Biomedical subjects
Publications and source records attributed to A Castot.
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ESTABLISHMENT: The European pharmacovigilance system has been operating since 1995 when the European Agency for the Evaluation of Medicinal Products as well as two new European registration procedures were established. STRUCTURE: This system is very similar to the French organization and is based on a decentralized collection and validation of safety data by member states and a centralized evaluation and decision making process at the European Agency for the Evaluation of Medicinal Products performed by the Committee for Proprietary Medicinal Products (CPMP) and its Pharmacovigilance Working Party. A EUROPEAN SYSTEM: In light of the experience gained, the European pharmacovigilance system moved to an interactive system which relies on a close cooperation between member states ensuring the common evaluation and management of safety concerns.
The French drug surveillance system is characterized by: a network of thirty one regional drug surveillance centres, located to provide convenient proximity to health care professionals; a causality assessment method, compulsory for all persons involved in drug surveillance, to assess the causal relationship between an adverse effect and one or more drugs; if necessary, an additional evaluation of the causal relationship will be performed using pharmaco-epidemiology methods; a Technical committee and a National Commission of Drug Surveillance which centralize and assess all the data in order to provide a consensual advice to the relevant authorities on necessary measures, to prevent, or reduce a drug related adverse effect; in the case of an inquiry, the drug surveillance department of the pharmaceutical company and the network of regional drug surveillance centers will pool their data with the aim to exchange information and ideas.
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OBJECTIVE: To show that germander (Teucrium chamaedrys), an herbal medicine used to facilitate weight loss, may be hepatotoxic and to delineate the nature of the injury. DESIGN: Retrospective study. SETTING: Liver units of several centers in the French Network of Pharmacovigilance. PATIENTS: Seven patients who developed hepatitis after germander administration and who had no other cause of liver injury. MEASUREMENTS: Clinical examination, liver function tests, various serologic tests, ultrasonography, and histologic study. RESULTS: Hepatitis characterized by jaundice and a marked increase in serum aminotransferase levels occurred 3 to 18 weeks after germander administration. Liver biopsy specimens in three patients showed hepatocyte necrosis. After discontinuing treatment with germander, jaundice disappeared within 8 weeks and recovery was complete in 1.5 to 6 months. In three cases, germander readministration was followed by the prompt recurrence of hepatitis. CONCLUSION: Germander may be hepatotoxic, which supports the view that herbal medicines are not always as safe as generally assumed.
Twenty-six patients developed acute hepatitis after taking Germander, an herbal medicine used to facilitate weight loss. Hepatitis occurred within 9 weeks of treatment and was characterized by jaundice and a high level of aminotransferases. Recovery was obtained between 1.5 and 6 months after withdrawal. In 12 cases, readministration was followed by prompt recurrence of hepatitis. The causal relationship is probable but the mechanism remains unclear: there was no relationship with the daily intake and the duration of treatment; there are no toxicological data on Germander compounds; contamination by an unidentified product is possible but has not been demonstrated. It should be emphasized that readministration of Germander produced recurrence of the hepatitis whenever it was performed. As a result, the French Ministry of Health recently decided to prohibit national-wide all Germander containing medicinal products.
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We report six women with severe acne lesions associated with taking amineptine, a tricyclic antidepressant. The lesions appeared after self-administration of high doses of the drug over long periods of time. They mainly occurred on the face, back, and thorax, but were also found on the extremities and in the perineal region. In five of the six cases, severity of cutaneous lesions appeared to be correlated with degree of overdose. The sixth patient never admitted having taken amineptine. Most of the patients had been unsuccessfully treated with isotretinoin for 18 months. In all six cases, chromatography of urinary 17-ketosteroids showed abnormal peaks and retention times which were different from those usually found for known steroids. In addition, the areas under these peaks were found to be a function of the degree of intoxication and of the clinical severity of the lesions. Mass spectrometry was used to qualitatively study urinary amineptine metabolites, disclosing compounds normally found only in trace amounts, as well as certain others heretofore not described in man. In two of the three patients who stopped taking amineptine, cutaneous lesions subsequently diminished, totally disappearing in the least severe case.
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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.
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We report the conclusions of consensus meetings organized by the "Direction de la Pharmacovigilance" of Roussel Uclaf, and attended by University Hospital Nephrologists, members of the National Network of Pharmacovigilance and representatives of Roussel Uclaf Drug Monitoring Department, in order to define more accurately, as regards drug-induced renal failure, the criteria and the terminology proposed by the French method of causality assessment of adverse drug reactions.
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The use of an official drug adverse reaction assessment procedure became compulsory in France in 1984. The method proposed various qualifications for the semiologic and chronologic criteria used to ascribe a disorder to a specific drug but did not define them. Consensus meetings have been organized in order to define, in the main pathological fields, the adverse reactions themselves and the various qualifications of the criteria. This paper reports the results of meetings attended by hematologists, members of the French national network of Pharmacovigilance and representatives of Roussel Uclaf Drug Monitoring Department for drug-induced granulocyte and platelet cytopenias. Participants studied (a) the limits of the time interval between the appearance of the adverse reaction and the beginning or the end of the treatment with the suspected drug; (b) interpretation of a possible rechallenge; and (c) diagnostic value of in vitro tests proposed to confirm the responsibility of a specific drug in a granulocytic or platelet cytopenia.
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