[Show abstract][Hide abstract] 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. · 6.25 Impact Factor
[Show abstract][Hide abstract] 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/ 12g ) 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. · 5.25 Impact Factor
[Show abstract][Hide abstract] 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. · 2.10 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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).
[Show abstract][Hide abstract] 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. · 2.01 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was: i) to carry out a structural analysis of ibogaine and noribogaine, ii) to identify products formed under light exposure (daylight or 254 nm, 20°C) of the two drugs in methanolic solutions, and iii) to examine the alkaloid contents of a specimen of root bark of the Tabernanthe iboga shrub using liquid chromatography‐electrospray mass spectrometry. After daylight exposure, two oxidation products were detected: ibochine and iboluteine from ibogaine, and desmethoxyibochine and desmethoxyiboluteine from noribogaine. After exposure to 254 nm of the ibogaine solution, another compound that could possibly be the analogous lactam of iboluteine was detected. From the liquid chromatography electrospray‐mass spectrometry analysis of the root barks of a specimen of the Tabernanthe iboga shrub, seven alkaloids were detected: ibochine (m/z 325), ibogaline (m/z 341), iboluteine (m/z 327), ibogaine (m/z 311), ibogamine (m/z 281) and voacangine (m/z 369). The last compound characterized by the protonated species (M+H) at m/z 309 has not been identified. In all samples, ibogaine was the principal alkaloid observed; its concentration ranged from 1.8 to 5.93 mg/g. For the other indole alkaloids, the peak areas of ibogaline, ibogamine and voacangine represent 11.9, 21.5, and 30.5% of that of ibogaine, respectively.
Journal of Liquid Chromatography & Related Technologies 01/2007; 30(8):1077-1092. · 0.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A liquid chromatography/electrospray ionization mass spectrometry (LC-ESI-MS) method was developed for the first time for the determination of ibogaine and noribogaine in human plasma and whole blood. The method involved solid phase extraction of the compounds and the internal standard (fluorescein) from the two matrices using OasisHLB columns. LC separation was performed on a Zorbax eclipse XD8 C8 column (5 microm) with a mobile phase of acetonitrile containing 0.02% (v/v) trimethylamine and 2mM ammonium formate buffer. MS data were acquired in single ion monitoring mode at m/z 311.2, 297.2 and 332.5 for ibogaine, noribogaine and fluorescein, respectively. The drug/internal standard peak area ratios were linked via a quadratic relationship to plasma (0.89-179 microg/l for ibogaine; 1-200 microg/l for noribogaine) and to whole blood concentrations (1.78-358 microg/kg for ibogaine; 2-400 microg/kg for noribogaine). Precision ranged from 4.5 to 13% and accuracy was 89-102%. Dilution of the samples had no influence on the performance of the method. Extraction recoveries were > or =94% in plasma and > or =57% in whole blood. The lower limits of quantitation were 0.89 microg/l for ibogaine and 1 microg/l for noribogaine in plasma, and 1.78 microg/kg for ibogaine and 2 microg/kg for noribogaine in whole blood. In frozen plasma samples, the two drugs were stable for at least 1 year. In blood, ibogaine and noribogaine were stable for 4h at 4 degrees C and 20 degrees C and 2 months at -20 degrees C. The method was successfully used for the analysis of a poisoning involving Tabernanthe iboga root.
Journal of Chromatography B 12/2006; 843(2):131-41. · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the present paper, we report for the first time the tissue distribution of ibogaine and noribogaine, the main metabolite of ibogaine, in a 48-year-old Caucasian male, with a history of drug abuse, found dead at his home after a poisoning involving the ingestion of root bark from the shrub Tabernanthe iboga. Ibogaine and noribogaine were quantified in tissues and fluids using a fully validated liquid chromatography-electrospray mass spectrometry method. Apart from cardiac tissue, ibogaine and noribogaine were identified in all matrices investigated. The highest concentrations were found in spleen, liver, brain, and lung. The tissue/subclavian blood concentration ratios averaged 1.78, 3.75, 1.16, and 4.64 for ibogaine and 0.83, 2.43, 0.90, and 2.69 for noribogaine for spleen, liver, brain, and lung, respectively. Very low concentrations of the two drugs were found in the prostatic tissue. Both ibogaine and noribogaine are secreted in the bile and cross the blood-brain barrier. Four other compounds were detected in most of the studied matrices. One of them was identified as ibogamine. Unfortunately, we were not able to positively identify the other three compounds because of the unavailability of reference substances. Two of them could possibly be attributed to the following oxidation products: iboluteine and desmethoxyiboluteine. The third compound could be ibogaline.
Journal of analytical toxicology 10/2006; 30(7):434-40. · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A specific and sensitive liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) method was developed for the determination of free and total ropivacaine in human plasma. The work-up procedure involved a simple precipitation of plasma proteins with methanol. Etidocaine served as the internal standard. After microscale equilibrium-dialysis, measurement of free ropivacaine levels was performed after direct injection of the dialysate into the chromatograph. The system used a Zorbax eclipse XD8 C8 analytical column packed with 5 microm diameter particles as the stationary phase. The mobile phase consisted of a 15-min gradient (mobile phase A: 0.05% (v/v) trimethylamine in acetonitrile, mobile phase B: 2mM ammonium formate buffer (pH 3)). Mass spectrometric data were acquired in single ion monitoring mode at m/z 275 for ropivacaine and m/z 277 for etidocaine. The drug/internal standard peak area ratios (plasma) or peak areas (dialysate) were linked via a quadratic relationship to concentrations. Precision ranged from 1 to 7.6% accuracy was between 92.6 and 109%. The lower limits of quantitation were 1 microg/l in plasma and 2 microg/l in the dialysate. This method was found suitable for the analysis of plasma samples collected during a clinical trial performed in 30 infants undergoing epidural anaesthesia or continuous psoas compartment block.
Journal of Chromatography B 03/2006; 831(1-2):91-8. · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This work is a review of one year of practice in LC-MS single-quad toxicological screening for patients with toxicological etiology admitted in an emergency unit. Systematic research using this technique was applied in three situations : sudden infant death syndrom, comatose patients with toxicological etiology, patients included in a systematic study with the emergency admission unit. Analytical results were confronted with conventional LC-DAD screening. Spectral datafrom toxicological screening with LC-MS identify several xenobiotics and their metabolites in a single analytic step, compatible with time delay involved in emergency treatments. In addition, screening detection limits are generally as low as therapeutic ranges. The main difficulty is to build a specific mass spectrum library for the most common toxic agents. In the case of a nomatch chromatographic peak, no chemical information is available from mass spectrum data; but shared data from LC-MS and LC-DAD will improve the identification. In our laboratory, LC-MS is actually used in first intention for urgent toxicological screenings. Nous rapportons le bilan d'une année d'application de la chromatographic liquide couplée à un détecteur de masse simple-quad (LC-MS) à des screenings toxicologiques dans le cadre de l'urgence hospitalière. Plus précisément ce type de screening a été appliqué à des cas de moit subite du nourrisson, des comas toxiques non renseignés par les bilans standards, et à une étude sur les bilans toxicologiques systématiques à l'accueil des Urgences. Les données analytiques obtenues ont été confrontées à celles obtenues par un screening conventionnel par chromatographic liquide couplée à un détecteur à barrette de diodes (HPLC-DAD). L'analyse des données indique que le screening toxicologique par LC-MS permet l'identification formelle de nombreuses molécules et de leurs metabolites en une seule étape analytique simple dans un délai compatible avec l'urgence clinique. De plus la sensibilité de la méthode permet de détecter des doses infra-thérapeutiques. Cependant sa limite majeure résidé dans la construction, à la charge de l'utilisateur, d'une bibliothèque spectrale spécifique suffisamment exhaustive pour les toxiques généralement rencontrés. Dans le cas de molécules non répertoriées, le croisement des don nées obtenues par l'utilisation conjointe des deux méthodes de screening, DAD et MS, conduit parfois à une identification. Au terme d'un an d'expérience, nous avons placé la LC-MS comme méthode analytique de première intention pour la réalisation des screenings toxicologiques urgents. L'optimisation du screening toxicologique par LC-MS doit permettre d'étendre le champ d'application de la méthode à d'autres besoins hospitaliers.