Olivier Mathieu

Université Montpellier, Montpelhièr, Languedoc-Roussillon, France

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Publications (26)49.58 Total impact

  • D. Hillaire-Buys, O. Mathieu
    06/2015; 27(2). DOI:10.1016/j.toxac.2015.04.007
  • 06/2015; 27(2). DOI:10.1016/j.toxac.2015.03.028
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    ABSTRACT: Aquatic organisms are exposed to pharmaceuticals present in natural waters, but few data are available on the accumulation of these substances in such organisms. The present study evaluated the in vivo bioconcentration of two anticonvulsants - carbamazepine (CBZ) and 10-hydroxy-10,11-dihydro-carbamazepine (10OH) - in marine mussels (Mytilus galloprovincialis) exposed to nominal 10μgL(-1) concentrations for one week. The bioconcentration factors (BCFs) were 3.9 and 4.5Lkg(-1) dry weight (dw) for CBZ and 10OH, respectively. CBZ accumulation reached an average tissue concentration of 29.3±4.8ngg(-1) dw, and 10OH accumulated up to 40.9±4.6ngg(-1) dw in tissues within one week, showing first-order kinetics. BCF obtained with linear QSAR models correctly estimated the CBZ bioconcentration and overestimated the 10OH bioconcentration to some extent. The detection of two metabolites (carbamazepine-10,11-epoxide and acridine) among the five sought suggested an active metabolism for CBZ. In contrast, none of the 10OH metabolites were detected in mussels exposed to 10OH. CBZ showed higher accumulation in the digestive gland, where some relevant metabolites were detected, than in other studied tissues. The implication of those findings on field biomonitoring is discussed. Copyright © 2015 Elsevier B.V. All rights reserved.
    Science of The Total Environment 06/2015; 532:564-570. DOI:10.1016/j.scitotenv.2015.05.067 · 4.10 Impact Factor
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    ABSTRACT: The prevalence of levamisole in urine samples of subjects positive for cocaine in the US was estimated at 78% (95%confidence interval or CI: 73%-83%). However, levamisole was not quantified, and at the time of this report, aminorex was not known to be a possible metabolite of levamisole in human. Moreover no data are available in Europe. The aim of this study was to determine the prevalence and concentration of levamisole and aminorex in positive cocaine urine toxicology tests, and in serum samples of cocaine-positive subjects driving under the influence of drugs or forensic autopsies. Consecutive urine toxicology samples tested positive for cocaine by immunoassay (EMIT, Siemens) from April to May 2014 at the toxicology laboratory of a French University Hospital, and blood samples of cocaine-positive subjects driving under the influence of drugs or forensic autopsies from April to December 2014 were analyzed by liquid chromatography-tandem mass spectrometry or LC-MS/MS (3200 QTrap, AB Sciex) to detect and quantify the presence of levamisole and aminorex. Forty-two urine samples tested positive for cocaine in 39 patients (79.5% males) with a median age of 43 [range: 20-51] years. Toxicological analyses were mainly required by addictions care centers (n = 17; 40%) in the context of the routine management of addict patients. Cocaine concentrations were above the limit of quantification for 33 patients, with a median value of 228 [0-645,000] ng/ml. Levamisole was detected in 32 urine samples (76%) (median concentration: 1,430 ng/ml, range: 30-258,000). Aminorex was never detected. During the study period, levamisole was detected in 87.5% of cocaine-positive blood samples of the subjects driving under the influence of drugs or forensic autopsies. In this prospective study, the prevalence of levamisole in cocaine-positive samples was 76%. Over this period, although clinical complications related to cocaine use were reported (agitation, road accident, and cardiac arrest), no complication specifically related to levamisole or aminorex was reported. Our results show a high prevalence of levamisole in samples of subjects positive for cocaine, close to the prevalence found in the US. This high prevalence raises issues with respect to well-identified health risks associated with regular consumption of levamisole.
    Clinical Toxicology 06/2015; DOI:10.3109/15563650.2015.1054499 · 3.12 Impact Factor
  • 06/2015; 27(2):S45. DOI:10.1016/j.toxac.2015.03.065
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    ABSTRACT: Background: A wide variety of somatic complications is reported or expected among cocaine users because of the adulterant levamisole. Most of the reports come from North America. Methods: To update the data on levamisole-adulterated cocaine in European countries, we present here a synthesis of data on samples seized by the police with the detection of levamisole, the amount of levamisole in cocaine samples, European drug information reports, and clinical cases. Results: Although there is a variation in the percentage of levamisole in cocaine samples between European countries, the trend is an increase of these percentages. As in North America, levamisole is becoming the most common cocaine adulterant. First European cases of complications secondary to the use of adulterated cocaine with levamisole were skin necrosis, vasculitis, and agranulocytosis. Levamisole postmortem data concerned two cases of complications leading to death, possibly related to levamisole or its metabolite (acute coronary syndrome, pulmonary hypertension). Conclusion: Even if it is difficult to have a global European view with comparable data, levamisole is present in European cocaine specimens and can lead to severe adverse health effects. However data on the prevalence of toxicity related to levamisole-adulterated cocaine abuse are missing.
    Journal of psychoactive drugs 11/2014; 46(5):389-92. DOI:10.1080/02791072.2014.959215 · 1.10 Impact Factor
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    ABSTRACT: Buprenorphine is largely prescribed for maintenance treatment in opioid dependence due to its safety profile. Nevertheless, fatalities at therapeutic dose have been described when associated with other central nervous system depressants, such as ethanol or benzodiazepines. Here, we report a case of death due to association of buprenorphine at therapeutic dose with benzodiazepines and ethanol. Although toxicity has been often attributed to its metabolite norbuprenorphine rather than to buprenorphine itself, in our case, norbuprenorphine was not detected in urine and bile and only in traces in blood. Moreover, the presence in blood of free buprenorphine but not of glucuronide metabolites argues for an unusual early death, at the beginning of buprenorphine metabolism. We propose that in the context of prior toxic impregnation, buprenorphine directly (and not via its metabolite norbuprenorphine) acted as a triggering factor by blocking the ventilatory response, rapidly leading to fatal respiratory depression.
    Journal of Forensic Sciences 10/2014; 60. DOI:10.1111/1556-4029.12621 · 1.31 Impact Factor
  • 06/2014; 26(2):S40. DOI:10.1016/S2352-0078(14)70083-6
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    ABSTRACT: Concentrations of the antiepileptic drugs carbamazepine (Cbz), oxcarbazepine (OxCz) and their main metabolites were predicted in a wastewater treatment plant (WTP) and in the vicinity of its submarine outfall located in a Mediterranean coastal zone. Refined predicted environmental concentrations (PECs) were calculated in effluents based on consumption data and human excretion rates. PECs were estimated in the sea using the hydrodynamic MARS 3D model integrating meteorological data, oceanic conditions (wind, tide, atmospheric pressure), freshwater and sewage inputs. Measured environmental concentrations (MECs) were compared to PECs to assess the estimation relevance. In the coastal zone, PEC and MEC were in the same magnitude range. Modeling of Cbz diffusion and advection just above the submarine outfall showed the influence of the thermocline during summer, with low diffusion of Cbz from the bottom to the surface. This work allowed understanding the dispersion of target compounds and deserved further development for a better acknowledgement of vulnerability at local scales.
    Environment international 04/2014; 68C:177-184. DOI:10.1016/j.envint.2014.03.025 · 5.66 Impact Factor
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    ABSTRACT: Introduction: Dipeptidyl peptidase IV (DPP-4) is ubiquitously expressed in various tissues and is upregulated during functional activation of different cell lines, including T-cells and endothelia. In the skin, many cell types including keratinocytes constitutionally express DPP-4 Some reports of adverse skin reactions in patients treated with DPP-4 (gliptins) have increased awareness towards skin-targeting side-effects of these anti-hyperglycaemic drugs. Herein we report a typical case of DRESS syndrome. Case report: : A 67-year-old female patient with morbid obesity (BMI 43), T2DM, hypertension and asthma was treated with metformin (2 550 mg tid), nebivolol (5mg od) candesartan /hydrochlorothiazide (15 mg/12,5 mg od), lercanidipine (20 mg od) and budesonide/formoterol (400 µg/ 12g ) for several years. She started vildagliptin / metformin 50 mg/1 000 mg (bid) in June 2011. In September, she presented a trunk rash and severe pruritus treated by topical corticosteroids and antihistaminics. One month later, her general condition impaired with fever and dysphagia. Vildagliptin / metformin and nebivolol were stopped. Laboratory tests showed eosinophilia (2 400/mm3) and creatininemia at 378 µM. She was hospitalized in intensive care unit with oligoanuria and 80% skin necrolysis with positive Nikolski, suggesting a toxic epidermic necrolysis. Following lactic acidosis, she received insulin, albumin and systemic corticosteroids. A course of IV immunoglobulin was performed without disease improvment. At this time, laboratory tests showed an increase of ASAT (219 UI) and ALAT (128 UI), monocytosis (1 842/mm3) and atypical lymphocytes. Histological examination revealed moderate edema with infiltration of eosinophils, in favor of DRESS syndrome . The patient condition was aggravated with pleuropulmonary damage. Outcome was delayed under corrective treatment and marked by multiple organ failure and two others episodes of skin exfoliation. Conclusion: Drug eruptions induced by (DPP-4) inhibitors "gliptins" are not rare. It is worth noting that in the preclinical setting gliptins induced ‘blistering-necrotic’ skin lesions in cynomolgus monkeys. The development of bullous ⁄ blistering dermatoses in T2DM patients on treatment with "gliptins" might be considered as a group drug adverse effect. The precise role of the increase of physiological incretins and the inhibition of DDP-4 in skin reactions remains to be defined.
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    ABSTRACT: Background. Consumption of substituted cathinones, frequently called 'legal highs' or 'designer drugs', is increasing in the European Union. In July 2012, the French Medicine Agency listed the substituted cathinone's chemical family as narcotic and psychotropic substances, to restrict their use and distribution. We present, here, the first documented cases of recreational use of 2-pyrrolidino valerophenone (PVP) associated with death for one patient, with post-mortem toxicological analysis. Case reports. Two men purchased the legal high Energy-3 (NRG-3). It can be sold as laboratory reagent and is available from Internet. The oldest died of sudden cardiac arrest. The other experienced visual hallucinations and psychotic symptoms for 24 h. He also presented bilateral mydriasis, sinus tachycardia and rhabdomyolysis. He reported an occasional intranasal use of NRG-3. Analysis of the powder and blood and urine from both men revealed the presence of PVP. Discussion and conclusion. PVP belongs to the substituted cathinones chemical family. These cases highlight the need for emergency physicians, toxicologists and networks of toxicovigilance to control the use of these substances and their dangers, quickly identify cases of severe poisoning associated with the use of new drugs and to develop detection methods.
    Clinical Toxicology 10/2013; 51(9). DOI:10.3109/15563650.2013.847187 · 3.12 Impact Factor
  • 17th International Symposium on Pollutant Responses in Marine Organisms; 05/2013
  • 22th SETAC Europe; 05/2012
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    ABSTRACT: Treated wastewater is being increasingly used for irrigation and aquifer replenishment through artificial recharge. However, wastewater reuse can result in contamination of exposed soil and groundwater by chemicals such as some pharmaceuticals and their metabolites. The fate of these molecules depends largely on their capacity to sorb onto soil and aquifer materials during infiltration. In this study, the sorption isotherm of carbamazepine (CBZ), an anti-seizure medication, and two of its metabolites, i.e. carbamazepine-10,11-epoxide (CBZ-EP) and 10,11-dihydro-10,11-dihydroxycarbamazepine (DiOH-CBZ), were determined in two soils in laboratory assays. In the field, the presence of CBZ and its metabolites were investigated in soil and in groundwater underlying an irrigated area with treated wastewater. The results showed that CBZ had the highest carbon normalised sorption coefficients in the two tested soils (irrigated soil and a Lufa SP2.4 reference soil) followed by CBZ-EP and DiOH-CBZ, indicating the relatively higher mobility of CBZ metabolites compared to CBZ. The chromatographic analysis revealed that CBZ and its two metabolites were present in treated wastewater used for irrigation and in groundwater. In soil samples, CBZ concentrations showed a build-up taking place with irrigation. The mobility of metabolites in soil and their potential biodegradation require further investigation.
    Chemosphere 03/2012; 88(1):49-54. DOI:10.1016/j.chemosphere.2012.02.050 · 3.50 Impact Factor
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    ABSTRACT: To assess 12-month survival, pharmacokinetics, immunologic and virologic efficacy, tolerance, compliance and drug resistance in HIV-infected children in Bobo-Dioulasso, Burkina Faso, receiving once-daily highly-active antiretroviral therapy as a combination of didanosine (DDI), lamivudine (3TC) and efavirenz (EFV). In the ANRS 12103 open phase II trial, HIV-infected children were examined at inclusion and monthly thereafter. CD4+ T-lymphocyte (CD4) count, plasma concentration of ribonucleic acid (RNA) of human immunodeficiency virus type 1 (HIV-1) and haematologic and biochemical parameters were measured at baseline and every trimester. HIV-1 resistance testing was performed in case of viral escape. Drug plasma concentrations were determined with high-performance liquid chromatography. From February 2006 to November 2007, 51 children (39% girls) with a mean age of 6.8 years were enrolled and treated for 12 months. At baseline, Z scores for mean weight-for-age and mean height-for-age were -2.01 and -2.12, respectively. Mean CD4% was 9.0. Median plasma HIV-1 RNA viral load was 5.51 log(10) copies per millilitre (cp/ml). Two children (3.9%) died and another 11 (22%) suffered 13 severe clinical events. At month 12, mean WAZ had improved by 0.63 (P < 0.001) and mean HAZ by 0.57 (P < 0.001). Mean CD4% had risen to 24 (P < 0.001). Viral load was below 300 RNA cp/ml in 81% of the children; HIV resistance mutations were detected in 11 (21.6%). The once-a-day combination of DDI + 3TC + EFV is an alternative first-line treatment for HIV-1-infected children. Dose adjustment should further improve efficacy.
    Bulletin of the World Health Organisation 06/2011; 89(6):451-8. DOI:10.2471/BLT.10.081646 · 5.11 Impact Factor
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    ABSTRACT: In industrialized countries, acute lymphoblastic leukaemia (ALL) is the most frequent cancer in children aged less than 15 years. High-dose methotrexate is a common component of many chemotherapeutic protocols for childhood with ALL. Our objective was to retrospectively evaluate the pharmacokinetics and plasma levels of high-dose methotrexate as it relates to event-free survival (EFS) in children with ALL. Relapsed patients and subjects in EFS were compared for MTX serum concentrations 24, 36, 48 and 72 h after the start of 24 h infusion. Clearance (Cl), area under the curve (AUC) and volume of distribution (V(d) ) of the drug were estimated by the NONMEM computer program and also compared between both groups. Among 69 children included, 54 (78·3%) were still in EFS, whereas 15 (21·7%) relapsed. The difference between relapsed and EFS patients for the pharmacokinetic parameters studied was not significant. On the contrary, the cohort studied was representative and known prognostic factors for relapse in ALL were significantly associated with relapse. Serum concentrations and pharmacokinetic parameters of MTX are not associated with outcome in ALL. Prognoses based on single-drug pharmacokinetic estimates within a complex multiple-agent protocol appear to be unreliable. However, therapeutic drug monitoring of high-dose methotrexate remains a useful tool for early detection of impaired elimination and for avoiding systemic toxicity.
    Journal of Clinical Pharmacy and Therapeutics 04/2011; 36(2):237-45. DOI:10.1111/j.1365-2710.2010.01179.x · 1.53 Impact Factor
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    ABSTRACT: Carbamazepine is a widely used anticonvulsive agent. Its metabolic pathway leads not only to the major active metabolite, carbamazepine-10,11-epoxide, but also to minor terminal metabolites such as iminostilbene and acridine. Carbamazepine is usually well-tolerated, but it may lead to rare, but serious, hypersensitive reactions associated with hypereosinophilia. The mechanisms of hypersensitivity reactions to carbamazepine are still largely unknown, and the implications of the cell-mediated immune response (Th1 pathway) or the humoral immune response (Th2 pathway) are still not understood in these reactions. It is also unclear whether the parent drug or its subsequent metabolites are the primary trigger agent. In our study, we performed ex vivo experiments to evaluate the stimulation of cytokine secretion by carbamazepine, carbamazepine-10,11-epoxide, iminostilbene and acridine. IL-5, IL-6 and IL-10 were quantified as markers of the Th2 pathway, and IL-2 and IFN-γ were used as markers of the Th1 pathway. Blood samples (n=24) were obtained from epileptic patients routinely treated with carbamazepine alone or co-treated with lamotrigine or valproate. The concentrations of cytokines in the plasma were determined before and after 3 h stimulation with drugs. We found a significantly positive effect of co-treatment with valproate on the basal level of IL-5 (p<0.01) and IL-10 (p<0.05). IL-5 production increased only in blood stimulated with a high level of acridine (33 μM), whereas IL-6 production was less specifically stimulated (p<0.05). Because IL-5 is the most potent stimulating factor of the eosinophils, we suggest that the potential helper effect of valproate and acridine can lead to hypersensitive reactions to carbamazepine in the context of the humoral immune response.
    Pharmacological reports: PR 01/2011; 63(1):86-94. DOI:10.1016/S1734-1140(11)70402-9 · 2.17 Impact Factor
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    ABSTRACT: Carbamazepine (CBZ) is a useful anticonvulsive drug associated with rare severe adverse drug reactions. The physio-pathological mechanisms of these reactions are unknown although evidence of immunological activation has been reported. The ability of 9-acridinecarboxaldehyde, a CBZ metabolite, to interact with leukocyte constituents was demonstrated, and catabolism of this compound into acridine (AI) and acridone (AO) was observed in vitro. In this study, we have assessed ex vivo the role of the extra-hepatic 9-acridinecarboxaldehyde pathway in the metabolism of CBZ. First, we verified the presence of the terminal metabolites AI and AO in CBZ-treated patients. Then, we tested ex vivo the transformation of CBZ, epoxy CBZ, iminostilbene, and AI into AO in the blood of these patients. We observed no direct formation of hydroxylated CBZ metabolites in isolated blood, and CBZ did not react with blood cells. Conversely, we detected a dose-dependent transformation of epoxy CBZ, iminostilbene, and AI into AO with individual variations from patient to patient. AO might thus be considered as a metabolite of 9-acridinecarboxaldehyde that does not react with cells (detoxicant pathway) as well as a marker of the formation of toxic AI derivatives (toxicant pathway).
    Xenobiotica 11/2010; 41(2):91-100. DOI:10.3109/00498254.2010.529955 · 2.10 Impact Factor
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    ABSTRACT: Many pharmaceuticals are excreted in wastewater as parent substances or metabolites subsequent to therapeutic or diagnostic application in medical care. This includes the antiepileptic carbamazepine, which is not removed during conventional wastewater treatment and was found to be ubiquitous in the aquatic environment. Some carbamazepine metabolites have also been found in treated wastewater, but only five of them have been studied to date. However, at least 30 carbamazepine metabolites have been identified in humans, including some pharmacologically active or genotoxic compounds. Oxcarbazepine, an antiepileptic which is increasingly used, generates metabolites common to those of carbamazepine. The present work focuses on the presence of carbamazepine, oxcarbazepine, and seven of their metabolites (carbamazepine-10,11-epoxide, 10-hydroxy-10,11-dihydrocarbamazepine, 10,11-dihydro-10,11-trans-dihydroxycarbamazepine, 2-hydroxy-carbamazepine, iminostilbene, acridine, and acridone) at three different treatment plants (conventional activated sludge, trickling filter, and stabilization ponds) selected in France. The main aim of this work was to identify selected compounds in wastewater after therapeutic use and to measure concentrations in influents and effluents at the three wastewater treatment plants. Except for iminostilbene, all of these compounds were detected in wastewater. The metabolite common to carbamazepine and oxcarbazepine, i.e., 10,11-dihydro-10,11-trans-dihydroxycarbamazepine, was detected at a higher concentration than the parent substances in wastewater. The presence of parent molecules was noted in inlet and outlet water samples. Carbamazepine, as expected, was not removed by conventional activated sludge treatment. Nevertheless, in a wastewater treatment plant with a 78-day hydraulic retention time, a 73% decrease in carbamazepine concentration was observed. For the first time, oxcarbazepine was found in environmental samples. A decrease in oxcarbazepine concentrations was observed at the three sewage treatment plants, with removal ranging from 24 to 73%. No metabolite removal was observed after activated sludge treatment. In the two other sewage treatments plants, the fate of the metabolites differed. The concentration of some metabolites, e.g., 10,11-dihydro-10,11-trans-dihydroxycarbamazepine and acridine, increased, possibly via different processes such as cleavage of glucuronide conjugates or biotic and abiotic degradation of parent compounds. The behavior of the studied substances is discussed in terms of the treatment process and hydraulic retention time.
    Archives of Environmental Contamination and Toxicology 10/2008; 56(3):408-15. DOI:10.1007/s00244-008-9202-x · 1.96 Impact Factor
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    ABSTRACT: We present a simple and reliable method for simultaneous determination of voriconazole and its main metabolite resulting from N-oxidation (UK-121,265), in human plasma. The work-up procedure used acetonitrile and potassium salts to precipitate plasma proteins. No internal standard was used. The chromatographic system used a LiChroCART® 250-4 cartridge packed with LiChrospher® 100 RP-8 (diameter particules, 5μm). The UV monochromatic detector was set on 260nm. The mobile phase consisted of a 60/40 (v/v) mixture of acetonitrile and water. The flow rate was 1mLmin−1. The retention times for voriconazole and its metabolite were 8.98 and 4.02min respectively, and total run time was 12min. The linearity of the method was investigated from 0.31 to 10.0mgL−1; the lowest limit of quantification was 0.30mgL−1. Precision ranged from 2.41% to 6.32% for voriconazole and 0.80% to 11.6% for the N-oxide voriconazole metabolite. Accuracy was between 93.0% and 101% for voriconazole and 90.0% and 101% for the N-oxide voriconazole metabolite. This rapid and accurate method could be interesting to investigate metabolite/voriconazole ratio with respect to CYP2C19 genetic status and CYP3A4 activity changes.
    Chromatographia 01/2008; 67(3):275-280. DOI:10.1365/s10337-007-0508-z · 1.37 Impact Factor