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SummaryBackground Inhibitors of dipeptidyl peptidase (DPP)-IV have been suspected in the onset of bullous pemphigoid for several years now. However, comparative studies assessing the link between DPP-IV inhibitor exposure and bullous pemphigoid have not yet been performed. Objectives To detect, from the French Pharmacovigilance Database (FPVD), a signal of risk of bullous pemphigoid during DPP-IV inhibitor exposure by comparative study. Methods All spontaneous reports of DPP-IV inhibitor-related bullous pemphigoid recorded in the FPVD between April 2008 and August 2014 were described. We conducted disproportionality analyses (case–noncase method) to assess the link between DPP-IV inhibitors and bullous pemphigoid, calculating reporting odds ratios (RORs). We also compared DPP-IV inhibitor-induced bullous pemphigoid reports rated per million defined daily doses dispensed during the study period. Results Among 217 331 spontaneous adverse drug reaction reports registered in the FPVD, 1297 involved DPP-IV inhibitors. Among these observations, 42 were bullous pemphigoid (vildagliptin, n = 31; sitagliptin, n = 10; saxagliptin, n = 1). The ROR for pooled DPP-IV inhibitors was 67·5 [95% confidence interval (CI) 47·1–96·9]. Disproportionality was also observed for each DPP-IV inhibitor: vildagliptin (ROR 225·3, 95% CI 148·9–340·9), sitagliptin (ROR 17·0, 95% CI 8·9–32·5) and saxagliptin (ROR 16·5, 95% CI 2·3–119·1). Analyses adjusted on dispensing data led to similar results. Conclusions These data confirm a strong signal for an increased risk of bullous pemphigoid during DPP-IV inhibitor exposure. This adverse drug reaction is observed for each DPP-IV inhibitor, suggesting a class effect. The signal was higher with vildagliptin than with the other DPP-IV inhibitors.

International audience; no abstract

International audience; Drug-induced adverse effects are one of the main avoidable causes of hospitalization in older people. Numerous lists of potentially inappropriate medications for older people have been published, as national and international guidelines for appropriate prescribing in numerous diseases and for different age categories. The present review describes the general rules for an appropriate prescribing in older people and summarizes, for the main conditions encountered in older people, medications that are too often under-prescribed, the precautions of use of the main drugs that induce adverse effects, and drugs for which the benefit to risk ratio is unfavourable in older people. All these data are assembled in educational tables designed to be printed in a practical pocket format and used in daily practice by prescribers, whether physicians, surgeons or pharmacists.; Les effets indésirables médicamenteux représentent l'une des principales causes évitables d'hospitalisation chez les sujets âgés. Un certain nombre de listes de médicaments potentielle-ment inappropriés chez les sujets âgés a été publié et il existe de nombreuses recommandations internationales pour le bon usage des médicaments par pathologie, et par tranche d'âge. La présente mise au point précise les règles générales de prescription des médicaments chez les sujets âgés et résume, pour les situations cliniques les plus fréquemment rencontrées, les médicaments sous-utilisés à tort et à recommander, les précautions d'emploi à observer pour réduire les effets secondaires des principaux médicaments pourvoyeurs d'effets indésirables et les médicaments dont le rapport bénéfice/risque est défavorable chez les sujets âgés. Ces recommandations sont synthétisées dans des tableaux didactiques conç us pour être imprimés dans un format de poche et être utilisés au quotidien par les prescripteurs quel que soit leur domaine d'activité, médicale, chirurgicale, ou pharmaceutique.

International audience; Predicting environmental concentrations of carbamazepine and oxcarbazepine and their main metabolites in a coastal system Predicting of environmental concentrations of pharmaceuticals is commonly done for risk assessment at a regional level. The difficulties appear for the prediction at a local level, where data available is scarce. This work developed a model to predict the behavior of carbamazepine (CBZ), oxcarbazepine (OxCz) and their main metabolites in a regional environmental system : a coastal zone with a WWTP submarine outfall. The model takes into account the initial CBZ and OxCz prescriptions, metabolisms and partial transformations of CBZ and OxCz into their metabolites, their fate in wastewater treatment plants and their flow to the coastal zone through the submarine outfall. Regional data on CBZ and OxCz prescription were obtained from the medical care system. CBZ and OxCz prescribed amounts have been studied over 6 months in view to calculate concentrations in wastewater treatment plant effluents and so allow for Predicted Environmental Concentrations (PECs) estimation. The human metabolic pathways of CBZ and OxCz required to include in the model the contribution of the major urinary metabolites: carbamazepine-10,11-epoxide, 10,11-dihydro-10,11-trans-dihydroxycarbamazepine, 10-hydroxy-carbamazepine and other hydroxylated derivatives. PECs lie in the ng/L level in the wastewater effluents and were compared to the measured concentrations (MECs). The diffusion in the coastal zone was estimated with an hydrodynamic numeric model (MARS 3D). The behavior in the coastal zone was qualitatively compared to measured concentrations obtained with POCIS passive samplers. Data on pharmaceuticals in the coastal zone are scare and PECs and diffusion model might therefore be useful for studying pharmaceutical transfer and fate in the coastal environment

Adenine nucleotides have been shown to stimulate insulin secretion by acting on P2 receptors of the P2Y type. Since there have been some discrepancies in the insulin response of different analogues of ATP and ADP, we investigated whether two different types of P2 receptors exist on pancreatic B cells. The effects of alpha,beta-methylene ATP, which is more specific for the P2X subtype, were studied in vitro in pancreatic islets and isolated perfused pancreas from rats, in comparison with the potent P2Y receptor agonist ADPbetaS. In isolated islets, incubated with a slightly stimulating glucose concentration (8.3 mM), alpha,beta-me ATP (200 microM) and ADPbetaS (50 microM) similarly stimulated insulin secretion; by contrast, under a non stimulating glucose concentration (3 mM), alpha,beta-me ATP was still effective whereas ADPbetaS was not. In the same way, in islets perifused with 3 mM glucose, alpha,beta-me ATP but not ADPbetaS induced a partial but significant reduction in the peak 86Rb efflux induced by the ATP-dependent potassium channel opener diazoxide. In the isolated pancreas, perfused with a non stimulating glucose concentration (4.2 mM), ADPbetaS and alpha,beta-me ATP (5-50 microM), administered for 10 min, induced an immediate, transient and concentration-dependent increase in the insulin secretion; their relative potency was not significantly different. In contrast, with a slightly stimulating glucose concentration (8.3 mM), ADPbetaS was previously shown to be 100 fold more potent than alpha,beta-me ATP. Furthermore, at 4.2 mM glucose a second administration of alpha,beta-me ATP was ineffective. In the same way, ADPbetaS was also able to desensitize its own insulin response. At 3 mM glucose, alpha,beta-me ATP as well as ADPbetaS (50 microM) induced a transient stimulation of insulin secretion and down regulated the action of each other. These results give evidence that pancreatic B cells, in addition to P2Y receptors, which potentiate glucose-induced insulin secretion, are provided with P2X receptors, which transiently stimulate insulin release at low non-stimulating glucose concentration and slightly affect the potassium conductance of the membrane.

1. Epidemiological and experimental data have shown that homocysteine may provoke vascular lesions and that moderate homocysteinaemia may constitute an independent risk factor for vascular disease. It is now documented that homocysteine damages human endothelial cells in culture, possibly by producing hydrogen peroxide in an oxygen-dependent reaction. 2. In this study, we have examined the direct effect of this sulphur amino acid on pancreatic vascular resistance. Experiments were performed on the vascular bed of the rat isolated pancreas perfused at constant pressure; thus, any change in pancreatic vascular resistance resulted in a change in the flow rate. D,L-Homocysteine perfused for one hour at three different concentrations (200 microM, 2 mM, 20 mM) did not induce any significant change in the flow rate per se. Homocysteine infusion for 30 min at a concentration of 200 microM or 2 mM abolished the endothelium-dependent vasodilatation induced by acetylcholine (0.05 microM), but did not modify adenosine (1.5 microM)-induced vasodilatation. 3. The effect of D,L-homocysteine (200 microM or 2 mM) cannot be ascribed to a direct antimuscarinic effect since 30 min pretreatment of rat ileum with these concentrations did not significantly change the contractile effect of increasing concentrations of acetylcholine (0.015-15 microM). 4. Preincubation of human umbilical vein endothelial cells with D,L-homocysteine (0.2-5.0 mM) had no significant effect on overall cell number or viability during 18 h of incubation; the endothelial cells exposed to concentrations up to 5 mM exhibited a spindle-shaped, whirled pattern. This pattern was reversed 48 h after the removal of homocysteine. A cytotoxic effect was seen after 18 h incubation in 10 mM D,L-homocysteine. 5. In conclusion, an acute infusion of homocysteine altered acetylcholine endothelium-induced vasodilation, whereas the adenosine vasodilatator effect was insensitive to the deleterious action of homocysteine in vitro.