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Biomedical subjects

Pierre Dayer

Publications and source records attributed to Pierre Dayer.

11 recordsLinked to original sources
PubMed2006

Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors.

BACKGROUND: Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown. METHODS: We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation. RESULTS: Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function. CONCLUSIONS: QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.

Adolescent↗
PubMed2006

CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis.

OBJECTIVE: To determine whether pharmacogenetic tests such as N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genotyping are useful in identifying patients prone to antituberculosis drug-induced hepatotoxicity in a cosmopolite population. METHODS: In a prospective study we genotyped 89 patients treated with isoniazid (INH) for latent tuberculosis. INH-induced hepatitis (INH-H) or elevated liver enzymes including hepatitis (INH-ELE) was diagnosed based on the clinical diagnostic scale (CDS) designed for routine clinical practice. NAT2 genotypes were assessed by fluorescence resonance energy transfer probe after PCR analysis, and CYP2E1 genotypes were determined by PCR with restriction fragment length polymorphism analysis. RESULTS: Twenty-six patients (29%) had INH-ELE, while eight (9%) presented with INH-H leading to INH treatment interruption. We report no significant influence of NAT2 polymorphism, but we did find a significant association between the CYP2E1 *1A/*1A genotype and INH-ELE (OR: 3.4; 95% CI:1.1-12; p = 0.02) and a non significant trend for INH-H (OR: 5.9; 95% CI: 0.69-270; p = 0.13) compared with other CYP2E1 genotypes. This test for predicting INH-ELE had a positive predictive value (PPV) of 39% (95% CI: 26-54%) and a negative predictive value (NPV) of 84% (95% CI: 69-94%). CONCLUSION: The genotyping of CYP2E1 polymorphisms may be a useful predictive tool in the common setting of a highly heterogeneous population for predicting isoniazid-induced hepatic toxicity. Larger prospective randomized trials are needed to confirm these results.

Adolescent↗
PubMed2005

[Genetic polymorphism and drug interactions: their importance in the treatment of pain].

OBJECTIVES: To evaluate the impact of certain genetic polymorphisms on variable responses to analgesics SOURCES: Systematic review, by means of a structured computerized search in the Medline database (1966-2004). Articles in English and French were selected. References in relevant articles were also retrieved. MAIN FINDINGS: Most analgesics are metabolized by CYP isoenzymes subject to genetic polymorphism. NSAIDs are metabolized by CYP2C9; opioids described as "weak" (codeine, tramadol), anti-depressants and dextromethorphan are metabolized by CYP2D6 and some "potent" opioids (buprenorphine, methadone or fentanyl) by CYP3A4/5. After the usual doses have been administered, drug toxicity or, on the contrary, therapeutic ineffectiveness may occur, depending on polymorphism and the substance. Drug interactions mimicking genetic defects because of the existence of CYP inhibitors and inducers, also contribute to the variable response to analgesics. Some opioids are substrates of P-gp, a transmembrane transporter also subject to genetic polymorphism. However, P-gp could only play a minor modulating role in man on the central effects of morphine, methadone and fentanyl. CONCLUSION: In the near future, pharmacogenetics should enable us to optimize therapeutics by individualizing our approach to analgesic drugs and making numerous analgesics safer and more effective. The clinical usefulness of these individualized approaches will have to be demonstrated by appropriate pharmacoeconomic studies and analyses.

Analgesics↗
PubMed2004

Codeine intoxication associated with ultrarapid CYP2D6 metabolism.

Life-threatening opioid intoxication developed in a patient after he was given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had three or more functional alleles, a finding consistent with ultrarapid metabolism of codeine. We attribute the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function.

Analgesics, Opioid↗
PubMed2004

DNA repair gene XRCC2 and XRCC3 polymorphisms and susceptibility to cancers of the upper aerodigestive tract.

Cigarette smoke can generate reactive oxygen species, which are capable of inducing double-strand breaks (DSBs) in DNA. Polymorphisms in XRCC2 and XRCC3 genes, involved in DSBs repair pathways, may alter an individual's susceptibility to smoking-related cancers. We investigated the effect of XRCC2 Arg(188)His and XRCC3 Thr(241)Met polymorphisms in cancer proneness in 121 oral/pharynx cancer cases, 129 larynx cancer cases and 172 noncancer controls, all Caucasian smokers. The XRCC2 His-allele was associated with a significantly increased risk of pharyngeal cancer (OR=2.9, 95% CI: 1.3-6.2). No significant associations were observed between the XRCC3 Thr(241)Met polymorphism and overall risk of developing UADT cancers. However, quite opposite to the expectations, a reduced risk of supraglottic cancer was found for carriers of the XRCC3 Met variant allele (OR=0.3, 95% CI: 0.2-0.7). These findings provide evidence for the view that polymorphisms in DNA repair genes may modify individual susceptibility to smoking-related cancers.

Adult↗
PubMed2004

A simplified analytical method for a phenotyping cocktail of major CYP450 biotransformation routes.

An efficient, fast and reliable analytical method was developed for the simultaneous evaluation of the activities of five major human drug metabolising cytochrome P450 (1A2, 2C9, 2C19, 2D6 and 3A4) with a cocktail approach including five probe substances, namely caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam. All substances were administered simultaneously and a single plasma sample was obtained 2h after the administration. Plasma samples were handled by liquid-liquid extraction and analysed by gradient high performance liquid chromatography (HPLC) coupled to UV and fluorescence detectors. The chromatographic separation was achieved using a Discovery semi-micro HS C18 HPLC column (5 microm particle size, 150 mm x 2.1 mm i.d.) protected by a guard column (5 microm particle size, 20 mm x 2.1 mm i.d.) The mobile phase was constituted of a methanol, acetonitrile and 20mM ammonium acetate (pH 4.5) with 0.1% triethylamine mixture and was delivered at a flow rate of 0.3 mL min(-1). All substances were separated simultaneously in a single run lasting less than 22 min. The HPLC method was formally validated and showed good performances in terms of linearity, sensitivity, precision and accuracy. Finally, the method was found suitable for the screening of these compounds in plasma samples.

Biotransformation↗
PubMed2002

Advances with analgesics and NSAIDs for the treatment of spinal disorders.

One of the major developments with regard to chronic non-malignant pain in these last few years has been a better understanding of the mechanisms that act to maintain pain, while inferences about the pathophysiology have facilitated therapeutic decision-making. This chapter reviews the strength of evidence for the therapeutic effect of pharmacological symptomatic approaches using non-steroidal anti-inflammatory agents, opioids and co-analgesics in acute and chronic back pain with an emphasis on the results of randomized controlled trials as well as on the need for long-term comparative trials of drug efficacy, toxicity and compliance.

Acute Disease↗
PubMed2002

Point: myeloperoxidase -463G --> a polymorphism and lung cancer risk.

Myeloperoxidase (MPO) is released from neutrophils in lung tissue in response to exposure to various pulmonary insults, including tobacco smoking. This enzyme is involved in the activation of an intermediate metabolite of benzo(a)pyrene to the highly reactive benzo(a)pyrene diol epoxide. A (-463)G --> A polymorphism in the promoter region of the MPO gene has been identified. The A allele is associated with a decreased transcriptional activity attributable to the disruption of a SP1-binding site. We therefore examined whether carriers of the A allele may be at reduced risk of lung cancer in a case-control study of 150 cases and 172 control individuals, all Caucasian smokers. Relative to subjects with the MPO G/G genotype, a significant decreased risk of lung cancer was found for carriers of the G/A genotype [odds ratio (OR) = 0.5, 95% confidence interval (CI): 0.29-0.88]. A reduction in risk, although not statistically significant, was also observed for subjects with the A/A genotype (OR = 0.84, 95% CI: 0.31-2.32). The lung cancer risk for carriers of one or two copies of the A allele was 0.55 (95% CI: 0.33-0.93). Because of the low prevalence of the A/A genotype, we also performed a meta-analysis of 2686 lung cancer cases and 3325 controls. The summary OR suggested a slight protective effect of the A/A genotype (OR = 0.86, 95% CI: 0.67-1.1), but this finding was strongly influenced by the results of a single large study. The meta-analysis restricted to studies comprising a homogeneous set yielded an OR of 0.68 (95% CI: 0.5-0.93). However, because of the heterogeneity in individual study results, additional large case-control studies are warranted to provide a more definitive conclusion.

Aged↗