among patients with classical features of autoimmune hepatitis is 9%. Minocycline and nitrofurantoin are implicated in 90% of cases. Female predominance, acute onset, and absence of cirrhosis at presentation are important clinical manifestations. Genetic factors affecting phase I and phase II transformations of the drug, polymorphisms that protect against cellular oxidative stress, and human leukocyte antigens that modulate the immune response may be important pathogenic components. Clinical judgment is the mainstay of diagnosis as structured diagnostic methods for drug-induced liver injury are imperfect. The covalent binding of a reactive drug metabolite to a hepatocyte surface protein (commonly a phase I or phase II enzyme), formation of a neoantigen, activation of CD8 T lymphocytes with nonselective antigen receptors, and deficient immune regulatory mechanisms are the main bases for a transient loss of self-tolerance. Discontinuation of the offending drug is the essential treatment. Spontaneous improvement usually ensues within 1 month. Corticosteroid therapy is warranted for symptomatic severe disease, and it is almost invariably effective. Relapse after corticosteroid withdrawal probably does not occur, and its absence distinguishes drug-induced disease from classical autoimmune hepatitis.

Topics: Adrenal Cortex Hormones; Anti-Infective Agents; Autoantibodies; Chemical and Drug Induced Liver Injury; Female; Hepatitis, Autoimmune; HLA Antigens; Humans; Immune Tolerance; Male; Minocycline; Nitrofurantoin; Oxidative Stress; Polymorphism, Genetic; Risk Factors; Sex Factors; Treatment Outcome

The removal from the marketplace of several widely prescribed drugs due to hepatotoxicity has attracted considerable attention. Now under extensive review are means by which we can better identify hepatic risk prior to federal approval. Assessment of risk-to-benefit ratios regarding a novel agent with hepatotoxicity issues (especially one for a life-threatening condition) requires considerable judgment and education on the part of prescribers and patients. The spectrum of drug-induced liver injury is broad with simulation of almost all unknown liver disorders. Drug-induced liver injuries often have a somewhat characteristic signature, as regards type of injury (hepatocellular vs cholestatic) and time of onset. The diagnosis of drug-induced liver injury is often one of exclusion with initial suspicion based on circumstantial evidence. Factors affecting susceptibility to drug-induced injury include age, sex, concomitant use of other drugs, and genetic polymorphism in metabolic pathways involved in activation or disposition of therapeutic drugs. Drug-drug interactions present particular problems in patients, often elderly, who are receiving several drugs simultaneously. Mechanisms of drug-induced liver injury are many and varied. With many drugs, intermediary products produced during metabolism are highly reactive and toxic. In these situations, the balance between the rate of production of the metabolite and the effectiveness of the drug may determine whether or not hepatic injury occurs.

Topics: Acetaminophen; Chemical and Drug Induced Liver Injury; Chromans; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Isoniazid; Kava; Liver; Male; Minocycline; Polymorphism, Genetic; Risk Assessment; Risk Factors; Thiazolidinediones; Troglitazone; Vitamin A

Minocycline is an antibacterial drug used in the treatment of acne. Concern has been expressed over the possibility of severe adverse reactions to minocycline, including hepatitis. This study set out to identify and characterise reported cases of hepatotoxicity associated with the use of minocycline.. A systematic review of the literature including a search of computerised databases and analysis of data from the Uppsala Monitoring Centre (WHO Collaborating Centre for International Drug Monitoring) was conducted. The review involved a search for original case reports involving liver damage in people using minocycline. Patients taking minocycline for reasons other than acne or those given intravenous minocycline were excluded. The search strategy involved an enquiry of computerised databases and a search for secondary references. Cases were then classified appropriately.. 65 reported cases of hepatitis or liver damage in association with minocycline from either case reports or case series were identified from the literature review. 58% of cases occurred in females and 94% were aged under 40 years. For 20 case reports there was insufficient information to classify the type of event, but for the remaining 45, 2 types of hepatic reaction were recognised: autoimmune hepatitis associated with lupus-like symptoms occurring after a median duration of exposure to minocycline of 365 days in females (n = 20) and 730 days in males (n = 9), hypersensitivity reaction associated with eosinophilia and exfoliative dermatitis occurring within 35 days of therapy (n = 16). Reports to the WHO of hepatic adverse drug reactions associated with minocycline accounted for 6% (493) of all minocycline-related adverse drug reactions (8025). The pattern of distribution in relation to exposure demonstrated 2 groups, similar to that described by the case reports.. Severe cases of minocycline-associated hepatotoxicity appear to be a hypersensitivity reaction and occur within a few weeks of commencing therapy. An autoimmune hepatitis usually presents after exposure to minocycline of a year or more, is more common in women and is sometimes associated with lupus-like symptoms.

Topics: Acne Vulgaris; Adolescent; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Humans; Male; Minocycline; Product Surveillance, Postmarketing; World Health Organization

Topics: Acne Vulgaris; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Humans; Minocycline

Minocycline is the most widely prescribed systemic antibiotic for the management of acne. In the past several years, increasing attention has been paid to the drug, both for its potential use as a disease-modifying antirheumatic agent and for its propensity to engender untoward autoimmune reactions, including serum sickness-like disease, drug-induced lupus, and autoimmune hepatitis. This paper reviews the evidence for minocycline as an anti-inflammatory and immunomodulatory agent, its utility in the treatment of rheumatoid arthritis, and the spectrum of adverse reactions that have been ascribed to the drug in the past 5 years.

Topics: Acne Vulgaris; Animals; Anti-Bacterial Agents; Arthritis; Arthritis, Rheumatoid; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Female; Humans; Lupus Erythematosus, Systemic; Male; Minocycline; Vasculitis

Topics: Adolescent; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Humans; Male; Minocycline

Drugs and other chemical toxins account for less than 5% of cases of jaundice or acute hepatitis and fewer cases of chronic liver disease, but they are an important cause of more severe types of hepatic injury. Drug reactions produce an array of hepatic lesions that mimic all known hepatobiliary diseases; this poses a diagnostic challenge for physicians and pathologists. Diagnosis of drug-induced hepatic injury is circumstantial, with positive rechallenge being the only factor that unequivocally implicates a particular agent. Nonetheless, other aspects of the temporal relationship between drug ingestion and adverse reaction, exclusion of other diseases, the presence of extrahepatic features of drug hypersensitivity and some findings on liver biopsy can lend support to the diagnosis. Some of these issues will be explored in this review by considering contemporary paradigms of drug-induced hepatic injury. Factors that predispose to dose-dependent hepatic injury will be considered in relation to acetaminophen, an example of acute hepatotoxicity, and methotrexate, an agent that can produce hepatic fibrosis. Flucloxacillin will be discussed as an example of drug-induced cholestatic hepatitis often associated with prolonged cholestasis and the vanishing bile duct syndrome. Minocycline and diclofenac will be mentioned as two drugs for which drug hepatitis is an exceedingly rare complication. Finally, the evidence that Chinese herbal medicines can be hepatotoxic will be reviewed.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites, Antineoplastic; Azathioprine; Chemical and Drug Induced Liver Injury; Diclofenac; Drugs, Chinese Herbal; Floxacillin; Humans; Immunosuppressive Agents; Liver Diseases; Minocycline; Penicillins

Two double-blind, randomized, placebo-controlled feasibility trials of minocycline in ALS were conducted. In Trial 1, 19 subjects received 200 mg/day or placebo for 6 months; there were no significant differences in adverse events (AE). In Trial 2, 23 subjects received up to 400 mg/day in an 8-month crossover trial. The mean tolerated dose was 387 mg/day, there was a trend toward more gastrointestinal AE (p = 0.057), and blood urea nitrogen and liver enzymes became elevated (p < 0.05). Using these data, the authors have designed and launched a phase III trial.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Chemical and Drug Induced Liver Injury; Double-Blind Method; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Hand Strength; Humans; Kidney Diseases; Male; Middle Aged; Minocycline; Neuroprotective Agents; Respiratory Muscles; Riluzole; Treatment Outcome

Background While tetracycline antibiotics are commonly prescribed in practice, the risk of drug-induced liver injury (DILI) remains controversial. Aim To evaluate the association of DILI with tetracycline antibiotics. Method All DILI cases of tetracycline antibiotics as primary suspected drugs were extracted from the US Food and Drug Administration adverse event reporting system (FAERS). The outcomes included severe DILI, hepatocellular injury, cholestatic injury, and liver failure. Disproportionality analyses were conducted by estimating the reporting odds ratio (ROR) and the information component (IC). Results A total of 1,435 liver injury cases associated with tetracycline antibiotics were identified. The DILI signal was detected in tigecycline, minocycline, and doxycycline. The RORs and the 95% confidence intervals (95% CI) of tigecycline, minocycline, and doxycycline were (ROR 5.85, 95% CI 4.96-6.91), (ROR 6.4, 95% CI 5.76-7.11), and (ROR 2.07, 95% CI 1.86-2.31), respectively. Compared to minocycline (ROR 5.5, 95% CI 4.94-6.12; IC 2.35, 95% CI 1.98-2.68) and doxycycline (ROR 1.91, 95% CI 1.71-2.12; IC 0.91, 95% CI 0.55-1.26), tigecycline showed a stronger association with hepatocellular injury (ROR 7.11, 95% CI 6.13-8.23; IC 2.68, 95% CI 2.16-3.13). Tigecycline also showed a stronger association with cholestatic injury (ROR 12.16, 95% CI 10.13-14.61; IC 3.51, 95% CI 2.79-4) than minocycline (ROR 3.23, 95% CI 2.59-4.04; IC 1.67, 95% CI 0.9-2.37) or doxycycline (ROR 2.86, 95% CI 2.47-3.31; IC 1.5, 95% CI 1-1.97). Tigecycline (ROR 6.56, 95% CI 4.57-9.41; IC 2.69, 95% CI 1.28-3.64) and minocycline (ROR 4.22, 95% CI 3.14-5.66; IC 2.06, 95% CI 1-2.93) showed a significant association with liver failure. Conclusion The data mining of FAERS suggested an association between DILI and tigecycline, minocycline, and doxycycline.

Topics: Adverse Drug Reaction Reporting Systems; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Doxycycline; Drug-Related Side Effects and Adverse Reactions; Humans; Liver Failure; Minocycline; Pharmacovigilance; Tigecycline; United States; United States Food and Drug Administration

Acetaminophen (APAP) hepatotoxicity, a leading cause of acute liver failure in western countries, is characterized by mitochondrial superoxide and peroxynitrite formation. However, the role of iron, especially as facilitator of lipid peroxidation (LPO), has been controversial. Our aim was to determine the mechanism by which iron promotes cell death in this context. Fasted male C57BL/6J mice were treated with the iron chelator deferoxamine, minocycline (inhibitor of the mitochondrial calcium uniporter) or vehicle 1 h before 300 mg/kg APAP. Deferoxamine and minocycline significantly attenuated APAP-induced elevations in serum alanine amino transferase levels and hepatic necrosis at 6 h. This protection correlated with reduced 3-nitro-tyrosine protein adducts; LPO (malondialdehyde, 4-hydroxynonenal) was not detected. Activation of c-jun N-terminal kinase (JNK) was not affected but mitochondrial release of intermembrane proteins was reduced suggesting that the effect of iron was at the level of mitochondria. Co-treatment of APAP with FeSO

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Deferoxamine; Hepatocytes; Iron; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred C57BL; Minocycline; Mitochondria, Liver; Oxidative Stress; Peroxynitrous Acid

Nitrofurantoin, minocycline, methyldopa and infliximab, have been found to induce autoimmune-like hepatitis (DI-AILH). Evidence for other drugs and herbal and dietary supplements (HDS) is unclear. The aims of the study were to establish criteria to define and review the published evidence of suspected DI-AILH. Search was undertaken in Pubmed using search terms "drug-induced liver injury," "autoimmune hepatitis," and "drug-induced autoimmune hepatitis." DI-AILH was defined as (1) drug as a potential trigger of liver injury with autoimmune features and histological findings compatible with AIH; (2) no or incomplete recovery or worsening of liver tests after discontinuation of the drug; (3) corticosteroids requirement or spontaneous recovery; (4) follow-up without immunosuppression (IS) and no relapse of AIH at least 6 months after discontinuation of IS; and (5) drugs potentially inducing AILH with a chronic course. Cases fulfilling the first four criteria were considered probable DI-AILH with three possible DI-AILH. A total of 186 case reports were identified for conventional drugs (n = 148; females 79%; latency 2.6 months) and HDS (n = 38; females 50%). The most commonly reported agents of DI-AILH were interferons (n = 37), statins (n = 24), methylprednisolone (MPS) (n = 16), adalimumab (n = 10), imatinib (n = 8), and diclofenac (n = 7). Tinospora cordifolia and Khat were the only HDS with probable DI-AILH cases. No relapses of AIH were observed when IS was stopped after interferons, imatinib, diclofenac, and methylprednisolone. Conclusion: Beyond well-recognized nitrofurantoin, methyldopa, hydralazine, minocycline, and infliximab as causes of DI-AILH, interferons, imatinib, adalimumab, and MPS were the best-documented agents leading to probable DI-AILH. Khat and Tinospora cordifolia were the only HDS found to be able to induce DI-AILH. Long-term immunosuppression appears to be rarely required in patients with DI-AILH due to these drugs.

Topics: Adalimumab; Chemical and Drug Induced Liver Injury; Diclofenac; Female; Hepatitis A; Hepatitis, Autoimmune; Humans; Imatinib Mesylate; Infliximab; Interferons; Methyldopa; Methylprednisolone; Minocycline; Nitrofurantoin

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Anti-Bacterial Agents; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Drug Overdose; Hepatocytes; Humans; Iron; Lysosomes; Male; Mice; Mice, Inbred C57BL; Minocycline; Mitochondria

► Abdominal pain ► Lower-leg itching ► Dark urine & yellow eyes.

Topics: Abdominal Pain; Acne Vulgaris; Adolescent; Analgesics; Antipruritics; Chemical and Drug Induced Liver Injury; Female; Glucocorticoids; Humans; Immunologic Factors; Minocycline; Mycophenolic Acid; Prednisolone; Pruritus; Treatment Outcome; Urine; White People

Topics: Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Glucocorticoids; Humans; Male; Minocycline; Polyarteritis Nodosa; Prednisolone

Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients.. Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina.. Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10. HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI.. Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.

Topics: Adolescent; Adult; Alleles; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Female; Genome-Wide Association Study; HLA-B35 Antigen; Humans; Male; Minocycline; Risk Factors; Young Adult

Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction and the mitochondrial permeability transition (MPT). Iron is a critical catalyst for ROS formation, and reactive oxygen species (ROS) play an important role in APAP-induced hepatotoxicity. Previous studies show that APAP disrupts lysosomes, which release ferrous iron (Fe(2+)) into the cytosol to trigger the MPT and cell killing. Here, our aim was to investigate whether iron released from lysosomes after APAP is then taken up into mitochondria via the mitochondrial electrogenic Ca(2+), Fe(2+) uniporter (MCFU) to cause mitochondrial dysfunction and cell death. Hepatocytes were isolated from fasted male C57BL/6 mice. Necrotic cell killing was assessed by propidium iodide fluorimetry. Mitochondrial membrane potential (ΔΨ) was visualized by confocal microscopy of rhodamine 123 (Rh123) and tetramethylrhodamine methylester (TMRM). Chelatable Fe(2+) was monitored by quenching of calcein (cytosol) and mitoferrofluor (MFF, mitochondria). ROS generation was monitored by confocal microscopy of MitoSox Red and plate reader fluorimetry of chloromethyldihydrodichlorofluorescein diacetate (cmH2DCF-DA). Administered 1h before APAP (10mM), the lysosomally targeted iron chelator, starch-desferal (1mM), and the MCFU inhibitors, Ru360 (100nM) and minocycline (4µM), decreased cell killing from 83% to 41%, 57% and 53%, respectively, after 10h. Progressive quenching of calcein and MFF began after ~4h, signifying increased cytosolic and mitochondrial chelatable Fe(2+). Mitochondria then depolarized after ~10h. Dipyridyl, a membrane-permeable iron chelator, dequenched calcein and MFF fluorescence after APAP. Starch-desferal, but not Ru360 and minocycline, suppressed cytosolic calcein quenching, whereas starch-desferal, Ru360 and minocycline all suppressed mitochondrial MFF quenching and mitochondrial depolarization. Starch-desferal, Ru360 and minocycline also each decreased ROS formation. Moreover, minocycline 1h after APAP decreased cell killing by half. In conclusion, release of Fe(2+) from lysosomes followed by uptake into mitochondria via MCFU occurs during APAP hepatotoxicity. Mitochondrial iron then catalyzes toxic hydroxyl radical formation, which triggers the MPT and cell killing. The efficacy of minocycline post-treatment shows minocycline as a possible therapeutic agent against APAP hepatotoxicity.

Topics: Acetaminophen; Animals; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Deferoxamine; Drug Evaluation, Preclinical; Hepatocytes; Iron; Iron Chelating Agents; Lysosomes; Male; Mice, Inbred C57BL; Minocycline; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Ruthenium Compounds; Starch

Topics: Acne Vulgaris; Anti-Bacterial Agents; Arizona; Chemical and Drug Induced Liver Injury; Drug Labeling; Humans; Judicial Role; Liability, Legal; Lupus Erythematosus, Discoid; Minocycline

Drug-induced autoimmune hepatitis is an acute and potentially severe side effect, particularly often reported after the long-term use of minocycline. The condition's characteristic biochemical findings are highly elevated transaminase levels, only mildly increased markers of cholestasis and bilirubin levels, an elevated IgG concentration and a high antinuclear antibody (ANA) titre.. A 14-year-old girl developed autoimmune hepatitis due to the long-term use of minocycline for acne vulgaris. She presented with icterus and very high transaminase levels. The patient made a full recovery after the medication was discontinued.. This type of autoimmune hepatitis can be differentiated from 'classic' autoimmune hepatitis by the patient's quick recovery after stopping the inducing drug and no relapse of the condition after the discontinuation of glucocorticoid therapy.

Topics: Acne Vulgaris; Adolescent; Anti-Bacterial Agents; Antibodies, Antinuclear; Chemical and Drug Induced Liver Injury; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Minocycline

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

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

Topics: Acute Disease; Aged, 80 and over; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Minocycline

Minocycline is an effective antibiotic widely used in the treatment of acne vulgaris. We report a previously well 20-year-old woman who developed liver dysfunction with jaundice and malaise following a 1 year course of minocycline for acne vulgaris. Serum antinuclear antibody was strongly positive (1 : 2560) and liver transaminases were grossly deranged. All other causes of liver disease were excluded. Both the clinical symptoms and laboratory abnormalities resolved spontaneously on stopping the drug. We review the three different types of hepatotoxicity associated with minocycline and draw evidence to support the diagnosis of minocycline-induced autoimmune hepatitis. This case supports the call to monitor patients on minocycline therapy for autoimmune disease of the liver and highlights the need for a multicentre prospective trial of the risks and benefits of long-term minocycline therapy.

Topics: Acne Vulgaris; Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Female; Hepatitis, Autoimmune; Humans; Minocycline

Topics: Adolescent; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Hepatitis, Autoimmune; Humans; Minocycline

A 28-year-old patient is described who presented with progressive dyspnoea and jaundice due to interstitial pneumonia and hepatitis. The most likely cause is a drug-related reaction to minocycline. We discuss the different kinds of drug-related reactions that are most likely involved.

Topics: Acne Vulgaris; Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Dyspnea; Humans; Lung Diseases, Interstitial; Male; Minocycline; Radiography, Thoracic

A 25-year-old woman with no history of liver disease developed liver dysfunction associated with severe jaundice and general malaise following a prolonged therapy with minocycline for acne vulgaris. Serum anti-nuclear antibody was detected and immunoglobulin G level was elevated. Symptoms resolved and liver function normalized following minocycline discontinuation and corticosteroid administration. Our diagnosis was drug-induced hepatitis with autoimmune features, as liver histology revealed acute hepatitis. Drug-induced hepatitis should be considered when liver dysfunction or systemic symptoms develops during long-term minocycline therapy.

Topics: Acne Vulgaris; Adult; Anti-Bacterial Agents; Antibodies, Antinuclear; Chemical and Drug Induced Liver Injury; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Minocycline

Topics: Acne Vulgaris; Adolescent; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Humans; Male; Minocycline; Treatment Outcome

We describe the clinical and liver biopsy morphologic features for 4 patients with minocycline-induced autoimmune hepatitis (group 1). We compared the serum laboratory values and liver biopsy findings from group 1 with those from 10 patients with sporadic autoimmune hepatitis (group 2). All patients in group 1 had positive serum antinuclear antibody titers, but none had positive serum anti-smooth muscle antibody titers. The morphologic findings of group 1 biopsies were those of autoimmune hepatitis in all 4 patients. In addition, 1 of these biopsy specimens also had scattered single eosinophils, unlike autoimmune hepatitis. The mean histologic activity index scores for patients in groups 1 and 2, respectively, were 6.7 and 5.4. No patients in group 1 had marked bridging fibrosis or cirrhosis, compared with 4 of 10 patients in group 2. Minocycline-induced autoimmune hepatitis is usually identical to sporadic autoimmune hepatitis. The absence of eosinophils does not exclude the possibility of a minocycline cause. In the absence of clinical or morphologic differences, a recent ingestion of minocycline should be excluded before the diagnosis of sporadic autoimmune hepatitis is established. Whether the drug is unmasking latent autoimmune hepatitis is unclear.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Antibodies, Antinuclear; Biopsy; Blood Sedimentation; Chemical and Drug Induced Liver Injury; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Liver; Liver Function Tests; Male; Middle Aged; Minocycline; Muscle, Smooth

Topics: Acne Vulgaris; Adult; Biopsy, Needle; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Liver Function Tests; Minocycline

Topics: Adverse Drug Reaction Reporting Systems; Anti-Bacterial Agents; Canada; Chemical and Drug Induced Liver Injury; Drug Eruptions; Eosinophilia; Fever; Humans; Lymphatic Diseases; Lymphocytosis; Minocycline

Minocycline can cause various types of hepatotoxicity. We report an 18-year-old male who developed a delayed onset of minocycline-induced cholestatic hepatitis with autoimmune features and neutropenia. He responded to withdrawal of the drug and a short course of corticosteroids. If minocycline is to be administered, then periodic monitoring for hepatoxicity is recommended.

Topics: Acne Vulgaris; Adolescent; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Hepatitis, Autoimmune; Humans; Male; Minocycline; Neutropenia

We report the case of a 19-year old black West Indian woman who had been treated for acne for two years with oral minocycline (50 mg per day) and topical of benzoyle peroxide (5%). She was admitted for fatigue, arthralgia, myalgia and widespread pruritus. We observed several skin lesions of hyperpigmentation, biological signs of hepatitis, and significant levels of antinuclear, anti-mitochondrial and anti-smooth muscle antibodies. Minocycline was immediately stopped. Two months later, all of the biological abnormalities had disappeared but the skin lesions seemed to be irreversible. Minocycline is largely used for the treatment of acne and may induce severe immuno-allergic reactions. Several cases of induced lupus, autoimmune hepatitis, eosinophilic pneumonia, hypersensitivity syndrome, serum-sickness-like illness and Sweet's syndrome have already been described. These side effects are rare but may be life-threatening. So, minocycline should be used as a second-line treatment for acne and should be avoided in black people whom seem to be at risk of such reactions. If, despite those precautions, minocycline-induced immuno-allergic reactions occur, the treatment should be immediately stopped and never prescribed again.

Topics: Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Female; Humans; Minocycline

Minocycline is widely prescribed for long-term treatment in acne. Major side effects are rare and include hepatitis and drug-related lupus. Hepatitis can be early and acute or late and chronic, whereas lupus presents as a tardive and insidious disease. We report a case of minocycline-induced lupus initially presenting as acute hepatitis, evolving to chronic cytolysis, in a young man treated for facial acne.

Topics: Acne Vulgaris; Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Humans; Lupus Erythematosus, Systemic; Male; Minocycline

A 17-year-old female patient who had been taking oral minocycline (50 mg twice daily) for 3 weeks for acne developed an eruption that progressed to an exfoliative dermatitis. This illness was also characterized by fever, lymphadenopathy, pharyngitis, a leukemoid reaction, lymphocytosis, eosinophilia, hepatitis, and noncardiogenic pulmonary edema. Dramatic improvement followed institution of corticosteroid therapy. Studies for infectious and collagen vascular diseases were negative. This severe illness was likely caused by minocycline, and we speculate that minocycline may have acted as a superantigen, causing lymphocyte over-activation and massive cytokine release.

Topics: Acne Vulgaris; Adolescent; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Eosinophilia; Female; Fever; Hematologic Diseases; Humans; Lymphocytosis; Minocycline

Topics: Acne Vulgaris; Anti-Bacterial Agents; Black People; Chemical and Drug Induced Liver Injury; Dermatitis, Exfoliative; Drug Eruptions; Eosinophilia; Humans; Minocycline; Retrospective Studies; Risk; Risk Assessment

Topics: Acne Vulgaris; Adolescent; Anti-Bacterial Agents; Antibodies, Antinuclear; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Female; Humans; Minocycline; Thyroiditis, Autoimmune

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Lupus Erythematosus, Systemic; Middle Aged; Minocycline

Monocycline is the most widely prescribed systemic antibiotic for acne largely because it needs to be given only once or twice a day and seems not to induce resistance. Up to April 1994 11 cases of minocycline induced systemic lupus erythematosus and 16 cases of hepatitis had been reported to the Committee on Safety of Medicines. An analysis of these cases together with seven other cases shows the severity of some of these reactions. Two patients died while taking the drug for acne and a further patient needed a liver transplant. Acne itself can induce arthritis and is often seen in association with autoimmine liver disease, but the clinical and biochemical resolution seen after withdrawal of the drug, despite deterioration of the acne, suggests a drug reaction. In five cases re-exposure led to recurrence. Because reactions may be severe early recognition is important to aid recovery and also to avoid invasive investigations and treatments such as corticosteroids and immunosuppresants. Safer alternatives should be considered for treating acne.

Topics: Acne Vulgaris; Adult; Aged; Anti-Bacterial Agents; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Female; Humans; Lupus Erythematosus, Systemic; Male; Minocycline; Syndrome

Tetracycline may cause fatty infiltration of the liver; more recently, it has been reported to cause intrahepatic cholestasis with bile duct depletion. However, minocycline, a derivative of tetracycline, is not generally recognized to be hepatotoxic. We report a series of six cases of presumed minocycline-induced liver injury; five of these patients had acute hepatitic illness, whereas one had a more prolonged course with histological evidence of chronic hepatitis. In addition, three patients demonstrated abnormal anti-nuclear antibody levels, and one had positive double-stranded DNA.

Topics: Acne Vulgaris; Adolescent; Adult; Anti-Bacterial Agents; Biopsy; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Female; Humans; Liver; Liver Function Tests; Male; Middle Aged; Minocycline

Topics: Adult; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Female; Humans; Hyperpigmentation; Minocycline

Topics: Acne Vulgaris; Anti-Bacterial Agents; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Humans; Lupus Erythematosus, Systemic; Minocycline; Risk Factors

A 39-year-old woman was evaluated for possible liver transplantation due to rapidly developing hepatic failure 4 weeks after initiation of oral minocycline 100 mg twice a day for the treatment of acne. The patient developed a maculopapular rash, malaise, fever, nausea, and vomiting 2 weeks prior to admission to the hospital. On admission, her symptoms rapidly progressed to liver failure characterized by rapidly rising liver enzyme levels, worsening encephalopathy, and coagulopathy. Viral hepatitis serologies and blood cultures were all negative. After intensive supportive care for 2 weeks, the patient's condition gradually improved and she was discharged with mildly elevated liver enzyme levels and pruritus, without need of liver transplantation. Minocycline-induced hepatic injury is an idiosyncratic reaction with a sensitization period that appears to be 3-4 weeks in duration. The characteristic features include rash, fever, lymphadenopathy, and eosinophilia, as well as severe alterations in liver function. The high liver enzyme levels and the significant prolongation of the prothrombin time suggest massive hepatocellular damage. In light of the profound liver damage that occurs with this adverse reaction, care should be taken in administering minocycline to patients who have concomitant liver disease. It is recommended that patients should be instructed as to the possible signs and symptoms of toxicity and be monitored for evidence of idiosyncratic reaction or liver failure.

Topics: Acne Vulgaris; Acute Disease; Administration, Oral; Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Function Tests; Minocycline

Minocycline (25 to 100 micrograms/g) dose dependently increased serum glutamic oxalacetic transaminase, urea, and bilirubin levels, and the hepatic triglyceride content in mice. In animals pretreated with phenobarbital to enhance minocycline metabolism, the effects on liver triglycerides were attenuated, while the changes in serum glutamic oxalacetic transaminase, urea, and bilirubin were enhanced. It is concluded that part of the toxic effects of minocycline may be produced by a metabolite of minocycline.

Topics: Animals; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Doxycycline; Female; Injections, Intravenous; Liver; Mice; Minocycline; Tetracycline; Triglycerides; Urea

Topics: Chemical and Drug Induced Liver Injury; Humans; Minocycline; Tetracyclines; Togaviridae

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Dermatitis, Exfoliative; Drug Eruptions; Female; Humans; Male; Minocycline; Tetracyclines

Minocycline hydrochloride hepatotoxic effect occurred in one patient. Unlike the usual histologic features of tetracycline-induced hepatic injury, fatty metamorphosis was predominantly macrovesicular . The patient recovered when drug therapy was withdrawn. Close observation of liver function variables is recommended in patients treated with high parenteral doses of minocycline, particularly in cases of pregnancy or renal disease.

Topics: Acute Disease; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Liver Diseases; Middle Aged; Minocycline; Tetracyclines

A pronounced leukemoid reaction consisting of WBC as high as 82,300/microliters was observed coexistent with a clinical picture of hepatitis in a young man taking oral minocycline. No etiologic source for the hepatitis was found. After complete recovery, an erroneous ingestion of a single dose of tetracycline reproduced his initial symptoms and a leukemoid reaction.

Topics: Adult; Chemical and Drug Induced Liver Injury; Humans; Leukemoid Reaction; Male; Minocycline; Tetracyclines