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Background Major depressive disorder (MDD) is a complex disorder with a significant public health burden. Depression remission is often associated with weight gain, a major risk factor for metabolic syndrome (MetS). The primary objective of our study was to assess prospectively the impact of response to antidepressant treatment on developing MetS in a sample of MDD patients with a current major depressive episode (MDE) and who are newly initiating their treatment. Methods In the 6-month prospective METADAP cohort, non-overweight patients, body mass index 2, with MDD and a current MDE were assessed for treatment response after 3 months of treatment, and incidence of MetS after 3 and 6 months of treatment. Outcome variables were MetS, number of MetS criteria, and each MetS criterion (high waist circumference, high blood pressure, high triglyceridemia, low high-density lipoprotein-cholesterolemia, and high fasting plasma glucose). Results In total, 98/169 patients (58%) responded to treatment after 3 months. A total of 2.7% (1/38) developed MetS out of which 12.7% (10/79) (p value < 0.001) had responded to treatment after 3 months. The fixed-effect regression models showed that those who responded to treatment after 3 months of follow-up had an 8.6 times higher odds of developing MetS (odds ratio = 8.58, 95% confidence interval 3.89–18.93, p value < 0.001). Conclusion Compared to non-responders, non-overweight patients who responded to treatment after 3 months of antidepressant treatment had a significantly higher risk of developing MetS during the 6 months of treatment. Psychiatrists and nurses should closely monitor the metabolic profile of their patients, especially those who respond to treatment.

Introduction La prévalence et les caractéristiques des symptômes respiratoires persistants après COVID-19 sont en grande partie inconnues. Les objectifs étaient de déterminer la prévalence et les caractéristiques de ces symptômes à distance du COVID-19 et les relations entre dyspnée, anomalies radiologiques et troubles fonctionnels. Méthodes Dans l’étude de cohorte COMEBAC (Consultation Multi-Expertise de Bicêtre Après Covid-19), 478 survivants hospitalisés ont été évalués par téléphone 4 mois après la sortie de l’hôpital et 177 qui avaient été hospitalisés en unité de soins intensifs (USI) ou présentant des symptômes persistants ont été évalués en hôpital de jour (HDJ). La présence d’une dyspnée et d’une toux qui n’existaient pas avant la COVID-19, et les résultats des EFR, de la tomodensitométrie à haute résolution du thorax et de l’échocardiographie ont été recueillis. Résultats Parmi les 478 patients, 78 (16,3 %) ont signalé une dyspnée et 23 (4,8 %) une toux, apparues depuis la COVID-19. Les patients présentant une dyspnée d’apparition récente étaient significativement plus jeunes (56,1 ± 12,3 versus 61,9 ± 16,6 ans), avaient eu une COVID-19 plus sévère (admission en USI 56,4 % versus 24,5 %) et un antécédent d’embolie pulmonaire pendant la COVID-19 plus fréquente (18,0 % versus 6,8 %) (tous les p ≤ 0,001) que les patients sans nouvelle dyspnée et parmi eux 23 (29,5 %) avaient un score de Nijmegen > 22. Parmi les patients réévalués en HDJ, la prévalence des lésions fibrosantes pulmonaires était de 19,3 %, avec une étendue lésionnelle

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 Des unites de pharmacogenetique moleculaire se sont mises en place au sein de laboratoires hospitaliers francais. L’impact clinique de ces nouvelles structures est encore limite et de nombreuses questions d’ordre organisationnel, ethique, juridique, technique, social et economique les concernant restent a resoudre. Leur multiplication ainsi que l’accroissement de leur activite et de leur champ d’application sont cependant previsibles. A terme, ces unites devraient contribuer a limiter le probleme de sante publique que posent actuellement dans notre pays les variations interindividuelles de reponse aux medicaments. Devant ces perspectives d’evolution, il semble indispensable que cette activite hospitaliere soit rapidement reconnue par les pouvoirs publics et les differents acteurs de la sante en France. Il semble aussi indispensable que les problemes qu’elle pose soient pris en consideration et qu’elle puisse beneficier comme les autres activites de genetique moleculaire, d’une structuration en un reseau national de prise en charge et de garanties de financements.

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 Les donnees evaluant le risque d’un nouveau produit sur le deroulement normal de la grossesse et le developpement de l’embryon, du fœtus et du nouveau-ne sont le plus souvent manquantes lors de la mise sur le marche d’un nouveau produit. Dans une telle situation, un plan de gestion de risque doit etre prepare par l’industriel et valide par les autorites de sante. Ce plan doit tenir compte des donnees acquises sur le medicament et de son utilisation therapeutique potentielle par des femmes en âge de procreer. L’obtention de donnees humaines post-AMM (autorisation de mise sur le marche) doit s’appuyer sur les nombreux acteurs tant prives que publiques impliques dans le recueil des donnees et leur evaluation. Leur organisation en reseau devrait permettre de les federer et d’optimiser leur action en harmonisant les donnees recueillies et leur suivi. Ceci permettrait de generer ou repondre rapidement a une alerte, de realiser des etudes collaboratives en pharmacologie et pharmacovigilance.

Les decouvertes de cibles therapeutiques et d'outils diagnostiques nouveaux sont aujourd'hui le fruit du developpement considerable de la biologie cellulaire et moleculaire et des biotechnologies. Apres le sequencage du genome humain, la pertinence des donnees obtenues par les techniques a haut debit, notamment celles issues de la genomique et de la proteomique, depend en premier lieu de l'assurance-qualite et de la tracabilite du materiel biologique a partir duquel sont effectuees les recherches, ainsi que des annotations qui qualifient les echantillons. Les Centres de Ressources Biologiques, qui incluent les biobanques, les cryobanques et les tumorotheques sont donc des infrastructures essentielles pour la decouverte d'outils innovants pour la prevention, le diagnostic et le traitement des maladies, et la mise au point de nouveaux medicaments. La constitution d'un reseau de Centres de Ressources Biologiques Humains sur des bases ethiques et juridiques harmonisees constitue aujourd'hui un enjeu majeur pour le developpement de la recherche medicale en Europe.

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

Continuing advances in life sciences and medical research are the result of the remarkable achievements of cell and molecular biology. In the post-sequencing era, the quality of the huge amount of data continuously generated by biotechnology, i.e. genomics, proteomics and high-throughput screening, depends on the quality assurance and the traceability of the original biological materials, including the annotations linked to these materials. Thus, biological resource centres are key infrastructures supporting biotechnology, bioprocessing and the development of new approaches in the prevention, diagnosis and treatment of diseases.

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.

Molecular pharmacogenetic units have recently been established in several hospital laboratories in France. The clinical impact of these units is still limited and numerous problems of organizational, ethical, legal, technical, social and economical nature remain to be resolved. However, an increasing number of these units, a rise in their activities and an enlargement of their scope of application are foreseeable in the future. Ultimately, these units would significantly contribute to limit the public health problem caused by interindividual variabilities in drug effects. In view of these prospects, it seems essential that such hospital activity should be quickly recognised by the authorities and the various health sectors in France. It is also essential that the problems that arise from such pharmacogenetic activities should be considered by the authorities and would profit from the organization of a national network and from financial guarantees.

Maternal and fetal risk is often high during pregnancy in sickle cell disease. Our objective was to evaluate the benefits of a transfusion program adapted to each pregnant patient, either by red cell transfusion or by automated red cell exchange, in sickle cell patients with a history of serious obstetrical and/or sickling complications.We managed 18 pregnancies in 14 patients (12 SS, 1 SC, 1 S/b-thalassemia), seven of whom had a history of one or more pregnancies, with severe maternofetal complications in nine out of 10 cases. The other seven patients were pregnant for the first time and were in care because of a history of severe sickling complications. The aim was to achieve a proportion of abnormal hemoglobin (hemoglobin S or S+C) below 50% and a hemoglobin level between 9 and 11 g/dL. The choice between transfusion and red cell exchange was made in the light of the hemoglobin level. Red cell exchange was done using a Fresenius Com. Tec blood cell separator. Patients had red cell exchange in 10 cases, and transfusions in five cases. In three cases, patients had successive transfusions and red cell exchange.No serious maternal complication was observed. No fetal or perinatal death occurred. In one case, delivery was induced at 36 weeks of gestation because of fetal distress and hypotrophy.Our study suggests that women with severe sickle cell disease, even if they have a serious obstetrical history, can carry their pregnancy to term, without major obstetric complications, through a combination of early management by a multidisciplinary team and a suitable policy of prophylactic transfusion or automated red cell exchange.

Single nucleotide polymorphisms (SNPs) can significantly affect human phenotypes. Detection of allelic variant carriers has become a major goal for clinical pharmacologists in order to study phenotype-genotype relationships. However, there is a crucial need for rapid, and validated pharmacogenetic tests. The aim of the study was to validate a new fluorescence PCR strategy for cytochrome P450 2C9 (CYP2C9) and multidrug resistance gene (MDR1) genotyping. Results of CYP2C9 and MDR1 genotypes determined with reference techniques were compared to those obtained by allelic discrimination assays employing fluorescent TaqMan probes. Sixteen subjects carrying CYP2C9*2 and CYP2C9*3 allelic variants (heterozygous and homozygous) previously identified by sequencing and 55 subjects previously genotyped for MDR1 exon 26 (C3435T) SNP by conventional PCR-RFLP were genotyped with fluorescent PCR. Fluorescent PCR gave 100 % accuracy with the results obtained with reference genotyping strategies for each of the 3 SNPs. Genotyping results with fluorescent PCR repeated on three consecutive occasions remained constant over time for each of the 3 SNPs. Allelic discrimination assays based on fluorescent PCR gave entire satisfaction for CYP2C9 and MDR1 genotyping. This reliable genotyping strategy can be easily used in clinical practice and should be further developed for additional SNPs identification.

To assess the age-associated changes over time of plasma paraxanthine/caffeine (PAX/CAF) ratios used as a probe for CYP1A2 activity.Intraindividual and interindividual variabilities in PAX/CAF ratio were compared by phenotyping with caffeine, 16 young and 16 elderly healthy subjects on five occasions.PAX/CAF ratio variability was comparable regardless of age (intraindividual CV: 17.6 +/- 6% and 16.2 +/- 5.9%, interindividual CV: 48.1 +/- 2.9% and 42.7 +/- 3.6% in young and elderly, respectively). The PAX/CAF ratio was lower in elderly than in young subjects (95% CI for the difference: 0.004, 0.32) but the difference was not significant in nonsmokers compared separately.The variability over time of the PAX/CAF ratio is not influenced by age.

Liver drug metabolism is a major source of drug interactions. Three major human in vitro models are employed to detect drug interactions in the preclinical phases of drug development: recombinant enzymes, human liver microsomes and primary human hepatocyte cell cultures. Results obtained from these models may vary during the different phases of drug development. Identification of the metabolic pathways, enzymes involved in drug metabolism (mainly cytochrome P450s), enzyme induction or inhibition allow us to detect the major pharmacokinetic drug interactions which can occur in man and to identify specific populations at risk for such interactions. In vitro models are essential to decide if and which future drug interaction studies should be performed in man. However, the clinical relevance of the potential pharmacokinetic drug interactions detected by these in vitro models remains to be determined and confirmed by human studies.

To determine the viability and differentiation of human hepatocytes immunoprotected by encapsulation and transplanted in rats without immunosuppression.Freshly isolated human hepatocytes were encapsulated in hollow fibers and transplanted in the peritoneal cavity of immunocompetent rats. The fibers were explanted for analysis at D3, D7 and D14 following transplantation. Morphological features under light and electron microscopy and gene expression were compared to those of non-transplanted encapsulated hepatocytes (D0). Human cytochrome P450 3A and albumin mRNAs were quantified by Northern blot. Cytochrome P450 3A proteins were detected by Western blot and cytochrome P450 3A enzyme activity was assessed by measuring the formation of 6beta-hydroxytestosterone by high performance liquid chromatography.Transplanted hepatocytes were more than 60 % viable and exhibited morphological criteria of hepatocytic differentiation up to D7. Albumin and cytochrome P450 3A transcripts were also detected up to D14. At D3 and D7, albumin mRNA levels were of 30 %, compared to control D0 hepatocytes, while cytochrome P450 3A5 and cytochrome P450 3A4 mRNA levels were 65 % and 0 %, respectively. Cytochrome P450 3A immunoreactivity was detected by Western blot up to D14 and 6beta-hydroxylase activity was 17 % at D3 compared to D0, supporting with disappearance of cytochrome P450 3A4 mRNA.Human hepatocytes remain viable for a short period, following encapsulation and intraperitoneal transplantation in rat. Other experimental conditions need to be tested to prevent or delay a decrease in hepatocyte specific gene expression.

Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is extensively metabolized by the liver in humans. The aim of the present study was to identify the human cytochrome P-450 (CYP) isoforms involved in zopiclone metabolism in vitro. Zopiclone metabolism was studied with different human liver microsomes and a panel of heterologously expressed human CYPs (CYP1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver microsomes, zopiclone was metabolized into N-desmethyl-zopiclone (ND-Z) and N-oxide-zopiclone (NO-Z) with the following K(m) and V(m) of 78 +/- 5 and 84 +/- 19 microM, 45 +/- 1 and 54 +/- 5 pmol/min/mg for ND-Z and NO-Z generation, respectively. Ketoconazole (CYP3A inhibitor) inhibited approximately 40% of the generation of both metabolites, sulfaphenazole (CYP2C inhibitor) inhibited the formation of ND-Z, whereas alpha-naphtoflavone (CYP1A), quinidine (CYP2D6), and chlorzoxazone (CYP2E1) did not affect zopiclone metabolism. The generation of ND-Z and NO-Z were highly correlated to testosterone 6beta-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p =.0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6alpha-hydroxylase; r = 0.76, p =.004). Recombinant CYP2C8 had the highest enzymatic activity toward zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3A4. CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, and CYP2C8 contributes significantly to ND-Z formation.

Both the antimalarial prodrug proguanil and the gastric proton pump inhibitor omeprazole are substrates for cytochrome P450 (CYP)2C19 and CYP3A. However, the relative contribution of each enzyme to proguanil bioactivation to cycloguanil and to the metabolism of omeprazole, as well as their potential to interact, remains to be examined. The bioactivation of proguanil to its active metabolite cycloguanil was studied in vitro in human liver microsomes and in vivo in 12 healthy subjects, in the absence and in the presence of omeprazole. The formation of cycloguanil from proguanil exhibited biphasic kinetic behavior in four of six human livers, indicating that at least two enzymes are responsible for this metabolic step. Cycloguanil formation activity did not correlate with immunoreactive CYP3A4 content or with CYP3A4 activity, as measured by testosterone 6beta-hydroxylation, suggesting that CYP3A4 plays a limited role in cycloguanil formation. Furthermore, troleandomycin (10 microM) inhibited only 10 to 17% of cycloguanil formation at proguanil concentrations of 100 and 500 microM. At a proguanil concentration of 20 microM, omeprazole at 10 microM inhibited cycloguanil formation in vitro by 47 +/- 59%. These in vitro results were consistent with the results of our in vivo study in healthy subjects, which showed a 32 +/- 11% decrease in proguanil apparent oral clearance and a 65 +/- 8% decrease in proguanil partial metabolic clearance to cycloguanil in the presence of omeprazole (both P.001). We conclude that in vitro studies of proguanil metabolism and interactions are predictive of in vivo situations, that CYP2C19 is the main enzyme responsible for proguanil bioactivation to cycloguanil and that omeprazole inhibits this biotransformation in vitro and in vivo by inhibiting this enzyme.

Dithiolethiones are thought to act as potent chemoprotective agents against aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in the rat by inducing glutathione S-transferases (GSTs). To determine whether these antioxidants can be similarly effective in human beings, we have investigated metabolism of AFB1, in primary human hepatocytes with or without pretreatment by oltipraz (OPZ), a synthetic derivative of the natural 1,2-dithiole-3-thione. Aflatoxin M1 (AFM1), glutathione conjugates of AFB1 oxides (AFBSGs), and unchanged AFB1 were quantitated in cultures derived from eight human liver donors. Parenchymal cells obtained from the three GST M1-positive livers metabolized AFB1 to AFM1 and to AFBSGs derived from the isomeric exo-and endo-8,9-oxides, whereas no AFBSGs were formed in the GST M1-null cells. Pretreatment of the cells with 3-methylcholanthrene or rifampicin, inducers of CYP1A2 and CYP3A4, respectively, caused a significant increase in AFB1 metabolism. Although OPZ induced GST A2, and to a lesser extent GST A1 and GST M1, it decreased formation of AFM1 and AFBSG, which involves CYP1A2 and CYP3A4. Inhibition by OPZ of AFB1 metabolism by reducing CYP1A2 and CYP3A4 was also demonstrated by decreased activity of their monooxygenase activities toward ethoxyresorufin and nifedipine, respectively. The significant inhibition by OPZ of human recombinant yeast CYP1A2 and CYP3A4 was also shown. These results demonstrate that AFBSG can be formed by GST M1-positive human hepatocytes only, and suggest that chemoprotection with OPZ is due to an inhibition of activation of AFB1, in addition to a GST-dependent inactivation of the carcinogenic exo-epoxide.

To determine whether long-term treatment with cilazapril (CIL) may improve pulse pressure (PP), arterial compliance and ankle-arm systolic index (AAI) in patients with lower-extremity arterial disease (LEAD). Indeed, in both systolic hypertension and LEAD, the increase in pulse pressure has been attributed to a reduced compliance.Thirteen patients (age: 65 +/- 5 yrs; AAI: 0.78 +/- 0.15; m +/- SD) were included in a double-blind randomized parallel study to compare the effects of a 6 month treatment with CIL (10 mg per day; n = 6) to those of placebo (PL; n = 7) Blood pressure, AAI and arterial compliance were determined at baseline (MO) and after 3 (M3) and 6 months (M6). Common carotid (CC) and common femoral (CF) artery compliances were noninvasively determined from pulsatile changes in arterial diameter (Wall Track System, Hoeks et al., 1990) and pressure (PP).Both groups were comparable at MO. Compared to PL, CIL significantly reduced PP (-22 +/- 4 vs -2 +/- 9 mmHg) and MAP (-16 +/- 11 vs -4 +/- 7 mmHg) and improved CC (+54 +/- 34 vs +5 +/- 21 mm2.mmHg-1.10(-3)) at M6. Weaker effects were observed at M3. No significant changes in AAI and CF compliance were observed.A direct effect of CIL on the large artery wall was suggested by 1) a greater reduction in PP than in MAP and 2) a disproportionately greater improvement in CC compliance compared with the reduction in distending pressure (MAP). These results indicate that long-term treatment with CIL may improve large artery function in patients with LEAD.

Between 1968 and 1991, 36 pregnancies were reported in 28 patients who had undergone kidney transplantation at the Necker hospital, Paris. Pregnancies with favourable graft outcome were compared with those accompanied by significant deterioration of graft function and requiring haemolysis. The risk factors for renal function deterioration during pregnancy in kidney-transplanted women were found to be an initial nephropathy induced or aggravated by a previous pregnancy, an alteration, even mild, of graft function, hypertension, even controlled by treatment, an HLA mismatch and several episodes of acute graft rejection soon after kidney transplantation.

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.