Laboratoire Of Pharmaco Toxicologie

Paris, France

Laboratoire Of Pharmaco Toxicologie

Paris, France
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Madelain V.,University Paris Diderot | Madelain V.,Laboratoire Of Pharmaco Toxicologie | Le M.P.,University Paris Diderot | Le M.P.,Laboratoire Of Pharmaco Toxicologie | And 11 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2017

Background: Obesity has high prevalence among HIV-infected patients. Increased adipose tissue mass affects the pharmacokinetics of numerous drugs, but few data are available for antiretroviral drugs. Objectives: In this study we aimed to explore the pharmacokinetics of antiretroviral drugs and the immunovirological response in obese patients with HIV infection. Patients and methods: We examined data from 2009 to 2012 in our hospital's database for HIV-1-infected patients who received an antiretroviral drug (abacavir, emtricitabine, lamivudine, tenofovir, efavirenz, etravirine, nevirapine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir or raltegravir). Obese patients were defined as those with BMI ≥30 kg/m2 and normal-weight patients as those with BMI 19-25 kg/m2. Plasma concentrations (C12/24) were compared for each antiretroviral drug using a Mann-Whitney test. Suboptimal dosing and virological outcome were assessed by logistic regression, adjusting on covariates. Results: We enrolled 291 obese and 196 normal-weight patients. Among the 12 analysed antiretroviral drugs, tenofovir, efavirenz and lopinavir C12 values were significantly lower in obese than normal-weight patients: 66 versus 86 ng/mL, 1498 versus 2034 ng/mL and 4595 versus 6420 ng/mL, respectively (P < 0.001). Antiretroviral drug C12/24 values weremore frequently below efficacy thresholds for obese than for normal-weight patients after adjustment for other covariates (P < 0.001). Although obese patients showed a higher CD4 count than normalweight patients (510 versus 444 cells/mm3, P < 0.001), the groups did not differ in virological failure rate. Conclusions: This study highlights the impact of obesity on antiretroviral drug plasma exposure, but identifies no consequence of this suboptimal exposure on the immuno-virological control in this population. © The Author 2016.

Desnoyer A.,Bichat Claude Bernard Hospital | Desnoyer A.,Laboratoire Of Pharmaco Toxicologie | Pospai D.,Bichat Claude Bernard Hospital | Le M.P.,Bichat Claude Bernard Hospital | And 19 more authors.
Journal of Hepatology | Year: 2016

Background & Aims Hepatitis C virus (HCV) infection is an independent risk factor for chronic kidney disease and leads to faster liver disease progression in patients requiring hemodialysis than in those with normal renal function. Little is known about the use of a sofosbuvir-containing regimen for infected patients on hemodialysis. We aimed to describe the pharmacokinetics, safety and efficacy of sofosbuvir in 2 dosing regimens and associated antiviral agents in HCV-infected patients requiring hemodialysis. Methods Multicenter, prospective and observational study of patients receiving sofosbuvir, 400 mg once daily (n = 7) or 3 times a week (n = 5), after hemodialysis with simeprevir, daclatasvir, ledipasvir or ribavirin was conducted. Drug plasma concentrations were determined by liquid chromatography-tandem mass spectrometry before and after a 4 h hemodialysis and 1.5 h after last drug intake at the end of hemodialysis. Results Plasma concentrations of sofosbuvir or its inactive metabolite sofosbuvir-007 did not accumulate with either regimen between hemodialysis sessions or throughout the treatment course. Sofosbuvir-007 extraction ratio (52%) was consistent with historical data. In one patient receiving the once daily regimen, sofosbuvir-007 half-life was slightly higher (38 h) than for patients with normal renal function receiving a full dose. Hemodialysis did not remove any other associated anti-HCV agents. Clinical and biological tolerance was good for all patients. Two relapses occurred with the 3 times a week regimen and none with the once daily. Conclusions A regimen including sofosbuvir, 400 mg once daily, could be proposed for HCV-infected patients requiring hemodialysis and should be associated with close clinical, biological, cardiovascular, and therapeutic drug monitoring. Lay summary Hepatitis C Virus (HCV) infection in hemodialysis patients is prevalent and aggressive. Effective anti-HCV treatment in these patients may stabilize their renal disease. However, sofosbuvir, the cornerstone of most anti-HCV-containing regimens, should not be administered to these patients until more data is available. In this pharmacokinetic study, sofosbuvir full dose (400 mg once daily) administered every day with another direct antiviral agent did not accumulate in hemodialysis patients and was safe and effective. © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Boulle C.,Montpellier University | Kouanfack C.,Central Hospital | Laborde-Balen G.,Montpellier University | Boyer S.,French Institute of Health and Medical Research | And 14 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2015

Background: Evidence of gender differences in antiretroviral treatment (ART) outcomes in sub-Saharan Africa is conflicting. Our objective was to assess gender differences in (1) adherence to ART and (2) virologic failure, immune reconstitution, mortality, and disease progression adjusting for adherence. Methods: Cohort study among 459 ART-naive patients followed up 24 months after initiation in 2006-2010 in 9 rural district hospitals. Adherence to ART was assessed using (1) a validated tool based on multiple patient self-reports and (2) antiretroviral plasma concentrations. The associations between gender and the outcomes were assessed using multivariate mixed models or accelerated time failure models. Results: One hundred thirty-five patients (29.4%) were men. At baseline, men were older, had higher body mass index and hemoglobin level, and received more frequently efavirenz than women. Gender was not associated with self-reported adherence (P = 0.872, 0.169, and 0.867 for moderate adherence, low adherence, and treatment interruption, respectively) or with antiretroviral plasma concentrations (P = 0.549 for nevirapine/efavirenz). In contrast, male gender was associated with virologic failure [odds ratio: 2.18, 95% confidence interval (CI): 1.31 to 3.62, P = 0.003], lower immunologic reconstitution (coefficient: 258.7 at month 24, 95% CI: 2100.8 to 216.6, P = 0.006), and faster progression to death (time ratio: 0.30, 95% CI: 0.12 to 0.78, P = 0.014) and/or to World Health Organization stage 4 event (time ratio: 0.27, 95% CI: 0.09 to 0.79, P = 0.017). Conclusions: Our study provides important evidence that African men are more vulnerable to ART failure than women and that the male vulnerability extends beyond adherence issues. Additional studies are needed to determine the causes for this vulnerability to optimize HIV care. However, personalized adherence support remains crucial. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Aknouche F.,Laboratoire Bio6Med | Guibert E.,Laboratoire Of Pharmaco Toxicologie | Tessier A.,Laboratoire Bio6Med | Alvarez J.-C.,Laboratoire Of Pharmaco Toxicologie | And 2 more authors.
Toxicologie Analytique et Clinique | Year: 2015

Oxycodone is a semi-synthetic opiate, derived from thebaine. It is a narco-tic analgesic proposed for relief of pain (moderate to severe, or chronic pain). Althoughfirst developed in 1916, oxycodone is available on the French market only since 2000, inimmediate release (OxyNorm®and OxyNormOro®, as capsule or injectable form and oralliquid, respectively) and controlled release (OxyContin®, as tablet). The delivery of oxy-codone follows the rules of drugs of abuse (special medical prescription, prescription forno more than 28 days). Numerous fatal overdoses have been described in the US, but arevery seldom in France as recreational use remains rare. We describe here 3 fatalities (2women and 1 man) involving oxycodone, including analytical procedures and interpretationthat occurred in 3 different cities of France. A general screening, involving immunoche-mistry and gas-liquid chromatography identified in each case oxycodone and some otherpharmaceuticals. Neither ethanol nor drugs of abuse were detected. Oxycodone was tes-ted by LC-MS/MS in the 3 cases. The following results were obtained in peripheral blood:case 1, oxycodone (2344 ng/mL) + alprazolam (112 ng/mL) + sertraline (1323 ng/mL); case 2,oxycodone (600 ng/mL) + zopiclone (1000 ng/mL) + mianserine (580 ng/mL) + citalopram(150 ng/mL); case 3, oxycodone (1400 ng/mL) + zopiclone (1850 ng/mL) + nordiazepam(395 ng/mL) + oxazepam (45 ng/mL). Due to the toxicological findings, all 3 deaths werelisted as acute oxycodone intoxication in a polydrug abuse situation. The discussion will befocused on the comparison of our results with the existing literature, the absence of drugabuse and the original circumstances of death. © 2014 Société Française de Toxicologie Analytique.

Descamps D.,University Paris Diderot | Descamps D.,French Institute of Health and Medical Research | Descamps D.,Laboratoire Of Virologie | Peytavin G.,University Paris Diderot | And 20 more authors.
Clinical Infectious Diseases | Year: 2015

Background. Dolutegravir has shown in vitro activity against human immunodeficiency virus type 2 (HIV-2). We report safety and efficacy data of regimens containing dolutegravir (50 mg twice daily) in antiretroviral-experienced, HIV-2-infected patients. Methods. HIV-2-infected patients experiencing virological failure to raltegravir received dolutegravir with optimized background antiretroviral combinations within the French Named Patient Program (NPP). Plasma HIV-2 RNA (pVL) was assessed at time of dolutegravir initiation (baseline), month 3, and month 6. Antiretroviral trough plasma concentrations (C12h) were determined using liquid chromatography coupled with tandem mass spectrometry. Results. Thirteen HIV-2-infected-patients, with a median duration of 15 years' infection and given 16 previous antiretroviral regimens, were included in NPP. Median follow-up was 9 months (min-max, 3-15 months). Median baseline pVL and CD4 cell count were 9544 copies/mL (inter quartile range [IQR], 3096-23 120 copies/mL) and 100 cells/μL (IQR, 77-171 cells/μL), respectively. Available integrase genotypic resistance patterns were Y143C/G/H/R (n = 5), Q148R/K (n = 2), and N155H (n = 4). Optimized background antiretroviral regimens conferring a genotypic sensitivity score ≤2 in 10 patients included nucleoside reverse transcriptase inhibitors associated with darunavir/ritonavir (n = 12), saquinavir/ritonavir (n = 2), and maraviroc (n = 3). At months 3 and 6, pVL was undetectable in 6 of 13 and 4 of 12 patients, respectively, and median CD4 count was 161 (101-188) cells/μL and 167 (135-1353) cells/μL, respectively. Median dolutegravir C12h was 4086 (1756-5717 ng/mL) ng/mL in 9 patients. No serious events were notified except 1 death from progressive multifocal leukoencephalopathy at month 4. Conclusions. Optimized dolutegravir-containing antiretroviral regimens supported by good plasma exposure provide a substantial initial efficacy rate for salvage therapy in heavily antiretroviral-experienced HIV-2-infected patients with virus harboring resistance to first-generation integrase inhibitors. Larger numbers of patients and longer follow-up are needed to confirm these findings. © 2015 The Author.

Achour S.,Laboratoire Central dAnalyses Medicales | Achour S.,Université Ibn Tofail | Rhalem N.,Center Antipoison Et Of Pharmacovigilance Du Maroc | Rhalem N.,Université Ibn Tofail | And 6 more authors.
Therapie | Year: 2012

Peganum harmala L. is commonly used in traditional medicine in Morocco for its sedative and emmenagogue properties but expose to the risk of overdose and poisoning. The aim of our study was to analyze a series of 200 cases of poisoning collected in poison control and pharmacovigilance center of Morocco in order to describe the epidemiological, clinical, therapeutic features and outcome of patients and indicate the toxicity of this plant used primarily for therapeutic purposes. Methods. This retrospective study performed over a period of twenty four years from January 1984 to December 2008. Results. The mean age of patients was 24.4±16.8 years with a female predominance (167 women against 33 men). Therapeutic circumstance was found in 32.5%, followed by suicide (28.5%) and abortion (13.5%). The symptomatology was dominated by neurological, gastrointestinal and cardiovascular signs respectively 34.4%, 31.9 % and 15.8%. The evolution has been specified in 114 cases, 7 deaths have been deplored with a fatality rate of 6.2%. © 2012 Société Française de Pharmacologie et de Thérapeutique.

Peytavin G.,Laboratoire Of Pharmaco Toxicologie | Peytavin G.,University Paris Diderot | Joly V.,Service de maladies infectieuses et tropicales | Joly V.,University Paris Diderot | And 2 more authors.
Journal des Anti-Infectieux | Year: 2014

Once-daily single-tablet regimen (STR) represents a significant recent advance in the simplification of antiretroviral therapy, facilitating adherence to complex and chronic treatments, and improving the quality of life of HIV-infected patients. The STR reduces the risk of treatment errors, particularly in situations of selective non-compliance and therefore, limits the risk of emergence of HIV resistance mutations. Galenic researches and pharmaceutical industry collaborations may allow STR combining drugs with favorable pharmacokinetic profiles as HIV-1 non-nucleosidic reverse transcriptase inhibitors (efavirenz or rilpivirine), integrase inhibitors (cobicistat-boosted elvitegravir or dolutegravir), and protease inhibitors (cobicistat-boosted darunavir) associated with either tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine. With the exception of renal or liver dysfunctions or drug-drug interactions requiring dose adjustments, the preferential use of STR should be recommended by guidelines in many antiretroviral-naïve or -experienced HIV-infected patients. © 2014 Elsevier Masson SAS.

Achour S.,Laboratoire Of Toxicologie | Achour S.,Université Ibn Tofail | Saadi H.,Service de gynecologie obstetrique | Turcant A.,Laboratoire Of Pharmaco Toxicologie | And 4 more authors.
Medecine et sante tropicales | Year: 2012

Peganum harmala L. (wild or Syrian rue) is commonly used as an emmenagogue and abortifacient in traditional medicine in the Middle East and North Africa including Morocco. The purpose of this report is to describe two cases of Peganumharmala L.poisoninginpregnantwomen. Both cases were treated successfully with good maternal-fetal outcome good for mother and child.

Bousliman Y.,Laboratoire Of Pharmaco Toxicologie | Eljaoudi R.,Laboratoire Of Pharmacologie Et Toxicologie | Elcadi M.A.,Laboratoire Of Pharmacologie Et Toxicologie | Basset T.,Laboratoire Of Pharmaco Toxicologie | And 5 more authors.
Annales de Biologie Clinique | Year: 2012

Paraphenylenediamine is an aromatic amine used as a hair dye; it is responsible for poisoning characterized by respiratory distress involving life-threatening. The objective of this work is the development and validation of an assay of para-phenylenediamine in the whole blood. The method is based on the determination of paraphenylene diamine in whole blood by gas chromatography-mass spectrometry after liquid-liquid extraction and derivatization. The validation protocol has included the study of the recovery factor of extraction, the measurement range, accurency, repetability and intermediate precision. The calibration curve was linear between 98 and 1350 μg/L (r = 0.999), the limit of detection and quantification were 37 μg/L and 63μg/L respectively. The accuracy were 94.7%. Coefficients of variation were (2.3/6.8/9.7%) for repeatability and (4.4/8.7/9.8%) for intermediate precision. The method is suitable for quantification of PPD in acute poisoning situations. A method for the determination of the paraphenylene diamine in the whole blood by gas chromatography coupled to mass spectrometry was developed. The validation of the method showed good linearity, good accuracy and low limit of quantification.

PubMed | Laboratoire Of Pharmaco Toxicologie
Type: Journal Article | Journal: Therapie | Year: 2010

To estimate the relative frequency of reported adverse drug reactions during the malaria chemoprophylactic period of the Moroccan contingent in Democratic Republic of Congo (DRC).The transversal survey involved all military personnel of the Moroccan contingent and was carried out using a questionnaire to be filled out by a multidisciplinary medical team. It was performed in all the military sites and the advanced posts accessible during the period of the study.The study involved 362 male military subjects. Ninety-four adverse drug reactions were described: neuropsychiatric (anxiety, irritability, dizziness...) [n=76], digestive (anorexia, diarrhea, nausea...) [n=42], cardiovascular (tachycardia, palpitation, precordialgia...) [n=5], musculoskeletal (arthralgia, cramps) [n=4], cutaneous (redness, purpura) [n=2], and other (n=13). No unexpected or serious adverse drug reaction was reported. The causality assessment score was determined in 94 cases. Two of these reports were rated likely, 12 possible and 80 doubtful. More adverse drug reactions were reported by subjects having medical and paramedical functions.During our study, mefloquine induced adverse drug reactions in a quarter of the treated subjects. Most of the adverse drug reactions were neuropsychiatric. No serious adverse drug reactions were reported underlying the interest of its use, even for long-term chemoprophylaxis.

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