Biomedical subjects

C Girre

Publications and source records attributed to C Girre.

At least 19 recordsLinked to original sources

PubMed1999

Rapid determination of valaciclovir and acyclovir in human biological fluids by high-performance liquid chromatography using isocratic elution.

A rapid high-performance liquid chromatographic assay with isocratic elution is developed for the simultaneous quantification of valaciclovir (VACV) prodrug and its active converted compound, acyclovir (ACV), in biological fluids of treated patients. For serum, the samples are deproteinized with perchloric acid in presence of 1-methylguanosine as the internal standard (IS). For urine and dialysis liquid, the samples are diluted with a mobile phase containing the IS, then filtered. VACV, ACV and the IS are separated on a SymmetryShield RP-8 column with acetonitrile-ammonium phosphate buffer as the mobile phase and detected at 254 nm. The chromatographic time is about 12 min. The relative standard deviations (RSD) of VACV and ACV standards are between 0.5 and 3.5%. Most endogenous nucleosides and their metabolites, psychotropic drugs and drugs of abuse are shown not to interfere with this technique. The method has been applied to study the pharmacokinetics of VACV and ACV in serum, dialysis liquid and urine of renal failure patients on continuous ambulatory peritoneal dialysis (CAPD) under oral treatment of VACV.

Acyclovir↗

PubMed1997

Impact of long-term ethanol consumption on CYP1A2 activity.

Ethanol is a well-known inducer of CYP2E1; whether or not it is an inducer of other cytochromes has not been investigated systematically. The aim of our study was to evaluate the impact of ethanol consumption on the activity of CYP1A2, which has been shown to be influenced by drugs (inhibited or induced). We evaluated CYP1A2 activity by the ratio of the molar urinary concentrations of the three end products of paraxanthine demethylation of caffeine to the molar concentration of a paraxanthine 8-hydroxylation product. This urinary metabolite ratio has previously been shown to correlate with caffeine clearance. The caffeine metabolites were measured in urine collected during the 3 hours after oral administration of 200 mg caffeine. The caffeine test was performed in 12 smokers (> 25 cigarettes/day) and 12 nonsmokers, all of whom were alcoholic inpatients (daily intake > 100 mg absolute ethanol), within the first 3 days of their hospital stay and after 14 days of abstinence from ethanol. In alcoholic patients who were smokers the molar urinary concentration ratio was 3.14 +/- 0.97 before withdrawal and 4.01 +/- 0.92 after 14 days of abstinence from ethanol. In contrast, in alcoholic patients who were nonsmokers it was 2.62 +/- 0.95 and 2.18 +/- 0.96 before and after withdrawal, respectively. In volunteers who were smokers the molar urinary concentration ratio was 5.02 +/- 1.51, whereas in volunteers who were nonsmokers it was 3.22 +/- 1.46. Our results confirm the well-known induction of CYP1A2 activity by tobacco smoking and show that this induction is masked by long-term ethanol consumption.

Adult↗

PubMed1996

Omeprazole and lansoprazole are not inducers of cytochrome P4501A2 under conventional therapeutic conditions.

OBJECTIVES: Claims that substituted benzimidazole molecules induce cytochromes P4501A2 are still controversial. This study was undertaken to evaluate their inducing potency under conventional therapeutic conditions. METHODS: Twelve healthy non-smoking young volunteers were given 20 mg omeprazole or 30 mg lansoprazole daily, in random order, for 2 weeks, separated by a 3 week wash-out period. We evaluated the CYP1A2 activity by the ratio of the molar urinary concentrations (CUM ratio) of the three end products of the paraxanthine demethylation of caffeine over the molar concentration of a paraxanthine 8-hydroxylation product. RESULTS: This urinary metabolite ratio has previously been shown to be correlated with caffeine clearance. There was slight but non-significant enhancement of the CUM ratio after 2 weeks of treatment with omeprazole (3.62 (1.58) on Day 15 vs 3.09 (1.43) on Day 1), and after lansoprazole (4.26 (2.3) vs 3.65 (2.36)). Similarly, one week of treatment did not significantly alter the CUM ratio after omeprazole or lansoprazole (3.11 (1.58) and 3.28 (1.59), respectively on Day 8). CONCLUSION: The results show that both omeprazole and lansoprazole in the daily recommended therapeutic doses of 20 mg and 30 mg, respectively, have no influence on the metabolism of caffeine, and therefore no influence on cytochrome CYP1A2 activity.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1995

Cytochrome P450 2E1 genotype and chlorzoxazone metabolism in healthy and alcoholic Caucasian subjects.

Susceptibility to cancer or ethanol-related liver diseases may be associated with a large variability in cytochrome P450 2E1 activity. This variability may be of genetic origin or reflect environmental factors. To test the role of genetics, the phenotype and genotype of this enzyme were determined in 42 non-alcoholic and 74 alcoholic patients hospitalized for detoxification treatment. Chlorzoxazone metabolism was used to assess CYP2E1 phenotype. Restriction length fragment polymorphisms with Rsa I or Pst I, and Dra I endonucleases were used to determine the two mutant alleles, Pst I/Rsa I-c2 and Dra I-C. A significant gender difference in basal CYP2E1 activity was observed in non-smoking controls (p < 0.05) but not in alcoholics or smokers. Subjects heterozygous for the C or c2 mutated allele did not show any difference in CYP2E1 activity at the basal level, compared with the wild type homozygotes. Conversely, patients with the mutated genotype appeared less inducible than the others after ethanol induction (p < 0.01).

Adult↗

PubMed1995

Decrease in cytochrome P4502E1 as assessed by the rate of chlorzoxazone hydroxylation in alcoholics during the withdrawal phase.

To evaluate cytochrome P4502E1 (CYP2E1) induction in alcoholics, the ratio of the concentrations of 6-hydroxychlorzoxazone (6-OH-CHZ) and chlorzoxazone (CHZ) was measured in blood 2 hr after CHZ ingestion using a HPLC method. This ratio was determined in controls and in alcoholic patients after 1, 2, 3, 4, 5, 8, and 21 days withdrawal. It was found to be 0.34 +/- 0.03 in 30 controls and 1.05 +/- 0.14 in 41 alcoholic patients within 2 days following ethanol withdrawal. This ratio decreased rapidly during withdrawal as attested by the short half-life of CYP2E1, which was found to be 2.5 days. Patients tested for CHZ metabolism after 8 or 21 days alcohol abstinence displayed the same ratio as controls [0.35 +/- 0.03 (n = 28) and 0.31 +/- 0.03 (n = 34), respectively]. No correlation was observed between gamma-glutamyltransferase, carbohydrate-deficient transferrin values, the amount of alcohol consumed/day, and the 6-OH-CHZ/CHZ ratio. There was no influence of smoking on the rate of CHZ hydroxylation, because smokers displayed the same ratio as nonsmokers [0.33 +/- 0.025 (n = 62) and 0.33 +/- 0.02 (n = 30), respectively]. The CHZ hydroxylation ratio seems to be a good reflection of the hepatic and extrahepatic CYP2E1 activity in humans.

Adult↗

PubMed1995

Alcohol consumption and visual contrast sensitivity.

Visual contrast sensitivity (VCS) was measured in 30 alcoholic patients and 52 controls. The results showed a significant reduction in VCS for all the spatial frequencies. The mean reduction for all spatial frequencies was 2.49 dB below the level of the control group. Optimal sensitivity corresponded to a lower spatial frequency in patients than controls, i.e. 1 cycle/degree (c/d) versus 2 c/d. Curves for VCS were normal for five patients. Abnormalities in VCS were suggestive of optic nerve dysfunction for 15 patients (50%), which were probable in seven cases (23%) and possible in eight others (27%). For 10 subjects, the abnormalities were indicative of ametropia. Daily alcohol intake and daily tobacco consumption were not significantly different in the patients who displayed VCS abnormalities, reflecting alcohol-tobacco amblyopia, from those who did not. The presence of higher gamma-glutamyl transpeptidase and mean corpuscular volume levels in patients who had VCS abnormalities indicative of alcohol-tobacco amblyopia suggests that alcohol consumption is involved in the development of these abnormalities.

Adult↗

PubMed1994

Assessment of cytochrome P4502E1 induction in alcoholic patients by chlorzoxazone pharmacokinetics.

Chlorzoxazone is mainly metabolized to 6-hydroxychloroxazone (6-OHchlorzoxazone) by the ethanol-inducible cytochrome P450 2E1 (CYP2E1). To evaluate the impact of ethanol consumption on the enzyme induction, the pharmacokinetics of chlorozoxazone and 6-OHchlorzoxazone were studied in alcoholic and control subjects. Fifteen alcoholic male inpatients (all smokers, daily intake 333 +/- 191 g of absolute ethanol) and 20 healthy male volunteers (10 smokers and 10 non-smokers, weekly intake < 100 g of absolute ethanol) participated in this study. Following a 12 hr fasting period, each subject was orally administered 500 mg of chlorzoxazone. Venous blood and urine samples were collected over a 10 hr period. Areas under the curve of plasma concentration versus time (AUC) of chlorzoxazone and 6-OHchlorzoxazone was calculated. The total plasma clearance of chlorzoxazone was measured as the dose/AUC ratio. The mean total plasma clearance was not different between smoker and non-smoker controls but it was enhanced by 73% in alcoholic patients. These results indicate a negligible and non-significant effect of cigarette smoking in controls but an increased metabolism of chlorzoxazone in alcoholic patients (P < 0.05). This increase was corroborated by the 2-fold enhancement of the 6-OHchlorzoxazone/chlorzoxazone AUC ratio, compared to controls. A good correlation was found between this AUC ratio and the 6-OHchlorzoxazone/chlorzoxazone concentration ratio at t = 2 hr in patients and in controls (r = 0.88 and 0.85, respectively, P < 0.01). The concentration ratio increased by 150% in alcoholic patients and decreased by 65% in the seven alcoholics tested after 7 days of alcohol abstinence. It is therefore concluded that the 6-OHchlorzoxazone/chlorzoxazone concentration ratio at t = 2 hr could constitute a simple and non-traumatic marker of CYP2E1 induction.

Adult↗

PubMed1994

Pharmacokinetics and absolute bioavailability of colchicine after i.v. and oral administration in healthy human volunteers and elderly subjects.

The pharmacokinetics of colchicine were studied in six healthy male and four elderly female volunteers after i.v. and oral administration. Plasma samples were collected over 72 h and assayed for colchicine by a specific and sensitive radioimmunoassay. Plasma concentration-time curves were fitted using a three-compartmental model after i.v. administration of 0.5 mg (healthy volunteers) and 1 mg (elderly group) colchicine. The first distribution half-life (t1/2 lambda 1) was short: 9.2 min in healthy volunteers and 3.0 min in the elderly group; the second distribution half-life (t1/2 lambda 2) was of the same order for both groups, 1.2 h. Plasma elimination half-lives were also in the same range: 30 h for healthy volunteers versus 34 h for the elderly subjects. Mean residence time was also in the same range in the two groups: 27 h in healthy volunteers and 21 h for elderly subjects. The volume of distribution (Vz) was 6.7 l.kg-1 for the healthy group and 6.3 l.kg-1 for the elderly group, while Vss was smaller: 4.2 l.kg-1 for healthy volunteers and 2.9 l.kg-1 for elderly subjects. Total body clearance was 10.5 l.h-1 for healthy and 5.5 l.h-1 for elderly subjects. After oral administration of 1 mg, lag-time was 14 min in healthy volunteers and 11 min in elderly subjects. Maximal plasma concentration was 5.5 ng.ml-1 at 62 min in the healthy group, while in the elderly group Cmax was 12 ng.ml-1 at 87 min. Mean absolute bioavailability of the tablet was the same in both groups, 44% for healthy volunteers and 45% for elderly subjects.

Administration, Oral↗

PubMed1993

High-performance liquid chromatographic determination of chlorzoxazone and 6-hydroxychlorzoxazone in serum: a tool for indirect evaluation of cytochrome P4502E1 activity in humans.

Chronic alcohol consumption is known to induce the enzyme cytochrome P4502E1 (CYP2E1), which is involved in the toxicity and carcinogenicity of a number of solvents and xenobiotics. It was recently suggested that in vivo chlorzoxazone metabolism could be a potential tool as a non-invasive probe for measuring CYP2E1 activity in humans. Therefore, a simple and sensitive method was developed for the determination of chlorzoxazone and its major metabolite 6-hydroxychlorzoxazone in both serum and urine. Biological samples were hydrolysed by Helix pomatia juice, deproteinized with perchloric acid, and then extracted using ethyl acetate. The compounds were separated by high-performance liquid chromatography on an octadecylsilane column with a mobile phase of acetonitrile-0.5% acetic acid in water (30:70, v/v) and detected at 287 nm. The linearity of the method was tested in the concentration range 0.5-20 micrograms/ml, and the limit of detection in biological samples was found to be 0.5 microgram/ml. Within- and between-run precision was below 5% and 10%, respectively, for both compounds at three concentrations (0.5, 10 and 20 micrograms/ml). The accuracy of the procedure was in the range 0.3-6%. Serum levels and urinary excretion of chlorzoxazone and its metabolite were studied in five healthy controls and five alcoholic patients, following oral administration of 500 mg of chlorzoxazone. The concentration ratio 6-hydroxychlorzoxazone/chlorzoxazone in blood was shown to be a valuable tool for the evaluation of CYP2E1 activity in humans.

Administration, Oral↗

PubMed1993

Increased metabolism of acetaminophen in chronically alcoholic patients.

The aim of this work was to determine whether the metabolism of acetaminophen increases in chronic alcoholics, and consequently whether the production of its hepatotoxic metabolite is enhanced. For this purpose, the pharmacokinetics of acetaminophen were compared in 12 alcoholic men and 12 healthy controls. After a 12-hr fast, the patients (on the 3rd hospital day) and volunteers were given 1 g of oral acetaminophen at 8.00 AM. Venous blood samples were drawn before drug intake and at regular intervals after to evaluate plasma acetaminophen concentrations. The elimination half-life of acetaminophen was significantly shorter in the alcoholic patients than in the controls (1.70 +/- 0.55 vs. 2.84 +/- 0.30 hr, p < 0.001). Similarly, total plasma acetaminophen clearance was significantly higher in the patients than in the controls (29.19 +/- 13.37 vs. 24.45 +/- 11.10 l/hr, p < 0.05). These results confirm that the metabolism of acetaminophen increases in chronic alcoholism and consequently suggest that its potential liver toxicity might be enhanced.

Acetaminophen↗

PubMed1991

Enhancement of propoxyphene bioavailability by ethanol. Relation to psychomotor and cognitive function in healthy volunteers.

The interaction between a single oral dose of 130 mg propoxyphene and 0.5 g/kg body weight ethanol was investigated in 12 healthy male volunteers by 9 objective performance tests, 8 visual analogue self-rating scales and the measurement of plasma propoxyphene, norpropoxyphene and ethanol concentrations, using a double-blind threeway crossover design. Volunteers were each given one of three treatments, propoxyphene + ethanol, placebo + ethanol and propoxyphene alone, separated by a two week interval. The performance tests were completed before and 1.25 and 4 h after drug intake, and the self-rating scales before and 1.25, 4 and 10 h after it. Ethanol was shown to enhance the bioavailability of propoxyphene by 25% probably by reducing its first-pass metabolism. However, despite this pharmacokinetic effect no pharmacodynamic interaction was found. Subjective ratings disclosed that the effect of ethanol on physical and mental sedation predominated over the effects of propoxyphene.

Biological Availability↗

PubMed1991

Comparison of performance of healthy volunteers given prazepam alone or combined with ethanol. Relation to drug plasma concentrations.

The interaction between a single dose of 20 mg of prazepam and 0.5 g/kg body weight ethanol was investigated in 12 healthy male volunteers by nine objective performance tests, eight visual analogue self-rating scales and measurement of prazepam and ethanol plasma concentrations, using a double-blind three-way crossover design. The volunteers were each given three treatments (prazepam+ethanol, placebo+ethanol and prazepam alone), separated by a 2-week interval. They completed the performance tests before treatment and 1.5 and 4 h thereafter, and the self-rating scales before treatment, 1.5, 4 and 8 thereafter. To determine prazepam and ethanol plasma levels, venous blood samples were drawn before drug intake and 0.25, 0.5, 1, 1.5, 3, 4, 5 and 8 h thereafter. In two of the performance tests: auditory reaction time and digit symbol substitution, the combination of prazepam and ethanol was shown to impair performance more than either drug taken alone 1.5 h after their administration. A similar result was found for the drowsiness scored in the self-ratings. The time needed to complete the two-symbol cancellation test was longer when the subjects received prazepam either alone or combined with ethanol. Simultaneous ingestion of prazepam and ethanol did not alter the bioavailability of either drug.

Adolescent↗

PubMed1991

Comparative effects on psychomotor performance of the muscle relaxant afloqualone, alone and with ethanol.

The purpose of this study was to investigate the interaction between 40 mg afloqualone, a new centrally acting muscle relaxant and 0.5 g/kg ethanol using a double-blind three-way cross-over trial in which subjects were each given afloqualone with ethanol, ethanol alone and afloqualone alone. We first compared the effects of 40 mg oral afloqualone and 15 mg diazepam (considered as a reference drug) on the psychomotor and cognitive performance and muscular relaxation of 12 healthy male volunteers. Performance was assessed by six objective tests and eight visual analogue self-rating scales. All the above treatments were separated by a 2-week interval. Volunteers performed the objective tests 1 h after drug ingestion, and the self-rating scale evaluations before drug intake and 1, 3.5, 6 and 8 h thereafter. Afloqualone impaired psychomotor performance less than diazepam as shown by the number of correct answers in the digit symbol cancellation test and the time needed to complete this test. However, the measurement of the frontalis muscle action potential showed that the muscle relaxant activity of 40 mg afloqualone was equivalent to that of 15 mg diazepam. Furthermore, afloqualone given at an effective relaxant dose did not enhance the effects of a single dose of ethanol which predominated on either psychomotor performance or subjective feelings.

Administration, Oral↗

PubMed1990

Comparison of the effect of two prazepam formulations on psychomotor and cognitive function in healthy volunteers.

A double-blind crossover design was used to evaluate the effect of two different formulations of prazepam, on motor and cognitive functions and subjective symptoms. Ten healthy male volunteers received 20 mg of prazepam both in tablet and liquid (as drops) formulation, separated by a 1 week interval. All subjects completed a battery of 9 performance tests 2.25 h and 4.75 h after drug intake (corresponding to the times of peak plasma concentration). They also rated themselves on eight visual analogue scales before, 2 h, 4.5 h and 8 h following drug intake. A significant difference between liquid drops and tablets was demonstrated in 4 of the 9 performance tests and 2 of the 8 items of the self rating scales. These results suggest that a single dose of prazepam administered in liquid drop form exhibits greater sedative properties than the same dose administered as tablets in healthy volunteers, probably as a result of more rapid absorption.

Chemistry, Pharmaceutical↗

PubMed1990

Effect of abstinence from alcohol on the depression of glutathione peroxidase activity and selenium and vitamin E levels in chronic alcoholic patients.

Glutathione peroxidase activity and selenium and vitamin E levels were measured in the plasma and erythrocytes of 25 chronic alcoholic patients without liver cirrhosis before and after 14 days of abstinence from alcohol, and compared with the levels in 25 sex- and age-matched healthy controls. Before abstinence, all three levels were shown significantly depressed in the alcoholic patients compared with the controls, in both plasma (80, 71, and 89% of control values) and erythrocytes (68, 70, and 83% of control values). After a 14-day abstinence period with no dietary supplementation, a trend towards normalization was noted in erythrocyte (vitamin E and glutathione peroxidase 74 and 91% of control values respectively), in whole blood selenium (82%) and plasma in vitamin E (74%). However, plasma selenium and glutathione peroxidase values were lower than pre-abstinence values (76% and 86% of control values respectively). Our results point to a deficiency in the antioxidant defense system of chronic alcoholics before the occurrence of severe liver disease. This lack of protection against lipoperoxides is all the more important in circumstances like chronic alcohol consumption, in which lipid peroxidation is known to increase. However, the present study also demonstrated that during 14 days of a normal diet free of ethanol, a rapid trend occurred towards the normalization of the factors.

Adult↗

PubMed1989

Zero-order absorption and linear disposition of oral colchicine in healthy volunteers.

The pharmacokinetics of colchicine has been studied in nine healthy male volunteers after oral doses of 0.5, 1, and 1.5 mg as tablets. Plasma and urine samples were collected over 48 h and analysed for colchicine by radioimmunoassay. Individual colchicine concentration profiles in plasma and urine were well described by a two-compartment open model with zero-order input. Considering the absorption variables as specific to each experiment, the lag time (0-0.35 h) and duration (0.39-2.38 h) of absorption were found to be independent of dose, while the zero-order rate constant of absorption (k0) increased linearly with dose. Disposition variables were taken as common to the three experiments, except in six subjects in whom renal excretion varied significantly across experiments in a dose-independent manner. For seven subjects the terminal half-life was 19.4 h, the oral apparent volume of distribution at steady-state (Vss/f) was 691 l, and the oral systemic clearance (CL/f) was 33.1 l.h-1. In the two other subjects, the values were unreliable, but the estimated terminal half-life was greater than 48 h, Vss/f ranged from 1690 to 3480 l, and CL/f was in the range of the other subjects in 1 subject, and it was about 15 l.h-1 in the other. In the latter subject, these estimates, together with the observation that plasma concentration reached a plateau at 2 to 5 h after ingestion, suggest enterohepatic cycling of colchicine. Overall, the disposition of colchicine was linear in the dose range 0.5-1.5 mg, with a long terminal half-life, and absorption obeyed zero-order kinetics, with k0 proportional to dose.

Administration, Oral↗

PubMed1989

High blood lead level in alcoholics: wine vs. beer.

One hundred and sixty one alcoholics (121 men and 40 women) were studied during a social rehabilitation program. All had a daily intake of ethanol higher than 1 g/kg/day. The mean lead blood level was 28 micrograms/100 ml and was as high as 72.5 micrograms/100 ml in one subject. Wine drinkers had a higher blood lead level (29.8 micrograms/100 ml) than beer or spirit drinkers (23.8 micrograms/100 ml). A significant correlation was found between the blood lead level and systolic and diastolic arterial blood pressure and this relation was independent of sex, weight or age. We conclude that a high blood lead level can be a risk factor for hypertension in alcoholics.

Adult↗

PubMed1989

Model-independent pharmacokinetics of colchicine after oral administration to healthy volunteers.

The pharmacokinetics of colchicine were studied after oral administration of three doses (0.5, 1.0 and 1.5 mg) to nine healthy male volunteers according to randomized cross-over design. Plasma and urine samples were collected during 48 h after ingestion, and assayed for colchicine levels by a specific and highly sensitive radio-immunoassay. Pharmacokinetic parameters t1/2 beta, AUC, MRT, CIT/F, CIR, Vd area/F) were calculated by model-independent methods and compared across doses by multiway analysis of variance. Terminal half-life (15.5-19.2 h), mean residence time (15.7-20.3 h), oral systemic (32.2-40.3 l/h) and renal (3.9-4.7 l/h) clearances, and oral volume of distribution (11.4-14.9 l/kg) did not differ significantly between doses, whereas the area under the concentration-time curve was proportional to dose. Our results show that: 1. within the dose range studied (0.5-1.5 mg), the pharmacokinetics of colchicine are linear; 2. monitoring colchicine levels up to 48 hours yields much larger estimates of terminal half-life and volume of distribution than previously reported from considerably shorter studies.

Administration, Oral↗