[Pharmacoepidemiology of diabetes: assessment of good use of oral antidiabetic drugs]. / Pharmacoépidémiologie du diabète : évaluation du bon usage des antidiabétiques oraux.

Diabetes' treatment is specific; therefore diabetic patients can be identified by the prescription of antidiabetic drugs. This pathology is characterized by chronicity and occurrence of complications which need additional medications. All the drugs have official use guidelines due to drug interactions and/or physiological status of the patients. To evaluate how these guidelines are followed in general practice, we used a data base from the French Health care System. Two thousand eight hundred and ninety eight (2 898) prescriptions on which, at least, one oral antidiabetic drug was noticed, were analysed. The number of drugs on each prescription was between 1 and 18 (mean (5,6 +/- 2,9)). Considering the drugs which need precautions of use in association with sulfonylureas, coprescription occurred with B-bloquants and non steroid anti-inflammatory drugs in 18 and 17 % of the cases respectively. The drugs which need precautions of use in association with biguanides were diuretics, oestrogens and/or progestatives and steroids, coprescribed in 28, 1, 1 % of the cases respectively. Percentages of coprescriptions which need precautions of use were quite high. The relevance of detected coprescriptions. and the compatibility between recommendations for "good prescription" and "real prescription practice" should be taken into account considering diabetic patients' characteristics.

[Pharmacoepidemiology of diabetes: contribution of a survey of health insurance cases]. / Pharmacoépidémiologie du diabète: apports d'une enquête des Caisses d'Assurance Maladie.

To determine the pattern of treatment of diabetes and its complications, data from a specific study performed by the French healthcare system were used. Between the 10th and 15th of May 1993, all the prescriptions for which a reimbursement was asked were registered with the age and sex of the subject for whom the prescription was written. Patients with a prescription of antidiabetic (AD) drugs were classified as diabetic. Among the 125,883 prescriptions at least one antidiabetic drug is present on 3339 (2.7%). The mean number of AD drugs prescribed is 1.3 and varies from 1 to 4. Eighty five per cent of the patients are treated with oral anti diabetic drugs alone (OAD) and 15% with insulin, alone (89%) or in association with OAD (11%). The total number of drugs (antidiabetic drugs included) prescribed for one patient varied from 1 to 18 (mean: 5.7) and is higher in women than in men. Drugs which are indicated in cardiovascular diseases (lipids lowering, blood pressure lowering drugs) are more frequent on "diabetic" prescriptions than on non diabetic ones. Most (66%) of the prescriptions are written on special forms (100% reimbursement). These forms are more often used for insulin treated patients (87%) than for non insulin treated patients (62%). Most (91%) of the prescriptions are written by a general practitioner. Taking into account the antidiabetic drugs specificity and the data base used, these results can be extrapolated to the all french diabetic population.

[Prevalence of Clostridium difficile and toxin A in feces of HIV infected patients]. / Prévalence de Clostridium difficile et de la toxine A dans les selles de patients VIH positifs.

Patients with AIDS are immunodeficient, receive multiple antibiotic treatments, occasionally anti-cancer chemotherapy and are often hospitalised; thus they are susceptible to develop a Clostridium difficile infection. The aim of this study was to evaluate the role of C. difficile in diarrhoea in this patient population. Therefore, C. difficile and toxin A which plays a major role in pathogenicity were examined in faecal samples of HIV infected patients. Between January 1991 and June 1992, 102 stool samples from 67 patients were studied. Ninety p. cent of these patients were hospitalised (length > 3 days), 80% had a diagnosis of AIDS stage IV, and 66% had diarrhoea. Nineteen point four p. cent of the patients were carriers of C. difficile. Different associations were found: 1) presence of non toxigenic strains and absence of toxin A in stool samples (6 patients), 2) presence of toxigenic strains and absence of toxin A in stool samples (6 patients), 3) presence of toxigenic strains and toxin A in stool samples (2 patients). None of the patients developed a colitis or pseudomembranous colitis. The carrier rate was identical to those found in other hospitalised populations without AIDS. The prevalence of C. difficile diarrhoea or colitis is low. In this study, AIDS patients do not seem to constitute a risk group for C. difficile intestinal pathology. However, carriers of C. difficile were subjected to strict hygiene rules to prevent nosocomial spread.

[3H]MK-801 binding to NMDA glutamatergic receptors in Parkinson's disease and progressive supranuclear palsy.

The interactions existing between glutamatergic and dopaminergic systems, notably in the basal ganglia, suggest that glutamatergic antagonists may have therapeutic interest in extrapyramidal disorders characterized by impaired dopaminergic transmission. The binding of [3H]dizocilpine maleate (MK-801) to glutamate receptors of the N-methyl-D-aspartate (NMDA)-subtype was characterized in temporal and frontal cortex, in hippocampus and in subcortical areas (caudate nucleus and putamen) from controls and patients with Parkinson's disease or progressive supranuclear palsy. The binding affinity (KD) and the maximal specific binding capacity (Bmax) of [3H]MK-801 were unchanged in all the cerebral regions studied in both diseases. This indicates the existence of preserved NMDA glutamate receptors, which is required for potential therapeutic efficacy of specific antagonists.

Regional differences in the sensitivity of cholinergic neurons to dopaminergic drugs and quipazine in the rat striatum.

Marked differences were found in the activity of choline acetylase (ChAc) in various discrete areas of the rat striatum. The richest cholinergic innervation was observed in the centrolateral part of the structure. A similar distribution was obtained by measuring acetycholine (ACh) levels in punches taken from frozen frontal serial slices. As revealed by the analysis of the topographical distributions of ChAc activity, ACh, 5-HT and DA, the regional cholinergic innervation differed markedly from that of aminergic terminals. Changes in ACh levels induced by drugs could be estimated in microdiscs of tissues punched from frozen slices. Apomorphine and haloperidol, which increased and decreased ACh levels respectively, induced similar effects in the various striatal areas examined. By contrast quipazine, a drug acting on 5-HT uptake and release and on serotoninergic receptors, selectively increased ACh levels in some areas of the striatum but not in others. The regional changes in ACh levels induced by quipazine were satisfactorily correlated with the regional distribution of 5-HT but not with that of DA. These results suggest that a limited population of striatal cholinergic neurons is under the inhibitory control of serotoninergic neurons. They also indicate that some striatal cholinergic neurons influenced by dopaminergic neurons are not controlled by serotoninergic neurons.

Effect of quipazine, a serotonin-like drug, on striatal cholinergic interneurones.

Quipazine (30 mg/kg i.p., 60 min), a serotonin-like drug increased ACh levels in the striatum (37%) but was without effect on the transmitter content in the hippocampus and the parietal cortex of the rat. Added in vitro(10(-5) M) or injected in vivo, quipazine did not affect choline acetylase and cholinesterase activities in striatal tissue. The drug effect on striatal ACh levels did not appear to be related to an interaction with dopamine metabolism. Indeed quipazine still increased striatal ACh levels after degeneration of the dopaminergic neurons had been induced by local injection of 6-OH-DA. p-Chlorophenylalanine (PCPA) pretreatment (300 mg/kg, 48 and 24 h before the experiment) definitely prevented the quipazine effect on ACh levels. This result suggested that the drug may partially act by its interference with 5-HT metabolism. 5-Methoxy-N,N-dimethyltryptamine (10 mg/kg, i.p., 30 min), a serotonergic agonist, induced a weak but significant increase in ACh levels. These data provide some preliminary evidence for the existence of an inhibitory control of the cholinergic interneurones by the serotonergic neurones projecting to the striatum. However, the lack of effect of 5-hydroxytryptophan (100 mg/kg i.p.), PCPA (2 x 300 mg/kg i.p.) and of Lilly 110 140 (10 mg/kg i.p.) and chlorimipramine (10 mg/kg i.p.), two potent inhibitors of 5-HT uptake, on striatal ACh levels indicate that further experiments are required to retain this hypothesis.

Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostriatal dopamine system.

The neurotoxic specificity of injections of 6-hydroxydopamine (6-OHDA) into areas containing either dopamine (DA) cell bodies (substantia nigra) or DA axon terminals (striatum) was studied. This selective effect was compared to the unspecific effects of copper sulfate (CuSO4) injection and electrocoagulation. One to two days after unilateral nigral injection of 2 mug of either 6-OHDA or CuSO4 into the nigra the volume of the unspecific lesions around the tip of the cannula was very similar. Only the 6-OHDA-induced lesions were associated with elective degeneration of the nigral DA neurons. Ten days after the administration of the same compounds the gliosis in the substantia nigra was much more extensive in CuSO4-than in 6-OHDA-treated rats; however, the reduction of DA concentrations in the ipsilateral striatum was only noticeable after 6-OHDA (-62%). A somewhat similar decrease of striatal DA levels (-52%) was observed after large electrocoagulation of the substantia nigra. Ten days after 6-OHDA (8mug) or electrolytic lesion of the striatum the Km for DA, serotonin and choline uptakes were similar in the striata of both sides, suggesting that the uptake process in the non-damaged neurons of the lesioned side was functionally normal. Following electrolytic lesion of the striatum, serotonin and choline Vmax values were decreased to about the same extent as the striatal reduction in weight and DA levels. When directly administered into the striatum 6-OHDA also produced a decline in DA concentration and Vmax but in contrast did not affect serotonin and choline uptake (Vmax), suggesting that the drug specifically destroyed dopaminergic neurons. The present data confirm that selective DA denervation can be achieved when appropriate amounts of the drug are injected into brain tissue in order to limit the unspecific lesion.

Oxotremorine- and atropine-induced changes of dopamine metabolism in the rat striatum.

The effects of various doses of oxotremorine and of atropine (30 min, i.p.) on the metabolism of dopamine were examined in the striatum of the rat. Changes in striatal dopamine metabolism were estimated by following either the accumulation of [3H] dopamine 15 min after intravenous injection of [3H] tyrosine or the accumulation of dopa (taken as an index of dopamine synthesis) in animals pretreated with a dopa decarboxylase inhibitor Ro4-4602. Oxotremorine, 0-1 mg kg-1, and atropine, 1 mg kg-1, did not affect dopamine metabolism. Oxotremorine, 0-5 and 1-5 mg kg-1, did not modify dopamine concentrations but increased the accumulation of [3H]dopamine. The drug enhanced dopa formation in animals pretreated with Ro4-4602. Atropine, 5 and 20 mg kg-1, increased the accumulation of [3H]dopamine but did not affect dopamine concentrations. The accumulation of dopa was not modified there being no difference from the saline value in animals pretreated with the dopa decarboxylase inhibitor at high dopamine metabolism and atropine reduced dopamine utilization.

Partial selectivity of 6-OHDA induced neuronal degeneration after intraissular injection in the brain with special reference to the nigro-striatal dopamine system.

The selectivity of 6-OHDA induced neuronal degeneration after intra-tissular injection in the brain is discussed considering the morphological and biochemical events occurring in the substantia nigra and in the striatum--after intranigral or intrastriatal application of the drug. The data suggest that a critical intratissular concentration of 6-OHDA is required to induce an elective neuronal degeneration. The importance of the non-specific damage can not be neglected when high doses of the drug are administered in the brain tissue.