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Unlabelled: The academic interest for pharmacovigilance appears to be very low, because of the judged weakness of a "significant" relationship between drug utilisation and pathological events. We have tried to collect the relevant surveys of the French pharmacovigilance network on cutaneous toxic reactions to show the use of this work for current medical knowledge. This study was limited to the most relevant reports: 1--Cutaneous disorders induced by local reactions to ketoprofen, bufexamac, paracetamol (i.v.) 2--Cutaneous disorders observed in systemic hypersensitivity syndromes: allopurinol, chlormezanone, pristinamycine 3--Photosensitisation (toxicity), including: Individual characteristics of patients Nature of the observed syndromes Induction time and evolution of the disease Imputation and apparent incidence of the cases observed, Results: 1--Concerning "contact" dermitis, erythematous skin reactions are the most frequently observed. The causality link is proved in 272 patients of the cases. The mean age of the patients is 40-50 and the induction time from one to ten days. 2--In the hypersensitisation syndromes, severe skin reactions, combined with general reactions (fever), are the most frequently observed. The mean age is 50-60 and the number of serious cases is high (4.5%). 3--Severe burns with bullous skin reactions are observed in phototoxicity cases. The mean age of the patients is 50. Time induction is short (ten days), the cases are frequently serious, but evolution appears good. In conclusion, the synthesis of pharmacovigilance surveys shows the value of this epidemiological approach to drug-induced skin reactions. It is regrettable that the results of this work are not more widely distributed.

Objectives: To evaluate the frequency of high levels of intact parathormone in an elderly population of hospitalized patients and to determine whether there are any correlations with different factors involved in phosphocalcium metabolism, nutritional status and renal function., Methods: Intact parathormone was assayed in all patients admitted to a geriatric ward (n = 200). Other laboratory tests included serum phosphorus, calcium, total albumin, prealbumin, ionized calcium, creatinine with calculation of the clearance and in 50 patients radioimmunoassay for 25 hydroxyvitamin D., Results: Intact parathormone was abnormally high (> 65 pg/ml) in 40 patients. Mean levels increased significantly with age and reached 70.5 pg/ml in patients 90 years of age and over. No correlation was found between intact parathormone and total serum calcium, corrected serum calcium, albumin or prealbumin. Inversely there was a significant correlation with serum phosphorus and creatinine and creatinine clearance. Serum levels of 25 hydroxyvitamin D were abnormally low in 82% of the patients. There was a constant and significant decrease in intact parathormone level 15 days after calcium and calcifediol substitution therapy in 13 patients., Conclusion: The frequency of hyperparathyroidism increases with age to affect nearly 1 out of 2 subjects over 90. It would be useful to determine a threshold level for elderly subjects with a major risk of bone fracture.

If the iatrogenic acute muscular syndromes (rhabdomyolysis) and hepatic diseases following hypolipidemic drugs therapy are very well known, the other unwanted effects associated with fibrate therapy are not well established. It is the reason why we have selected, in the computerised data base of side effects from the French Network of "Centres de Pharmacovigilance" organisation, the pathological events associated with fibrate therapy during five years (1985 to 1989) (with exception for the acute muscular and hepatic diseases). The 277 side effects represent 67% of the side effects in which the product is regarded as "suspect" (S). These effects were observed in 132 men (mean age = 57 years) and 145 women (mean age = 61 years). The most frequently encountered products are: fénofibrate (Lipanthyl) for 30%; ciprofibrate (Lipanor); gemfibrozil (Lipur); bézafibrate (Befizal); each for about 10%. The mean doses used were the same that suggested in the french therapeutic dictionary ("Vidal"). The unwanted effects observed were: Skin reactions: 22.8% Blood disturbances (and hemorrhage): 9.8% Gl diseases (pancreatitis), Libido and psychic disturbances, nervous system disorders: about 6% each. All clotting disturbances (5.8%) are interactions with coumarin derivatives. The incidence of serious side effects was low and the recovery very good in 80.9% of cases: no death. In conclusion, the toxicity of fibrates (with exception for rhabdomyolysis and hepatic reaction) appears unimportant: the most frequently observed side effects are skin reactions and blood disturbances (interactions) and rarely nervous system, psychic or libido disturbances. The recovery is good, and the general toxicity of all products appear to be of the same order of magnitude.

One hundred and eighty five whole blood samples were analysed for cyclosporine levels by fluorescence polarization immunoassay (FPIA) and high performance liquid chromatography (HPLC). 123 came from 4 heart transplant recipients (mean age +/- SD: 47.50 +/- 20.56 years) and 62 from 4 liver transplant recipients (44.50 +/- 16.52 years). FPIA was done on plasma and whole blood in heart transplant recipients, on plasma in the liver recipients. HPLC was always done on whole blood. The results show a good correlation between FPIA on plasma (y) and HPLC (x) in liver recipients (n = 62, r = 0.935, y = 1.23x + 70 ng/ml), slightly worse between FPIA on plasma (y) and HPLC (x) in heart recipients (n = 64, r = 0.610, y = 0.78x + 189 ng/ml) and mediocre for FPIA on whole blood (y) and HPLC (x) in heart recipients (n = 123, r = 0.566, y = 1.35x + 594 ng/ml).

Cisplatin (CDDP) is known to induce nephrotoxicity. In this retrospective study, we have investigated the evolution of plasma creatinine in long term therapy with CDDP. We have studied case history, mode of administration of CDDP and associations with other chemotherapeutic agents or drugs which could potientiate CDDP renal damage (non steroidal anti-inflammatory agents, analgesics, antibiotics, antihypertensive agents, diuretics and contrast media). Mean creatinine concentration versus time rises significantly. This elevation is significantly higher in patients with hypertension, diabete, one functional kidney, or abdominoperineal irradiation. The association with other drugs has not proved a real influence on creatinine evolution.

The influence of thyroid hormones upon the inductive effects on microsomal enzymes and the hepatic proliferation produced by different fibrates was studied in the male rat. A pharmacological dose of triiodo-L-thyronine significantly lowers the total cytochrome P450 content induced by some equi-effective doses of clofibrate, ciprofibrate, bezafibrate and fenofibrate. The ethoxycoumarin O-deethylase activity (ECOD) is concomitantly decreased. On the contrary, L-T3 accentuates the specific inductive effect of fibrates on bilirubin-UDPGT activity. Hypothyroid has little or no influence upon the effect of fibrates towards cytochrome P450 content and ECOD activity. On the other hand, this thyroid status significantly lowers the CN- palmitoyl coenzyme A dehydrogenase, which is a marker enzyme of the peroxisome proliferation caused by the different fibrates. These results indicate a possible modulation of thyroid hormones within the fibrates induction mechanism in the rat.

The authors report the case of erythema multiforme characterized by its cephalic onset and its rise after association phenytoin and cranial irradiation, for glioblastoma with epileptic fits. Eight similar cases are observed in literature with the same timing. Benign outcome is not always the rule because 2 patients died. This type of reaction being not forseeing, and outcome very varying, we suggest to avoid phenytoin in patients having a cerebral tumor revealed by epilepsy and needing a cranial irradiation.

The influence of thyroid hormones on microsomal drug metabolizing enzymes was studied in hypothyroid newborn rats and chick embryos. Administration of 3,5,3'-triiodo-L-thyronine strongly decreased the microsomal cytochrome P 450 content in hypothyroid new-born rats and thus could render the rat pup more susceptible to hepatotoxicity from drugs. The drug metabolizing system in 20 days old chick embryos was less sensitive to the effects of thyroid hormone, but administration of phenobarbital was accompanied by a strongly induction effect on microsomal enzyme activities.

Male Wistar rate were treated with benfluorex, 50 mg/kg/p.p. daily for 7 days. The administration of benfluorex markedly increased the activity of ethoxycoumarin deethylase without increase of cytochrome P 450 levels in hepatic microsomes. The activity of bilirubin glucuronosyl transferase is so much increased with benfluorex than phenobarbital but this effects are not additive. Benfluorex alone affected the fatty acid composition of microsomal lecithins and when given with phenobarbital benfluorex modified the phenobarbital-induced changes in the fatty acid composition of microsomal lecithins. Electrophoresis of microsomal proteins showed non sensitive induction of any proteins with benfluorex.

1. Male Wistar rats were treated with tiadenol, 200 mg/kg/ p.o. daily for 7 days. 2. The administration of tiadenol markedly increased the activity of bilirubin glucuronosyl transferase in hepatic microsomes. Cytochrome P 450 levels and ethoxycoumarin deethylase activity were more slightly increased. 3. Electrophoresis of microsomal proteins showed the induction of a protein with a molecular weight of about 72,000. 4. Tiadenol alone only slightly affected the fatty acid composition of microsomal lecithins and cephalins. When given with phenobarbital, however, tiadenol modified the phenobarbital-induced changes in the fatty acid composition of microsomal lipids.

Rats fed a dietary peroxidized fish oil showed an increase in cytochrome P-450 content and ethoxy-coumarin deethylase (ECDE) activity in liver microsomes. Administration of DL-alpha-tocopherol led to different effects according to the extent of the peroxidation in the fish oil. In rats fed a de-peroxidized oil, the inductive effect of phenobarbital on UDP-glucuronosyltransferase (UDGPT) activity was depressed by tocopherol. By the same time, induction of P-450 and ECDE remained unchanged, that of epoxide hydrase slightly increased. By contrast tocopherol strongly potentiated the inductive effect of phenobarbital toward UDPGT activity (group I substrates) in rats fed the peroxidized fish oil. The modification of the inductive effect of phenobarbital in combination with tocopherol on UDPGT activities was concomitant with an increase in seric transaminase activity and with a reverse effect as revealed from the study of the rate of fluorescent probes penetration in microsomes. The possible toxicity of the strong dose of tocopherol is discussed.

A cholesterol rich diet fed to rats was found to increase the cytochrome P 450 content in hepatic microsomes. Furthermore, the variations of the same parameters promoted by 3,5,3'-triiodo-L-thyronine were strongly reduced in cholesterol supplemented rats. Cholesterol prevented the inducing effects of phenobarbital but did not oppose its decreasing effect on maximal fluorescence of ANS and PNA introduced into the microsome suspensions.

Male Wistar rats were treated daily for 7 days with clofibrate (250 mg/kg/d), benfluorex (50 mg/kg/d), tiadenol (200 mg/kg/d), nicoclonate (100 mg/kg/d) or hexanicit (50 mg/kg/d). The cytochrome P 450 level and ethoxycoumarin deethylase activity (ECDE) in liver microsomes were markedly increased by administration of clofibrate and slightly increased by tiadenol. Benfluorex only increased the activity of ECDE and nicoclonate and hexanicit had no effect. Clofibrate, tiadenol and benfluorex increased the activity of microsomal bilirubin UDP-glucuronosyltransferase. On the other hand, the nicotinic derivatives were ineffective. Tiadenol clearly enhanced the inductive effects of phenobarbital.

Decreased elimination of sotalol (160 mg) is found in patients with renal insufficiency. Simulation of plasma concentrations at steady-state exhibits moderately higher concentrations when creatinine clearance is between 10 and 30 ml/min and very high plasma concentrations when creatinine clearance is less than 10 ml/min suggesting, if treatment is absolutely necessary, monitoring in these cases and the reduction of the dose in major renal insufficiency.

The effect of peroxidized soybean oil in the diet of male Wistar rats was studied on hepatic drug metabolizing enzymes and their phenobarbital induction and compared to that of natural soybean diet in the same conditions. No hepatomegaly or increase in serum transaminases occurred, however growth was inhibited after ingestion of peroxidized soybean oil. In addition, the protein biosynthesis of epoxide hydrase determined by immunochemistry was largely stimulated by this treatment; but the corresponding activity measured with benzo(a)pyrene 4-5 oxide as a substrate was increased in weaker proportions. This induction was limited to epoxide hydrolase only, since the enzymes of phase one were not affected and UDP glucuronosyltransferase activities toward group I substrates were randomly activated. The induction of epoxide hydrolase may affect only one or several isoforms of the membrane enzyme which are not necessarily specific to benzo(a)pyrene 4-5 oxide activity determination of the enzyme.