[Fatal hepatitis probably caused by exifone (Adlone)].
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
G Babany
Publications and source records attributed to G Babany.
[Fatal fulminant hepatitis in 2 women taking toloxatone (Humoryl)].
We report two cases of fulminant hepatitis which might be due to toloxatone, a new type-A monoamine oxidase inhibitor. Hepatitis occurred 20 days after the beginning of toloxatone administration in the first case and 138 days after the reintroduction of treatment in the second case. Clinical features included vomiting and jaundice, followed by asterixis and coma. Histologically, hepatic cell necrosis was predominant in the centrilobular area in the first case, and affected the entire lobule in the second case. Both patients died despite emergency liver transplantation.
Acute Disease↗
Inhibitory effects of nilutamide, a new androgen receptor antagonist, on mouse and human liver cytochrome P-450.
The effects of nilutamide were studied first with human liver microsomes. At concentrations expected in the human liver (110 microM), nilutamide inhibited hexobarbital hydroxylase, benzphetamine N-demethylase, benzo(a)pyrene hydroxylase and 7-ethoxycoumarin O-deethylase activities by 85, 40, 35 and 25%, respectively. There was no in vitro inhibition of NADPH-cytochrome c reductase activity, no in vitro loss of CO-binding cytochrome P-450, and no spectral evidence for the in vitro formation of a possible cytochrome P-450Fe(II)-nitroso metabolite complex. Other studies were performed with mouse liver microsomes. Nilutamide (550 microM) did not significantly increase the consumption of NADPH by aerobic microsomes, and did not modify the kinetics for the reduction of cytochrome P-450 by NADPH-cytochrome P-450 reductase in an anaerobic system. Nilutamide (22 microM) produced either a type I or a type II binding spectrum. Kinetics for the inhibition of hexobarbital hydroxylase were consistent with competitive inhibition. A last series of experiments was performed after administration of nilutamide in mice. Thirty minutes after administration of doses (15 or 30 mumol.kg-1 i.p.) similar to those used in humans, the hexobarbital sleeping time was increased by 40 and 60%, respectively. There was no evidence, however, for the irreversible inactivation of microsomal enzymes since CO-binding cytochrome P-450 and monooxygenase activities remained unchanged in liver microsomes from mice killed 1 or 6 hr after administration of nilutamide (30 mumol.kg-1 i.p.). These results show that nilutamide inhibits hepatic cytochrome P-450 activity, and suggest that inhibition may actually occur after therapeutic doses of nilutamide in humans.
Androgen Receptor Antagonists↗
Genetic predisposition to drug hepatotoxicity: role in hepatitis caused by amineptine, a tricyclic antidepressant.
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.
Adolescent↗
Fibrin ring granulomas and allopurinol.
To test the hypothesis that allopurinol-associated granulomatous hepatitis may present itself with fibrin-ring granulomas, we requested details of such cases, as reported to the World Health Organization, from 13 national adverse reaction monitoring centers, and as reported in the literature. Details and histology of 6 cases were obtained and reviewed. All consisted of acute hypersensitivity signs with fever, rash, arthralgia, or eosinophilia as hallmarks, starting within 6 wk of commencing treatment with allopurinol. In all cases there were either epithelioid granulomas or granulomalike lesions, but none of these contained fibrin rings. It is concluded that, if fibrin-ring granulomas are a manifestation of allopurinol-induced granulomatous hepatitis, this feature is probably uncommon.
Adult↗
Genetically determined oxidation polymorphism and drug hepatotoxicity. Study of 51 patients.
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.
Adolescent↗
Alcoholic-like liver lesions induced by nifedipine.
We report the case of a 78-year-old patient suffering from alcoholic-like liver injury, consisting of steatosis and Mallory bodies, caused by the calcium channel blocker, nifedipine.
Aged↗
Clotiazepam-induced acute hepatitis.
We report the case of a patient who developed acute hepatitis with extensive hepatocellular necrosis, 7 months after the onset of administration of clotiazepam, a thienodiazepine derivative. Clotiazepam withdrawal was followed by prompt recovery. The administration of several benzodiazepines, chemically related to clotiazepam, did not interfere with recovery and did not induce any relapse of hepatitis. This observation shows that clotiazepam can induce acute hepatitis and suggests that there is no cross hepatotoxicity between clotiazepam and several benzodiazepines.
Administration, Oral↗
Effect of liver disease on dextromethorphan oxidation capacity and phenotype: a study in 107 patients.
1. The O-demethylation of dextromethorphan to dextrorphan exhibits a genetically-controlled polymorphism, co-segregating with that of debrisoquine hydroxylation. Dextromethorphan has been proposed as a test compound to assess drug oxidation polymorphism. 2. We studied the effects of liver disease of varying severity on dextromethorphan oxidation capacity. Phenotyping was performed using the urinary dextromethorphan/dextrorphan metabolic ratio after oral administration of 40 mg dextromethorphan hydrobromide in 56 patients with cirrhosis and in 51 patients with moderately severe liver disease. 3. Dextromethorphan oxidation capacity was impaired in cirrhotic patients and, to lesser extent, in non cirrhotic patients, as compared with 103 control subjects. 4. The impairment in dextromethorphan oxidation induced by liver disease, was however, much less than that caused by the genetic deficiency. As a result, the prevalence of the poor metabolizer phenotype remained in the same range in patients with cirrhosis (1.8%) and with moderately severe disease (2.0%) as in controls (3.9%). 5. This observation shows that, although liver disease causes some impairment of dextromethorphan O-demethylation, this impairment is not sufficient to modify the assignment of phenotypes.
Adult↗
In vivo evaluation of the effects of altered cyclosporine metabolism on its immunosuppressive potency.
The dose-response and plasma concentration-response relationships of cyclosporine after both inducing and inhibiting its metabolism were studied in a mouse heart transplant model. The metabolism of cyclosporine was altered by coadministering phenobarbital and cimetidine as metabolism inducing and inhibiting agents, respectively. We found that phenobarbital depressed the immunosuppressive potency of cyclosporine by enhancing its metabolism resulting in lower cyclosporine blood levels. On the other hand, when cimetidine was administered concurrently with cyclosporine, the immunosuppressive effect was enhanced due to inhibition of the metabolism of cyclosporine which produced higher cyclosporine blood levels. When graft survival was evaluated relative to blood cyclosporine concentrations, however, it appeared that cimetidine had a direct negative effect on the survival of transplanted organs independent and contrary to its effect on the accumulation of cyclosporine. The immunosuppression produced by cyclosporine at these elevated blood levels was less than expected. The accrued data support the conclusion that cyclosporine and not its metabolites are primarily responsible for its immunosuppressive activity in the mouse.
Animals↗
[Hepatitis probably caused by exifone (Adlone)].
Exifone, a drug recently proposed for the treatment of cognitive deficiencies of old age, has been marketed in France beginning in April 1988. This report concerns 2 patients who developed jaundice after taking this drug for 2 and 5 months, respectively. Serum aminotransferase was markedly increased. There was no hepatic failure. In both cases, histologic examination of a liver sample showed centrilobular hepatocyte necrosis and cholestasis. Necrotic cells were infiltrated with numerous red blood cells and scarce inflammatory cells. These lesions were associated with alterations of the walls of centrilobular veins. Discontinuation of exifone was followed by the prompt disappearance of jaundice. Complete recovery occurred within 6 and 12 weeks, respectively.
Aged↗
Peliosis hepatis induced by 6-thioguanine administration.
A patient with acute myeloblastic leukaemia developed jaundice revealing peliosis hepatis after receiving 6-thioguanine for two months. Peliosis hepatis was severe and was associated with mild lesions of centrilobular veins. Withdrawal of 6-thioguanine was followed by a progressive improvement of liver dysfunction. This report shows that 6-thioguanine, a thiopurine already reported to be responsible for veno-occlusive disease of the liver, can induce peliosis hepatis. This suggests that some liver vascular disorders caused by thiopurines (6-thioguanine, azathioprine and 6-mercaptopurine), particularly peliosis hepatis, veno-occlusive disease, sinusoidal dilatation and perisinusoidal fibrosis, might be related syndromes caused by similar lesions at different sites.
Chemical and Drug Induced Liver Injury↗
Metoprolol-induced hepatitis: rechallenge and drug oxidation phenotyping.
Explore the source record for details and available documents.
Chemical and Drug Induced Liver Injury↗
Evaluation of the in vivo dose-response relationship of immunosuppressive drugs using a mouse heart transplant model: application to cyclosporine.
We have developed a 2-week bioassay that quantitates the effect of immunosuppressive drugs on organ allograft rejection. This assay is not only rapid and reliable, but also simple and relatively inexpensive and sparing of test substances. We refined the method by which neonatal mouse hearts are transplanted into pouches in the pinnae of ears of adult recipient mice and used cyclosporine treatment as an example of how this method might be generally applied to study the dose-response relationship of immunosuppressive drugs. Five- to 10-week-old C3H/km mice were used as cardiac recipients, and unsexed newborn BALB/c (allograft) or C3H/km (isograft) mice (24-48 hr old) were used as cardiac graft donors. The heart grafts were examined by two independent observers every other day at 10- to 20-fold magnification for up to 14 days. The immunosuppressive effect of cyclosporine was studied at doses of 3, 7.5, 15, 22.5 and 30 mg/kg per day administered i.p. The accrued data were analyzed by two methods: dose-response curves at days 12 and 14 and mean survival scores from day 8 to day 14. The dose-response curves on days 12 and 14 were similar, and the calculated ED50 values were 9.83 and 15 mg/kg/day, respectively. The results of this study demonstrate the potential usefulness and the sensitivity of the ear-heart transplantation bioassay for relative potency evaluations of immunosuppressive drugs.
Animals↗
[Hepatitis probably caused by Plethoryl. Apropos of 7 cases].
Seven patients developed acute hepatitis after receiving Plethoryl for obesity for 4 to 16 weeks. Jaundice was generally associated with or preceded by asthenia, nausea and pruritus. Serum aminotransferase activities were markedly increased whereas alkaline phosphatase and gamma-glutamyltransferase activities were moderately elevated. There was no hepatic failure. In all cases, Plethoryl administration was promptly discontinued. In 6 cases, jaundice disappeared within 2 to 4 weeks, and recovery occurred within 2 to 5 months. In one case, however, jaundice disappeared within 12 weeks and recovery took 10 months.
Acute Disease↗
Chronic active hepatitis caused by benzarone.
We report a case of chronic active hepatitis caused by benzarone, a benzofuran derivative used in Europe for the treatment of peripheral venous disorders. Jaundice and serum alanine aminotransferase activity increased while drug administration was continued, but promptly decreased when it was eventually interrupted. Liver lesions were those of chronic active hepatitis. Anti-smooth muscle antibodies were present at a titer of 1:500 and disappeared 8 months after withdrawal of benzarone.
Alanine Transaminase↗
Hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria. A spectrum from asymptomatic occlusion of hepatic venules to fatal Budd-Chiari syndrome.
In a series of 40 patients with Budd-Chiari syndrome, 5 (12%) were found to be afflicted with paroxysmal nocturnal hemoglobinuria. The clinico-pathological features in these 5 patients and in 26 well-documented previously reported cases could be ascribed to three groups of increasing severity: thrombosis limited to small-sized hepatic veins with no or transient ascites, partial thrombosis of large-sized hepatic veins with chronic ascites, and complete thrombosis of large-sized hepatic veins with a life-threatening course. These three groups did not differ with regard to sex, age, and duration and characteristics of paroxysmal nocturnal hemoglobinuria. In view of the relationship between prognosis and the extent of hepatic vein obstruction, we suggest that early therapy directed toward limiting the extension of thrombosis, or toward dissolving formed thrombi, should improve the prognosis of this severe complication of paroxysmal nocturnal hemoglobinuria.
Adult↗
Chronic liver disease after low daily doses of amiodarone. Report of three cases.
A few cases of alcohol-like chronic liver disease have recently been described in patients on high daily doses of amiodarone (400-600 mg) for 5-24 months. We report here 3 cases in which similar lesions were observed after low daily doses of amiodarone. Daily dosage was 200 mg in 2 cases, 400 mg then 200 mg in the third one, and duration of therapy ranged between 36 and 60 months. Symptomatology was limited to hepatomegaly and/or mild elevation of serum aminotransferases. Liver biopsy showed alcohol-like lesions with fibrosis in 2 cases and cirrhosis in 1 case. Electron microscopy disclosed hepatic phospholipidosis. These cases indicate that chronic liver disease may be observed even when amiodarone is prescribed at low daily dosage, provided that duration of treatment is long. They also suggest that rather than the daily dosage, the cumulative dose of amiodarone is a major factor in the development of hepatic injury.
Aged↗