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PURPOSE: Cyclines are broad-spectrum antibiotics often used in acne. Side effects might occur precociously or more insidiously during long term treatment such in acne. The aim of this study is to review all adverse effects recently reported in this indication. CURRENT KNOWLEDGE AND KEY POINTS: A literature review from 1997 to 2001 has been conducted. Seventy-six articles reporting 250 cases have been found. Data analysis indicated that minocycline is the most widely incriminated molecule. Seventy-two cases revealed autoimmune disorders : lupus like syndrome associated or not with autoimmune hepatitis, 5 cases developed vasculitis. These reactions occurred in long term treatment (several weeks to several months). Fifteen cases of hypersensitivity syndromes and 3 cases of serum sickness like illness have been reported. These reactions occurred within the first weeks of exposure. Twenty-four cases of pseudotumor cerebri and 123 cases of abnormal pigmentations (skin, nails, mouth, bones or organs) have also been found. Eight cases presented other diseases. FUTURE PROSPECTS AND PROJECTS: Adverse effects of cyclines might be serious and sometimes unknown. Long term treatment by tetracyclines must be researched in patients presenting such symptoms. Moreover, several adverse drug reactions might be avoided by an optimal use of the drug (oesophageal ulcerations, photosensitivity) or by shorter periods of treatment (autoimmune disorders, pigmentations); only DRESS are drug adverse reactions unpredictable and sometimes severe.

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We report 4 cases of hepatic injury in patients treated with a dextropropoxyphene-paracetamol combination in which the causal relationship with dextropropoxyphene can be suspected. These four cases show similarities with the 29 cases found in international publications. Hepatotoxicity occurs more frequently among old patients and women. Clinically, this condition can mimic a biliary tract disease with sometimes few or no symptoms. Biochemical criteria can show cholestatic, mixed or cytolytic hepatitis. Intrahepatic cholestasis may be found in liver biopsies sometimes suggesting cholangitis. Outcome is favourable on withdrawal of the drug. The mechanism of action of dextropropoxyphene is discussed.

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Disulone (dapsone + ferrous oxalate) is a sulphone marketed in France since 1958 and authorized in P. Carinii prophylaxis in HIV+ cotrimoxazole intolerant patients, bullous dermatosis, leprosy and polychondritis. Between 1983 and 1998, 249 adverse reactions were reported to French pharmacovigilance centres and Aventis, the manufacturer. Every side-effect was reviewed and the causal relationship was assessed on the basis of the French method for causality assessment. Main side-effects were divided as follows: 117 blood dyscrasias (generally neutropenia and agranulocytosis, rarely methaemoglobinaemia, haemolysis, macrocytosis, anaemia, aplastic anaemia, haemochromatosis and sulphaemoglobinaemia); 29 hypersensitivity syndrome; 39 cutaneous reactions, generally rash; 27 liver injuries (cholestatic, cytolytic and mixed hepatitis); 27 neurological and psychiatric side-effects including 7 axonal neuropathy; 10 gastrointestinal effects, generally nausea and vomiting. Five deaths were reported (4 septicaemia including one case not due to dapsone and 1 digestive bleeding due to underlying disease). In the other cases the outcome was favourable. The results were compared with the published references. It would seem to be important to reinforce information to prescribers about the possible serious adverse reactions with dapsone, particularly hypersensitivity syndrome and agranulocytosis, that can cause death if the drug is not stopped in time.

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Taste disorders, generally poorly studied, have various causes. From 1985 to 1997, 305 observations of taste disorders imputed to drugs were notified to Regional Pharmacovigilance Centres. Patients were on average 54.4 years old and 58 per cent were women. Quantitative as well as qualitative disorders have been observed. Drugs mainly found were: angiotensin converting enzyme inhibitors, terbinafine, zopiclone, D-penicillamine, imidazole derivatives, quinolones, macrolides, carbimazole and calcium channel blockers. The outcome was favourable for 60.3 per cent of patients. The possible efficacy of zinc is discussed. It is generally considered that taste disorders are not a serious side-effect, but they can reduce the quality of life and lead to poor compliance with treatment.

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INTRODUCTION: Spontaneous dissection of cervical and visceral arteries are rare and usually associated with an underlying arterial disease. EXEGESIS: The authors report the unusual case of a 50-year-old woman with high blood pressure who presented spontaneous dissection of cervico-cephalic, renal and hepatic arteries and of the descending aorta. She had been taking ergotamine tartrate for ten years for migraine. She also suffered from Raynaud's syndrome worsened by treatment. CONCLUSION: The respective roles of arterial dysplasia, chronic ergotism, renovascular hypertension and migraine are discussed.

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PURPOSE: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed. Since their release unexpected adverse effects such as bleeding disorders have been described. METHODS: Thirty patients with either hematoma or muco-cutaneous bleeding have been selected from case reports of the Saint-Etienne Pharmacovigilance center and from a literature review. RESULTS: The female/male sex-ratio was 3:4 and the mean age 42 years. Two newborns who had been exposed in utero to SSRIs were also included in the study. Eleven patients presented an underlying disease or were at risk. Various adverse effects such as bruising, hematoma, petechiae or purpura, epistaxis, and more rarely intestinal hemorrhage, ocular bleeding or cerebral hemorrhage were encountered. Symptoms were sometimes associated with prolonged bleeding time and platelet aggregation disorders and usually resolved within two days to four months after treatment discontinuation. CONCLUSION: Hematoma and muco-cutaneous bleeding would therefore be related to treatment, including selective serotonin reuptake inhibitors. However, these adverse effects are still poorly known and rarely reported. The main mechanism suggested would be a decrease in serotonin platelet leading to a defect in platelet aggregation. However, an increase in capillary fragility or susceptibility related to the patient's condition might be involved. Study of hemostasis history in patients requiring treatment with SSRIs might be of value.

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Although infrequent, hepatitis associated with amoxicillin and clavulanic acid combination is probably underestimated. Except for cases with few symptoms, a time interval between stopping treatment and the first manifestations (jaundice in most cases), sometimes of several weeks, may hinder diagnosis. We report 9 patients who exhibited this characteristic. The delay between stopping treatment and the onset of hepatitis varied from 13 days to 6 weeks after stopping the drug. Other causes of jaundice were excluded. Male sex, advancing age, or prolonged treatment (more than 10 days) may increase the risk. Complete recovery occurs within 1 to 4 months after discontinuation of treatment. The mechanism is unclear. Clinical and biological signs of hypersensitivity may suggest an immunoallergic reaction.

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A prospective drug prescription and descriptive study was undertaken in a sample of 214 pregnant women in the department of the Loire. This population was randomized using pregnancy declaration files from the French Health Care Centre. Data recording was retrospective. A total of 2064 drugs have been prescribed; 90 per cent of women received at least one drug during the course of pregnancy with an average of 11.5 drugs per woman. Antispasmodics are mainly prescribed in the first trimester while vitamins, mineral supplements, antianemics and vasoactive agents are found in the third trimester. Prescriptions do not rise with age but increase in urban areas. Use of PDD/DDD (Prescribed Daily Dose/Defined Daily Dose) is an estimation of prescription customs. For ketoprofen, it is 1.6 in the last trimester, although this drug is contra-indicated.

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In France, three over-the-counter products containing quinine exist to treat cramps. This study aims to analyse data on spontaneous reports to the French System of Pharmacovigilance of adverse reactions to quinine drug products. From 1985 to 1996, we reviewed 58 adverse reaction reports. Most involved hypersensitivity reactions: rash, pruritus, generalized anaphylaxis, thrombopenia and hepatitis. Cinchonism is rarely observed at the usually low dose of quinine in this indication. No fatal outcome has been notified as described in the USA and Australia. The Food and Drug Administration (FDA) decided that prescription of quinine drug products should not be used any longer in the treatment of muscle cramps. Immuno-allergic reactions are potentially serious and must be avoided by giving clear information to patients and prescribers, and looking into the history of such reactions in patients in respect of the quinine drug and also tonic water.

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A bezoar is a mass of undigested material which may form within the lumen of the gut. Some drugs have the potential to form bezoars. In the majority of patients, there is a clear predisposing factor. We present here the data of the French System of Pharmacovigilance on sucralfate and a literature review. Two distinct populations were involved: 16 adults and 5 newborn babies. All were hospitalized in intensive care units. The children were very low birth weight newborn babies, all of whom presented with abdominal distension or acute occlusion. The abdominal radiograph revealed an opaque mass filling the contour of the stomach. Adults presented an oesophageal bezoar around a nasogastric tube. Risk factors for bezoar formation were severe illness, gut hypomotility, dehydration, overdosage, nasogastric tube feeding. Sucralfate is used in the management of peptic ulcer. At pH < 4, extensive polymerization occurs and a sticky viscid gel is formed. In view of this inquiry, the French System of Pharmacovigilance decided to advise caution for adults in intensive care unit being fed by nasogastric tube and contraindication in premature babies and dysmature newborn babies receiving sucralfate.

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This paper introduces some comments on the complete text of Good Pharmacovigilance Publishing Practices, which forms appendix number 2 of the Good Pharmacovigilance Practices now published by the French Drug Agency, as was Good Clinical Practices. Each good practice is printed in italic and presented in a frame; the following comments are designed to facilitate its application. The technical terms that are used in this text are presented according to the glossary in Good Pharmacovigilance Practices.

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AIMS: To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database. METHODS: The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non-case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA). RESULTS: 428 of 93,338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33-48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25-2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57-112)), disopyramide (OR 32 (22-46)), nifedipine (OR 2.16 (1.32-3.51)), diltiazem (OR 1.76 (1.01-3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16-3.16)) and frusemide (OR 1.89 (1.31-1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5-1.4) and 1.2 (0.7-2.2), respectively). The same was found for other drugs except cibenzoline. CONCLUSION: The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.

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UNLABELLED: The French drug surveillance (pharmacovigilance) system is based on a network of 31 regional centres which receive adverse drug reaction (ADR) reports from health professionals and are drug information centers. Cases are entered into a common database, with causality scores. This database contains large amounts of data, which may be used for pharmaco-epidemiological studies. As an example, all cases in which an antihypertensive drug, suspect or not, was cited were identified. ACE-inhibitor cough was also explored. RESULTS: Since 1985, > 70,000 case reports have been entered into the database. 63 per cent were reported by specialists, 20 per cent by GPs. 54 per cent came from University Hospitals, 21 per cent from private practice. The most numerous age group was 60 to 69. The overall sex ratio (F/M) was 1.28, the female preponderance being most marked at < 39 and > 70 years of age. 43 per cent took only one drug, 20 per cent two drugs, 13.4 per cent three, and 24 per cent > three drugs. The most frequently reported effects concerned the skin and appendages (15 per cent), general status and central nervous system (9.5 per cent each), platelets, liver, and GI systems (6 per cent each). Outcome was favourable in 74 per cent. Dechallenge was positive in 71 per cent, rechallence in 6 per cent. 3.4 per cent of the patients died; in 2.2 per cent death was related to a reaction. Causality assessment indicated close temporal relationship (C2 or C3) in 69 per cent of cases; in 51 per cent of cases, no other obvious cause was found. 66 per cent of the reactions were labelled when reported. The database could also be used to explore drug utilisation: as an example, we studied the age and sex distribution of reports containing antihypertensive drugs, irrespective of their possible causal role in the reaction. Antihypertensives were mentioned in 14 per cent of the reports. The age distribution was skewed towards greater age, with a maximum of 70 years. F/M was 1.57, with more M use < 20 and 30-59, whereas F were more common between 20-29 and 60 years. beta-blockers were more often associated with patients under 70, whereas above 70 diuretics and centrally acting antihypertensive drugs were more often reported. This could be related to greater use or worse tolerance of these drugs. As an example of the exploration of a specific drug-reaction relationship, we explored the relationship between the use of ACE inhibitors (ACEI) and cough. ACE inhibitors were present in 6 per cent of cases, but in 75 per cent of reports of cough. F/M was 1.29 (NS) for all reports concerning ACEI, 1.28 for cough unrelated to ACEI, 2.1 for cough with ACEI (P < 0.05). Cough was present in 12 per cent of all reports concerning ACEI. There was no clear difference between ACEI for cough or sex ratio; women cough more with ACEI. This does not seem related to greater ACEI use by women or to greater sensitivity of women to cough. The reason for this sex difference remains to be explained. There are large amounts of essentially underutilized data in drug surveillance databases. How they can or should be used remains to be validated.

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