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Resume • L’etude S.AGES avait pour objectif principal de decrire les caracteristiques cliniques et les modalites de prise en charge des patients diabetiques de type 2 (DT2) âges, suivis en France en medecine generale. • Il s’agit d’une etude de suivi de cohorte, non interventionnelle, nationale et multicentrique, qui a inclus 959 patients DT2 âges de plus de 65 ans, suivis par 227 medecins generalistes. Les resultats a l’inclusion montrent qu’une proportion importante de ces malades presentait une HbA 1c

The cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of most antidepressants. Comedication with a potent CYP2D6 inhibitor can convert patients with extensive metabolizer (EM) or ultra-rapid metabolizer (UM) genotypes into poor metabolizer (PM) phenotypes. Since comedication is frequent in depressed patients treated with antidepressants, we investigated the effect of the CYP2D6 composite phenotype on antidepressant efficacy, taking into account both the CYP2D6 genotype and comedication with CYP2D6 inhibitors. 87 Caucasian in patients with a major depressive episode were prospectively treated with flexible doses of antidepressant monotherapy as well as comedications and genotyped for the major CYP2D6 alleles (CYP2D6*3 rs35742686, *4 rs3892097, *5 del, *6 rs5030655, and *2xN). They were classified for CYP2D6 composite phenotype and assessed for antidepressant response after 4 weeks. In terms of genotypes (g), 6 subjects were UMg, 6 PMg, and 75 EMg. Ten patients were coprescribed a CYP2D6 inhibitor, resulting in the following composite phenotypes (cp): 5 UMcp, 16 PMcp, and 66 EMcp. Whereas none of the CYP2D6 genotypes were significantly associated with antidepressant response, UMcp had a lower antidepressant response than PMcp or EMcp (respectively: 39.0 ± 17.9, 50.0 ± 26.0, and 61.6 ± 23.4, p = 0.02). Despite small sample size, this study suggests that a CYP2D6 composite phenotype, taking into account both genotype and comedications with CYP2D6 inhibitors, could predict CYP2D6 substrate antidepressants response. Thus, to optimize antidepressant response, CYP2D6 genotype could be performed and comedications with CYP2D6 inhibitors should be avoided, when prescribing CYP2D6 substrate antidepressants.

Resume But de l’etude La grossesse chez la femme drepanocytaire est a haut risque maternel et fœtal. Notre objectif etait d’evaluer l’interet d’un programme transfusionnel prophylactique adapte, soit par des transfusions de globules rouges, soit par des echanges erythrocytaires automatises, chez des patientes drepanocytaires ayant des antecedents de complications obstetricales et/ou vaso-occlusives severes. Patientes et methodes Nous avons suivi 18 grossesses chez 14 patientes (12 SS, 1 SC, 1S/β-thalassemie). Sept avaient eu une ou plusieurs grossesses anterieures avec, dans neuf cas sur dix, des complications maternofœtales graves. Sept ont ete prises en charge des leur premiere grossesse en raison d’antecedents de complications drepanocytaires severes. Le but etait d’obtenir un taux d’hemoglobine anormale (hemoglobine S ou S + C) inferieur a 50 % et un taux d’hemoglobine entre 9 et 11 g/dL. Le choix entre transfusions simples et echanges erythrocytaires etait fonction du taux d’hemoglobine. Les echanges erythrocytaires ont ete realises a l’aide d’un separateur de cellules (Com. Tec, Laboratoires Fresenius). Dans dix cas, les patientes n’ont eu que des echanges erythrocytaires. Dans cinq cas, seules des transfusions simples ont ete realisees. Dans trois cas, les patientes ont beneficie successivement de transfusions et d’echanges erythrocytaires. Resultats Aucune complication maternelle grave et aucune mort fœtale ou perinatale n’ont ete observees. Dans un cas, l’accouchement a ete declenche a 36 semaines d’amenorrhee du fait d’une souffrance fœtale avec hypotrophie. Conclusion Les femmes atteintes d’un syndrome drepanocytaire majeur peuvent, meme en cas d’antecedents obstetricaux severes, mener a terme une grossesse sans grave complication obstetricale grâce a l’association d’une prise en charge precoce par une equipe multidisciplinaire et d’une politique transfusionnelle preventive adaptee.

Data required to asses the risk of a new drug regarding the normal course of pregnancy as well as embryo, fetal and neonate development, are often missing when a new product is launched. In such a situation, a risk management plan is to be developed by the industrial and validated by regulatory authorities. This risk management plan is to take into account the data benefits on the drug and its potential therapeutic use by women as being of childbearing age. The obtaining of post licence human data is to be built on many players, both private and public, involved in the data collection and evaluation. The setting up of such a network would allow them to join together and optimize their action by standardizing the data collected and their follow up. This should help to generate or rapidly respond to an alert, to conduct collaborative pharmacovigilance pharmacology studies.

Resume Le sujet de la table ronde etant initialement tres vaste, il avait ete convenu avec les participants de le recentrer sur les therapies cellulaires (TC) impliquant des cellules autologues utilisees dans des situations de reconstruction tissulaire, d’immunomodulation et de transduction. La TC autologue concerne aussi bien des pratiques tres innovantes que des produits utilises en routine depuis plusieurs annees. Le cadre reglementaire de la TC est maintenant finalise en France. Ce dernier met en exergue le fait qu’un produit de TC est intrinsequement lie a son procede de preparation. L’objectif de cette table ronde etait de definir les pre-requis indispensables a prendre en compte lors du developpement de therapies impliquant des preparations cellulaires ex vivo et ce, afin de s’assurer de la securite d’emploi de tels produits. Les differentes etapes du developpement d’un produit de therapie cellulaire (PTC) ont ete envisagees : (i) contraintes de production permettant de garantir la qualite du produit ; (ii) developpement non clinique : importance de modeles animaux pertinents pour demontrer la preuve du concept et affiner les specifications du PTC ; (iii) developpement clinique : specificite methodologique du developpement d’un PTC. Les problemes inherents a l’utilisation des produits therapeutiques annexes (PTA) au cours du developpement d’un PTC ont ete souleves. Des mesures ont ete envisagees pour qu’a terme l’approvisionnement et la qualite d’un PTA ne constituent pas des facteurs limitants pour le developpement de la TC en France. Enfin, une information des professionnels de sante et des industriels concernant la biovigilance s’est averee necessaire.

The topic of the round table being very broad, it was agreed with the participants that the discussion should be focused on autologous cell therapy (CT) used in tissue repair, immunomodulation or gene transduction. Autologous CT is actually comprised of both very innovative procedures as well as of products used in routine clinical practice. In France, the regulatory framework for CT has now been finalised, underlining the fact that a CT product (CTP) is intrinsically linked to the process used in its preparation. The objective of this round table was to define the essential prerequisites for the development of therapies involving ex vivo cell preparations and, more specifically, to address the issues associated with patient safety during the course of product development. The different stages of CTP development were considered: (i) requirements for CTP manufacturing in order to guarantee product quality; (ii) nonclinical development, and selection of appropriate animal models to provide the proof of the concept and support the definition of CTP specifications; and (iii) clinical development and methodological specificities of CTP development. The specific problems associated with the use of ancillary therapeutic products (ATPs) during the development of a CTP were discussed. Actions were proposed to ensure long-term supply of ATPs, which may be a significant bottleneck for the development of CT in France. Eventually, new regulatory provisions will come into force in the area of biovigilance, and it was deemed necessary for healthcare and industry professionals to be appropriately involved in the implementation phase.

Objective Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth. Methods Ibuprofen was administered on days 3, 4, and 5 by a 15-minute intravenous infusion of 10, 5, and 5 mg/kg, respectively, with the aim of closing the ductus arteriosus. Blood samples were drawn at time zero and at 0.5, 1, 2, 4, 12, and 24 hours after the first and third doses. Ibuprofen plasma concentrations were assayed by HPLC. Results A total of 27 premature infants were included (gestational age, 28.6 ±1.9 weeks; birth weight, 1250 ±460 g; values are mean ±standard deviation). Ibuprofen pharmacokinetics followed a 2-compartment open model. Between the first and third doses (day 3 and day 5) there was a significant decrease of the volume of distribution of the central compartment (Vdc) (0.244 versus 0.171 L/kg; P = .03) and area under the plasma concentration-time curve (524 versus 447 mg · h/L; P = .01). The decrease in Vdc was most pronounced in patients with a closing ductus. Total body clearance and plasma half-life did not change significantly. No significant differences were observed in ibuprofen peak plasma concentrations after the first and third doses in relation to ductal status after treatment. Conclusion Ibuprofen pharmacokinetics showed a large interindividual variation in premature infants during treatment for patent ductus arteriosus, and significant changes may occur between day 3 and day 5 after birth in those infants with a closing ductus. These findings may have implications for the treatment schedule with ibuprofen in patients with patent ductus arteriosus. Clinical Pharmacology & Therapeutics (2001) 70, 336–343; doi: 10.1016/S0009-9236(01)13478-8

Evaluate the impact of educational intervention in decreasing ADEs in elderly patients in a hospital setting.Randomised prospective study.The study was performed in France in the Paris area, in 16 rehabilitation geriatric centres of APHP (Assistance Publique - Hôpitaux de Paris). Patient capacity per centre varied from 15 to 57 with a total of 526.All the patientsor = 65 years hospitalized during the 4 week study period were included.During a first 2 week phase without intervention ADE's were recorded in all centres. Then units were then randomised for an educational intervention or not. The educational phase lasted 1 week, without ADE tracking. Then, both types of units (I+ and I-) recorded ADEs for 2 weeks. Possible drug-related incidents were detected using a standardized check list (nurses) and a weekly review of all charts by investigators. Possible drug-related incidents were analysed by a group of reviewers selected from the authors to classify them as ADE or not.576 patients (mean age: 83.6 +/- 7.9 years) were consecutively included. The mean number of drugs at inclusion was 9.4 +/- 4.24 drugs per patient. 223 out of 755 events were considered "probable" ADEs (29.5%). Among the 223 ADEs, 62 (28%) could have been prevented. The main outcome of this trial was the change in the proportion of ADEs in elderly patients in the intervention-units, compared to the control group. The main errors were: to high a dose (26%), double therapy (21%), under dose (13%), inappropriate drug (13%), drug-drug interaction (6%), previous same adverse drug reaction (3%) and miscellaneous (11.18%). After a specific educational intervention program, there were fewer ADEs in the intervention group (n = 38, 22%) than in the control group (n = 63, 36%; p = 0.004).Educational programs could help reduce the prevalence of ADEs by 14% and encourage physicians to change outdated prescription habits.

Lupus anticoagulant was present in this case of paraneoplastic scleroderma revealed by hemolytic-uremic syndrome, suggesting that the autoantibody played a significant role in the sequence of events leading to anuria. Reviewing the literature we found several observations of paraneoplastic scleroderma, and in other series cases of scleroderma-linked (and in rare instances cancer-linked) antiphospholipid autoantibodies. Search for antiphospholipid antibodies should be considered in patients with systemic scleroderma as well as in patients with metastatic cancer. Presence of such procoagulant autoantibodies might predict future complications and should influence treatment strategy.

Rationnel L’hemorragie digestive haute (HDH) est un effet indesirable severe des AINS. Tous les AINS en dehors de l’acide acetyl salicylique (aspirine) sont pour une part metabolises par le CYP2C9. Un deficit allelique en cytochrome CYP2C9*3 pourrait etre un facteur de risque d’HDH liee aux AINS et non a l’aspirine. Patients et Methodes De 2004 a 2007 nous avons mene une etude prospective multicentrique cas controle dans laquelle tous les patients admis pour une HDH ayant pris un AINS ou de l’aspirine etaient inclus. Resultats 204 patients ont ete inclus ; 16 etaient exclus en raison de la prise concomitante d’AINS et aspirine. Parmi les 188 patients restants, 131 avaient pris de l’aspirine et 57 un AINS (non salicyle). Dans le groupe aspirine, 12 patients (9,2 %) etaient porteur de l’allele CYP2C9*3 contre 19 (33,3 %), p Conclusion Cette etude confirme l’importance du portage du variant CYP2C9*3 chez les patients presentant une hemorragie digestive haute sous AINS non salicyle.

were expressed as the number of positive neurons (mean±SEM) per dentate gyrus in a 10-mm section. Group comparisons were conducted using ANOVA and post-hoc Bonferroni tests. Results: In control rats we observed 5.4±1.5 P(Ser10)Ac(Lys14)-H3+ neurons and 1.7±0.5 Fos+ neurons per dentate gyrus in a 10-mm section. The novelty challenge evoked significant increases in P(Ser10)-Ac(Lys14)-H3+ (+81%, P< 0.05) and Fos+ neurons (+132%, P< 0.05) which were dose-dependently blocked by Lorazepam pre-treatment. FG7142 significantly increased the number of dentate P(Ser10)-Ac(Lys14)-H3+ (+103%, P< 0.05) and Fos+ (+335%%, P< 0.05) neurons in control rats when compared with the vehicle group and this increase was even further enhanced in the novelty-challenged animals. The GABAergic drugs differentially influenced behaviour in the novel cage. Detailed analysis of the behavioural changes is currently in progress. Discussion: Our results show that GABA is a powerful modulator of novelty-induced changes in histone H3 modifications and associated gene expression which is in keeping with this neurotransmitter’s role in controlling dentate neuron excitability. It is thought that excitation of dentate neurons requires overcoming of the tonic GABAergic inhibition exerted on these neurons. Our study shows that this GABA action includes the modulation of epigenetic and gene expression processes which, we have hypothesised, play an important role in the adaptation of the organism to the stressful event.

Anuria complicated the malignant phase of hypertension in twelve patients (ten males and two females). Five were black; five had primary hypertension; one had HBs virus angiitis; the six remaining cases suffered from previously documented renal disease, including two with Berger's disease. Renal angiography showed interruption of renal blood flow as far as the main branches of the renal artery and/or a false impression of 'cortical necrosis' and of 'renal infarcts'. In contrast, renal biopsy did not show irreversible vascular damage. Thus, anuria was mainly functional and due to active renal vasoconstriction. This was confirmed by the subsequent course; diuresis resumed after 1 week to 24 months of dialysis. Repeat angiography in six cases showed recovery of renal circulation and disappearance of 'cortical infarcts', even when plasma renin activity remained elevated and hypertension was not controlled. In one case captopril induced a new reversible episode of anuria. These observations suggest that active vasoconstriction with prolonged anuria might be due to some vasoconstrictive substance other than angiotensin II.