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P Dayer

Publications and source records attributed to P Dayer.

At least 37 records · Page 2Linked to original sources
PubMed1999

A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin.

Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of therapeutic agents such as S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of mephenytoin, which represent approximately 13-23% of Asians and 3-5% of Caucasians. Several polymorphisms contribute to this phenotype. We have isolated two new allelic variants that contribute to the PM phenotype in Caucasians. CYP2C19*7 contained a single T --> A nucleotide transversion in the invariant GT at the 5' donor splice site of intron 5. The second PM allele, CYP2C19*8, consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg substitution. In a bacterial expression system, CYP2C198 protein exhibited a dramatic (approximately 90% and 70%) reduction in the metabolism of S-mephenytoin and tolbutamide, respectively, when compared with the wild-type CYP2C191B protein. Restriction fragment length polymerase chain reaction tests were developed to identify the new allelic variants.

Alleles↗
PubMed1999

Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan.

Dextromethorphan (DEM)-mediated N-methyl-D-aspartate receptor blockade may result from an action of unchanged DEM or its active metabolite, dextrorphan (DOR). In humans, DEM is metabolized into DOR by the polymorphic enzyme CYP2D6. We therefore investigated the impact of quinidine (Qd), a selective inhibitor of CYP2D6, on DEM disposition and the contribution of CYP2D6 phenotype on DEM antinociceptive and neuromodulatory effects. Using a randomized, double-blind, crossover, placebo-controlled design, healthy volunteers (n = 7) received Qd (50 mg Qd sulfate orally) or a placebo and, 12 h later, either DEM (50 mg DEM hydrobromide orally) or a placebo. DEM and DOR pharmacodynamics were assessed for their antinociceptive and neuromodulatory effects. Antinociceptive effects were assessed over 4 h by subjective pain threshold and RIII nociceptive reflex (RIII) monitoring. Neuromodulatory effects were studied using the primary and secondary hyperalgesia induced by the topical application of capsaicin. Two of seven subjects were genotypic CYP2D6 PM. Pretreatment of EM by Qd suppressed DOR formation and increased the plasma level of DEM to the levels of poor metabolizers. In poor metabolizers, DEM induced a significant increase in objective (+45%) and subjective (+35%) pain thresholds. In extensive metabolizers, only a slight and short-lasting increase in the subjective threshold was observed, whereas no effect was seen on the objective threshold. DEM modulates secondary hyperalgesia compared with DOR. The CYP2D6 phenotype affects the disposition of DEM and the production of the active metabolite DOR. The impact of the CYP2D6 phenotype is of major importance for the spinal antinociceptive and neuromodulatory effects of DEM.

Adult↗
PubMed1998

[Influence of sex on reporting pain].

In many epidemiological pain studies, women more frequently report more intense, frequent and long-lasting or chronic transient pain than men. In our retrospective study including hospitalised patients referred to a pain centre, prevalence of headaches, musculoskeletal pain and somatoform pain was observed in women, as described in the literature. Generally pain intensity was higher in women and pain was more frequently controlled in men, but when intensity and pain control were compared according to the pain aetiologies, no gender difference was found. Drug treatments were adapted to pain aetiologies, which accounted for the observed differences. In hospitalised patients the significant differences observed in intensity, pain control and treatment reflect the heterogeneity of pain aetiologies rather than gender differences.

Adult↗
PubMed1998

Association between lung cancer and microsomal epoxide hydrolase genotypes.

Microsomal epoxide hydrolase (mEH) is involved in the metabolism of tobacco-derived carcinogens. Polymorphisms in exons 3 and 4 of the EPHX gene have been reported to be associated with variations in mEH activity. We examined whether the predicted mEH activity modified the lung cancer risk among 150 cases and 172 controls, all French Caucasian smokers. A significant association was found between predicted mEH activity and lung cancer (P < 0.02), with a dose-effect relationship (P < 0.005). The risks associated with intermediate and high activities, compared to low activity, were 1.65 (95% CI, 0.95-2.86) and 2.66 (95% CI, 1.33-5.33), respectively. The effect of mEH activity on lung cancer risk was not significantly modified by smoking exposure, CYP1A1 genotype, or GSTM1 genotype. mEH may thus be an important genetic determinant of smoking-induced lung cancer.

Adult↗
PubMed1998

[Antibiotic utilization in a university geriatric hospital and drug formularies].

UNLABELLED: Inappropriate use of antibiotics needlessly increases drug expenditures, enhances the emergence of antimicrobial resistance in hospitals and heightens the risk of toxicity, especially in elderly patients. This population is very sensitive to inappropriate drug treatment because of pharmacological and pharmacokinetic changes, reduced homeostatic functional reserve, multiple underlying diseases (e.g. renal failure) and polypharmacy (leading to drug interactions and side effects). To assess antibiotic prescription in a geriatric university hospital with a restrictive drug formulary, we analyzed data extracted from the Drug Kardex (a standardized synthesis of all prescribed medicines) during 4 cross-sectional drug utilization studies, carried out in 1996 on all hospitalized patients. RESULTS: 1138 patients' Kardex have been analyzed. 20% of these patients received one or more antibiotic treatments. In total 268 antibiotic treatments (AB) were prescribed, 84 in March, 44 in June, 71 in September and 66 in December. 21 different AB were used, the five most frequently prescribed AB being amoxycillin-clavulanic acid, ceftriaxone, ciprofloxacin, metronidazole, co-trimoxazole and representing 69% of all AB. Most of the AB were given in an oral form (63%) and in one standard dose. Dose adjustments in these very old patients with a high percentage of renal failure were apparently rarely done. The choice of rather broad spectrum AB may be due to the fact that obtaining an appropriate bacteriological culture from elderly patients with respiratory tract infections is difficult, but was also due to a lack of diagnostic subcategorization of the infection. Undesirable effects of the restrictive drug formulary were also noted: large utilization of ciprofloxacine (only fluoroquinolone on the hospital's drug list) for urinary tract infections instead of other more appropriate antibiotics. CONCLUSION: It is important to individualize antibiotic drug therapy with respect to underlying diseases, site of infection and antibiotic sensitivity patterns, especially in elderly patients. Restrictive hospital drug formularies are not sufficient to assure rational drug use, but should be associated with broader educative measures.

Aged↗
PubMed1998

[Retrospective study of drug-induced agranulocytosis in hospitalized patients in Geneva and comparison with cases reported to IOCM].

In a retrospective study, 19 cases classified as idiosyncratic drug-induced agranulocytosis were found among 162 files of patients hospitalized in internal medicine clinics of the university hospital where this diagnosis had been coded. This would give an estimated incidence of 2.6 cases per million inhabitants per year for the Geneva area. In most cases several drugs were implicated in causation of the episodes. Suspected drugs were those commonly reported in the literature, but also some drugs which might already have been taken to treat infectious complications of agranulocytosis. A comparison of the Geneva cases with those notified to the Swiss Intercantonal Office for the Control of Medicines reveals a similar profile of involved drugs.

Adult↗
PubMed1998

[Factors associated with refractory cancer pain].

Cancer pain can be effectively controlled in most patients by classical pharmacological treatment. We retrospectively studied the characteristics and factors associated with non responsive pain. Between 1989 and 1996, 1767 patients were referred to our pain center; 831 (47%) had cancer pain and from 787 evaluable cases 118 (15%) experienced non-controlled pain whereas good pain control was achieved within a few days in 669 (85%) patients. Gender, age, cancer type, metastasis, initial pain intensity, nociceptive or neuropathic components and administration of adjuvant therapies were similar in both groups. On the other hand, diffuse pain, abdominal pain, terminal care, near death and doses of strong opioids were significantly different. Factors associated with therapeutic failure were conflicts, life and complications and breakthrough pain. In the presence of refractory cancer pain the factors predictive of therapeutic failure should be identified in order to optimize individual pain treatment.

Adult↗
PubMed1998

[Genetic and environmental effects on neuromodulation and the antinociceptive effect of dextromethorphan].

Administration of NMDA antagonists leads to attenuation or disappearance of some symptoms of central sensitization, such as secondary hyperalgesia. However, the side effects of NMDA antagonists to a large extent counterbalance the expected benefits, thus preventing wide or prolonged use. Dextromethorphan and its metabolite dextrophan, on the other hand, are established and safe drugs. Experimentally they both antagonize the NMDA receptor. This study evaluates the effects of dextromethorphan and its metabolite in pain models using electrical stimulation for testing the antinociceptive effect and capsaicin-induced hyperalgesia. Dextromethorphan shows clear antinociceptive as well as neuromodulary effects, both depending heavily on the cytochrome P450 2D6 phenotype (CYP2D6).

Adult↗
PubMed1998

Function of human alveolar macrophages after a 3-day course of azithromycin in healthy volunteers.

Azithromycin (AZM) is a new macrolide antibiotic with a high intracellular/extracellular concentration ratio. Immunomodulatory and antiinflammatory properties have been reported with other macrolides, especially erythromycin. The aim of the present study was to evaluate the effect of AZM on the production of proinflammatory mediators by alveolar macrophages (AM) up to 4 weeks after a 3-day course of AZM (500 mg, once a day). Nineteen non-smoking healthy male subjects were investigated with bronchoscopy and bronchoalveolar lavage. Group 1 received no treatment. Groups 2, 3, and 4 were bronchoscoped 1, 7 and 30 days, respectively, after AZM administration. AZM concentrations were simultaneously measured in plasma and in AM extracts. In serum, AZM levels were higher in group 2 (32.8 +/- 14.2 micrograms/l), at the lower limit of detection in group 3 (2.8 +/- 1.7 micrograms/l), and no longer detectable in group 4. In AM extracts, the highest concentrations were measured in group 2 (51.6 +/- 28.3 ng/microliter) and in group 3 (31.8 +/- 17.2 ng/microliter), and were detected up to 30 days after treatment in group 4 (2.9 +/- 2.3 ng/microliter). There was no significant differences between groups for blood or BAL proinflammatory cytokines levels (TNF-alpha, IL-1 beta, IL-6), and for superoxide generation by AM. We conclude that a 3-day course of AZM 500 mg/day in healthy subjects does not alter the proinflammatory cytokine profile in blood and in AM despite the prolonged tissue impregnation by this drug.

Adolescent↗
PubMed1998

Lack of acetaminophen ceiling effect on R-III nociceptive flexion reflex.

OBJECTIVE: The analgesic efficacy of intravenous doses of acetaminophen (paracetamol) 0.5 g, 1 g and 2 g (administered as propacetamol) was assessed in 11 healthy subjects in a randomised, double-blind, placebo-controlled crossover study. The antinociceptive effect was assessed over 8 h by measurement of the nociceptive flexion reflex threshold (R-III) in response to selective transcutaneous electrical stimulations. RESULTS: After acetaminophen 0.5 g, R-III increased to a mean maximum of 23% over baseline values; after 1 g to 28%, and after 2 g to 40%. The AUC(0-8 h) of the analgesic effects and the AUC(0-8 h) of plasma concentrations closely correlated and were dose-dependent: rs = 0.37, for R-III and rs = 0.94, for the plasma concentrations. Intravenous acetaminophen exerted a dose-dependent central antinociceptive effect.

Acetaminophen↗
PubMed1998

Use of the label "litigation neurosis" in patients with somatoform pain disorder.

The use of the term "litigation neurosis"--a condition with controversial clinical significance--might correspond to the expression for a difficult physician-patient relationship. The characteristics of patients with a DSM-III-R diagnosis of somatoform pain disorder who had been labeled "litigation neurosis" by their physicians were explored. Among 74 patients referred to a pain clinic, 30% had been labeled litigation neurosis, and among 81 patients referred while claiming disability benefits, 19% had been thus categorized. The attribution of this label was neither correlated to actually being involved in a claim for disability benefits nor to involvement in legal action. Patients who had been designated with litigation neurosis were characterized by a lower educational level, a higher rate of DSM-III-R major depression, and a much higher frequency of personality disorders than patients who were not thus labeled. We postulate that the communication style of patients with this constellation of characteristics, in particular the presence of psychiatric comorbidity, may have engendered a difficult doctor-patient relationship, leading physicians to use the label in the absence of objective evidence of litigation or involvement in legal action. We agree that the inappropriate use of labels such as "litigation neurosis" should be questioned.

Adult↗
PubMed1998

An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians.

The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism exhibits marked racial heterogeneity, with the poor metabolizer PM phenotype representing 13-23% of oriental populations, but only 2-5% of Caucasian populations. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) have been described, which account for more than 99% of Oriental poor metabolizer alleles but only approximately 87% of Caucasian poor metabolizer alleles. Therefore, additional defects presumably contribute to the poor metabolizer in Caucasians. Recent studies have found a third mutation CYP2C19*4, which accounts for approximately 3% of Caucasian poor metabolizer alleles. A fourth rare mutation (CYP2C19*5A) (C99,A991,Ile331;C1297T,Arg433-->Trp) resulting in an Arg433 to Trp substitution in the heme-binding region has been reported in a single Chinese poor metaboliser outlier belonging to the Bai ethnic group. The present study identifies a second variant allele CYP2C19*5B (C99-->T; A991-->G, Ile331-->Val; C1297-T, Arg433-->Trp in one of 37 Caucasian poor metabolizers. The frequency of the CYP2C19*5 alleles is low in Chinese (approximately 0.25% in the Bai ethnic group) and Caucasians (< 0.9%). However, these alleles contribute to the poor metabolizer phenotype in both ethnic groups and increases the sensitivity of the genetic tests for identifying defective alleles to approximately 100% in Chinese poor metabolizers and 92% in Caucasian poor metabolizers genotyped in our laboratory. The Arg433 to Trp mutation in the heme-binding region essentially abolishes activity of recombinant CYP2C19*5A toward S-mephenytoin and tolbutamide, which is consistent with the conclusion that CYP2C19*5 represents poor metabolizer alleles.

Alleles↗
PubMed1998

N-acetyltransferase NAT1 and NAT2 genotypes and lung cancer risk.

Acetyltransferases, encoded by the NAT1 and NAT2 genes, are involved in the activation/inactivation reactions of numerous xenobiotics, including tobacco-derived aromatic amine carcinogens. Several allelic variants of NAT1 and NAT2, which cause variations in acetylation capacity, have been detected. The NAT2 slow acetylator phenotype/genotype has been inconsistently associated with lung cancer and, to date, the role of NAT1 polymorphism in lung cancer has not been reported. The effect of NAT1 and NAT2 genetic polymorphisms on individual lung cancer risk was evaluated among 150 lung cancer patients and 172 control individuals, all French Caucasian smokers. The NAT1 alleles (*3, *4, *10, *11, *14, and *15) and the NAT2 alleles (*4, *5, *6, *7) were differentiated by polymerase chain reaction-based restriction fragment length polymorphism methods using DNA extracted from peripheral white blood cells. Genotypes were classified according to current knowledge of the functional activity of the variant alleles. The NAT1*10 and NAT1*11 alleles were considered as rapid alleles, the NAT1*4 and the NAT1*3 as normal alleles and NAT1*14 and NAT1*15 as slow-acetylation alleles. Logistic regression analyses were performed taking into account the age, sex, smoking and occupational exposures. A significant association was observed between lung cancer and NAT1 genotypes (P(homogeneity) < 0.02) with a gene dose effect (P(trend) < 0.01); compared with homozygous rapid acetylators, the lung cancer risk was 4.0 (95% confidence interval 0.8-19.6) for heterozygous rapid acetylators, 6.4 (95% confidence interval 1.4-30.5) for homozygous normal acetylators and 11.7 (95% confidence interval 1.3-106.5) for heterozygous slow acetylators. None of the individuals were homozygous slow acetylators. Similar results were obtained whatever the adjustment considered. No significant association was found between NAT2 genotype and lung cancer. The NAT1 polymorphism may thus be an important modifier of individual susceptibility to smoking-induced lung cancer.

Acetyltransferases↗
PubMed1998

Role of glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes in modulating susceptibility to smoking-related lung cancer.

Glutathione S-transferases GSTM1, GSTM3, GSTP1 and GSTT1 are involved in the detoxification of active metabolites of several carcinogens in tobacco smoke. We studied the potential role of GSTM3 and GSTP1 gene polymorphisms either separately, or in combination with GSTM1 and GSTT1 gene polymorphisms, in susceptibility to lung cancer using peripheral blood DNA from 150 lung cancer patients and 172 control individuals, all regular smokers. The frequencies of GSTM3, AA, AB and BB genotypes were 70.7%, 24.0% and 5.3% in cases and 72.7%, 24.4% and 2.9% in control individuals respectively. The frequencies of GSTP1, AA, AG and GG genotypes were 44.7%, 44.0% and 11.3% in cases and 50.0%, 37.2% and 12.8% in control individuals respectively. When studied separately, neither GSTM3 nor GSTP1 genotypes contributed significantly to the risk of lung cancer. Although failing to reach statistical significance, the combined GSTM3 AA and GSTP1 (AG or GG) genotype conferred a nearly threefold risk when the GSTM1 gene was concurrently lacking (odds ratio 2.9, 95% confidence interval 0.7-12.1). Significant interactions were observed between pack-years of smoking and the combined GSTM3 AA and GSTP1 (AG or GG) genotype, or the combined GSTM3 AA, GSTP1 (AG or GG) and GSTM1 null genotype. The combination of these three a priori at risk genotypes conferred an increased risk of lung cancer among smokers with a history of at least 35 pack-years (odds ratio 2.7, 95% confidence interval 1.2-6.0), but not in lighter smokers, probable because of the lower average number of pack-years of smoking found among control individuals with this genotype combination.

Aged↗
PubMed1998

A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin.

The 4'-hydroxylation of the S-enantiomer of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism shows marked interracial heterogeneity, with the poor metabolizer (PM) phenotype representing 2 to 5% of Caucasian and 13 to 23% of Asian populations. Two defective CYP2C19 alleles, CYP2C19*2 and CYP2C19*3, have been described which account for approximately 87% of Caucasian and > 99% of Oriental PM alleles. The present study identifies a new allele (CYP2C19*4) in Caucasian PMs which contains an A-->G mutation in the initiation codon. A new polymerase chain reaction-restriction fragment length polymorphism genotyping test was developed, and the incidence of this allele was examined in a European Caucasian population which had been phenotyped for mephenytoin metabolism. One of nine putative PMs was heterozygous for CYP2C19*2/CYP2C19*4, which suggests that CYP2C19*4 represents a defective allele. Six of the seven remaining putative PMs available for genotyping were explained by CYP2C19*2. The frequency of the CYP2C19*4 allele in Caucasians was 0.6%. An additional Caucasian PM from a separate study was also heterozygous for CYP2C19*2 and CYP2C19*4. To verify that CYP2C19*4 represented a defective CYP2C19 allele, the initiation codon of the normal CYP2C19*1 cDNA was mutated to a GTG, and both cDNAs were expressed in yeast. Recombinant CYP2C19 protein was detected by Western blot analysis of colonies transformed with CYP2C19*1 cDNA, but not in those transformed with CYP2C19*4 cDNA. The two cDNAs were also used in an in vitro coupled transcription/translation assay. CYP2C19 protein was translated only from the CYP2C19*1 allele. These data indicate that CYP2C19*4 represents a new PM allele.

Alleles↗