dextromethorphan and Chemical-and-Drug-Induced-Liver-Injury

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

Dextromethorphan, a wildly used over-the-counter antitussive drug, is reported to have anti-inflammatory effects. Previously, we and others have demonstrated that dextromethorphan at micromolar doses displays potent hepatoprotective effects and enhances mice survival in a sepsis model. Moreover, we also observed potent anti-inflammatory and neuroprotective effects of subpicomolar concentrations of dextromethorphan in rodent primary neuron-glial cultures. The purpose of this study was to provide a proof of principle that ultralow dose dextromethorphan displays anti-inflammatory and cytoprotective effects in animal studies. Here, we report that subpico- and micromolar doses of dextromethorphan showed comparable efficacy in protecting mice from lipopolysaccharide/d-galactosamine (LPS/GalN)-induced hepatotoxicity and mortality. Mice were given injections of dextromethorphan from 30 min before and 2, 4 h after an injection of LPS/GalN (20 μg/600 mg/kg). Our results showed that dextromethorphan at subpicomolar doses promoted survival rate in LPS/GalN-injected mice. Ultralow dose dextromethorphan also significantly reduced serum alanine aminotransferase activity, TNF-α level and liver cell damage of endotoxemia mice. Mechanistic studies using primary liver Kupffer cell cultures revealed that subpicomolar concentrations of dextromethorphan reduced the NADPH oxidase-generated superoxide free radicals from Kupffer cells, which in turn reduced the elevation of its downstream reactive oxygen species (iROS) to relieve the oxidative stress and decreased TNF-α production in Kupffer cells. Taken together, these findings suggest a novel therapeutic concept of using ultralow doses of dextromethorphan for the intervention of sepsis or septic shock.

Topics: Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dextromethorphan; Endotoxins; Galactosamine; Kupffer Cells; Lipopolysaccharides; Mice; Oxidative Stress; Protective Agents; Reactive Oxygen Species; Sepsis; Shock, Septic; Survival Rate

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

CoricidinHBP (Schering-Plough Health Care Products, Inc, Memphis, TN) is a popular over-the-counter product abused by teenagers for its potent euphoric properties. Clinically significant signs and symptoms after ingestion are usually short-lived and commonly include tachycardia, hypertension, somnolence, and agitation. We report 2 cases of severe toxicity from CoricidinHBP in adolescents that required prolonged hospitalization. The first case demonstrates prolonged anticholinergic complications from a suicidal attempt with CoricidinHBP. The second case demonstrates significant acetaminophen-induced hepatotoxicty from recreational use of CoricidinHBP Maximum Strength Flu. Adolescent abuse of these products is encouraged because of the easily accessible medium of the Internet. The significant morbidity seen in our cases clearly demonstrates the need for vigilance by health care professionals regarding the abuse of over-the-counter products.

Topics: Acetaminophen; Adolescent; Antidepressive Agents; Chemical and Drug Induced Liver Injury; Chlorpheniramine; Depression; Dextromethorphan; Drug Combinations; Drug Overdose; Emergency Medical Services; Female; Humans; Nonprescription Drugs; Phenylpropanolamine; Substance-Related Disorders

A case of a 68-years-old female who was symptomatically treated with the codeine analog dextromethorphan because of a flu-like syndrome is herein reported. Five days later, she developed a cholestatic syndrome without fever or abdominal pain. Dextrometorphan was withdrawn and a rapid clinical improvement was observed, associated with decreasing levels of biochemical markers of cholestasis. Normal values were reached two months later. This type of adverse drug reaction, its potential pathogenic mechanisms and the therapeutic consequences are discussed.

Topics: Acute Disease; Aged; Antitussive Agents; Chemical and Drug Induced Liver Injury; Cholestasis; Dextromethorphan; Female; Humans

The influence of genetically determined oxidation polymorphism on drug hepatotoxicity has been poorly investigated and results are controversial. We studied drug oxidation capacity in 51 patients with hepatitis caused mainly by drugs undergoing oxidative metabolism, using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. Phenotyping was performed using the metabolic ratio (MR) calculated as MR = 0-10 h urinary output of dextromethorphan/0-10 h urinary output of dextrorphan (the main oxidative metabolite), after oral administration of 40 mg dextromethorphan hydrobromide. Dextromethorphan oxidation capacity was similar in patients and in 103 control subjects as judged by: (a) the prevalence of each phenotype (5.9% versus 3.9% for the poor metabolizer phenotype and 94.1% versus 96.1% for the extensive metabolizer phenotype; (b) the frequency distribution histograms of log metabolic ratio; (c) the mean values of dextromethorphan and dextrorphan urinary outputs and of log metabolic ratio for each phenotype. These results show that hepatotoxicity of several drugs, including amineptine, amodiaquine and Plethoryl, is related neither to an impairment in dextromethorphan oxidation capacity nor to an unusually high capacity to oxidize this drug.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemical and Drug Induced Liver Injury; Cohort Studies; Dextromethorphan; Dextrorphan; Female; Humans; Levorphanol; Male; Middle Aged; Oxidation-Reduction; Phenotype; Polymorphism, Genetic

Amineptine-induced immunoallergic hepatitis is unpredictable. It may be related to its oxidation into a reactive metabolite acting as hapten. We have looked for a possible genetic predisposition involving drug oxidation capacity and/or cell defense mechanisms in nine patients with previous amineptine hepatitis. Drug oxidation capacity was assessed using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. The eight patients tested had the extensive metabolizer phenotype. The susceptibility to amineptine metabolites was studied by an in vitro test assessing the destruction of the patients' lymphocytes by reactive metabolites generated from amineptine by a standardized oxidation microsomal system. Lymphocyte death increased with the dose of amineptine (1 to 2.5 mM); it was increased by preincubation with trichloropropene oxide, but was absent when amineptine was omitted or when the oxidation system was not operating. Mean lymphocyte death was twice higher in the nine patients with amineptine hepatitis than in 17 healthy controls. In contrast, when the test was performed with acetaminophen (3 to 10 mM), lymphocyte death was similar in controls and in patients. Basal epoxide hydrolase activity toward benzo[a]pyrene-4,5-oxide and glutathione concentration was similar in lymphocytes from controls and patients. Family studies showed an increased susceptibility to amineptine metabolites in lymphocytes from several first-degree relatives of two patients. These results show that amineptine hepatitis occurs in patients with extensive dextromethorphan oxidation capacity but with an increased susceptibility to amineptine reactive metabolites, probably related to a genetic deficiency in a cell defense mechanism.

Topics: Adolescent; Adult; Antidepressive Agents, Tricyclic; Cell Survival; Chemical and Drug Induced Liver Injury; Dextromethorphan; Dextrorphan; Dibenzocycloheptenes; Family Health; Female; Humans; Lymphocytes; Male; Middle Aged; Oxidation-Reduction; Phenotype

Acetaminophen, a commonly used medication, is present in many over-the-counter remedies. In recent years, its potential to cause severe liver injury has been increasingly appreciated. Chronic abusers of alcohol may be particularly susceptible to hepatotoxicity from acetaminophen. We report two cases of unintentional liver injury associated with ingestion of Nyquil, a liquid cold remedy containing acetaminophen and 25% alcohol.

Topics: Acetaminophen; Adult; Alcoholism; Chemical and Drug Induced Liver Injury; Dextromethorphan; Doxylamine; Drug Combinations; Ephedrine; Female; Humans; Levorphanol; Liver; Male; Middle Aged; Necrosis; Nonprescription Drugs; Promethazine; Pseudoephedrine; Pyridines

Topics: Acetaminophen; Adult; Alcoholism; Chemical and Drug Induced Liver Injury; Dextromethorphan; Doxylamine; Drug Combinations; Ephedrine; Humans; Hypnotics and Sedatives; Levorphanol; Male; Nonprescription Drugs; Promethazine; Pseudoephedrine; Pyridines