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P Dayer

Publications and source records attributed to P Dayer.

At least 55 records · Page 3Linked to original sources
PubMed1998

Larynx cancer risk in relation to glutathione S-transferase M1 and T1 genotypes and tobacco smoking.

Glutathione S-transferase (GST) isoenzymes are involved in the detoxification of several tobacco smoke-derived carcinogens. It is thus conceivable that deficiency in GST activity due to homozygous deletion of the GSTM1 and GSTT1 genes (the null genotypes) may modulate susceptibility to smoking-induced cancers. The effects of the GSTM1 and GSTT1 null genotypes on laryngeal cancer risk were evaluated using peripheral blood DNA from 129 larynx cancer patients and 172 noncancer controls, all of whom were regular smokers. Increased larynx cancer risk was related to the GSTM1 null genotype [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.0-2.8]. The OR associated with the GSTT1 null genotype was increased, although not significantly (OR = 1.4, 95% CI = 0.7-2.9). Individuals with concurrent lack of GSTM1 and GSTT1 genes had a doubled, although not significant, risk for larynx cancer when compared with those having at least one of these genes (OR = 2.0, 95% CI = 0.8-5.2) and had almost a 3-fold risk (OR = 2.7, 95% CI = 1.0-7.4) when compared with those with both genes. Moreover, a significant interaction between the GSTM1 genotype and levels of tobacco consumption (P < 0.05) was found; the GSTM1 null genotype was associated with an increased risk of larynx cancer among smokers of 20 g/day or less (OR = 2.9, 95% CI = 1.3-6.3) but not among heavier smokers (OR = 1.0; 95% CI = 0.5-2.0). In contrast, the GSTT1 null genotype posed an increased, although not significant, risk among long-term smokers (OR = 2.3, 95% CI = 0.9-5.4).

Aged↗
PubMed1998

Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin.

A genetic polymorphism in the metabolism of the anticonvulsant drug S-mephenytoin has been attributed to defective CYP2C19 alleles. This genetic polymorphism displays large interracial differences with the poor metabolizer (PM) phenotype representing 2-5% of Caucasian and 13-23% of Oriental populations. In the present study, we identified two new mutations in CYP2C19 in a single Swiss Caucasian PM outlier (JOB 1) whose apparent genotype (CYP2C19*1/CYP2C19*2) did not agree with his PM phenotype. These mutations consisted of a single base pair mutation (G395A) in exon 3 resulting in an Arg132-->Gln coding change and a (G276C) mutation in exon 2 resulting in a coding change Glu92-->Asp. However, the G276C mutation and the G395A mutation resided on separate alleles. Genotyping tests of a family study of JOB1 showed that the exon 2 change occurred on the CYP2C19*2 allele, which also contained the known splice mutation in exon 5 (this variant is termed CYP2C19*2B to distinguish it from the original splice variant now termed CYP2C19*2A). The exon 3 mutation resided on a separate allele (termed CYP2C19*6). In all other respects this allele was identical to one of two wild-type alleles, CYP2C19*1B. The incidence of CYP2C19*6 in a European Caucasian population phenotyped for mephenytoin metabolism was 0/344 (99% confidence limits of 0 to 0.9%). Seven of 46 Caucasian CYP2C19*2 alleles were CYP2C19*2B(15%) and 85% were CYP2C19*2A. The Arg132Gln mutation was produced by site-directed mutatgenesis and the recombinant protein expressed in a bacterial cDNA expression system. Recombinant CYP2C19 6 had negligible catalytic activity toward S-mephenytoin compared with CYP2C19 1B, which is consistent with the conclusion that CYP2C19*6 represents a PM allele. Thus, the new CYP2C19*6 allele contributes to the PM phenotype in Caucasians.

Alleles↗
PubMed1997

[Pharmacology of tramadol].

(+/-)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It is a central analgesic with a low affinity for opioid receptors. Its selectivity for mu receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for mu receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol. After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse. Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required.

Administration, Oral↗
PubMed1996

[Drug-induced hepatic involvement, something to consider!].

A retrospective study over the last 5 years on drug-induced liver injury was performed in the Internal Medicine Department of the University Hospital of Geneva. According to WHO and Council for International Organizations of Medical Sciences (CIOMS) criteria for drug-induced liver adverse events, 142 cases were identified, with 255 drugs fulfilling causality criteria of certain, probable or possible. 63 patients (44%) suffered severe consequences of liver injury, including 9 deaths. Drugs reported belonged to the therapeutic classes of antibiotics (43%), cardiovascular (20%), analgesics (10%), gastrointestinal (9%), psychotropic (7%), and others (11%). Despite bias inherent to the retrospective methodology, only 10% of the side effects were spontaneously reported to the pharmaco-vigilance board. This is in accordance with the known reporting rate. It can be concluded that spontaneous reports are to be regarded only as signals.

Adult↗
PubMed1996

The effect of tobacco on lung cancer risk depends on CYP2D6 activity.

The genetically determined P450 CYP2D6 activity is suspected to be involved in lung carcinogenesis by activating carcinogens contained in tobacco smoke. Therefore, lung cancer risk should depend on both smoking exposure and CYP2D6 activity. The extent to which CYP2D6 activity, determined by using dextromethorphan, could modify the effect of tobacco was evaluated from a study on 128 lung cancers and 157 controls. A strong interaction was observed; the effect of tobacco on lung cancer risk rose with increasing CYP2D6 activity (P < 0.001). Increasing levels of smoking increased lung cancer risk only among smokers with the highest CYP2D6 activity, and CYP2D6 was a risk factor only among heavy smokers. Smokers with both the highest CYP2D6 activity and daily tobacco consumption were at very high risk for lung cancer. These results may explain discrepant results of previous studies on the association between CYP2D6 activity and lung cancer.

Age Factors↗
PubMed1996

Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam.

OBJECTIVE: The nature of the enzyme(s) catalysing the biotransformation of lornoxicam to one of its major metabolites, 5'-hydroxy-lornoxicam, has been investigated in human liver microsomes. The reaction kinetics were characterised, the affinity of lornoxicam for three major human drug metabolising cytochrome P-450 isozymes (CYP2C9, CYP2D6 and CYP3A4) was determined, and inhibition of the reaction by known substrates (diclofenac, ibuprofen, mefenamic acid, phenytoin, tolbutamide and warfarin) and the prototype inhibitor (sulphaphenazole) of CYP2C9 was investigated. RESULTS: Lornoxicam 5'-hydroxylation displayed single enzyme Michaelis-Menten kinetics, with a KM of 3.6 mu mol center dot l-1 and a Vmax of 2.6 nmol center dot h-1 center dot mg-1 microsomal protein. The apparent affinity of lornoxicam was high for CYP2C9, but negligible for CYP3A4 and CYP2D6. Inhibition of lornoxicam 5'-hydroxylation by CYP2C9 substrates and sulphaphenazole competitively and completely inhibited lornoxicam 5'-hydroxylation (Ki = 0.31 mu mol center dot l-1 as well as lornoxicam clearance (Ki = 0.33 mu mol center dot l-1), partial metabolic clearance (fm) = 0.95). CONCLUSION: 5'-Hydroxylation appears to be the only cytochrome P-450 catalysed metabolic reaction of lornoxicam by human liver microsomes and this major in vivo biotransformation pathway is catalysed virtually exclusively by CYP2C9.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors.

OBJECTIVE: The affinity of (+)-, (-)- and (+/-)- fluvastatin, a new synthetic HMG-CoA reductase inhibitor developed as a racemate, for specific human P450 monooxygenases in liver microsomes was compared with that of the pharmacologically active acidic forms of lovastatin, pravastatin and simvastatin. METHODS: Affinity was determined as the inhibitory potency for prototype reactions for 3 major drug metabolising enzymes: diclofenac 4'-hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), and midazolam 1'-hydroxylation (CYP3A4). RESULTS: Lovastatin acid, pravastatin and simvastatin acid displayed moderate affinity for all three P450 isozymes (estimated Ki > 50 micromol.1(-1)). Racemic and (+)- and (-)-fluvastatin showed moderate affinity (estimated Ki > 50 micromol.1(-1)) for CYP2D6 and CYP3A4, whereas their affinity for CYP2C9 was high (estimated Ki < 1 micromol.1(-1)). Diclofenac 4'-hydroxylation was competitively and stereoselectively inhibited, with measured Ki's of 0.06 and 0.28 micromol.1(-1) for (+)- and (-)- fluvastatin, respectively. CONCLUSION: Fluvastatin selectively inhibits a major drug metabolising enzyme (CYP2C9), the (+)-isomer (pharmacologically more active) showing 4-5 fold higher affinity. As already reported for lovastatin and simvastatin, in vivo drug interactions by inhibition of liver oxidation of CYP2C9 substrates (e.g. hypoglyceamic sulphonylureas and oral anticoagulants) may be expected.

Aryl Hydrocarbon Hydroxylases↗
PubMed1996

Interindividual variability in catalytic activity and immunoreactivity of three major human liver cytochrome P450 isozymes.

OBJECTIVE: Interindividual variations in immunoreactivity and function of three major human drug metabolising P450 monooxygenases has been investigated in liver microsomes from 42 Caucasians (kidney donors or liver biopsies). METHODS: Diclofenac 4'-hydroxylation, dextromethorphan O-demethylation and midazolam 1'-hydroxylation, measured by HPLC in incubates, were used as probes to determine CYP2C9, CYP2D6 and CYP3A4 function kinetics, respectively. Immunoquantification of the three isoforms was achieved by Western blotting, using rabbit polyclonal antibodies raised against human CYP2C9 and human CYP3A4, and mouse monoclonal antibody raised against human CYP2D6. RESULTS: Diclofenac 4'-hydroxylation exhibited Michaelis-Menten kinetics with kM = 3.4 mumol.l-1 and Vmax = 45 nmole.mg-1 P.h-1. Relative immunoreactivity of CYP2C9 was correlated with Vmax and CL(int). Dextromethorphan O-demethylation in EM (extensive metabolisers) liver microsomes also showed Michaelis-Menten kinetics, with kM = 4.4 mumol.l-1 and Vmax = 5.0 nmol.mg-1 P.h-1. Relative immunoreactivity of CYP2D6 was correlated with Vmax and CL(int). Midazolam 1'-hydroxylation also exhibited Michaelis-Menten kinetics with kM = 3.3 mumol.l-1 and Vmax = 35 nmol.mg-1 P.h-1. Relative immunoreactivity of CYP3A4 was correlated with Vmax and CL(int). Immunoreactivity and function were correlated for each isozyme, but there was no cross correlation between isozymes. CONCLUSION: The velocity of metabolite formation (Vmax) by the three major human drug metabolising P450 monoxygenases is correlated with their immunoreactivity in liver microsomes. Interindividual variation was much larger for Vmax than kM. Interindividual variability was more pronounced for CYP2D6, probably due to the presence of several different functional alleles in the population of extensive metabolisers.

Adult↗
PubMed1996

Stereoselective interaction between piroxicam and acenocoumarol.

1. An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers. 2. Eight healthy male volunteers received an oral dose of 4 mg rac-acenocoumarol on days 1 and 8, plus 40 mg piroxicam orally 2 h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24 h interval. 3. The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: Cmax+28.0% (s.d.23.8), P < 0.05; AUC(0, 24 h)+47.2% (21.5), P < 0.005; and t1/2 +38.0% (34.5), P < 0.01. A concomitant decrease of CL/F was observed: -30.8% (10.0), P < 0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: Cmax: +9.5% (s.d.36.6), AUC(0, 24 h): + 15.4% (23.4), t1/2: +19.9% (42.0), and CL/F: -9.8% (20.5). V/F remained unchanged for both enantiomers. 4. Piroxicam plasma AUC(0, 24 h) correlated closely with R- and S-acenocoumarol AUCs on day 1 (r = 0.901, P < 0.005 and r = 0.797, P < 0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol (r = 0.903, P < 0.001) and S-acenocoumarol (r = 0.711, P < 0.05). 5. Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.

Acenocoumarol↗
PubMed1996

Concentrations of azithromycin in tonsilar and/or adenoid tissue from paediatric patients.

Azithromycin levels in tonsillar and/or adenoid tissue were determined in children (1.6-7.5 years old) who were scheduled for surgical removal of their tonsils and/or adenoids. The children received azithromycin oral suspension 10 mg/kg once daily for 3 days. Tissue samples were obtained during surgery 1 (n = 4), 2 (n = 5), 4 (n = 6), or 8 (n = 5) days after the last dose of azithromycin. Serum samples were also obtained from four children in each of these groups at the time of surgery. Mean tissue concentrations of azithromycin were 10.33 +/- 3.01, 7.21 +/- 4.04, 9.30 +/- 3.74 and 1.49 +/- 0.48 mg/kg, respectively, 1, 2, 4 and 8 days after the last dose. At the corresponding times, serum concentrations were markedly lower: 47.25 +/- 19. 19, 14.00 +/- 8.45, 8.00 +/- 2.16 and < 4 micrograms/L, respectively. The mean tissue:serum concentration ratios were, 227 +/- 54, 547 +/- 184 and 956 +/- 355, respectively, 1, 2 and 4 days after treatment. No adverse events attributable to azithromycin were observed in any of the 23 children who had received at least one dose of azithromycin. The study shows that levels of azithromycin in tonsillar and adenoid tissue were consistently higher than in serum and remained elevated up to 8 days after the end of dosing, supporting the use of a short-course (3-day), once-daily regimen of azithromycin in the treatment of upper respiratory tract infections.

Adenoids↗
PubMed1996

Contribution of monoaminergic modulation to the analgesic effect of tramadol.

1. In humans, the central analgesic effect of tramadol 100 mg orally is only partially reversed by the opioid antagonist naloxone (0.8 mg intravenously). As suggested by in vitro and animal data tramadol analgesia may thus result from an action on opioid as well as monoaminergic pathways. We therefore investigated the effect of alpha 2-adrenoceptor antagonism with yohimbine on tramadol analgesia. 2. Healthy volunteers (n = 10) received tramadol (100 mg orally), followed (+3 h) by yohimbine (0.1 mg kg-1 intravenously), and yohimbine + naloxone (0.8 mg intravenously) and their respective placebo according to a randomized, double-blind crossover, placebo (P) controlled design. Analgesia was assessed over 8 h by subjective pain threshold (pain intensity numerical scale--PINS) and objective pain threshold (RIII nociceptive reflex--RIII) monitoring. 3. Tramadol induced a significant increase in both pain thresholds. Peak analgesic effect was observed at 3.7 h (RIII + 39.6 +/- 3.9% and PINS 50.1 +/- s.e.mean 5%) and the analgesia lasted about 6 h. 4. Yohimbine significantly reversed the analgesic effects of tramadol for 2.8 h with a maximum decrease of 97 +/- 4% (RIII) and 67 +/- 12% (PINS), whereas the addition of naloxone abolished tramadol effects throughout the study period with a decrease of 90 +/- 6% (RIII) and 79 +/- 9% (PINS), P < 0.05). 5. Yohimbine alone did not significantly reduce pain thresholds. 6. alpha 2-Adrenoceptor antagonism reverses tramadol effects, thus pointing to the significant role of monoaminergic modulation and the synergy with opioid agonism in tramadol antinociception after a single oral dose.

Adrenergic alpha-Antagonists↗
PubMed1996

Effects of CYP2D6 activity and tobacco on larynx cancer risk.

The genetically determined capacity of the cytochrome P450 CYP2D6 is suspected to be involved in the activation of tobacco carcinogens. From a multicentric case-control study carried out to analyze the interaction between host and environmental factors on tobacco-related cancers, we reported recently that the effect of tobacco on lung cancer risk rose with increasing CYP2D6 activity, and the effect of CYP2D6 activity rose with increasing tobacco consumption. The aim of the present report was to investigate whether results on lung cancer could be observed for larynx cancer, from a study on 140 cases and 157 controls. A weak interaction between increasing levels of both CYP2D6 activity and average daily consumption of tobacco was found (P = 0.12). The only significant interaction between these two factors was observed when CYP2D6 activity was considered with the two conventional phenotypes (P < 0.05). A dose-response effect of tobacco on larynx cancer risk was found only among one-third of the smokers with the highest level of CYP2D6 activity, and CYP2D6 was a risk factor only among heavy smokers. The highest risk for larynx cancer was then observed among smokers having both the highest levels of CYP2D6 activity and daily consumption of tobacco. The interaction between CYP2D6 activity and tobacco was weaker for larynx cancer than that reported previously for lung cancer. However, the similarities in the results found for these two cancers, i.e., a greater effect of tobacco among smokers with the highest CYP2D6 activity, reinforce the hypothesis that this activity could modify the effect of tobacco on cancer risk.

Aged↗
PubMed1995

In vivo inhibition profile of cytochrome P450TB (CYP2C9) by (+/-)-fluvastatin.

BACKGROUND: (+/-)-Fluvastatin is a synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that selectively and competitively inhibits P450TB (CYP2C9) in vitro. The potential for kinetic interactions in vivo between fluvastatin and P450TB substrates was therefore investigated in healthy volunteers. METHODS: Diclofenac (25 mg orally) oxidation was used as a marker of P450TB activity on days 0, 1, and 8 of fluvastatin treatment (40 mg/day). RESULTS: Diclofenac peak concentration (Cmax) increased over time (0.28 [SD, 0.12], 0.38 [0.20], and 0.45 [0.4] mg/L on days 0, 1, and 8, respectively). Oral clearance was reduced on days 1 and 8 (14% and 15%, respectively). A time-dependent decrease in urinary metabolic ratio (MR, 4'-hydroxydiclofenac/diclofenac) was noted (1.07 [0.34], 0.90 [0.23] and 0.70 [0.18] on days 0, 1, and 8, respectively [p < 0.0001]) for the first 4 hours. The interaction was clear in only some individuals; MR reduction was related to baseline MR and it was more pronounced in subjects with a higher baseline MR (p < 0.01). Fluvastatin Cmax (0.18 [0.11] and 0.32 [0.1] mg/L on days 1 and 8, respectively) and area under the curve (0.28 [0.12] and 0.43 [0.15] hr.mg/L on days 1 and 8, respectively; p < 0.001) increased over time. Diclofenac MR reduction was correlated with fluvastatin concentrations. CONCLUSIONS: Interactions between fluvastatin and P450TB substrates (phenytoin, oral anticoagulants, oral hypoglycemic agents, and nonsteroidal antiinflammatory drugs) may occur, at least in some patients.

Adult↗
PubMed1994

[Which analgesic dosage of paracetamol?].

The purpose of this study was to evaluate the dose-response of paracetamol and to assess its plasma concentration-effect relationship. According to a randomized, double-blind, and placebo controlled design healthy volunteers (n = 11) received 0.5, 1 and 2 g paracetamol (as propacetamol) intravenously (15 min). The extent of analgesic effect was measured over 8 hours by objective pain threshold (R-III) monitoring after selective transcutaneous electrical stimulation of the ipsilateral sural nerve. Maximal R-III threshold increase is at 2 hours after 0.5 g and 2.5 hours after 1 g and 2 g. The delayed peak effects, when compared to peak plasma concentrations, draw counter clockwise hysteresis. Duration of paracetamol antinociceptive effect increased concomitantly to dosage increment. Intravenous paracetamol exerts a dose-dependent central analgesia.

Acetaminophen↗