ajmaline and Chemical-and-Drug-Induced-Liver-Injury

Ajmaline is a pharmaceutical agent now administered globally for a variety of indications, particularly investigation of suspected Brugada syndrome. There have been previous reports suggesting that repetitive use of this agent may cause severe liver injury, but little evidence exists demonstrating the same effect after only a single administration.. A 33-year-old man of Libyan origin with no significant past medical history underwent an ajmaline provocation test for investigation of suspected Brugada syndrome. Three weeks later, he presented with painless cholestatic jaundice which peaked in severity at eleven weeks after the test. Blood tests confirmed no evidence of autoimmune or viral liver disease, whilst imaging confirmed the absence of biliary tract obstruction. A liver biopsy demonstrated centrilobular cholestasis and focal rosetting of hepatocytes, consistent with a cholestatic drug reaction. Over the course of the next few months, he began to improve clinically and biochemically, with complete resolution by one year post-exposure.. Whilst ajmaline-related hepatotoxicity was well-recognised in the era in which the drug was administered as a regular medication, clinicians should be aware that ajmaline may induce severe cholestatic jaundice even after a single dose administration.

Topics: Adult; Ajmaline; Brugada Syndrome; Chemical and Drug Induced Liver Injury; Humans; Jaundice, Obstructive; Male; Severity of Illness Index; Voltage-Gated Sodium Channel Blockers

A 60 years old woman was admitted for jaundice and fever which appeared after a treatment with ajmaline-butabarbital for two-weeks. Abdominal ultrasound examination and endoscopic retrograde cholangiography were normal. Mitochondrial antibodies were absent. Jaundice persisted for three years, associated with diffuse cutaneous xanthomatosis. Five years later, alkaline phosphatases remained elevated. A liver biopsy showed vanishing interlobular bile ducts with centrolobular cholestasis and ductular proliferation. We suggest that ajmaline can induce long lasting cholestasis due to damage to the intrahepatic bile ducts. The responsibility of butabarbital and the relationship with primary biliary cirrhosis are discussed.

Topics: Ajmaline; Barbiturates; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Combinations; Female; Humans; Liver; Middle Aged

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: Ajmaline; Alanine Transaminase; Alkaline Phosphatase; Anti-Arrhythmia Agents; Bilirubin; Biomarkers; Brugada Syndrome; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Female; Humans; Middle Aged; Serum Albumin; Serum Albumin, Human; Time Factors

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

2 cases of cholestatic hepatitis due to preajmaline recovered when the drug was stopped. One was a 40-year-old woman, and the other a 74-year-old man whose jaundice lasted for 8 months. Approximately 40 patients with preajmaline-induced hepatitis have been described in the literature. All recovered except 1, who developed biliary cirrhosis while using preajmaline in conjunction with other hepatotoxic drugs.

Topics: Adult; Aged; Ajmaline; Chemical and Drug Induced Liver Injury; Cholestasis; Female; Humans; Male

Intrahepatic cholestasis and aplastic anemia after N-propylajmaline. A 43 year old female patient taking oral contraceptives for more than five years received the antiarrhythmic drug N-propylajmaline for treatment of ventricular arrhythmia. After twelve days (total dosage 510 mg N-propyl-ajmaline) acute severe intrahepatic cholestasis and aplastic anemia developed. The erythropoeisis improved after three weeks of treatment with corticosteroids. However, despite treatment with phenobarbital the jaundice receded very slowly. Even after nine years of follow-up cholestatic enzymes are still significantly elevated although serum bilirubin levels are in the normal range. This case report demonstrates that antiarrhythmic drugs may induce nearly irreversible intrahepatic cholestasis and severe hematological disturbances.

Topics: Adult; Ajmaline; Anemia, Aplastic; Biopsy; Cardiac Complexes, Premature; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Diagnosis, Differential; Female; Humans; Liver; Liver Function Tests; Prajmaline

Topics: Aged; Ajmaline; Atrial Fibrillation; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Hepatitis B; Humans; Male

We report the cases of 3 patients in whom ajmaline-induced acute hepatitis was followed by anicteric cholestasis persisting for more than 1 year after cessation of administration of the drug. Ajmaline was given for 8-16 days before the onset of acute hepatitis. Jaundice was preceded by fever, chills and abdominal pain, and was associated with hypereosinophilia. The initial lesions included centrilobular cholestasis and portal inflammatory infiltration. Jaundice lasted for 3 weeks to 11 months. In these 3 patients liver tests were still abnormal 17-26 months after ajmaline withdrawal; histological examination, performed 9-26 months after the onset of jaundice, showed a decreased number of interlobular bile ducts, ductular proliferation, and mild portal fibrosis; circulating immune complexes were demonstrated. These observations demonstrate that prolonged cholestasis can follow ajmaline-induced acute hepatitis. Persistence of cholestasis long after the withdrawal of ajmaline suggests some form of autoimmunity.

Topics: Acute Disease; Adult; Ajmaline; Antigen-Antibody Complex; Chemical and Drug Induced Liver Injury; Cholestasis; Estrogens; Female; Humans; Time Factors

Topics: Ajmaline; Arrhythmias, Cardiac; Chemical and Drug Induced Liver Injury; Cholestasis; Diagnosis, Differential; Humans; Male; Middle Aged; Prajmaline

Topics: Ajmaline; Chemical and Drug Induced Liver Injury; Humans; Male; Middle Aged

Seven further cases with n-propyl-ajmaliumbitartrate (NPAB)-associated liver damage observed between 1976 and 1980 in two collaborating institutions are reported. The cause/effect relationship could be classified as probable in three cases and as potential in the remaining four patients. No drug rechallenge was carried out. In the clinical management, definite exclusion of biliary tract obstruction had a clear priority over histologic documentation of the degree of the transient liver damage. Follow-up data after 2 years 8 months to 5 years 9 months by personal reinvestigation of three patients and by questionnaire to family physicians and patients in the remaining four cases gave no clinical or serologic indication of persisting or relapsing liver damage. Liver biopsies were not considered to be warranted in the follow-up of these asymptomatic patients with normal liver function tests.

Topics: Adult; Aged; Ajmaline; Arrhythmias, Cardiac; Chemical and Drug Induced Liver Injury; Female; Follow-Up Studies; Humans; Liver Function Tests; Male; Middle Aged; Prajmaline

Topics: Ajmaline; Animals; Cell Membrane; Cell Separation; Chemical and Drug Induced Liver Injury; Chlorpromazine; In Vitro Techniques; Liver; Liver Diseases; Male; Rats; Rats, Inbred Strains

The authors report the case of a patient with ajmaline hepatitis. The clinical presentation suggested angiocholitis; serum bilirubin concentration and the activity of alkaline phosphatase were markedly increased; serum transaminase activity was moderately increased; the prothrombin time remained normal. After interruption of the drug, the outcome was favorable, with complete recovery within 2 months. Histologic examination of a liver specimen obtained early after the onset of jaundice showed inflammatory cells in the portal tracts and mild hepatocytic lesions. Electron microscopy disclosed dilatation of the endoplasmic reticulum. The microfilamentous network of the hepatocytes was reduced and disorganized. Biliary canaliculi were enlarged with absent or blunted microvilli. There was evidence for passage of bile products from the biliary caniculi into the space of Disse. These aspects are reminiscent of those observed in animals after the administration of cytochalasin B. It is suggested that ajmaline may, in some patients, trigger an immune response which then alters the microfilamentous network of the hepatocytes, and may, thereby, produce cholestasis.

Topics: Aged; Ajmaline; Biopsy, Needle; Chemical and Drug Induced Liver Injury; Humans; Liver; Male; Microscopy, Electron; Tachycardia

Topics: Ajmaline; Biopsy; Cardiac Complexes, Premature; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Humans; Liver; Liver Function Tests

Topics: Adult; Aged; Ajmaline; Chemical and Drug Induced Liver Injury; Denmark; Female; Humans; Male; Middle Aged

The authors report the cases of 4 patients with jaundice following the administration of ajmaline. The disease had a pseudo- angiocholitic onset with fever, chills and pruritus in the 4 patients and abdominal pains in 2 patients. Serum transaminase activity and serum alkaline phosphatase activity were increased in the 4 patients. Blood eosinophilia was found in 3 patients. Liver lesions included predominantly centrilobular cholestasis, mild hepatocytic lesions, and portal inflammation. After the interruption of the drug administration, recovery occurred in the 4 patients. Two patients resumed the intake of ajmaline; transient hepatitis recurred in these 2 patients.

Topics: Adult; Aged; Ajmaline; Chemical and Drug Induced Liver Injury; Female; Humans; Male; Middle Aged; Tachycardia

It is reported on lesions of the liver parenchyma after the application of dihydralazin and detajmium bitartrate with description of the clinical and morphological findings. By means of the morphological findings got in liver biopsy a clinically supposed acute virus hepatitis could be excluded. After the application of dihydralazin group cell necroses and an inflammation of the periportal fields, after detajmium bitartrate a typical intrahepatic cholestasis was in the front. The knowledge of medicamentous side-effects may avoid diagnostic and therapeutic errors in the individual case.

Topics: Adult; Ajmaline; Biopsy; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Dihydralazine; Female; Humans; Hydralazine; Liver; Necrosis

Topics: Aged; Ajmaline; Arrhythmias, Cardiac; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Drug Hypersensitivity; gamma-Glutamyltransferase; Humans; Liver Diseases; Male; Transaminases

Topics: Ajmaline; Chemical and Drug Induced Liver Injury; Cholestasis; Female; Humans; Middle Aged; Spironolactone

Topics: Aged; Ajmaline; Chemical and Drug Induced Liver Injury; Humans; Liver; Male

Liver damage was found in five patients (three men, two women) who were receiving prajmalium bitartrate. The cause was proven by re-exposure which was positive in all instances. The illness tended to start with acute fever and severe upper abdominal pains. When the drug was continued in one case, laparotomy was performed for suspected obstructive jaundice. Another patient had been admitted for operation because of jaundice. On re-exposure the most striking feature was a definite rise in glutamate-dehydrogenase. Prajmalium bitartrate is thus no better tolerated by the liver than ajmalin: both clinically, biochemically and morphologically the two drugs affect the liver similarly.

Topics: Acute Disease; Aged; Ajmaline; Chemical and Drug Induced Liver Injury; Female; Glutamate Dehydrogenase; Humans; Jaundice; Liver; Male; Middle Aged

The authors report on four cases of immediate hepatotoxic reaction following diagnostic re-exposure. In checking 27 patients who had received NPAB treatment for the first time, four were found to have a hepatotoxic reaction that developed within 13--20 days after beginning the treatment. In view of the significance of NPAB for the treatment of cardiac rhythm disorders, further such studies are required in order to define the actual risk involved in this procedure.

Topics: Adult; Ajmaline; Antibodies; Arrhythmias, Cardiac; Bilirubin; Chemical and Drug Induced Liver Injury; Cholestasis; Eosinophils; Female; Humans; Kidney Tubules; Liver; Middle Aged; Muscle, Smooth; Thyroid Gland; Transaminases

Topics: Aged; Ajmaline; Chemical and Drug Induced Liver Injury; Cholestasis; Female; Humans; Liver Cirrhosis, Biliary; Male; Methyltestosterone; Middle Aged; Xanthomatosis