Oral Communication Abstracts

Fundamental & Clinical Pharmacology

PHARMACOLOGIE CARDIOVASCULAIRE CO-001 Cutaneous iontophoresis of treprostinil, a prostacyclin analogue, increases microvascular blood flux in diabetic malleolus area M Hellmanna,b, M Roustitc, F Gaillard-Bigotd, JL Cracowskic aClinical Pharmacology Department, Inserm CIC1406, University Hospital, Grenoble (France); b Noninvasive Cardiac Diagnostics Department, Medical University, Gdansk, Poland – Grenoble (France); cClinical Pharmacology Department, Inserm CIC1406, Grenoble University Hospital, Univ Grenoble-Alpes – Grenoble (France); dClinical Pharmacology Department, Inserm CIC1406, Grenoble University Hospital – Grenoble (France) Introduction: Diabetic foot ulcers are one of the most common and serious complications of diabetes mellitus. Few drugs are effective into enhancing the healing of microvascular skin ulcers. The main objective of the present study was to determine whether iontophoresis of treprostinil, a prostacyclin analogue, increases skin microvascular blood flux in the malleolus area of healthy subjects and diabetic patients. Material and methods: We recruited 12 healthy subjects and 12 type 2 diabetic patients. Cathodal iontophoresis (40 mC/cm²) of treprostinil 250 lM and NaCl 0.9% was performed in the malleolus area. Skin hyperaemia was quantified using non-invasive laser speckle contrast imaging, and expressed as cutaneous vascular conductance (CVC). Results: In healthy controls and diabetic patients, treprostinil 250 lM induced a significant increase in CVC compared with NaCl (for diabetic patients, AUC0-4 h was 16181 + /- 6709; vs. 2219 + /- 3616% BL.min, respectively; P = 0.002). In both groups, peak hyperaemia was obtained between 30 min and 1 h after the end of treprostinil iontophoresis and flux remained higher than baseline up to 6 h after the end of iontophoresis. No significant side-effect occurred. Discussion/Conclusion: Cutaneous iontophoresis of 250 lM treprostinil increases microvascular blood flux in malleolus area in healthy volunteers and diabetic patients, without inducing systemic or local side-effects. Topical administration of prostacyclin analogue administered through iontophoresis combines the advantages of drug therapy and local low-intensity current application providing a potential innovative, well-tolerated therapy of microvascular skin ulcers. Treprostinil cathodal iontophoresis should be further investigated as a new local therapy for diabetic ulcers. CO-002 Regular exercise activates cardioprotective signalling pathways but does not induce mitochondrial adaptations in both lean and obese mice in the absence of myocardial ischemia C Barau, L Portal, V Martin, D Morin, A Berdeaux, B Ghaleh, S Pons Inserm U 955 Equipe 03, Faculte de Medecine, Universite Paris Est Creteil – Creteil (France) Introduction: Comorbidities such as obesity are serious risk factors for cardiovascular diseases and prevent the ability of cardioprotective strategies to protect the myocardium against infarction. We particularly reported that post-conditioning failed to reduce infarct size in obese mice secondary to dysregulation of Akt and ERK1/2 pathways. However, we recently showed that regular exercise was able to restore cardioprotection in obese mice by increasing the phosphorylation state of these kinases and consequently by improving the resistance of mitochondrial permeability transition pore (mPTP) to opening at the onset of coronary artery reperfusion. This study aimed at determine whether the beneficial adaptations induced by exercise develop as a pre-emptive mechanism, i.e., before ischemia-reperfusion or rather specifically at reperfusion. Material and methods: Wild-type (WT) and obese (ob/ob) mice were assigned to sedentary conditions or regular treadmill exercise (1 h/day, 5 days/7, 4 weeks, 4° slope, 10–30 cm/s). Pro-survival kinases involved in the Reperfusion Injury Salvage Kinase pathway, as Akt, ERK1/2 and PKCe and the corresponding phosphatases, PTEN and MKP-3, were studied using Western Blot analysis in the absence of ischemic event. We also investigated mitochondrial respiration and mPTP opening was assessed by monitoring mitochondrial calcium retention capacity. Results: Exercise significantly increased the phosphorylation of Akt and ERK1/2 and concomitantly reduced the expression of the corresponding phosphatases PTEN and MKP-3 in both WT and ob/ob animals. Moreover, it induced a translocation of PKCe from the cytosol to mitochondria in WT and in ob/ob mice. Importantly, despite the modifications induced in the phosphorylation state of these kinases, exercise did not affect the calcium concentration required to open mPTP and respiratory parameters neither in WT nor in ob/ob animals. Discussion/Conclusion: Although exercise enhanced the phosphorylation of the pro-survival kinases, it did not induce pre-emptive mitochondrial adaptations that are known to be mandatory for cardioprotection. Therefore, this activation of survival pathways needs to be combined with stress conditions, i.e., ischemiareperfusion, to initiate downstream signalling pathways which converge to mitochondria and inhibit mPTP opening at the onset of reperfusion. CO-003 Chronic oral intake of the omega 3 EPA:DHA 6:1 formulation protects against Angiotensin II-induced hypertension and endothelial dysfunction in rats Z Rasul, G Silva, T Ribeiro, F Zgheel, C Auger, VB Schini-Kerth UMR CNRS 7213 Laboratoire de Biophotonique et Pharmacologie, Faculte de Pharmacie, Universite de Strasbourg – Illkirch (France) Introduction: Regular intake of fish products is associated with a reduced risk of cardiovascular diseases. The beneficial effect has been attributed at least in part to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA have been shown to cause endothelium-dependent nitric oxide (NO)-mediated relaxations of isolated blood vessels, with an optimized ratio of EPA:DHA 6:1. The aim of

the present study was to determine whether chronic intake of EPA:DHA 6:1 affects hypertension and endothelial dysfunction induced by angiotensin II (Ang II). Material and methods: Male Wistar rats daily received 500 mg/kg of either EPA:DHA 6:1 (omega 3) or corn oil (control) for 5 weeks. After 1 week, rats underwent sham surgery or surgery with implantation of an osmotic mini-pump infusing Ang II (0.4 mg/kg/days) for 4 weeks. Blood pressure was monitored by tail sphyngomanometry, and the reactivity of second branch mesenteric artery rings using myographs. Results: Infusion of Ang II to rats induced within 7 days a pronounced increase of systolic blood pressure, which reached 215.6  8.5 mmHg compared to 136.8  6.2 mmHg (n = 8) in the control group after 21 days. The hypertensive response to Ang II was markedly reduced in the omega 3 group reaching 169.0  7.8 mmHg whereas the omega 3 treatment alone had no effect (136.0  4.2 mmHg). In second branch mesenteric arteries, relaxations to acetylcholine (Ach) were markedly reduced in the Ang II group affecting the endotheliumdependent hyperpolarization (EDH)-mediated component to a greater extent than the NO-mediated component. The NAPDH oxidase inhibitor (VAS-2870) improved both components in the Ang II group. Pronounced endothelium-dependent contractile responses to Ach were observed in the Ang II group compared to the control group, which were abolished by indomethacin. Chronic intake of EPA:DHA 6:1 prevented the Ang II-induced endothelial dysfunction both by improving the relaxations and by reducing endothelium-dependent contractile responses to Ach. Discussion/Conclusion: The present findings indicate that chronic intake of EPA:DHA 6:1 prevented the development of hypertension and endothelial dysfunction induced by the infusion of Ang II to rats. The Ang II-induced endothelial dysfunction involves NADPH oxidase, indicating a redox-sensitive mechanism. The beneficial effect of EPA:DHA 6:1 is mediated by an improvement of both the NO- and the EDH-mediated relaxations as well as a reduction of endothelium-dependent contractile response most likely by preventing oxidative stress.

  PHARMACOLOGIE MOLECULAIRE ET PRE-CLINIQUE CO-004 Chronic oral intake of a standardized Crataegus extract prevents DOCA-salt-induced hypertension, and alteration of cardiac, vascular and renal structures and functions in rats: Role of oxidative stress T Ribeiroa, C Augera, Q Jabeena, G Silvaa, IA Medeirosb, N Boehmc, L Monassierd, VB Schini-Kerthe aUMR CNRS 7213 Laboratoire de Biophotonique et Pharmacologie, Faculte de Pharmacie, Universite de Strasbourg – Illkirch (France); bUniversidade da Paraiba, Joao Pessoa – Joao Pessoa (Brazil); cInstitut d’Histologie et INSERM U1119, Universite de Strasbourg, Faculte de Medecine, Strasbourg – Strasbourg (France); dEA 7296 Laboratoire de neurobiologie et pharmacologie cardiovasculaire, Faculte de Medecine, Universite de Strasbourg – Strasbourg (France); eUMR CNRS 7213 Laboratoire de Biophotonique et Pharmacologie, Faculte de Pharmacie, Universite de Strasbourg – Joao Pessoa (Brazil) Introduction: Hypertension is a leading risk factor for the development and progression of chronic heart, vascular and renal diseases. The hypertension-induced end target organ damage is characterized by alterations of the heart, vascular and kidney functions and structure associated with oxidative stress. The present study has examined the possibility that a standardized polyphenol-rich Crataegus extract prevents hypertension-induced end target organ damage in an experimental model of hypertension, the DOCA-salt non-nephrectomized rat. Material and methods: Male Wistar rats were divided into a control group, a Crataegus extract group (100 or 300 mg/kg/day in the diet), a DOCA-salt group (50 mg/kg i.p. per week) and DOCA-salt + Crataegus extract group for 6 weeks. Systolic arterial blood pressure (SBP) and target organ damage (vasculature, heart and kidney) were examined. Results: The DOCA-salt treatment increased systolic blood pressure, and this effect was associated with the induction of pronounced endothelium-dependent contractile responses in second order mesenteric resistance artery rings to acetylcholine. The increased contractile response was prevented by indomethacin (a cyclooxygenase inhibitor) and associated with vascular oxidative stress as assessed using dihydroethidine, a reduced expression of eNOS, and an increased expression of NADPH oxidase subunits (gp91 phox, p47 phox), COX-1 and COX-2. Echocardiography and histological analyses indicated left ventricular (LV) hypertrophy, fibrosis, and impaired systolic and diastolic cardiac functions associated with oxidative stress in the DOCA-salt group. Renal dysfunction characterized by increased urea and uric acid plasma levels, glomerular and arteriolar hypertrophy, tubulo-interstitial fibrosis associated with oxidative stress was observed in the DOCA-salt group. Discussion/Conclusion: Chronic intake of the Crataegus extract significantly reduced in a dose-dependent manner systolic blood pressure, target end organ damage in the heart and kidney, and improved the vascular function by preventing oxidative stress and the expression of target molecules. Thus, the Crataegus extract was able to retard the hypertension-induced end organ damage in the heart, kidney and resistance arteries most likely by preventing oxidative stress. CO-005 M3 receptor as a key target of N,N-diethyl-m-toluamide (DEET) to promote angiogenesis S Legeaya, N Clerea, V Apaire-Marchaisb, B Lapiedb, R Andriantsitohainaa, S Faurea aInserm U1063, Stress Oxydant et Pathologies Metaboliques (SOPAM), Universite d’Angers – Angers (France); bUPRES EA 2647 Recepteurs et Canaux Ioniques Membranaires (RCIM), Universite d’Angers – Angers (France) Introduction: It has been suggested that muscarinic pathway can lead to proangiogenic effects in endothelial cells. The insect repellent N,N-diethyl-mtoluamide (DEET) recently proposed as an inhibitor of human acetylcholinesterase has been reported to potentiate tumor development. As angiogenesis is a criti-

© 2015 The Authors. Fundamental and Clinical Pharmacology © 2015 Societe Francßaise de Pharmacologie et de Therapeutique, 29 (Suppl. 1), 1–19

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Abstracts – Oral Communications 2015

cal step in tumorigenesis and since it has been demonstrated that donepezil, another inhibitor of human acetylcholinesterase, is able to promote angiogenesis, the present study was designed to test the potential effect of DEET on different processes leading to neovascularization. Material and methods: Human Umbilical Vein Endothelial Cells (HUVECs) were incubated for 24 h with DEET at concentrations similar to that found in plasma of exposed individuals (10 5M) or in the environment (10 8M). Calcium signaling in presence of both concentrations of DEET was also investigated in HUVEC and in human embryonic kidney (HEK) 293 cells expressing recombinant Galpha (q/11)-coupled muscarinic M3 receptors (HEK/M3). In vivo vascularization was assessed by using Matrigelâ plug model and U87MG tumor cells xenagraft in Nude mice daily treated with DEET for 28 days. Involvement of muscarinic pathway was evaluated with selective muscarinic M3 antagonist parafluorohexahydrosiladiphenidol (pFHHSiD) or with M3 siRNA. Results: Both concentrations of DEET increased proliferation, migration and adhesion, in vitro capillary length of HUVECS in culture on matrigel and in vivo vascularization of Matrigelâ Plug. These cellular processes were associated with focal adhesion kinase (FAK) phosphorylation and stress fibers. Both concentrations of DEET also stimulated NO production through an increase of peNOS-Ser/ peNOS-Thr ratio. Blockade or silencing M3 muscarinic receptor subtype abolished the pro-angiogenic properties of DEET in both in vitro and in vivo conditions. DEET also potentiates carbachol-induced calcium signaling in HEK/M3. Moreover, tumorigenesis following U87MG cells injection in Nude mice was increased by administration of DEET due to enhanced tumor microvascular density. Discussion/Conclusion: These data underscore a novel property of DEET as a pro-angiogenic toxic, via the involvement of M3 muscarinic receptor subtype that could explain its potentiating effect on tumor development [1-3]. References: [1] Kakinuma Y. et al., Donepezil, an acetylcholinesterase inhibitor against Alzheimer’s dementia, promotes angiogenesis in an ischemic hindlimb model. J. Mol. Cell. Cardiol. (2010) 48, p. 680–693. [2] Fradin M.S., Day J.F. Comparative efficacy of insect repellents against mosquito bites. New Eng. J. Med. (2002) 4, p. 3–8. [3] Corbel V. et al., Evidence for inhibition of acetylcholinesterases in insect and mammalian nervous systems by the insect repellent deet. BMC Biology, (2009) 5, 7:47, p. 1–11. CO-006 Etanercept improves endothelial function in Rat Adjuvant-Induced Arthritis: mechanisms involved P Totosona, K Maguin-Gatea, A Monnierb, A Tessierb, C Marieb, C Pratia,c, D Wendlingc, C Demougeota aEA 4267 “Fonctions et Dysfonctions Epitheliales”, FHU INCREASE, Faculte de Medecine-Pharmacie – Besancßon (France); bInserm U1093 “Cognition, Action et Plasticite Sensorimotrice”, UFR Sante – Dijon (France); c Service de Rhumatologie, CHU Minjoz – Besancßon (France) Introduction: Growing evidence indicate that increased cardiovascular risk associated to Rheumatoid Arthritis (RA) is secondary to the presence of endothelial dysfunction (ED) [1]. To date, the effect of anti-arthritic drugs used on RAinduced ED is still controversial [2-3]. In the present study, we investigated the effect of the anti-TNFa Etanercept on endothelial function in the model of adjuvant-induced arthritis (AIA) rats. Material and methods: AIA was induced by an intradermal injection of Mycobacterium butyricum in the tail of male Lewis rats. At the first signs of arthritis, AIA rats received Etanercept (10 mg/kg/ 3 days, s.c) or saline (control AIA) for 21 days. Arthritis score was daily evaluated. At the end of treatment, endothelial function was studied in pre-constricted aortic rings relaxed by cumulative concentrations of acetylcholine (Ach, 10 11-10 4 moles/liter) in the presence or not of inhibitors of NOS (L-NAME), COX-2 (NS398), Arginase (nor-NOHA), EDHF (apamin/charybdotoxin) and superoxide anions production (Tempol). Aortic expression of eNOS, phospho-eNOS, COX-2, Arginase-2, p22phox and p47phox was evaluated by western blotting. Results: As compared to control AIA, Etanercept significantly reduced arthritis score ( 34%, P < 0.001). This effect was associated with a significant improvement of Ach-induced relaxation (P < 0.05). However, no correlation was found between the arthritis score and Ach-induced relaxation (Emax) (r = 0.195; P = 0.246, all AIA rats). The results showed that the beneficial effect of Etanercept relied on increase in NOS activity and a decrease in COX-2 and Arginase activities as well as O2-° production. These effects are secondary to increased eNOS expression and phosphorylation and decreased COX-2, Arginase-2 and p22phox expressions. By contrast, EDHF production and p47 expression were unaffected by the treatment. Discussion/Conclusion: Our data demonstrated that Etanercept improved endothelial function in AIA, via an impact on the NOS, Arginase, COX-2 and NADPH oxidase pathways. The lack of correlation between endothelial function and arthritic score in AIA suggests that improved endothelial function evoked by Etanercept is independent on the reduction of systemic inflammation but rather related to direct vascular effects. References: [1] Sandoo A. et al. Vascular function and morphology in rheumatoid arthritis: a systematic review. Rheumatology (Oxford) 2011;50:2125–2139. [2] van Breukelen-van der Stoep D.F. et al. Cardiovascular risk in rheumatoid arthritis: how to lower the risk? Atherosclerosis. 2013 Nov;231(1):163–72. [3] Steyers CM 3rd, Miller FJ Jr. Endothelial dysfunction in chronic inflammatory diseases. Int J Mol Sci. 2014 Jun;15(7):11324–49. CO-007 Imidazoline-like drug improve insulin sensitivity through a direct stimulation of adiponectin secretion in primary adipocytes M Weiss, F Traversi, P Bousquet, H Greney, N Niederhoffer Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, Faculte de Medecine, Universite de Strasbourg – Strasbourg (France) Introduction: Altered adiponectin (a major insulin sensitizer adipokine) signaling has been proposed as a key factor in the development of insulin resistance

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and thus, in the pathogenesis of metabolic syndrome. We previously showed that imidazoline I1 receptor (I1R) ligands can improve insulin sensitivity and glucose tolerance partly through increased adiponectin plasma levels. The objective of this study was to explore possible direct actions of I1R ligands on adipocytes. Material and methods: Experiments were carried out in primary adipocytes isolated from the epididymal white adipose tissue of aged male Wistar rats. Expression of I1R on adipocytes was verified with competition binding assays using [125I] para-iodoclonidine. In order to evaluate the effect of LNPs on adiponectin secretion, primary adipocytes were treated with increasing concentrations of LNP509, an I1R ligand, in the presence or not of the I1R antagonist efaroxan. In order to identify the intracellular signaling pathways involved in the action of LNPs, wortmannin (PI3K-inhibitor), IBMX (phosphodiesterase blocker) and AS1842856 (FOXO1 inhibitor) were added 45 min prior LNP509 exposure. After 3 h, the culture medium was collected and adiponectin content was measured by ELISA assay. Results: Competition binding assays confirmed the expression of I1R in adipocyte membrane. Treatment by LNP509 dose-dependently induced adiponectin secretion: from 18  5 ng/mL at 10 9 M to 66  15 ng/mL at 10 4 M; P ≤ 0.05 vs. medium alone (25 ng/mL). Interestingly, the adiponectin secretion induced by the highest LNP509 concentration was similar to the one elicited by 10 lM insulin (61 ng/mL); the secretion was totally prevented by a pretreatment of the cells with efaroxan. The LNP509-induced adipokine secretion was unchanged by PI3K-inhibition, but was reduced after phosphodiesterase and FOXO1 blockade ( 80% and 44% respectively, compared to LNP509 alone). Discussion/Conclusion: Our data show that I1R ligands directly act on adipocytes to promote adiponectin secretion. Since LNP-induced secretion of adiponectin was almost abolished by enhancing cAMP levels and was largely reduced after FOXO1 inhibition, the following transduction cascade can be proposed: I1R ? inactivation of adenylate cyclase ? increase of cAMP ? inactivation of SIRT1/FOXO1 ? activation of PPARg ? increase of adiponectin synthesis. Future studies should confirm the proposed signaling pathways. CO-008 Study of the antiepileptic drugs transport through the blood-brain barrier in children R Soaresa, S Chhunb, V Julliena, M Doc, G Noyaletc, C Chirona, G Ponsa, A Mabondzoc a Inserm U1129 (Infantile Epilepsies and Brain Plasticity), Paris Descartes University, CEA/DSV/I2BM – Paris (France); bInserm U1151, INEM, Paris Descartes University, Medicine Faculty Paris Descartes – Paris (France); cCEA/DSV/iBiTec-S (Service de Pharmacologie et Immunoanalyse) – Paris (France) Introduction: Drug resistant epilepsy remains a major concern in pediatrics despite the large number of anti-epileptic drug (AEDs) available. Resistance to AEDs may be related to adaptive mechanisms that oppose their brain penetration. Recent research has covered the role of the adult Blood-Brain Barrier (BBB) in this protective mechanism through altered expression of efflux pumps e.g. P-glycoprotein (P-gp) and Breast Cancer Resistance protein (BCRP). In the present work we aimed at studying the impact of valproic acid (VPA) on P-gp, BCRP efflux transporters function and in the expression of selected ABC and SLC transporters genes in immature rat brain microvessels. Material and methods: Post-natal day 21 (P21) and P56 rats (n = 5) were treated for 5 days with VPA (400 mg/Kg/days and 350 mg/Kg/days) through subcutaneous osmotic pumps. Changes in BBB transporters P-gP and BCRP function was measured after the infusion of digoxin and prazosin as P-gP and BCRP substrates respectively and calculation of brain/blood partition coefficients (Kp, brain) in steady-state conditions. For gene expression analysis, rat brain microvessels were extracted and the mRNA levels were semi-quantified by qRT-PCR. Data were analyzed by 2-way ANOVA followed by Bonferoni-corrected t-student post-hoc analysis and considered significant if P ≤ 0.05. Results: After 5 days, digoxin Kp (meanSD) increased from 0.070  0.01 to 0.136  0.016 in P21 rats and from 0.042  0.02 to 0.077  0.07 in P56, both differences being statistically significant (P < 0.01). A trend to decrease prazosin Kp (0.467  0.057 vs. 0.370  0.023) was noticed in P21 but was not statistically significant. Although P-gP and BCRP mRNA levels were significantly higher in P56 than in P21 rat brain microvessels (P-gP P < 0.01, BCRP P < 0.05), VPA treatment did not change both genes expression. Nonetheless, we observed a statistically significant 4-fold increase (2-DDCt) in the expression of Slc22a6 gene (OAT1, organic anion transporter 1) after VPA treatment in P21 rats (P < 0.01), suggesting possible interaction between VPA and OAT1. Discussion/Conclusion: P-gp function decreased significantly after VPA treatment in both P21 and P56 rats while a trend to increase BCRP function was observed only in P21 rats. VPA did not have an impact on the expression of PgP and BCRP genes. OAT1 transporter expression was significantly increased in P21 rat brain microvessels after VPA treatment. Taken together, these results show a differential impact of VPA in efflux transporters at the blood brain barrier according to age. CO-009 The promoting effect of phosphate and indoxyl sulfate on human aortic smooth muscle cells calcification is amplified by endothelial cells and may be associated to an inhibition of the osteopontin secretion Y Bennisa, M Husseinb, P Grossa, I Sixa, K Zibarab, G Briccaa, S Kamela aCentre Universitaire de Recherche en Sante, Unite INSERM 1088, CHU d’Amiens – Amiens (France); bDepartment of Biology, Lebanese University – Beyrouth (Lebanon) Introduction: Vascular calcification is a consequence of processes involving the osteochondrogenic switch of vascular smooth muscle cells (SMCs) or their apoptosis. In chronic kidney disease (CKD), both intimal and medial calcifications are agravated. Indoxyl sulfate (IS), an indolic uremic toxin that accumulates in CKD patients, is known to increase endothelial cells (ECs) dysfunction and both IS and inorganic phosphate (Pi) accelerate vascular calcification. However, whether the endothelium is involved in promoting vascular calcification in CKD is not yet clarified. Material and methods: We studied the role of ECs in the calcifications induced by human aortic SMCs exposed to Pi (3 mM) and IS (200 lM). In vitro calcifications were quantified by alizarin-red staining and viability of hASMCs and secre-

© 2015 The Authors. Fundamental and Clinical Pharmacology © 2015 Societe Francßaise de Pharmacologie et de Therapeutique, 29 (Suppl. 1), 1–19

Abstracts – Oral Communications 2015

tion of osteoponin (OPN), a marker of osteochondrogenic switch that acts as an inhibitor of calcification, were measured by WST-1 assay and ELISA respectively. Results: We observed that along with its proapoptotic and calcifying effect on human aortic SMCs, Pi induced the secretion of OPN. We also showed that IS was able to significantly amplify these effects, decreasing viability of SMCs (in % of control, 83.2  3.2 with Pi vs. 67.9  8.1 with Pi and IS, n = 3, P < 0.05) and increasing calcium deposition (in % of control, 177.9  31.9 with Pi vs. 262.7  140.7 with Pi and IS, n = 4, P < 0.05) and OPN secretion from SMCs (OPN in pg/mL, 430  28 with Pi, 531  11 with Pi and IS vs. 366  19 without treatment, n = 3, P < 0.05). Moreover, treating SMCs with conditioned media from endothelial cells (EC-CM) induced calcification that was amplified when conditioned media were harvested from endothelial cells treated with Pi and further more with both Pi and IS (in % of control, 153.9  0.1 for EC-CM, 273.8  48.9 for EC-CM with Pi and 487.1  37.6 for EC-CM with Pi and IS, n = 3, P < 0.05). In parallel, while no effect of EC-CM was observed on SMCs viability, conditioned media from endothelial cells treated with Pi reduced the OPN secretion from SMCs and this effect was promoted by IS (OPN in pg/mL, 383  7 with EC-CM, 333  13 with EC-CM associated to Pi and 283  8 with EC-CM associated to Pi and IS vs. 366  19 without treatment, n = 3, P < 0.05). Interestingly, no effect of Pi neither of IS was found regarding osteopontin secretion from endothelial cells. Discussion/Conclusion: These results suggest that EC, exposed to high Pi and IS, can induce vascular calcification by a mechanism that may not depend on the SMCs apoptosis but that may involve the OPN secretion inhibition.

COMMUNICATIONS EN PHARMACOLOGIE CLINIQUE CO-010 DPP-4 inhibitors and the risk of community-acquired pneumonia in patients with type 2 diabetes JL Failliea, KB Filionb, V Patenaudec, P Ernstb, L Azoulayb aPharmacovigilance Regional Center, Department of Medical Pharmacology and Toxicology, CHRU Montpellier University Hospital - Montpellier (France); bDepartment of Epidemiology, Biostatistics, and Occupational Health, McGill University - Montreal (Canada); cCentre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital - Montreal (Canada) Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors may alter the immune response and increase the risk of infections, but evidence for this association is limited. Thus, the objective of this study was to determine whether the use of DPP-4 inhibitors is associated with an increased risk of community-acquired pneumonia. Material and methods: The United Kingdom Clinical Practice Research Datalink (CPRD) and the Hospital Episodes Statistics (HES) database were used to conduct a nested case-control analysis within a cohort of new users of anti-diabetic drugs between 2007 and 2012. Incident cases of hospitalized community-acquired pneumonia were matched with up to 20 controls on age, duration of treated diabetes, calendar year, and duration of follow-up. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of hospitalized community-acquired pneumonia associated with current use of DPP-4 inhibitors compared with current use of two or more oral anti-diabetic drugs. Results: The cohort included 49 653 patients, of whom 562 were hospitalized for community-acquired pneumonia during follow-up (incidence rate: 5.2/1000 person-years). Compared with current use of two or more oral anti-diabetic drugs, current use of DPP-4 inhibitors was not associated with an increased risk of hospitalized community-acquired pneumonia overall (adjusted OR: 0.80, 95% CI: 0.50–1.29) or according to duration of use (p-trend = 0.57). Discussion/Conclusion: The use of DPP-4 inhibitors was not associated with an increased risk of hospitalization for community-acquired pneumonia. Additional research is needed to assess the association between these drugs and other serious infections. CO-011 Pregnancy outcomes after preconceptional exposure to methotrexate for ectopic pregnancy L Lagarcea, N Bernard-Phalipponb, P Carlierc, S Phelipot-Latesd, MC PeraultPochate, D Bourneau-Martina, Association Francßaise Des Centres Regionaux De Pharmacovigilancef aCentre regional de pharmacovigilance CHU Angers – Angers (France); bCentre regional de pharmacovigilance Hospices civils de Lyon – Lyon (France); cCentre regional de pharmacovigilance Hopital Fernand Widal – Paris (France); dCentre regional de pharmacovigilance CHU Strasbourg – Strasbourg (France); eCentre regional de pharmacovigilance CHU Poitiers – Poitiers (France); f AFCRPV (France) Introduction: Methotrexate (MTX) is a known teratogenic drug used off-label in the treatment of ectopic pregnancies (EP). As MTX polyglutamated derivatives remains into the cells during several weeks, it is recommended to avoid conception during 3–6 months following MTX therapy. A study [1] comparing pregnancies occurring within (n = 45) or more than (n = 80) 6 months after the last MTX dose for EP showed similar malformation rates, and another study [2] did not find any increase of malformation risk among women treated with MTX prior to conception for rheumatic diseases. We report the follow-up of pregnancies after preconceptional exposure to MTX for EP. Material and methods: Prospective cases of pregnancy occurring within 3 months after MTX injection for an EP recorded in the Terappel database were analyzed. Exclusion criteria were requests received after 22 weeks after the last menstrual period (LMP) to ensure a purely prospective design. Data on maternal history and drug exposures were collected during the first contact, and pregnancy outcomes were documented at follow-up. Results: Data were obtained on 52 pregnant women. The median age of patients was 28 (18–38), and the median gestational age at inclusion was 7 weeks after LMP (3–22). The time between the last MTX injection and conception ranged from 12 days to 13 weeks and the total MTX dose was between 40 and 210 mg. Out of 45 pregnancies with known outcome, there were 39 live births (87%), 3

spontaneous abortions (6.7%) occurring 63–94 days after MTX exposure, 2 elective terminations, and 1 medical termination after premature rupture of membranes, oligohydramnios and arthrogryposis (48 mg of MTX 9 and 8 weeks before conception). Two additional cases of major malformations were observed among 40 examinable babies or fetuses: tetralogy of Fallot (MTX 6 weeks before conception), and cerebral ventriculomegaly with normal karyotype (50 mg of MTX 9 to 13 weeks before conception). The resulting rate of major malformations was 7.5% (95% CI: 1.6–20.4). Discussion/Conclusion: Although this prospective study shows a major malformation rate higher than expected in the general population, the observed malformations are not consistent with the typical pattern of methotrexate embryopathy. However the case of tetralogy of Fallot is reminiscent of previously published cases with MTX exposure during early pregnancy. Owing to the small sample size, more powerful studies are needed to confirm or refute these findings. References: [1] Reprod Toxicol 2009;27(1):85–7. [2] Arthritis Rheum 2014, 66(5):1101–10. CO-012 Consequences of medicines withdrawal on spontaneous reporting: the examples of tetrazepam and pioglitazone in France CP Pageota, FH Haramburub, AP Parientec aUniversite de Bordeaux , Inserm U657, CHU de Bordeaux – Bordeaux (France) ; bInserm U657, CHU de Bordeaux – Bordeaux (France); cUniversite de Bordeaux, Inserm U657, CHU de Bordeaux, CIC Bordeaux CIC1401 – Bordeaux (France) Introduction: Health authorities communicate regularly on risk of adverse effects (AEs) by press releases, “Dear Doctor letters”, warnings, but very few medicines are withdrawn from the market. Caution in withdrawal decisions is related to the fact that it will induce drug switches especially for patients with chronic diseases, and potentially increase AE frequency for the initiated drugs. This study aimed at describing the changes in spontaneous reporting related to the withdrawal of tetrazepam and pioglitazone, both withdrawn after safety alerts and for safety reasons, in France. Material and methods: Using data from the French spontaneous reporting database (Base Nationale de Pharmacovigilance, BNPV), we analysed data for tetrazepam, pioglitazone and some of their alternates from the twelve months period preceding the first official safety alert (tetrazepam: 2013/01/11; pioglitazone: 2011/ 04/19), to the twelve months period following the product date of withdrawal (tetrazepam: 2013/07/08; pioglitazone: 2011/07/11). Data of spontaneous reporting were analysed considering the changes in the: i) number of reports of AEs apparented to that which motivated withdrawal (tetrazepam: cutaneous AEs; pioglitazone: bladder cancer); ii) total number of reports. Mean numbers of reports were estimated for the periods before alert, from alert to withdrawal, and following withdrawal. Results: Mean of total number of reports per month increased from pre-alert to post-withdrawal period for tetrazepam alternates: thiocolchicoside: 2.6 vs. 6.6 reports/month; methocarbamol: 0.6 vs. 1.1 reports/month; diazepam: 6.5 vs. 11.2 reports/month. Considering pioglitazone alternates, changes in mean of total number of reports were only observed for DPP-4 inhibitors (15.7 vs. 8.5 reports/month). Potential change was observed for glinides (3.9 vs. 3.2 reports/month). None was highlighted for GLP-1 analogs (6.8 vs. 6.8 reports/month), sulfonylureas (10.3 vs. 10.1 reports/month), or a-glucosidase inhibitors (1.4 vs. 1.3 reports/month). Discussion/Conclusion: These preliminary results confirm that the withdrawal of a medicine can have short-term consequences on the number of reports for therapeutic alternates. How much this can be related to an increase in alternate use or to notoriety will be distinguished by studying concomitant changes in alternates level of use. If related to new users switching from the drug withdrawn towards other drug, these changes in reporting could be studied as one indicator of the potential health impact of drugs withdrawals. CO-013 Drug-induced gingival bleeding: a case/non-case study from the French Pharmacovigilance Database E Bondon-Guittona, T Mourguesa, V Rousseaua, MJ Jean-Pastorb, J Cottinc, G Drablierd, JL Montastruca aService de Pharmacologie Medicale et Clinique, Centre Midi-Pyrenees de Pharmacovigilance, Pharmacoepidemiologie et Informations sur le Medicament, Pharmacop^ole Midi-Pyrenees, INSERM U 1027, CHU, Faculte de Medecine de l’Universite de Toulouse – Toulouse (France); bCentre Midi-Pyrenees de PharmacoVigilance, de PharmacoEpidemiologie et d’Informations sur le Medicament, H^opital Sainte-Marguerite AP-HM – Marseille (France); cCentre Midi-Pyrenees de PharmacoVigilance, de PharmacoEpidemiologie et d’Informations sur le Medicament, Hospices civils de Lyon – Lyon (France); dCentre Midi-Pyrenees de PharmacoVigilance, de PharmacoEpidemiologie et d’Informations sur le Medicament, Centre Hospitalier regional Universitaire – Angers (France) Introduction: Gingival bleeding (GB) is an adverse drug reaction (ADR) well known with antithrombotic drugs, what can be also related to other drugs or to drug interactions. We reviewed all spontaneous notifications of drug-induced GB, in France. We also investigated the association between exposure to antithrombotic drugs and the occurrence of GB. Material and methods: We selected GB cases registered in the French Pharmacovigilance Database between 1984 and September 30th, 2014. A descriptive analysis was performed as well as a case/non-case study to measure the association between GB and exposure to antithrombotic drugs. Cases were the reports of GB, and all other ADRs were non-cases. Exposure was defined by the presence in the report of at least one antithrombotic drug for which chronology of administration was assessed “compatible” with ADR occurrence according to the French method of imputation. Reporting odds ratios (ROR) with the relevant 95% confidence intervals (95CI) were calculated. Results: We found 454 cases of GB and most of them were “serious” (58.4%). Patients were more frequently women (54.6%). The frequencies of GB reports increased with age. Median age was 65 years [4–98]. Evolution was favorable in 80% of cases. An increased INR or a thrombopenia were frequently associated with the GB (115 cases, 25.3% and 79 cases, 17.4% respectively). The drugs

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most frequently involved were: (i) antithrombotic drugs (308 cases, 67.8%) with fluindione (132, 29.1%), acetylsalicylic acid (45, 9.9%), rivaroxaban (44, 9.7%), acenocoumarol (37, 8.1%) and warfarine (32, 7.0%); (ii) neurological drugs (97, 21.4%) with paracetamol (17, 3.7%) and paroxetine (11, 2.4%) and (iii) cardiovascular drugs (96, 21.1%) with furosemide (20, 4.4%) and amiodarone (17, 3.7%). These drugs, except fluindione and rivaroxaban, were mainly involved in case of association. Disproportionality was found for rivaroxaban (ROR: 26.5 [95% CI 19.4–36.3]), warfarine (14.7 [10.2–21.1]), acenocoumarol (11.9 [8.5– 16.7]), fluindione (11.4 [9.3–14.0]) and acetylsalicylic acid (1.7 [1.2–2.5]). Discussion/Conclusion: Gingival bleeding is often a “serious” ADR but evolution was favorable in most of cases. This study showed a significant association between GB and exposure to antithrombotic drugs, particularly rivaroxaban. GB was also due to drug interactions with amiodarone, paracetamol or paroxetine. Furosemide is not known to induce GB or interact with antithrombotic drugs but thrombopenia is expected with this drug. CO-014 Optic neuritis related to tumor necrosis factor-a antagonists: description of 30 cases in a nationwide pharmacovigilance database MA Lavillea, B Mosquetb, C Breuillyc, M Cohend, A Fromonte, H Zephyrf, A Coquerelb, G Deferg, N Deracheg aOphtalmologie, CHU de Caen – Caen (France); b Centre regional de pharmacovigilance de basse Normandie, CHU de Caen – Caen (France); cNeurologie, Centre hospitalier de Cornouaille – Quimper (France); d Neurologie, CHU de Nice – Nice (France); eNeurologie, CHU de Dijon – Dijon (France); fNeurologie, CHRU de Lille – Lille (France); gNeurologie, CHU de Caen – Caen (France) Introduction: Tumor necrosis factor-a antagonists (anti-TNFa) indicated in different inflammatory diseases included rheumatic and bowel diseases may have neurological side effects. Among them, few cases of optic neuritis (ON) were reported whatever anti-TNFa category. The objective was to study French reported cases of anti-TNFa-related ON. Material and methods: We included all spontaneous reports of ON related to anti-TNFa recorded in the French pharmacovigilance database until May 2013 and included in databases of French Multiple Sclerosis centers network (Club Francophone de la Sclerose en Plaques). Results: Thirty cases of ON related to anti-TNFa in 28 patients [25F/3M] with mean age at 43 years [14.8 years] were identified. Of these cases, 12 (42.85%) occurred during exposure to infliximab, 10 (35.7%) during adalimumab and 8 (28.57%) during etanercept, mainly required because inflammatory bowel disease. Mean durations of treatment were 8.5, 13.5 and 9 months for infliximab, adalimumab and etanercept, respectively. We analyzed data concerning visual field, cerebral MRI, visual evoked potential and cerebrospinal fluid. Clinical characteristics of ON were not specific, pain was rarely reported and ON was unilateral in 18 patients (64.28%) and bilateral in others. In most cases, anti-TNFa was discontinued, and less than half received corticosteroid. Improvement was observed in 21/28 (75%) patients and none of them developed multiple sclerosis. Discussion/Conclusion: ON is probably the most frequent of the rarely occurring demyelinating events related to TNF-a antagonists. No specific sign (clinical, biological or radiological) was identified. Prognosis seems favorable after discontinuation. It is crucial to report systematically adverse drug effect to pharmacovigilance database to have robust data for future guidelines. CO-015 Child psychomotor development after in utero exposure to an antiepileptic drug monotherapy C Marcona, H Geniauxb, A Coubretb, B Godeta, J Massardierc, ML Laroched a Service de Neurologie, CHU – Limoges (France); bCentre Regional de Pharmacovigilance de Limoges, CHU – Limoges (France); cService de GynecologieObstetrique, HME – Lyon (France); dCentre Regional de Pharmacovigilance de Limoges, CHU – Limoges (France) Introduction: Antiepileptic (AE) drugs teratogenicity is well known. The impact of new AE drugs except lamotrigine on child psychomotor development is less established. The aim of the study was to assess the psychomotor development of children exposed in utero to an AE drug monotherapy. Material and methods: Data issued from Limoges and Lyon pharmacovigilance database (Terappel, Gerappel) and from the obstetrical database of the Lyon Hospital were used to include women treated with an AE drug monotherapy over their whole pregnancy who gave birth to a living child (1/4/2003–31/4/2012). In all children aged 15 months to 10 years, development disabilities were studied using a standardized questionnaire. In those aged ≤6 years, the risk of development delay was assessed according to the Child Development Inventory (French version). A multivariate analysis was conducted to determine, for each AE drug, the risk of development disabilities, adjusted to sex, age, socio-economic level, fetal suffering, delivery mode, prematurity, periconceptional folic acid, psychotropic drugs, alcohol and tobacco use. Results: Of 98 women and 145 children were included (age: 14–120 months; girls: 53.8%/boys: 46.2%), exposed to lamotrigine (LTG): 46, sodium valproate (VPA): 25, carbamazepine (CBZ): 20, levetiracetam (LEV): 17, phenobarbital (PB): 13, oxcarbazepine (OXC): 9, topiramate (TPM): 8, gabapentin or clobazam (GBP/CLBZ): 7. In 32.4% of all children, a development disability was diagnosed: global difficulties (6.2%), language difficulties (24.8%), behavioral disorders (14.5%), motor problems (9.0%). Risk factors were: exposition to PB (OR = 6.8, CI95%: 1.5–29.9), VPA (5.6, 1.7–18.5), LEV (4.4, 1.1–17.2), VPA (3.2, 0.8– 12.9) vs. LTG; periconceptional folic acid (0.3, 0.1–0.9) vs. no prevention. In 40% of children aged ≤6 years, a risk of development delay was diagnosed. Factors associated to this risk were: exposure to VPA (OR = 7.5, 1.7–32.6), PB (5.2, 0.7–40.6), LV (3.7, 0.9–13.9), CBZ (0.6, 0.1–3.6) vs. LTG. Discussion/Conclusion: Our results confirm that the in utero exposure to PB and VPA induces development impairment. Contrary to the literature, LEV was associated to a risk of development disabilities in this study. Moreover, folate supplementation seemed to protect against development impairment. The main limit of this study was its lack of power. Further studies are needed to confirm these results.

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CO-016 PharmacoCyberVigilance: new tool to improve Adverse Drug Detection? A Pagesa, L Palossea, E Guittona, I Lacroixa, C Damase-Michela, A Herxheimerb, JL Montastruca, H Bagheria aPharmacologie – Toulouse (France); bCochrane – Londres (United Kingdom) Introduction: Internet is changing the way people learn about health and illness particularly in chronic diseases. Health sites are among the most popular resources on the web. As reported by other authors, patients’ sharing experiences on a website could be an interesting source of information about drug knowledge and Adverse Drug Reactions (ADRs). Pharmaceutical companies already collect social media postings and analyze them for ADRs. We summarize data of three studies performed to analyse ADRs extracted from patient’ internet narratives. Material and methods: Three studies were performed for three topics on different health websites: 1) Benfluorex: to describe the characteristics of ADRs reported for benfluorex in three periods: before benfluorex withdrawal in November 2009, during the communication of the risk of valvulopathy in social media (between November 2009 and November 2010) and after the risk communication; 2) Oral antineoplasic Drugs: to describe the characteristics of ADRs reported on online discussions and compare them to those reported by health professionals as recorded in the French PharmacoVigilance Database (FPVD); 3) Drug and pregnancy: French Online chats about drugs and pregnancy and evaluate the quality and reliability of data shared by internet users Results: The following results could be underlined: 1) Online consumer postings showed that there were drastic changes in consumer’s’ xx perceptions following media coverage; 2) The characteristics of ADRs are different on websites (more musculoskeletal ADRs concerning mainly protein kinase inhibitors and hormone antagonists) compared to FPVD (more cutaneous ADRs); 3) Between 115 postings, 34% recommended drugs not well evaluated or potentially at risk during pregnancy. Discussion/Conclusion: Data of the literature and our three studies show that 1) ADRs reported on websites are considered by patients to be relevant enough to be shared; 2) Data from websites could be used as a source of data to detect ADRs alongside conventional pharmacovigilance; 3) Concerning drug use in pregnancy, information shared in online chats could be at risk for pregnant women. CO-017 Antipsychotics and Congenital Malformations: an Analysis of French Spontaneous Reporting data F Montastruca, F Salvob, M Arnaudb, B Begaudb, A Parienteb aINSERM, UMR1027-Pharmacoepidemiology, Universite de Toulouse, Toulouse, France – Centre Midi-Pyrenees de PharmacoVigilance, de Pharmacoepidemiologie et d’Informations sur le Medicament, Centre Hospitalier Universitaire de Toulouse – Toulouse (France); b Inserm, U657, Universite de Bordeaux, Service de Pharmacologie Medicale, CHU de Bordeaux – Bordeaux (France) Introduction: In a study exploring competition in signal detection from spontaneous reporting data, we investigated the masking effect of extrapyramidal syndrome reports on signal detection for antipsychotics. Among signals revealed by unmasking procedures, three concerned antipsychotics and congenital malformation. As these results from a methodological exploration were obtained from ancient data (1984–2000), we aimed at investigating this potential signal of disproportionality using more recent ones. Material and methods: We used data from the French Pharmacovigilance database (Base Nationale de Pharmacovigilance, BNPV) and considered all reports from January1st, 2000 to August 1st, 2010. Detection of Signals of Disproportionate Reporting (SDRs) was performed using the Proportional Reporting Ratio (PRR), which defines SDRs as drug-reports associations with PRR≥2, v2 ≥ 4, and nexposed cases≥3. First, to investigate potentialities of drug competition effects, SDR detection was performed considering the SOC “Congenital, familial and genetic disorders” (SOC congenital) and considering drugs according to the Anatomical Therapeutical Chemical classification (ATC) level 3. Second, SDR detection for antipsychotics (all combined) was performed for SOC congenital and related HLGT after removing from the database used all reports related to potential drug competitors. Third it was performed after removing additionally all reports of extrapyramidal syndrome, a demonstrated event competitor for SDRs related to antipsychotics. Results: Drug competition analysis using SDR detection for the SOC Congenital and for drugs according to ATC level 3 revealed that most SDRs and cases were related to L01 drugs (antineoplastic agents); no SDR appeared for antipsychotics at this stage (seven cases, PRR = 0.7). Drug competition was handled removing all reports associated to antineoplastic agents and to antiepileptics from the database. After this, no SDR was found associating antipsychotics to the SOC Congenital, but one appeared for the HLGT “Congenital and hereditary disorders NEC” (three cases out of 14, PRR = 7, v2 = 7.8). This was enforced after removing reports of extrapyramidal syndromes (PRR = 8, v2 = 9). Discussion/Conclusion: A SDR for antipsychotics and congenital abnormalities was unmasked, which relied only on three exposed cases reported in the BNPV between 2000 and 2010. Analyses using larger spontaneous reporting databases are needed to better characterise this potential signal before considering conducting pharmacoepidemiology studies on that topic. CO-018 Toxic Epidermal Necrolysis and paracetamol: evaluation of French Pharmacovigilance database C Guya, B Lebrun-Vignesb, V Grasc, M Zenutd, MMJ Jean-Pastore aCHU – SaintEtienne (France); bCHU – La Pitie Salpetriere (France); cCHU – Amiens (France); d CHU – Clermont-Ferrand (France); eCHU – Marseille (France) Introduction: Stevens – Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions, mostly associated with drug intake. Although rare, these reactions are a public health concern because of the

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high mortality rate and associated incapacitating sequelae. On August 1st, 2013, the FDA informed the public that paracetamol has been associated with a risk of rare but serious skin reactions as SJS/TEN. Epidemiologic studies considered paracetamol as a potential risk, but more data would be needed to confirm or refute it. The aim of this retrospective study was to analyse reports of paracetamol as a suspected drug for SJS/TEN in French pharmacovigilance database (BNP). Material and methods: All cases of TEN/SJS, with paracetamol coded as a suspected drug, registered in BNP from January 2002 to December 2013, were extracted. Two MedDRA preferred terms were selected: “Toxic Epidermal Necrolysis” and “Stevens-Johnson syndrome”. Validated cases (diagnosis, probable Index Date (ID), sufficient chronology) were confirmed by an expert group (dermatologists and pharmacovigilant seniors). For assessment of causality, ALDEN score [1] was applied on each suspect active substance (SAS), with a notoriety score of 1 for paracetamol. Then cases were classified relative to the SAS with the highest score. Results: After exclusion of 15 non validated cases, we analysed 113 cases (47 Lyell, 52 SJS, 14 SJS/TEN overlap) concerning 93 adults and 20 children. Sex distribution showed 62 females, 51 males. ALDEN score was calculated for 577 SAS (mean 5.1 SAS/case). In 32 cases, paracetamol had the highest score and was distributed in “very unlikely” or “unlikely” in 12, “possible” in 13 and “probable” in 7. For these 20 “possible” or “probable” cases, a protopathic bias must be strongly discussed in 13, and Mycoplasma Pneumoniae infection was proved in 2. In 81, the remaining cases, paracetamol score was inferior or equal to others SAS. Discussion/Conclusion: ALDEN score is time consuming but is an essential work tool for discuss assessment of drugs in SJS/TEN. For application, it is necessary to have precise diagnosis, ID and chronology of all suspected drugs. In view of these first results, causality of paracetamol is weak even though with a notoriety score of 1. New ALDEN score taking into account a “possible” ID instead of “probable” will be calculated. Reference: [1] Sassolas, B. et al. ALDEN, an Algorithm for Assessment of Drug Causality in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Clin Pharmacol Ther. 2010;88,60–68.

FIBRINOLYSE CO-019 In situ formulations of S-nitrosoglutathione prolong its effect and protect from stroke M Parenta, A Boudiera, J Perrina, C Vignerona, N Violleb, JF Bissonb, I Lartauda, F Dupuisa aUniversite de Lorraine – Nancy (France); bETAP, ETologie APpliquee, rue Bois de la Champelle – Vandoeuvre-les-Nancy (France) Introduction: S-nitrosoglutathione (GSNO) has protective effects on stroke but suffers from a short life time. We developed in situ forming implants or microparticles to lengthen its in vivo delivery and systemic effects in order to enlarge postoutcome cerebroprotection following stroke using one single administration. Material and methods: Implants were based on a biocompatible biodegradable poly(lactide-co-glycolide), FDA-approved N-methyl-2-pyrrolidone and GSNO. This mixture was emulsified with an external oily phase for microparticles. After subcutaneous injection, the polymer precipitates, forming a solid matrix entrapping GSNO which will then be released in a sustain fashion. After one single administration to Wistar rats, arterial pressure was recorded with telemetry for 3 days (n = 14), whole-blood platelet aggregation by Multiplate analyzer for 7 days (n = 58), and neurological score, cerebral infarct size and edema volume were measured 24 and 48 h after obstruction of the middle cerebral artery by autologous blood clots (n = 30). Results: Unloaded GSNO (3.75–30 mg/kg) dose-dependently ( 56  6 mmHg at 30 mg/kg) and transiently (40 min) decreased mean arterial pressure. The fall in pulse pressure ( 50%) lasted up to 120 min. GSNO-loaded formulations at 30 mg/kg induced slighter ( 10 mmHg) but longer (18 h) decreases in mean and even longer decreases in pulse (up to 42 h for microparticles) pressures. Unloaded GSNO and 7.5 mg/kg-loaded formulations showed a transient platelet hyper-aggregability (24 h) and then decreased aggregation during 5–6 days. Formulations at 30 mg/kg prevented hyper-aggregability. GSNO-loaded (30 mg/kg) microparticles injected 2 h after stroke reduced neurological score at 24 and 48 h ( 62 and 75%, vs. empty microparticles and unloaded GSNO 7.5 mg/kg) and divided infarct size by 5 and edema volume by 6 (vs. empty microparticles) at 48 h. Corresponding implants only reduced infarct size and edema volume by 1.5–3 times. Discussion/Conclusion: The longer effects on arterial pressures vs. unloaded GSNO suggest sustained delivery of GSNO-loaded formulations. Formulations at 30 mg/kg prevented transient platelet hyper-responsiveness and, more efficiently for microparticles, afforded cerebroprotection against the consequences of stroke. CO-020 Haemorrhagic adverse effects of oral anticoagulants and compliance with recommendations for prescription H Peyrouzeta, A Dunkaneb, F Haramburub aCIC-P 1401 – Service de Pharmacologie Medicale – Bordeaux (France); bCentre Regional de Pharmacovigilance – Bordeaux (France) Introduction: For many years, vitamin K antagonists (VKAs) were the only available oral anticoagulant agents. For some years a new therapeutic class has been developed: the direct oral anticoagulants (DOAs), arousing the hope they could induce fewer haemorrhagic effects. The objective of this study was to describe haemorrhagic adverse effects (AEs) of VKAs and DOAs. A secondary objective was to examine the conditions of prescriptions with regards to recommendations for proper use, in order to determine what part of AEs could be due to non-compliance with recommendations. Material and methods: All cases of haemorrhagic AEs with VKAs or DOAs reported to our pharmacovigilance centre in 2013 were included in the study.

Conditions of prescription were assessed according to the contraindications, special warnings and precautions for use provided in the Summary of Product Characteristics. Results: Eighty-seven haemorrhagic AE cases were included in the study: 60% were due to DOAs and 40% to VKAs. For both DOAs and VKAs, the more frequent AEs were digestive and cerebral haemorrhages; 17% had a fatal outcome. For DOAs, 10 (19%) haemorrhagic AEs concerned patients with at least one contraindication: lesion at risk for major bleeding (n = 7), severe renal impairment (n = 2) or patient with prosthetic valves (n = 1) (for the latter two only for dabigatran). Moreover, 6 (11%) haemorrhagic AEs concerned patients with at least one special warning or precaution for use: co-treatment with aspirin or non-steroidal anti-inflammatory drug (n = 5), age over 75 years without dose adjustment or severe renal impairment for a patient treated with rivaroxaban (n = 1). For VKAs, 4 (11%) haemorrhagic AEs concerned patients with at least one contraindication to the treatment: co-treatment with aspirin in patients with peptic ulcer (n = 2), co-treatment with miconazole (n = 1) or severe hepatic impairment (n = 1). Moreover, 18 (51%) AEs concerned patients with at least one special warning: lesion at risk for major bleeding (n = 10), co-treatment with aspirin (n = 8) or severe renal impairment (n = 3). Discussion/Conclusion: Over half of the haemorrhagic AE cases reported to our centre in 2013 and due to oral anticoagulants were related to DOAs. Our data cannot allow to compare haemorrhagic risk due to both classes since a reporting bias probably exists. Nevertheless, this study shows that 30% of haemorrhagic AEs related to oral anticoagulant treatment may be due to prescription in spite of the existence of a contraindication and thus could have been preventable. CO-021 Hemorrhagic and thrombotic effects of oral anticoagulants: a comparative study of adverse drug reactions between Vitamin K Antagonists (VKA) and Direct Oral Anticoagulants (DOA) L Chebane, V Rousseau, D Abadie, E Guitton, F Montastruc, G Durrieu, H Bagheri, JL Montastruc Service de Pharmacologie Medicale et Clinique, Centre Midi-Pyrenees de Pharmacovigilance, Pharmacoepidemiologie et Informations sur le Medicament, Pharmacop^ole Midi-Pyrenees, INSERM U 1027, CHU, Faculte de Medecine de Toulouse – Toulouse (France) Introduction: Several clinical trials have discussed differences in the rate of major bleedings between VKA and DOA [anti Xa (xabans) and anti IIa (dabigatran)] as well as a possible higher risk of gastrointestinal bleedings with a lower rate of intracranial hemorrhage with DOA. However, these data came from clinical trials and not from real life. The present study was performed to compare pharmacovigilance notifications of hemorrhagic and thrombotic adverse drug reactions (ADRs) between VKA and DOA. Material and methods: All notifications registered between 1st January 2009 (first marketing of dabigatran) and 1st September 2014 in the Midi-Pyrenees Pharmacovigilance database with oral anticoagulants (VKA, DOA) (defined as “suspect”) were included. Cases with more than one anticoagulant were excluded. The main characteristics of the patients (age, gender, medical history), drugs (suspected or associated) and ADRs (bleedings or thrombosis, seriousness, evolution) were compared using v2 and Z tests. Results: During this 5.5 year period, 760 ADRs including VKA or DOA and corresponding to the inclusion criteria were registered in the database, i.e. 507 (67%) with VKA and 253 (33%) with DOA. For bleedings, there was no significant difference in mean age (78 years) and sex ratio in the two groups. “Serious” ADRs were more frequent with VKA (97%) than with DOA (85%) (P < 0.001). There was significantly more muscular bleeding with VKA (n = 24, 4%) than with DOA (0) (P < 0.005) without difference in digestive, cutaneous or subcutaneous, cerebral or ENT bleedings. There were more associated suspected drugs with VKA (n = 232, 46%) than with DOA (n = 58, 35%) (P < 0.01). When analysis of bleedings was restricted to medical indications, similar results were found. The number of reported thrombosis with VKA was too low (4 vs. 86 with DOA) to allow statistical comparison. However, thrombotic patients with DOA appeared to be older (72  8.8 [53–62] years) than those with VKA (70.6  10.9 [60–86] years). Discussion/Conclusion: According to our data, there is no difference in the localization of bleedings between VKA and DOA, except for muscular bleedings, more frequent with VKA. Despite the mandatory limits of spontaneous reporting, these results did not confirm data from clinical trials, suggesting, once more, the interest of investigations in real clinical practice.

PHARMACOLOGIE CLINIQUE, METHODOLOGIE ET ESSAIS CLINIQUES CO-022 Serious adverse drug reactions related to non-investigational drugs occurring in academic clinical trials: another source of safety information for risk assessment? A Gimberta, N Petitpainb, AL Colinc, M Beckerb, V Martya, P Olivier-Abbald a Unite de securite et de vigilance du CHU de Bordeaux – Bordeaux (France); bCentre Regional de Pharmacovigilance de Lorraine, unite de vigilance des essais cliniques du CHU de Nancy – Nancy (France); cCentre Midi-Pyrenees de Pharmacovigilance et Direction de la Recherche du CHU de Toulouse, unite de vigilance des essais cliniques – Toulouse (France); dService de Pharmacologie Medicale et Clinique, Centre MidiPyrenees de Pharmacovigilance, Service de Pharmacologie Medicale et Clinique du CHU de Toulouse, unite de vigilance des essais cliniques – Toulouse (France) Introduction: Sponsors of clinical trials (CT) have to collect and assess all serious adverse events (SAE) occurring in their CT. SAE reasonably related to the investigational medicinal product (IMP) are reported to the competent authorities as regulation requirements. SAE related to another cause, such as a non-experi-

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mental medicinal product (NIMP), are ruled out of any clear pharmacovigilance reporting requirements. Potentially, the national Pharmacovigilance system could not take into account these NIMP-related serious adverse reactions (SAR) in the current risk evaluation of marketed products responsible for these SAR. The aim of this study is to assess quantitatively and qualitatively NIMP-related SAR recorded by three academic sponsors (University Hospital of Bordeaux, Nancy and Toulouse). Material and methods: Between 2009 and October 2014, we extracted from the sponsor’s safety database all cases of SAR (fatal or life-threatening, hospitalization or prolongation of hospitalization, or permanent or significant disability or important medical event) possibly related to NIMP. We performed a retrospective descriptive study. Results: The three sponsors received 366 NIMP-related SAR, notified in 297 cases, corresponding approximately to 5% of all cases reported during the whole period (n = 5870). According to the type of CT, NIMP-related SAR corresponded to 5.1% of all cases reported in drug CT, 6.8% in medical device CT, 4% in “not health products” CT and 17.9% in biotherapy CT respectively. Of them, 10% were fatal (n = 30/297). NIMP involved in cases were mainly immunosuppressive, antithrombotic (oral anticoagulant, antiplatelet or thrombolytic drugs), central nervous system drugs (benzodiazepine, antidepressant), chemotherapy and antibiotics. Some of these drugs are followed by a risk management plan (e.g rivoxaban). The most frequent adverse reactions were nervous, gastrointestinal and hematological disorders. Discussion/Conclusion: Our results showed that NIMP-related SAR were about 5% of all notified SAE in three non-commercial CT and were probably lost for national safety evaluation if not transferred to pharmacovigilance centers (CRPV). This work highlights the need of interaction between CT safety teams and CRPV and/or French health products Agency to record these SAR into the National Pharmacovigilance Database. French regulation should take this into account to optimize drug risk assessment especially for recent authorized drugs. CO-023 Peripheral vasoconstriction induced by beta-blockers: a systematic review and network meta-analysis C Khouria, T Jouveb, JL Cracowskib, S Blaisec, C Villiera, PH Carpentierc, M Roustitb aPharmacovigilance department, Grenoble University Hospital – Grenoble (France); bClinical Pharmacology Unit, Inserm CIC1406, Grenoble University Hospital & Univ Grenoble-Alpes – Grenoble (France); cVascular Medicine Department, Grenoble University Hospital – Grenoble (France) Introduction: Raynaud’s phenomenon (RP) and cold extremities have long been described as vascular adverse effects of beta-blockers. Whether beta-blockers should be avoided in patients with peripheral vascular disease depends on pharmacological properties (e.g. preferential binding to b1-adrenoreceptors or intrinsic sympathomimetic activity, ISA). However, this has not been confirmed in experimental studies. Our objective was to perform a network meta-analysis (NMA) in order to assess the comparative risk of peripheral vasoconstriction of different beta-blockers. Material and methods: This systematic review and NMA complies with the PRISMA statement. Randomized controlled trials reporting peripheral vasoconstriction as an adverse effect of beta-blockers and controls were included. The quality of direct comparisons was rated according to the methods of the GRADE working group [1]. Sensitivity analyses were conducted using meta-regression model including possibly confounding covariates (latitude, properties of the betablockers -e.g. ISA, vasodilation-, drug indication, drug doses). The protocol and the detailed search strategy are available online (PROSPERO registry CRD42014014374). Results: Among 2238 records screened, full texts of 829 studies were assessed for eligibility. Finally, 38 studies including 60 609 patients were selected. Overall, peripheral vasoconstriction was reported in 9.4% of patients with beta-blockers, and 5.3% in the control groups (P < 0.001), with heterogeneity among drugs: atenolol, propranolol, metoprolol and carvedilol had significantly higher risk, whereas pindolol, acebutolol and oxprenolol had not. Sensitivity analyses did show any influence of the dose. Discussion/Conclusion: Our results suggest that beta-blockers have variable propensity to enhance peripheral vasoconstriction, and that it is not related to preferential binding to b1-adrenoreceptors. Of note, these findings challenge FDA and French recommendations regarding precautions and contra-indications of use of beta-blockers, and suggest that beta-blockers with ISA have a lower risk of peripheral vasoconstriction. Reference: [1] Puhan MA, Schunemann HJ, Murad MH, Li T, Brignardello-Petersen R, Singh JA, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ. 2014;349(sep24 5):g5630–g5630. CO-024 Safety of dose-ranging phase II trials testing direct oral anticoagulants: a meta-analysis of 35 studies including 16 233 patients M Mombleda, JC Legaa, C Chapelleb, L Bertolettic, P Mismettic, Q Reynaudd, I Durieud, F Gueyffiera, S Laportee aUMR 5558, Laboratoire de Biometrie et Biologie Evolutive, CNRS, Claude Bernard University Lyon 1 – Lyon (France); bInserm, CIE3 – Saint-Etienne (France); cGroupe de Recherche sur la Thrombose, EA3065, Universite de Saint-Etienne, Jean Monnet – Saint-Etienne (France); dDepartement de Medecine Interne et Vasculaire, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Universite Claude Bernard Lyon 1 – Lyon (France); eUnite de Recherche Clinique, Innovation, Pharmacologie, Centre hospitalo-universitaire de Saint-Etienne – SaintEtienne (France) Introduction: The goal of the randomised phase II trials studies is to determine the optimal dose for conducting subsequent phase III trials, the doses associated with unsatisfactory profiles being dropped out. Thus, because of a theoretical over- or underexposure to the drug and unpredictable effects on efficacy and

6

safety according to administrated doses, the participation of patients in these trials appears to be particularly altruist. The aim of this study is to assess the safety of phase II dose-ranging studies and the individual benefit of participants, based on recent phase II studies testing direct oral anticoagulants (DOA). Material and methods: A meta-analysis was performed to evaluate the risk of treatment failures in phase II DOA studies conducted in major orthopedic surgeries (MOS), atrial fibrillation (AF), venous thromboembolism (VTE), and acute coronary syndrome (ACS). We searched for The Cochrane Library, MEDLINE, EMBASE, and dedicated databases (up to October 2013) for all dose-ranging studies comparing DOA to standard treatments. Treatment failure (main outcome) was defined as the occurrence of major thrombosis (ischemic stroke, ACS, proximal deep venous thrombosis, and pulmonary embolism) or major bleeding. Secondary outcomes included all thrombosis (major thromboses and distal venous thrombosis) and clinically relevant bleeding, and all-cause mortality. Results: 35 studies (16 233 patients, 715 events) assessing 14 DOA in 19 MOS, 10 AF, 4 VTE, and 1 ACS trials were included. For the main outcome, data for major bleeding and thrombosis events were lacking in ACS and VTE. Overall, the treatment effect of DOAs for main outcome was not unfavorable (RR 0.91; 95% CI 0.68–1.22). This result was consistent for the MOS (RR 0.95; CI 0.72–1.27) and AF (0.29; CI 0.09–2.18) trials. DOA administration led to a trend in reduction of all thrombosis and clinically relevent bleeding (RR 0.90; CI 0.74–1.03). The results were similar in analyses according to indications (MOS: RR 0.90, CI 0.74–1.10; AF: RR 0.86, CI 0.56–1.31; VTE: RR 0.76, CI 0.48–1.20; ACS: 0.77, CI 0.36–1.64). There was a trend in mortality reduction by DOA (RR 0.69; CI 0.46–1.03). Discussion/Conclusion: The designs of phase II dose-ranging studies appear to be safe in the development of DOA. Overall, the patients might draw benefits for participating in DOA phase II studies. CO-025 The reporting of harms in randomized controlled trials funded by the “Programme Hospitalier de Recherche Clinique”, a French national funding scheme S Crepin, R Favier, L Merle Service de Pharmacologie, Toxicologie et Pharmacovigilance – Limoges (France) Introduction: Evidence across diverse medical fields suggests that the reporting of harm in clinical trials is inadequate and receives less attention than efficacy outcome. However, accurate information on harms in medical interventions is essential for evidence-based practice. In 1992, a French funding scheme called the “Programme Hospitalier de Recherche Clinique” (PHRC) was created to develop clinical research in French hospitals. The aim of this study was to describe the prevalence and completeness of harm reporting in the published randomized controlled trials (RCT) funded by the PHRC scheme. Material and methods: We performed a literature search in Pubmed for all protocols funded by a PHRC between 2004 and 2009 (endpoint: 31/01/2014). Only RCT with drugs were selected. Each article was reviewed by two independent investigators and data on articles characteristics and compliance with Consort Harms were extracted with a standardized form containing the 10 recommendations and its 18 items. Qualitative and quantitative parameters of harms reporting were assessed. Results: 23 articles met the criteria for analysis. Three different medical areas represented 60% of the articles (oncology/blood disorder, emergency care/anaesthetics/pain and neuro/psychiatry). The median number of items reported was 12 (interquartile range = 1–18). Across individual criteria, there existed considerable variation in the quality of reporting. The most frequently met recommendations concerned presentation of absolute risk of each adverse effect per arm (78%), balanced discussion of benefits/harms (74%), methods used to collect harm-related information (65%), adverse events mentioned in abstract and data on death in each arm (both 61%). 48% of the articles placed some restriction on reporting thresholds on harms data. 60% of the articles reported harm results in a table. The space allocated to harms was equal to 18% of the total space allocated to the results section. Less than 20% of articles had less space allocated to harms in the results section than space dedicated to authors list and affiliation. Discussion/Conclusion: We analysed qualitative and quantitative indicators of the adequacy of harms reporting by 23 articles of clinical trials funded by the PHRC. The articles met a median of 12 items (over 18). Mean percentage space of the results section given to harm-related data was 18%. There is a room for improvement in some aspects of harm reporting in clinical trials. This improvement can be obtained by participation of safety unit in writing of the articles. CO-026 Sudden cardiac and sudden unexpected death related to antipsychotics: a systematic review, meta-analysis, and meta-regression of observational studies F Salvoa, A Parientea, S Shakirb, P Robinsonc, M Arnauda, SHL Thomasd, R Emanuele, A Fourrier-Reglata, N Mooref, M Sturkenboomg, L Hazellh aINSERM U657 – Bordeaux (France); bDRSU – Southampton (united kingdom); cADERA, CIC1401 – Bordeaux (France); dNewcastle University – Newcastle (united kingdom); e University of Bologna – Bologna (Italy); fINSERM U657, CIC1401 – Bordeaux (France); gErasmus Medical Centre – Rotterdam (Netherlands); hDRSU – Southampton (United Kingdom) Introduction: Antipsychotics may generate ventricular arrhythmias by blocking the cardiac potassium channel hERG. This may result in sudden cardiac or unexpected death (SCD/SUD). Limited data on individual antipsychotics is available. Material and methods: Systematic review and meta-analysis of observational studies investigating risk of SCD/SUD in patients using specific antipsychotic compound compared with non-users. Pooled adjusted Odds Ratio (OR) of SCD/SUD with 95% confidence intervals (CI) were computed for each drug specifically and for any antipsychotic use vs. non-use. Heterogeneity was studied by using the Q

© 2015 The Authors. Fundamental and Clinical Pharmacology © 2015 Societe Francßaise de Pharmacologie et de Therapeutique, 29 (Suppl. 1), 1–19

Abstracts – Oral Communications 2015

statistic and I2 index. Potential causes of heterogeneity, as hERG blockade potency, were explored using meta-regression analyses. Results: Two cohort studies (740 306 person-years), and four case-control studies (2557 cases; 17 664 controls) were included. Among the nine studied antipsychotics, heterogeneity was found in the association with SCD/SUD (Q = 20.0, P = 0.01; I2 = 60.0%). Among marketed drugs, the risk was significantly increased for quetiapine (OR 1.7, 1.3–2.2), olanzapine (OR 2.0, 1.5–2.7), risperidone (OR 3.0, 2.4–3.9), haloperidol (OR 3.0, 1.6–5.5), and for clozapine (OR 3.7, 1.9–6.9). Meta-regression showed that increasing hERG blockade potency was associated with an increased risk of SCD/SUD (P < 0.01). Discussion/Conclusion: This meta-analysis demonstrated that the risk of SCD/ SUD differed between individual antipsychotics, and that hERG blockade potency could be an explanatory factor for this difference in real-life situations. This should be considered when initiating antipsychotic treatment, in particular as indications for these have been widened to non-schizophrenic patients in whom arrhythmogenic risk is less extensively studied. CO-027 Evolution of patients who experienced venous thromboembolism despite thromboprophylaxis after a medical immobilization A Meraha, M Guinzarlya, L Bertolettib, M Monrealc aCIC – Saint-Etienne (France); b Universite Jean-Monnet – Saint-Etienne (France); cHospital Universitari Germans Trias i Pujol – Barcelona (Spain) Introduction: Thromboprophylaxis is recommended for patients immobilized for acute medical diseases as chronic heart or respiratory failures, stroke, cancer or infection. It is unclear if patients who experienced venous thromboembolism (VTE) despite Thromboprophylaxis (T+ group) have a different outcome during the first months after VTE than those in whom Thromboprophylaxis was not prescribed (T- group). Material and methods: We used the RIETE database to compare the outcome (death, fatal pulmonary embolism, VTE recurrences, major bleeding) during the first 3 months of all patients with objectively confirmed symptomatic VTE in the two months after an immobilization for an acute medical disease, according to the use of thromboprophylaxis. Results: Thromboprophylaxis had been prescribed in 1313 (37.2%) of the 3527 included patients. Their main clinical characteristics are presented in table I.

Clinical

Age (mean

characteristics

years SD)

Prophylaxis

No prophylaxis

(N = 1313)

(N = 2214)

74  11

73  12

P-Value 0.012

Gender (male)

634 (48%)

1100 (50%)

0.422

Inpatients at the

648 (50%)

808 (37%)

G; rs1799971) and COMT (c.675G>A -p.Val158Met-; rs4680) single-nucleotide polymorphisms was investigated using bivariate analysis (student test and spearman correlations) and a linear mixed model. Results: A hundred and nine patients were included, 66 underwent surgery on general anaesthesia and 43 on spinal anaesthesia. The mean postoperative MED consumption over 5 days was 78.2  32.1 mg. In bivariate analysis, the mean MED requirement was higher in patients taking weak opioids before surgery (87.8  35.4 vs. 72.2  28.5, P = 0.01) and who did not practice physical activity before surgery (80.2  31.6 vs. 64.3  25.8, P = 0.05). The MED requirement was inversely correlated with age (q = 0.25, P = 0.001), the level of anxiety (q = 0.25, P = 0.01) and the mean pain intensity at rest over 5 days (q = 0.5, P < 0.000). The MED requirement according to the genotype for OPRM1 was not significantly different (GG = 86.6  28.1 mg, AG = 74.9  31.4, AA = 78.7  32.6). Using a linear mixed model, the MED consumption (adjusted for the mean daily level of post-operative pain) was found to decrease linearly over time ( 1.28 mg per day, P < 0.001). The age was the only factor associated with the MED consumption at baseline ( 0.18 mg per year, P = 0.006). MED consumption was not influenced by the anaesthesia, although pain was lower in the group spinal anaesthesia. Genetics and pain thresholds did not predict MED consumption. Discussion/Conclusion: In the context of multimodal analgesia after knee replacement, the variability in morphine opioid requirement is mainly but not entirely explained by the mean postoperative pain intensity and by theage. References: [1] Fischer HB, et al. Anaesthesia 2008,63:1105-1123. [2] Kessler ER, et al. Pharmacotherapy 2013,33:383-391. CO-073 Atropinic burden of medications during pregnancy and psychomotor childhood development: a cohort study in EFEMERIS AB Beau, JL Montastruc, I Lacroix, F Montastruc, C Hurault-Delarue, C DamaseMichel Service de Pharmacologie Medicale et Clinique, CHU Toulouse, Pharmacop^ole Midi-Pyrenees, Faculte de Medecine, Inserm 1027 – Toulouse (France) Introduction: Many drugs possessing atropinic proprieties are prescribed in general population. Pregnant women are not an exception. These proprieties can expose patients to central nervous system as well as peripheral adverse drug reactions especially in case of vulnerable subjects like the elderly. We hypothesized that exposure to atropinic burden during pregnancy may affect the development of the fetus nervous system resulting into psychomotor problems during childhood. Material and methods: Women from EFEMERIS, a French database including prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes, who delivered between July 1, 2004 and December 31, 2010, were included. Each medication was identified to have no (score = 0), small (score = 1) or strong (score = 3) atropinic properties according to Duran list. The total burden of atropinic per women was constructed by adding the score of each medication prescribed during pregnancy. The total atropinic burden was then categorized: no [0], low [1-8] or high [≥9]. Data for psychomotor development were extracted from children medical certificates completed at ages 9 and 24 months. Multivariable logistic regressions were used to assess associations between atropinic burden and psychomotor development. Results: During the study period, 43 740 women gave birth. 33% of women had a low and 1% a high atropinic burden during pregnancy. 23% of the women were exposed to atropinic drugs during the first trimester, 11% during the second and 9% during the third. 8% of the drugs prescribed had atropinic proprieties. Women with high atropinic burden were older, had more long-term adverse health conditions, were more frequently smokers or unemployed, suffered more from diabetes, and received twice more medications prescribed during pregnancy

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except atropinic ones compared to women with no atropinic burden. Weight at 9 months and 24 months of infants exposed to high atropinic burden were lower compared to those of unexposed women. More infants of high-exposed mother to atropinic burden had psychomotor problems such as problems to “repeat syllable at 9 months”, to “name a picture at 24 months” or to “walk at 24 months” compared to infants of unexposed women (P < 0.05). Discussion/Conclusion: Atropinic drugs are largely prescribed to pregnant women (around one third). Women with high atropinic burden during pregnancy had more comorbidies compared to unexposed women. Infants of highexposed women seem to have lower psychomotor development compared to those of unexposed. CO-074 Training program: impact on healthcare professionals? L Gaboriaua, M Bronnecb, L Wainsteina, C Grosclaudec, L Moretd, P Jollieta, C Victorri-Vigneaua aDepartment of clinical pharmacology, Center for evaluation and information on pharmacodependence, University hospital – Nantes (France); b Addictology department, University hospital – Nantes (France); cDepartment of anesthesiology, University hospital – Nantes (France); dDepartment of public health, University hospital – Nantes (France) Introduction: No guidelines can be found for managing acute pain in chronic opiate users. In fact, this situation is usually a challenging and complex clinical situation and healthcare professionals seem to be concerned about this situation. Regular questions on this subject and a particular investigation have shown a specific training need to improve pain care in these vulnerable patients. This training program was supported by “Fondation de France”. We aimed to assess immediate impact of a training session on healthcare professional’s knowledge. Material and methods: This training program was conducted in several structures involved in addiction or in acute pain. It was containing three parts: pain in opiate dependent patients, pharmacology of opiates and acute pain care strategies in opiate users. A 10-questions-test was performed just before and after the training session. Five questions assessed theoretical concepts and five questions assessed practical knowledge. Results: At this time, 586 healthcare professionals (from 23 healthcare institutes) followed this training program. For each training session, immediate session mean mark was significantly higher than before session mean mark. The global mean mark before the training session was 3.8 out of 10. The global mean mark after the training session was 8.3 out of 10. Discussion/Conclusion: Immediate impact of each training session was positive on theoretical and on practical knowledge. Particularly, in this training program, professionals raised the balance between theory and practice. This training session was also included in late program of future health professionals (pharmacists, dentists. . .). CO-075 The apelin administration improves insulin sensitivity: proof of concept in healthy overweight volunteers A Sommeta, C Thalamasb, L Cazalsc, E Lamic, I Castand, F Calvasb, M Galitzkyb, P Valetd, P Gourdyc aPharmacologie Medicale et Clinique – Toulouse (France); b Centre d’Investigation Clinique – Toulouse (France); cService de Diabetologie, CHU – Toulouse (France); dINSERM/UPS UMR1048 – Toulouse (France) Introduction: Apeline is an adipokin which improves glucose tolerance in different murin models by stimulating insuline snsitivity of peripheric tissues (squelettal muscles and adipose tissue). The aim of this proof-of-concept study “APELINS” was to study the influence of the administration of apelin on insulin sensitivity in human. Material and methods: Non-diabetic overweight male volunteers (32.8  6.8 years, BMI 27.6  1.4 kg/m², 5.4  0.3% HbA1c) were included in this randomized, cross-over, double-blind, phase 1 trial. Effects of two doses of (PYR1)-Apeline-13 vs. placebo: 9 nmol/kg (n = 8) and 30 nmol/kg (n = 8) were tested. Each volunteer performed two hyperinsulinemic euglycemic clamps (1 mU/kg/min) for 4 h at intervals of 7–21 days. Sensitivity basal insulin was estimated by the glucose infusion rate (DPG) from the 90th to the 120th minute (step 1), then the test material was infused for 2 h and its effect appreciated by DPG the 210th to the 240th minute (step 2). The primary endpoint was the difference between the DPG to step 2 and the DPG to step 1 (DDPG). Results: At low dose (9 nmol/kg), the apelin administration results in a non-significant increase in DDPG placebo (+ 2.21  0.54 vs. 1.57  0.53 + mg/kg/ min, P = 0.06). However, a significant improvement in insulin sensitivity was observed with a dose of 30 nmol/kg (DDPG: + 1.72  0.47 mg/kg/min with apelin vs. + 0.89  0.62 mg/kg/min for placebo, P = 0.03). The safety of two doses of apelin was satisfactory, especially for cardiovascular events. Discussion/Conclusion: Demonstrating the insulin-sensitizing effect of apelin in humans, our results open new perspectives for therapeutic alternatives research targeting insulin resistance in type 2 diabetics.

TSO CO-076 Psychoactive prescription drugs injected, sniffed and inhaled: main trends in 2013 through the national program OPPIDUM E Fraugera, D Amaslidoub, A Giocantic, D Braunsteina, Q Boucheriea, X Thirionc, J Micallefa aCentre d’Addictovigilance PACA Corse, Service de Pharmacologie clinique et pharmacovigilance, H^opitaux de la Timone – Assistance Publique H^opitaux de Marseille, Aix-Marseille Universite, Institut des Neurosciences Timone UMR 7289 CNRS – Marseille (France); bCentre d’Addictovigilance PACA Corse, Service de Pharmacologie clinique et pharmacovigilance, H^opitaux de la Timone – Assistance Publique H^opitaux de Marseille – Marseille (France); cCentre d’Addictovigilance PACA

© 2015 The Authors. Fundamental and Clinical Pharmacology © 2015 Societe Francßaise de Pharmacologie et de Therapeutique, 29 (Suppl. 1), 1–19

Abstracts – Oral Communications 2015

Corse, centre associe, Laboratoire de sante publique, Faculte de Medecine, EA 3279, Aix-Marseille Universite – Marseille (France) Introduction: In drug abuse monitoring, diverted route of administration is relevant information. The objective of the study was to determine which psychoactive prescription drugs are injected, sniffed or inhaled in 2013. Material and methods: OPPIDUM is an annual, cross-sectional survey that is based on data from specialized care centers that included subjects presenting a drug dependency or under opiate maintenance treatment. For each psychoactive substance consumed the week before inclusion, route(s) of administration used is filled (oral/sublingual, snorted, inhaled, injected) and a ratio of route of administration (number of injection (or sniff or inhalation) divided by the number of described ways of administration) is estimated. For each route, the repartition of prescription drugs is reported. Data from 2013 are compared with 2008 data. Results: In 2013, 5245 subjects have been included and have described the consumption of 10 727 psychoactive substances including 68% of prescription drugs. In 2013, prescription drugs represented 51% of all psychoactive drugs injected (vs. 34% in 2008). The most injected prescription drugs are high dosage buprenorphine (52%), morphine (36%) and methylphenidate (5%). In 2013, prescription drugs represented 20% of all psychoactive drugs snorted (vs. 16%). The most snorted were high dosage buprenorphine (77%), ketamine (6%) and morphine (5%). In 2013, prescription drugs represented 9% of all psychoactive drugs inhaled (vs. 5%). In 2013, the most inhaled drugs were high dosage buprenorphine (58%), methadone (8%) and codeine (8%). Between 2008 and 2013, the proportion of morphine injected has increased (63% to 79%), the same trend is observed for methylphenidate (40% to 60%) and buprenorphine (8% to 14%). Discussion/Conclusion: Because routes of administration affect pharmacokinetic and pharmacodynamic proprieties, it is important to assess diversion of prescription drugs. This study highlighted the important part of prescription drugs injected like morphine and methylphenidate as “signal” of drug abuse in real setting. CO-077 Assessment of risks associated with SLAM practice: survey from the French network of addictovigilance centers A Batissea, C Eidenb, MA Cournec, S Djezzara, H Peyriereb aCentre d’addictovigilance – Paris (France); bCentre d’addictovigilance – Montpellier (France); c ANSM – Paris (France) Introduction: The SLAM phenomenon is an increasingly popular practice, in Paris and London gay scene, defined by three characteristics: injection, sexual party and psychostimulant drugs. Users report to practice slam to put them into the good mood and desinhibition state. The French Medical Agency requested a risk assessment of SLAM by the analysis of complications related to this practice notified to the French network of addictovigilance centers. Material and methods: All cases of complications related to SLAM practice, including cases of abuse and/or dependence, and somatic and psychiatric complications, were analysed. Among the three criteria that define slam (psychostimulants consumption, in sexual context and intravenous route) only cases with at least two criteria were included in the analysis. Results: Between January 2008 and December 2013, 51 cases were collected. Users were exclusively men, with a mean age of 40 years, having psychostimulants exposure in sexual context, mainly in men having sex with men (MSM) context (100%, n = 35). The prevalence of HIV infection was 82% (n = 32) with a high level of HIV/Hepatitis C virus (VHC) co-infection (50%, n = 16). Main psychostimulants reported are synthetic cathinones (89.5%). Cathinones users tended to be polydrug users: near the twice reported use also other psychoactive substances (GBL, ketamine, MDMA, cannabis, LSD. . .). Route of administration was intravenous in 60.8% of cases. The main complications were psychiatric disorders in 50% (psychotic symptoms, agitation, anxiety, suicidal ideas or attempt

and two cases presented forensic problem, acute intoxication in 25% (including three deaths), dependence and abuse in 17% and infectious complications in 8% (with two cases of VHC seroconversion and one case of VIH/VHC seroconversion). Discussion/Conclusion: Health professionals as well as users should be aware of the physical (cardiovascular) and behavioural (psychic, fast dependence syndrome) toxicity of cathinones. This practice of SLAM is associated with poor adherence to antiretrovirals, and consequently an increase of the infectious risk. It is urgent to inform users of the practice of the associated risks and implement risk mitigation procedures. Risk reduction policy must be targeted to the population of MSM with specific interventions both on risky sexual behavior and substance use. CO-078 A parachute to land softly? A Daveluya, H Geniauxa, C Eidenb, C Chenafc, S Deheuld, A Bouchere, M Spadarif, M Gerarding, G Miremont-Salamea, F Haramburua aCentre d’addictovigilance, service de pharmacologie medicale, CHU, INSERM, U657 – Bordeaux (France); b Centre d’addictovigilance – Montpellier (France); cCentre d’addictovigilance – Clermont-Ferrand (France); dCentre d’addictovigilance – Lille (France); eCentre d’addictovigilance – Lyon (France); fCentre d’addictovigilance – Marseille (France); g Centre d’addictovigilance – Nantes (France) Introduction: Parachuting (or bombing) is a technique of drug delivery where medicines or illicit drugs are ingested by wrapping the substance of choice in a covering (cigarette paper, toilet paper, paper towel, etc.). Case reports have been published [1-2], hypothesizing pharmacokinetic rationale for using a parachute. However, data describing the technique, the substances used, the context and the reasons for using a parachute are sparse. The aim of this study was to assess cases of parachute reported to the French Addictovigilance Network. Material and methods: All cases reported to addictovigilance centres, in which a parachute was used, up to July 2014, were assessed. Data from the OPPIDUM programme were also used. To be included, cases had to mention both the practice of parachute and the substance supposedly used. Results: Parachuting was identified in 31 cases. One case occurred in 2006, one in 2011, 14 in 2012, 9 in 2013 and 6 up to July 2014. Patients were mostly men (58%); the mean age was 27 years. The context of use was mostly recreational. Complications were present in 22 cases, of which 7 were serious (2 deaths). The term parachute was specified in 21 cases, the use of cigarette paper in nine cases and of plastic wrap in 1. The substance most frequently used was MDMA (58%). Discussion/Conclusion: All but one of the cases have been reported in the last 4 years, bringing up the hypothesis of a recent emerging practice. Similarly, in the literature, the first case was published in 2006 [1], thereafter numerous articles have been published since 2010. However, the technique is mentioned as early as the year 2000 on web forums. In France, its use was mentioned in 2001 for amphetamines, then in 2004 also for opium and MDMA. Clearly the technique is becoming more visible since the spread of research chemicals and does not seem specific to one particular drug. In the present study, seriousness was probably more related to the substance itself than to the technique. However, a fatal case described in the literature [2] was obviously related to the technique of parachuting, as the autopsy revealed a wadded paper towel within the larynx having induced airway obstruction. Thus, parachuting may not be as safe as users think. Moreover, parachuting offers the possibility to consume large amounts of substances with an enhanced risk of toxicity. References: [1] Hendrickson RG et al. Clin Toxicol 2006;44:379-82 [2] Kenerson KL et al. Am J Forensic Med Pathol 2012;33:173-5

© 2015 The Authors. Fundamental and Clinical Pharmacology © 2015 Societe Francßaise de Pharmacologie et de Therapeutique, 29 (Suppl. 1), 1–19

19

Abstracts of the 19th Annual Meeting of French Society of Pharmacology and Therapeutics, 36th Pharmacovigilance Meeting, 16th APNET Seminar, 13th CHU CIC Meeting, 21-23 April, 2015, Caen, France.

Abstracts of the 19th Annual Meeting of French Society of Pharmacology and Therapeutics, 36th Pharmacovigilance Meeting, 16th APNET Seminar, 13th CHU CIC Meeting, 21-23 April, 2015, Caen, France. - PDF Download Free
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