olanzapine and Chemical-and-Drug-Induced-Liver-Injury

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

Atypical antipsychotics commonly cause isolated asymptomatic increase in the aminotransferase levels. Furthermore, the strategy in the choice of antipsychotic agent must take into account hepatic tolerance because of the non-negligible incidence of liver disorders among the psychiatric population. The aim of this article is to better understand the strategy to adopt during an increase of liver enzymes in a psychotic patient under atypical neuroleptic treatment.. A clinical case is presented of a female patient treated for psychotic decompensation with increase of liver enzymes (Olanzapine). Her treatment was changed several times over a period of 7 years and laboratory investigations were conducted simultaneously.. It seems that the increase of liver enzymes is slightly more frequent with Clozapine and Olanzapine than Risperidone, Perazine and Haloperiol.. The different mechanisms of hepatotoxicity are unknown at present but it seems that the hypersensibility mechanism is likely to be dose dependent. During an increase of enzymes, it is important to combine a control of hepatic enzymes with a reduction of neuroleptic dosage. Discontinuation should be considered if a continued increase of enzymes above certain values is shown or if a clinical symptom appears. We note also that some risk factors were found, including geriatric or pedopsychiatric age, obesity, and association with active ingredients or addictive substances responsible for hepatic disorders.

Topics: Age Factors; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Clozapine; Dose-Response Relationship, Drug; Female; Haloperidol; Humans; Liver; Middle Aged; Olanzapine; Perazine; Risk Factors; Risperidone; Transaminases

Antipsychotics used to treat schizophrenia can cause drug-induced liver injury (DILI), according to the Roussel Uclaf Causality Assessment Method. The role of oxidative stress in triggering injury in these DILI cases is unknown. We repeatedly administrated two second-generation antipsychotics, aripiprazole and olanzapine, at laboratory alert levels to study underlying mechanisms in stress prevention upon acute oxidative stress. The drugs were administered continuously for up to 8 weeks. For this, hepatoma Fao cells, which are suitable for metabolic studies, were used, as the primary hepatocytes survive in the culture only for about 1 week. Four stress responses-the oxidative stress response, the DNA damage response and the unfolded protein responses in the endoplasmic reticulum and mitochondria-were examined in H

Topics: Antioxidants; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Chemical and Drug Induced Liver Injury; Hepatocytes; Humans; Hydrogen Peroxide; Olanzapine; Oxidative Stress

The ancient Chinese herbal formula Longdan Xiegan Tang (LXT, also called Gentiana Longdancao Decoction to Drain the Liver) treats insulin resistance- and inflammation-associated liver injuries in clinical practice.. To investigate the molecular mechanisms underlying LXT-elicited improvement of the liver injuries.. Male rats were co-treated with olanzapine (5 mg/kg) and LXT extract (50 and 500 mg/kg) for eight weeks. Blood parameters were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry.. The present results demonstrate that LXT attenuates liver injury and hepatic insulin resistance by regulating the ACE2/Ang (1-7)/Mas axis-mediated anti-inflammatory pathway in rats. Our findings provide a better understanding of LXT for treatment of insulin resistance- and inflammation-associated liver injuries.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Cytokines; Drugs, Chinese Herbal; Fasting; I-kappa B Kinase; Insulin Resistance; Liver; Male; NF-kappa B; Olanzapine; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled

Olanzapine is effective to treat for schizophrenia and other mood disorders, but limited by side effects such as weight gain, dyslipidemia, and liver injury. Obesity in the US is at epidemic levels, and is a significant risk factor for drug-induced liver injury. Obesity incidence in the psychiatric population is even higher than in the US population as a whole. The purpose of this study was to test the hypothesis that obesity worsens olanzapine-induced hepatic injury, and to investigate the potential protective effects of sulforaphane. 8-week old female C57BL/6 mice were fed either a high-fat or low-fat control diet (HFD and LFD). Mice also received either olanzapine (8 mg/kg/d) or vehicle by osmotic minipump for 4 weeks. A subset of mice in the HFD + olanzapine group was administered sulforaphane, a prototypical Nrf2 inducer (90 mg/kg/d). Olanzapine alone increased body weight, without a commensurate increase in food consumption. Olanzapine also caused hepatic steatosis and injury. Combining olanzapine and HFD caused further dysregulation of glucose and lipid metabolism. Liver damage from concurrent HFD and olanzapine was worse than liver damage from high-fat diet or olanzapine alone. Sulforaphane alleviated many metabolic side effects of olanzapine and HFD. Taken together, these data show that olanzapine dysregulates glucose and lipid metabolism and exacerbates hepatic changes caused by eating a HFD. Activation of the intrinsic antioxidant defense pathway with sulforaphane can partially prevent these effects of olanzapine and may represent a useful strategy to protect against liver injury.

Topics: Animals; Antioxidants; Antipsychotic Agents; Body Weight; Chemical and Drug Induced Liver Injury; Diet, Fat-Restricted; Diet, High-Fat; Fatty Liver; Female; Humans; Isothiocyanates; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Obesity; Olanzapine; Oxidative Stress; Prevalence; Sulfoxides

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Humans; Intellectual Disability; Male; Olanzapine; Stress Disorders, Post-Traumatic; Vitamin E

Topics: Adult; Animals; Antipsychotic Agents; Carnitine; Chemical and Drug Induced Liver Injury; Coenzyme A Ligases; Dogs; Fatty Acid-Binding Proteins; Fatty Liver; Female; Hep G2 Cells; Hepatocytes; Humans; Liver; Madin Darby Canine Kidney Cells; Male; Mice, Inbred C57BL; Olanzapine; Solute Carrier Family 22 Member 5; Up-Regulation

Numerous drugs cause hepatotoxicity clinically or biologically. Neuropsychiatric drugs constitute 16% of these drugs. The occurrence of hepatotoxicity induced by the use of olanzapine is expressed by the researchers. In such cases, generally the dose of olanzapine is reduced or the drug is completely discontinued and the treatment of the patient fails. The aim of this study is to report the case for whom elevated liver enzymes were observed but the process was managed without changing treatment dose and drug and to discuss this case with literature information. The present study has characteristics of being the first in the literature concerning management of the process.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Humans; Liver Function Tests; Olanzapine; Rats

The aim of the study was to investigate the possible protective qualities of thymoquinone (TQ) against the side-effects of olanzapine (OLZ) in an experimental model in rat liver with histologic and biochemical assessments.. Experimental procedures were performed on 35 female Sprague Dawley rats. Rats were randomly divided into five groups as: group 1: control; group 2: OLZ; group 3: OLZ+TQ-1; group 4: OLZ+TQ-2; and group 5: OLZ+TQ-3.. The results showed that a 2‑week administration of OLZ (4 mg/kg, once a day for the first week, 8 mg/kg once a day for the second week, p.o.) and treatment with TQ (25, 50, 100 mg/kg, once daily, p.o.) significantly reduced weight gain induced by OLZ. In addition, TQ increased the total antioxidant status (TAS), high-density lipoprotein cholesterol (HDL), insulin levels and decreased serum oxidative stress index (OSI), total oxidant status (TOS), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), low density lipoprotein cholesterol (LDL), glucose, triglycerides (TG) and total cholesterol (CH) levels significantly (p < 0.05).. This study revealed that treatment with TQ might protect liver tissue against the side-effects of OLZ. TQ could be an effective course of therapy to enhance therapeutic efficacy (Tab. 4, Fig. 4, Ref. 47).

Topics: Alanine Transaminase; Animals; Antipsychotic Agents; Aspartate Aminotransferases; Benzodiazepines; Benzoquinones; Blood Glucose; Chemical and Drug Induced Liver Injury; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Female; gamma-Glutamyltransferase; Liver; Olanzapine; Oxidative Stress; Protective Agents; Rats; Rats, Sprague-Dawley; Triglycerides

There is limited, poorly characterized information about adverse events occurring during maintenance treatment of bipolar disorder. We aimed to determine adverse event rates during treatment with lithium, valproate, olanzapine, and quetiapine.. We conducted a propensity score adjusted cohort study using nationally representative United Kingdom electronic health records from January 1, 1995, until December 31, 2013. We included patients who had a diagnosis of bipolar disorder and were prescribed lithium (n = 2148), valproate (n = 1670), olanzapine (n = 1477), or quetiapine (n = 1376) as maintenance mood stabilizer treatment. Adverse outcomes were chronic kidney disease, thyroid disease, hypercalcemia, weight gain, hypertension, type 2 diabetes mellitus, cardiovascular disease, and hepatotoxicity. The propensity score included important demographic, physical health, and mental health predictors of drug treatment allocation. The median duration of drug treatment was 1.48 y (interquartile range 0.64-3.43). Compared to patients prescribed lithium, those taking valproate, olanzapine, and quetiapine had reduced rates of chronic kidney disease stage 3 or more severe, following adjustment for propensity score, age, and calendar year, and accounting for clustering by primary care practice (valproate hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.45-0.69; p < 0.001, olanzapine HR 0.57; 95% CI 0.45-0.71; p < 0.001, quetiapine HR 0.62; 95% CI 0.47-0.80; p < 0.001). Hypothyroidism was reduced in those taking valproate (HR 0.60; 95% CI 0.40-0.89; p = 0.012) and olanzapine (HR 0.48; 95% CI 0.29-0.77; p = 0.003), compared to those taking lithium. Rates of new onset hyperthyroidism (valproate HR 0.24; 95% CI 0.09-0.61; p = 0.003, olanzapine HR 0.31; 95% CI 0.13-0.73; p = 0.007) and hypercalcemia (valproate HR 0.25; 95% CI 0.10-0.60; p = 0.002, olanzapine HR 0.32; 95% CI 0.14-0.76; p = 0.008, quetiapine HR 0.23; 95% CI 0.07-0.73; p = 0.013) were also reduced relative to lithium. However, rates of greater than 15% weight gain on valproate, olanzapine, and quetiapine were higher (valproate HR 1.62; 95% CI 1.31-2.01; p < 0.001, olanzapine HR 1.84; 95% CI 1.47-2.30; p < 0.001, quetiapine HR 1.67; 95% CI 1.24-2.20; p < 0.001) than in individuals prescribed lithium, as were rates of hypertension in the olanzapine treated group (HR 1.41, 95% CI 1.06-1.87; p = 0.017). We found no significant difference in rates of chronic kidney disease stage 4 or more severe, type 2 diabetes mellitus, cardiovascular disease, or hepatotoxicity. Despite estimates being robust following sensitivity analyses, limitations include the potential for residual confounding and ascertainment bias and an inability to examine dosage effects.. Lithium use is associated with more renal and endocrine adverse events but less weight gain than commonly used alternative mood stabilizers. Risks need to be offset with the effectiveness and anti-suicidal benefits of lithium and the potential metabolic side effects of alternative treatment options.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Cardiovascular Diseases; Chemical and Drug Induced Liver Injury; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypercalcemia; Hypertension; Lithium Compounds; Longitudinal Studies; Male; Middle Aged; Olanzapine; Propensity Score; Quetiapine Fumarate; Renal Insufficiency; Thyroid Diseases; Valproic Acid

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

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

Topics: Adult; Anticonvulsants; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Hypersensitivity; Drug Therapy, Combination; Female; Humans; Lithium Carbonate; Liver Function Tests; Neutropenia; Olanzapine; Retreatment; Thrombocytopenia; Valproic Acid

Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in increased toxicity (inflammatory stress hypothesis). Aiming to develop a robust ex vivo screening method to study inflammatory stress-related IDILI mechanisms and to find biomarkers that can detect or predict IDILI, mouse precision-cut liver slices (mPCLS) were coincubated for 24 h with IDILI-related drugs and lipopolysaccharide. Lipopolysaccharide exacerbated ketoconazole (15 μM) and clozapine (45 μM) toxicity but not their non-IDILI-related comparators, voriconazole (1500 μM) and olanzapine (45 μM). However, the other IDILI-related drugs tested [diclofenac (200 μM), carbamazepine (400 μM), and troglitazone (30 μM)] did not cause synergistic toxicity with lipopolysaccharide after 24 h of incubation. Lipopolysaccharide further decreased the reduced glutathione levels caused by ketoconazole or clozapine in mPCLS after 24 h of incubation, which was not the case for the other drugs. Lipopolysaccharide significantly increased nitric oxide (NO), cytokine, and chemokine release into the mPCLS media, while the treatment with the drugs alone did not cause any substantial change. All seven drugs drastically reduced lipopolysaccharide-induced NO production. Interestingly, only ketoconazole and clozapine increased the lipopolysaccharide-induced granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. Pilot experiments showed that diclofenac and troglitazone, but not carbamazepine, demonstrated synergistic toxicity with lipopolysaccharide after a longer incubation of 48 h in mPCLS. In conclusion, we have developed an ex vivo model to detect inflammatory stress-related liver toxicity and identified ketoconazole, clozapine, troglitazone, and diclofenac as drugs that showed synergistic toxicity with lipopolysaccharide. Reduced glutathione, G-CSF, and GM-CSF were identified to be potential biomarkers for IDILI-inducing drugs mediated by inflammatory stress, and mPCLS appear to be a promising screening tool to further unravel the mechanism of IDILI.

Topics: Animals; Benzodiazepines; Biomarkers; Carbamazepine; Cell Survival; Chemical and Drug Induced Liver Injury; Chemokines; Chromans; Clozapine; Cytokines; Diclofenac; Drug Synergism; Female; Glutathione; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; In Vitro Techniques; Ketoconazole; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Nitrogen Oxides; Olanzapine; Pyrimidines; Thiazolidinediones; Triazoles; Troglitazone; Voriconazole

Topics: Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Cholestasis; Humans; Liver Function Tests; Male; Middle Aged; Olanzapine; Schizophrenia, Paranoid

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; Adult; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Clozapine; Hepatitis C, Chronic; Humans; Male; Olanzapine; Schizophrenia, Paranoid; Time Factors

We present a case of a 17-year-old man with first-episode schizophrenia who developed olanzapine-induced hepatitis, cholestasis, and splenomegaly, all of which were reversed after ceasing olanzapine. Clinicians prescribing olanzapine should be aware of this possible hepatotoxicity. Patient education, vigilance from clinicians, and careful clinical examination can help detect this complication early.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; China; Cholestasis; Humans; Male; Olanzapine; Schizophrenia; Splenomegaly

Olanzapine is a widely used second generation antipsychotic drug. Case reports of intoxications have been published, but reports in the literature of non-fatal intoxications of olanzapine containing repeated measurements of serum levels are scarce. Therefore, this case of non-fatal olanzapine intoxication is presented, in which 19 blood samples were drawn during 2 weeks. The highest (initial) measured value was estimated at 800 pg/L. This patient ingested 550 mg of olanzapine resulting in clinical signs of intoxication, including seizures. Because the patient was found the day after the intoxication, the initial concentration had probably been higher. The pharmacokinetics of olanzapine has been described as linear and dose-proportional throughout the therapeutic dosing range. Large overdoses, however, have been described to show non-linear pharmacokinetics. In this study's series of serum concentrations, a two-phase elimination was seen, with an initial elimination half-life of about 24 h during the first 3 days, followed by a second phase with a half-life of about 2.5 days. The patient in this case recovered completely. Because the elimination time after intoxication can be considerably longer than expected, it is recommended that the patient's serum concentrations after intoxication be monitored.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Drug Overdose; Half-Life; Humans; Liver Diseases; Liver Function Tests; Male; Olanzapine; Seizures; Suicide, Attempted

Atypical antipsychotics commonly cause isolated asymptomatic increase in the aminotransferase levels. Among these atypical antipsychotics, mostly transient, asymptomatic increase in hepatic enzymes has been reported with olanzapine, however olanzapine rarely may induce a clinical and/or biological hepatic toxicity. The pathogenesis of olanzapine-associated hepatotoxicity is not well known and is mostly a transient phenomenon. However, substantial and lasting changes may occur and result in symptomatic hepatitis. In the following case report, we report on a 44-year-old female patient diagnosed as Bipolar Disorder Type I, whose liver enzyme levels increased ten fold of normal ranges during the third year of the olanzapine treatment and returned to the normal levels within three weeks after olanzapine discontinuation. Although significant liver enzyme elevations are uncommon during olanzapine treatment, based on reports of serious hepatotoxicity, controlled and longitudinal research are needed to learn side effects of this drug on liver. Clinicians should be aware of possible hepatotoxic effects of atypical antipsychotics and should monitor the liver enzyme levels whenever they feel necessary.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Olanzapine; Psychiatric Status Rating Scales

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Female; Humans; Olanzapine; Pirenzepine

Hypersensitivity syndrome is defined as a drug-induced complex of symptoms consisting of fever, rash, and internal organ involvement. The hypersensitivity syndrome is well recognized as being caused by anticonvulsants. Olanzapine is an atypical antipsychotic agent whose side effects include sedation, weight gain, and increased creatinine kinase and transaminase levels. To date, there have been no reports of hypersensitivity syndrome related to this drug. A 34-year-old man developed a severe generalized pruritic skin eruption, fever, eosinophilia, and toxic hepatitis 60 days after ingestion of olanzapine. After termination of olanzapine treatment, the fever resolved, the skin rash was reduced, eosinophil count was reduced to normal, and the transaminase levels were markedly reduced. Clinical features and the results of skin and liver biopsies indicated that the patient developed hypersensitivity syndrome caused by olanzapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Diagnostic Errors; Drug Eruptions; Drug Hypersensitivity; Dyspnea; Eosinophilia; Fever; Humans; Male; Olanzapine; Pirenzepine; Pruritus; Respiratory Hypersensitivity; Respiratory Insufficiency; Schizophrenia, Paranoid; Syndrome

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Arrhythmias, Cardiac; Benzodiazepines; Canada; Chemical and Drug Induced Liver Injury; Hematologic Diseases; Humans; Olanzapine; Pirenzepine; Selective Serotonin Reuptake Inhibitors