Anne Garat

Centre Hospitalier Régional Universitaire de Lille, Lille, Nord-Pas-de-Calais, France

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Publications (18)25.51 Total impact

  • 06/2015; 27(2). DOI:10.1016/j.toxac.2015.03.046
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    ABSTRACT: Une enfant âgée de 29 mois présente une altération de la conscience peu après l’ingestion accidentelle de colle professionnelle pour revêtement de sol. Lors de sa prise en charge au domicile, elle est comateuse (Glasgow 6), tachycarde (130/min), hypotendue (80/40 mmHg). Elle est intubée après induction, sédation. L’évolution est marquée par des troubles du rythme à type de torsades de pointe (traitées par sulfate de magnésium) et épisodes récidivants de tachycardie ventriculaire lente avec accès de bradycardie (traités par bicarbonate de sodium, gluconate de calcium et adrénaline en continu) et par un état de mal convulsif (traité par clonazépam puis midazolam). La fillette décèdera 6 heures après l’ingestion. La biologie retrouvait une acidose métabolique (pH : 7,32) lactique (2,26 mmol/L). Des échantillons de colle et d’urine ont été analysés. L’analyse par CPG-SM de l’échantillon de colle retrouvait des xylènes et de l’alcool benzylique. Dans l’urine, ni le trichloroéthylène, ni ses métabolites (acide trichloroacétique et trichloroéthanol) n’ont été détectés par CG-SM. Si l’acide méthylhippurique (métabolite du xylène) et l’acide benzoïque (métabolite de l’alcool benzylique) n’ont également pas été retrouvés, une forte concentration d’acide hippurique (2928 mg/L ; 20,9 g/g de créatinine) a été mesurée par CL-UV/BD. L’acide hippurique provient de la conjugaison du glycocolle avec l’acide benzoïque, métabolite de l’alcool benzylique. Les résultats des analyses toxicologiques confortent le diagnostic d’intoxication par l’alcool benzylique, principal constituant de cette colle. Cet alcool benzylique est un solvant à fois cardiotoxique et dépresseur du système nerveux central, responsable du « gasping syndrome » essentiellement décrit chez le jeune enfant.
    12/2014; 27(1). DOI:10.1016/j.toxac.2014.11.003

  • 54ème réunion de l'association Italo-Belgo-Franco-Suisse, Palazzo della Societa Elettrica Sopracenerina SES - Piazza Grande 5 - 6600 Locarno - Svizzera; 09/2014

  • Analytical, Clinical and Forensic Toxicology Meeting, Société Française de Toxicologie Analytique, Grand-Théâtre, Bordeaux, France; 06/2014

  • 06/2014; 26(2):S29-S30. DOI:10.1016/S2352-0078(14)70060-5
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    ABSTRACT: We report an uncommon case of a young white man found dead in a hotel room after cyanide poisoning in a context of suicide. Cyanide was apparently ordered on the Deep Web. The purpose of this case is to compare it with a review of literature about cyanide poisoning (clinical facts and epidemiology), toxic deaths in hotel and scientific observations about black-market and illegally-ordered products on the Dark Web.
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    ABSTRACT: Traffic-related volatile organic compounds (VOCs) pollution has frequently been demonstrated to be a serious problem in the developing countries. Benzene and 1,3-butadiene (BD) have been classified as a human carcinogen based on evidence for an increased genotoxic and epigenotoxic effects in both occupational exposure assessment and in vivo/in vitro studies. We have undertaken a biomonitoring of 25 traffic policemen and 23 office policemen in Beirut, through personal air monitoring, assessed by diffusive samplers, as well as through the use of biomarkers of exposure to benzene and BD. Personal benzene, toluene, ethylbenzene, and xylene (BTEX) exposure were quantified by GC-MS/MS, urinary trans, trans-muconic acid (t,t-MA) by HPLC/UV, S-phenyl mercapturic acid (S-PMA), monohydroxy-butenyl mercapturic acid (MHBMA) and dihydroxybutyl mercapturic acid (DHBMA) by ultra-performance liquid chromatography-electrospray tandem mass spectrometry (UPLC/ESI(-)-MS/MS) in MRM (Multiple Reaction Monitoring) mode. We found that individual exposure to benzene in the traffic policemen was higher than that measured in traffic policemen in Prague, in Bologna, in Ioannina and in Bangkok. t,t-MA levels could distinguish between office and traffic policemen. However, median MHBMA levels in traffic policemen were slightly elevated, though not significantly higher than in office policemen. Alternatively, DHBMA concentrations could significantly distinguish between office and traffic policemen and showed a better correlation with personal total BTEX exposure. DHMBA, measured in the post-shift urine samples, correlated with both pre-shift MHMBA and pre-shift DHMBA. Moreover, there was not a marked effect of smoking habits on DHBMA. Taken together, these findings suggested that DHBMA is more suitable than MHBMA as biomarker of exposure to BD in humans. Traffic policemen, who are exposed to benzene and BD at the roadside in central Beirut, are potentially at a higher risk for development of diseases such as cancer than office policemen.
    Chemosphere 10/2013; 96. DOI:10.1016/j.chemosphere.2013.09.034 · 3.34 Impact Factor

  • Diabetes & Metabolism 03/2013; 39:A38. DOI:10.1016/S1262-3636(13)71773-7 · 3.27 Impact Factor
  • I Larivière · A Garat · P Nisse · M Mathieu-Nolf ·
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    ABSTRACT: Triptans are recommended to treat acute migraine. Pediatric data remain insufficient for making decisions in cases of triptan poisoning. Consequently, hospitalization is often warranted as a precautionary measure. This study aims to more accurately estimate the risks incurred when a young child ingests triptan tablets. This study reviewed all cases of acute triptan poisoning listed by the Lille poison center between January 2000 and December 2009 in children younger than 6 years. Cases with certain ingestion, no drug interactions, and no other known etiology were selected. The gravity of each case was estimated by the poisoning severity score and follow-up was conducted by phone. A cohort of 84 patients was collected: 6% were lost to follow-up. The mean intake was 1.22 tablets (range, 0.25-6), for the most part zolmitriptan (64.2%), eletriptan (14.3%) and naratriptan (14.3%). Fifty-nine children (74.5%) were admitted to the hospital and 20 children monitored at home. The majority received evacuation or adsorbing treatment. Symptoms were not frequent (13%) and were well tolerated, in particular on the hemodynamic level (ten cases of PSS1). The adverse events observed were tachycardia (4 cases), arterial hypertension (1 case), dyspnea (2 cases), drowsiness (2 cases), marbling of the extremities (1 case), vomiting (3 cases), and digestive pain (1 case). The 2 cases of dyspnea, induced by 2.5mg and 7.5mg of zolmitriptan, respectively, were associated with cardiovascular symptoms and were left untreated. According to its pharmacological action, the potential risk of a serotoninergic syndrome is a concern with triptan intake. No severe complication was recorded, so based on this study, our guidelines were updated. The response should be less alarmist, but a watchful attitude should be retained. Hospitalization should not be systematic, but focused on the patient's cardiac history, the dose, and the symptomatology. If the child remains at home, specific action should be managed: an adsorbing treatment and close monitoring by phone remain essential.
    Archives de Pédiatrie 03/2012; 19(3):254-9. DOI:10.1016/j.arcped.2011.12.014 · 0.41 Impact Factor
  • P Nisse · F Saulnier · A Garat · M Mathieu-Nolf ·

    Annales francaises d'anesthesie et de reanimation 02/2012; 31(2):176-7. DOI:10.1016/j.annfar.2011.10.033 · 0.84 Impact Factor
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    ABSTRACT: The aim of this study was to determine the frequencies of TPMT and ITPA polymorphisms in Crohn's disease patients of Tunisian origin and to compare them with allele frequencies previously reported in other populations of various ethnic origins. ITPA (c.94C>A and IVS2+21A>C) and TPMT (c.238G>C, c.460G>A and c.719A>G) mutations and genotypes were assessed in 208 Tunisian subjects (78 males/130 females) by polymerase chain reaction-restriction fragment length polymorphism and allele-specific-PCR methods. Genotyping of ITPA revealed frequencies of 6% and 7.9% for c.94C>A and IVS2+21A>C, respectively. Accordingly, deficient or diminished ITPA phenotype can be predicted to concern 2.4% of Tunisians. The observed frequencies of the c. 238G>C, c.460G>A and c.719A>G TPMT polymorphisms were 0, 0.24 and 1.44%, respectively. This study provides the first analysis of TPMT and ITPA mutant allele frequency in individuals of Tunisian origin. Unlike in Caucasians, TPMT*3C which harbours the c.719A>G polymorphism appears to be the most common mutant allele in Tunisians. In contrast, ITPA mutant allele frequency distribution appears to be similar to that observed in Caucasians.
    Gastroentérologie Clinique et Biologique 01/2012; 36(2):178-84. DOI:10.1016/j.clinre.2011.12.001 · 1.64 Impact Factor

  • La Presse Médicale 11/2011; 41(4):441-2. DOI:10.1016/j.lpm.2011.10.008 · 1.08 Impact Factor
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    ABSTRACT: Tramadol is a synthetic, centrally acting analgesic for the treatment of moderate to severe pain. The marketed tramadol is a racemic mixture containing 50% (+)tramadol and 50% (-)tramadol and is mainly metabolized to O-desmethyltramadol (M1) by the cytochrome P450 CYP2D6. Tramadol is generally considered to be devoid of any serious adverse effects of traditional opioid receptor agonists, such as respiratory depression and drug dependence. A 22-year-old Caucasian female patient was admitted to our ICU in refractory cardiac arrest requiring extracorporeal membrane oxygenation. This aggressive support allowed resolution of multi-organ dysfunction syndrome. Repeated blood analyses using liquid chromatography-tandem mass spectrometry confirmed high concentrations of both tramadol and its main metabolite O-desmethyltramadol. Genotyping of CYP2D6 revealed the patient to be heterozygous for a duplicated wild-type allele, predictive of a CYP2D6 ultrarapid metabolizer (UM) phenotype, confirmed by calculation of the tramadol/M1 (MR1) metabolic ratio at all time points. We here report a case of near-fatal isolated tramadol cardiotoxicity. Because of the inhibition of norepinephrine reuptake, excessive blood epinephrine levels in this CYP2D6R UM patient following excessive tramadol ingestion could explain the observed strong myocardial stunning. This patient admitted intermittent tramadol consumption to gain a "high" sensation. In patients with excessive morphinomimetic effects, levels of tramadol and its main metabolite M1could be measured, ideally combined with CYP2D6 genotyping, to identify individuals at risk of tramadol-related cardiotoxicity. Tramadol treatment could be optimized in these at-risk individuals, consequently improving patient outcome and safety.
    European Journal of Clinical Pharmacology 06/2011; 67(8):855-8. DOI:10.1007/s00228-011-1080-x · 2.97 Impact Factor
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    ABSTRACT: Adverse effects of thiopurine drugs occur in 15-28% of patients and the majority is not explained by thiopurine-S-methyltransferase deficiency. Furthermore, approximately 9% of patients with inflammatory bowel disease are resistant to azathioprine therapy. Recently, the small guanosine triphosphatase, Rac1, was identified as an important molecular target of 6-thioguanine triphosphate, one of the active metabolite of thiopurines such as azathioprine. To date, no functional genetic polymorphism of the human Rac1 gene had been reported. Evidence for functional genetic polymorphisms of the human Rac1 gene and to investigate their relative contribution to the development of toxicity induced by azathioprine treatment in patients with inflammatory bowel disease. We first screened for polymorphisms in the Rac1 gene in genomic DNA samples from 92 unrelated Caucasian individuals. The functional consequences of identified polymorphisms were assessed in vitro using transient transfection assays in Jurkat and A549 cell lines. The relationship between polymorphisms of Rac1 and thiopurine response or hematotoxicity was studied in 128 patients under thiopurine treatment. Three single nucleotide polymorphism and one variable number tandem repeat were identified in the promoter region of Rac1 gene. Interestingly, in Jurkat T cells, the c.-289G>C substitution and c.-283_-297[3] variable number tandem repeat displayed a significantly increased promoter activity (P<0.01) of 150 and 300%, respectively, compared with that of the wild-type sequence. Patients with thiopurine-S-methyltransferase mutations presented a significantly increased probability of developing hematotoxicity (odds ratio=5.68, 95% confidence interval=1.45-22.23, P=0.00625). Moreover, among the 75 patients who did not develop hematotoxicity, there was a marginally overrepresentation of functional genetic polymorphisms of Rac1 (odds ratio=0.18, 95% confidence interval=0.02-1.49, P=0.079). This study constitutes the first report of a functional genetic polymorphism that could affect Rac1 expression and thus modulate the risk of adverse drug reaction in patients under thiopurine treatment. A larger scale (case-control) study should enable us to confirm or cancel these preliminary results.
    Pharmacogenetics and Genomics 03/2011; 21(6):313-24. DOI:10.1097/FPC.0b013e3283449200 · 3.48 Impact Factor
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    ABSTRACT: Human type II inosine monophosphate dehydrogenase (IMPDH2) is a key enzyme in the purine nucleotide biosynthetic pathway and constitutes a pivotal biological target for immunosuppressant and antiviral drugs. Several Single Nucleotide Polymorphisms (SNP) affecting the IMPDH2 gene sequence have been reported with potential functional relevance and could impact drugs response. We aimed to determine the frequency of three of these polymorphisms, namely g.3375C>T (Leu(263)Phe), c.-95T>G and IVS7+10T>C, in Caucasians, Tunisians, Peruvians and Black Africans (Gabonese and Senegalese). The g.3375C>T and c.-95T>G polymorphisms are rare with a Minor Allele Frequency ≤1.0% in our populations, whereas the third variant, IVS7+10T>C, is more frequent and displays large interethnic variations, with an allelic frequency ranging from 14.6% in the French Caucasian population studied to less than 2% in Black African and Peruvian populations. This ethnic-related data might contribute to a better understanding of the variability in clinical outcome and/or dose adjustments of drugs that are IMPDH inhibitors such as mycophenolic acid.
    Molecular Biology Reports 12/2010; 38(8):5185-8. DOI:10.1007/s11033-010-0668-z · 2.02 Impact Factor
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    ABSTRACT: Inosine 5'-monophosphate dehydrogenase (IMPDH), which catalyzes a key step in the de novo biosynthesis of guanine nucleotide, is mediated by two highly conserved isoforms, IMPDH1 and IMPDH2. In this study, IMPDH2 genetic polymorphism was investigated in 96 individuals of Caucasian origin. Four single-nucleotide polymorphisms were identified, comprising one previously described single base-pair substitution in the close vicinity of the consensus donor splice site of intron 7 (IVS7+10T>C), and three novel polymorphisms, one silent substitution in exon 9 (c.915C>G), one single base-pair insertion (g.6971_6972insT) within the 3'-untranslated region of the gene, and one substitution located in the promoter region (c.-95T>G) in a transcription factor binding site CRE(A) (cyclic adenosine monophosphate [cAMP] response element). Considering the nature and location of this latter polymorphism, its functional relevance was examined by transfecting HEK293 and Jurkat cell lines with constructs of the related region of IMPDH2/luciferase reporter gene. The c.-95T>G mutation leads to a significant decrease of luciferase activity (HEK293: 55% decrease, p < 0.05; Jurkat: 65% decrease, p < 0.05) compared with the wild-type promoter sequence and, therefore, is likely to determine interindividual differences in IMPDH2 transcriptional regulation. These results might contribute to a better understanding of the variability in clinical outcome and dose adjustments of certain immunosuppressors that are metabolized through the IMPDH pathway or that are IMPDH inhibitors.
    Genetic Testing and Molecular Biomarkers 10/2009; 13(6):841-7. DOI:10.1089/gtmb.2009.0096 · 1.46 Impact Factor
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    Anne Garat ·
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    ABSTRACT: The thiopurine drugs, azathioprine, 6-mercaptopurine and 6-thioguanine, have been used for decades for their cytotoxic and immunosuppressive properties in the treatment of leukemias, chronic inflammatory or autoimmune diseases and in the prevention of allograft rejection. However, some patients treated with conventional doses of these molecules develop very severe side effects. The deficient activity of the thiopurine S-methyltransferase (TPMT), an enzyme involved in thiopurine inactivation, is one of the key factors in the myelotoxicity of these drugs. The determination of the TPMT phenotype by genotyping test is a preventive measure before the initiation of thiopurine therapy and is based on the identification of the most common inactivating mutations of the TPMT gene. First, our study consisted in the functional analysis of four new allelic variants of TPMT, using an heterologous expression system, the yeast S. cerevisiae. The non-functional character of two of those variants was demonstrated. However, TPMT deficiency explain only about 30 % of cases of thiopurine myelotoxicity, suggesting the existence of other genetic abnormalities affecting other genes involved in the response toward thiopurines. Accordingly, we studied the genetic polymorphism of two other proteins, the inosine monophosphate dehydrogenase type 2 (IMPDH2), a key enzyme in the production of the active metabolites of thiopurine, and the RhoGTPase RAC1, which is one of the pharmacological targets of these molecules. Some of the polymorphisms that we identified in those two genes seem to affect in vitro the expression and / or activity of these proteins and, therefore, could contribute to inter-individual variations of the response to thiopurine
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    ABSTRACT: Human thiopurine S-methyltransferase (TPMT, EC is a key enzyme in the detoxification of thiopurine drugs widely used in the treatment of various diseases, such as inflammatory bowel diseases, acute lymphoblastic leukaemia and rheumatic diseases. The TPMT gene is genetically polymorphic and the inverse relationship between TPMT activity and the risk of developing severe hematopoietic toxicity is well known. In this study, the entire coding sequence of TPMT, together with its 5'-flanking promoter region, was analysed in patients with an intermediate phenotype for thiopurine drug methylation. Four polymorphisms were identified, two previously described, c.356A>C (p.Lys(119)Thr, TPMT*9) and c.205C>G (p.Leu(69)Val, TPMT*21), and two novel missense mutations, c.537G>T (p.Gln(179)His, TPMT*24) and c.634T>C (p.Cys(212)Arg, TPMT*25). Structural investigations, using molecular modeling, were undertaken in an attempt to explain the potential impact of the amino acid substitutions on the structure and activity of the variant proteins. Additionally, in order to determine kinetic parameters (K(m) and V(max)) of 6-thioguanine (6-TG) methylation, the four variants were expressed in a recombinant yeast expression system. Assays were performed by HPLC and the results were compared with those of wild-type TPMT. The p.Leu(69)Val and the p.Cys(212)Arg substitutions encode recombinant enzymes with a significantly decreased intrinsic clearance compared to that of the wild-type protein, and, consequently, characterise non-functional alleles of TPMT. The p.Lys(119)Thr and the p.Gln(179)His substitutions do not affect significantly the catalytic activity of the corresponding variant proteins, which prevents to unambiguously describe these latter alleles as defective TPMT variants.
    Biochemical pharmacology 08/2008; 76(3):404-15. DOI:10.1016/j.bcp.2008.05.009 · 5.01 Impact Factor

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