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Biomedical subjects

G Paintaud

Publications and source records attributed to G Paintaud.

At least 37 records · Page 2Linked to original sources
PubMed1998

Acetylation polymorphism expression in patients before and after liver transplantation: influence of host/graft genotypes.

The consequences of liver transplantation on NAT2 activity were studied in 58 patients of Caucasian origin and compared with a group control of 119 unrelated healthy individuals of the same ethnic origin. Acetylation phenotypes were determined using caffeine as a probe drug before and repeatedly after liver transplantation. NAT2 genotypes were determined with three separate polymerase chain reactions to detect either the NAT2*4 wild-type allele or the NAT2*5A, NAT2*6A and NAT2*7A mutated alleles, associated with a decrease in NAT2 enzyme activity. In patients, the molar urinary elimination ratio AFMU/(AFMU+1X+1U) appeared more reliable than AFMU/1X for assessing the acetylation phenotype and fitted better with the various haplotypes. The variation of xanthine oxidase activity as measured by the 1U/1X urinary elimination ratio, appeared to be responsible for the poor phenotype prediction from the AFMU/1X ratio in post-transplanted patients. Regardless of the pathologic conditions of the treatment in progress, the genotype of the liver played an overwhelming role in the phenotypic expression of NAT2 compared with the genotype of other organs, where NAT2 was expressed in patients who presented a chimerism after liver transplantation.

Acetylation↗
PubMed1998

Methodological issues in pharmacokinetic-pharmacodynamic modelling.

This article presents the theoretical and practical aspects involved in the design and analysis of pharmacokinetic-pharmacodynamic modelling studies. The main features of the protocol of pharmacokinetic-pharmacodynamic studies are discussed with special focus on experimental designs in relation to individual and population approaches. Some basic pharmacodynamic models (such as linear, log-linear, hyperbolic and sigmoid models) are presented as well as more complex time-dependent models (effect compartment and physiological indirect response, tolerance models) which are required when the concentration-effect relationship shows a hysteresis loop. The methods of estimation, with special focus on the individual and populations approaches, are covered, along with the way pharmacodynamic models and methods of estimation can be applied to real data and the information required to criticise the results of modelling. We also present some real problems frequently encountered when performing pharmacokinetic-pharmacodynamic modelling and give some potential solutions (problems with hysteresis loops, lack of convergence, problems with residuals). The last section discusses the significance of pharmacodynamic parameters.

Humans↗
PubMed1997

Natriuretic efficiency of frusemide as a consequence of drug input rate.

AIMS: The aim of the present study was to investigate the influence of the rate of delivery of frusemide to its site of action on the effect and efficiency of the drug. METHODS: Frusemide 30 mg was administered as a bolus dose, a slow-rate infusion and a bolus dose in combination with 2 g of probenecid in a three way cross-over design to seven healthy volunteers. Urinary volume and contents of frusemide and sodium were measured in samples collected over 10 h. RESULTS: Total natriuretic response was 40% higher (P < 0.001) after the infusion and 20% higher (P < 0.05) after the combined treatment with probenecid, as compared with the bolus dose. Total natriuretic efficiency did not differ between the infusion (0.013 mmol microg(-1)) and the combined treatment with probenecid (0.015 mmol microg(-1)), but was significantly higher as compared with the bolus dose (0.009 mmol microg(-1)). Natriuretic effect data were modeled according to the sigmoid Emax model and the frusemide excretion rate with maximum efficiency (ER(effmax)) was calculated from the estimated parameters. For both the frusemide infusion and the combined treatment with probenecid, the time course of delivery of frusemide into the urine consistently approached ER(effmax) more closely than was the case for the bolus dose. The natriuretic effect vs frusemide excretion rate curves were shifted to the right, and the estimated values of the sigmoid Emax model were higher for EC50 and lower for the slope factor after the bolus dose, which may indicate tolerance development for this treatment. CONCLUSIONS: Slowing the delivery of frusemide to the site of action increased the efficiency of the drug, leading to an increased natriuretic response.

Adult↗
PubMed1996

A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients.

OBJECTIVE: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. METHODS: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. RESULTS: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng.h.ml-1, Cmax was 832 vs 871 ng.ml-1 and tmax was 2 vs 2 h, after ursodiol and placebo, respectively. CONCLUSION: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely.

Administration, Oral↗
PubMed1996

Pharmacodynamic modeling of furosemide tolerance after multiple intravenous administration.

OBJECTIVE: Physiologic indirect-response models have been proposed to account for the pharmacodynamics of drugs with an indirect mechanism of action, such as furosemide. However, they have not been applied to tolerance development. The aim of this study was to investigate the development of tolerance after multiple intravenous dosing of furosemide in healthy volunteers. METHODS: Three repetitive doses of 30 mg furosemide were given as rapid intravenous infusions at 0, 4, and 8 hours to eight healthy volunteers. Urine samples were collected for a period up to 14 hours after the first dose. Volume and sodium losses were isovolumetrically replaced with an oral rehydration fluid. RESULTS: Tolerance was demonstrated as a significant decrease in diuretic and natriuretic response over time. Total mean diuresis was 35% lower (p < 0.01) and total mean natriuresis was 52% lower (p < 0.0001) after the third dose of furosemide compared with the first dose. However, there were considerable interindividual variations in the rate and extent of tolerance development for both diuresis and natriuresis. Pharmacokinetic-pharmacodynamic modeling of tolerance development was performed with use of an indirect-response model with an additional "modifier" compartment. This model gave an accurate description of the diuretic and natriuretic data after multiple dosing of furosemide and enabled the estimation of a lag-time for tolerance and a rate constant for tolerance development. Physiologic counteraction was demonstrated as a significant increase in plasma active renin levels (p < 0.00001) and a decrease in atrial natriuretic peptide levels (p < 0.005) during the day, concomitantly with the development of a negative sodium balance. This may be viewed as physiologic reflections of the modifier in our model. CONCLUSION: Indirect-response models may be successfully applied for tolerance modeling of drugs after multiple dosing.

Adult↗
PubMed1996

Skin localization of alveolar echinococcosis of the liver.

Alveolar echinococcosis is a rare parasitic disease caused by the intrahepatic growth of Echinococcus multilocularis larvae. Secondary localizations can be observed; pulmonary metastases are the most frequent and are observed in 22% of patients. Other extrahepatic localizations are less frequent. We describe two patients with abdominal skin involvement. To our knowledge, this has never before been reported. In both patients, the liver lesion was located in the left lobe, and larvae probably spread to the skin via the falciform ligament. In one patient albendazole therapy was effective.

Aged↗
PubMed1996

Inhibition of caffeine metabolism by 5-methoxypsoralen in patients with psoriasis.

Eight patients with psoriasis were given 200 mg caffeine orally with or without 1.2 mg kg-1 of 5-methoxypsoralen. Blood and urine samples were collected over a 2-day period. During 5-methoxypsoralen coadministration, the apparent volume of distribution of caffeine remained unchanged, but oral clearance (CLp.o.) decreased from 9.5 +/- 3.8 (mean +/- s.d.) to 3.2 +/- 0.51 h-1 (P < 0.01). The area under the plasma concentration-time curve (AUC) increased from 24 +/- 9 to 73 +/- 29 mg 1(-1) h (P < 0.001). This decrease in CLp.o. with increased AUC was consistent with a CYP1A2-dependent inhibition of caffeine N-demethylation which was further supported by significant decreases in the (AFMU+1U+1X)/17U and (AFMU+1U+1X)/17X urinary metabolic ratios.

5-Methoxypsoralen↗
PubMed1996

Effect of the transition from intravenous to oral dosing on cyclosporin-A trough concentrations in liver transplant patients.

Cyclosporin A (CsA) absorption is low and variable after liver transplantation, and during the intravenous-oral transition period CsA concentrations may not be maintained within the therapeutic range. Trough whole blood CsA concentrations were measured by high-performance liquid chromatography before and after the transition period in 27 liver transplant patients. Mean (SD) CsA concentrations decreased from 291 (92) to 198 (96) ng/ml (p < 0.001). When analyzed on individual charts, a decrease was observed in 15 of 27 patients and it was associated with a duration of 2 days or less (p < 0.01) and a total bilirubin value below 3.5 mg/dl (p < 0.05). Our results show that, despite therapeutic drug monitoring, CsA blood concentrations may decrease during the intravenous-oral transition period.

Administration, Oral↗
PubMed1995

The influence of food intake on the effect of two controlled release formulations of furosemide.

Differences in the urinary excretion rate of furosemide may explain discrepancies observed between the bioavailability and the total diuretic effect of different formulations of this drug. Furosemide was given at a dose of 60 mg as two oral controlled release (CR) formulations (FR and LR), with and without breakfast, in a randomized, four-treatment, four-period, crossover design to 28 healthy volunteers. Urinary volume, and contents of furosemide and sodium, were measured in samples taken over 24 h. The extent and rate of absorption of furosemide from FR were decreased after breakfast as compared to fasting: the mean (SD) of total furosemide excreted decreased from 11.38 (3.12) to 7.73 (1.67) mg, p < 0.0001, and the median (range) mean residence time increased from 6.3 (4.1-9.3) to 9.5 (5.9-11.8) h, p < 0.001. On the other hand, the extent of absorption of LR was increased after breakfast, from 8.04 (3.32) to 9.45 (1.83) mg, p < 0.05, without a significant change in MRT. FR had a higher extent and rate of absorption than LR during fasting, but its extent of absorption was lower than that of LR in the postprandial state. Interestingly, the total fraction of furosemide absorbed, as estimated from total furosemide excretion, was not correlated with the total diuresis (r2 = 0.079) and the differences in drug response compared among the four periods were much smaller than would be expected from the differences in amount absorbed. This discrepancy may be explained by differences in urinary excretion rate of furosemide and, related to this, differences in efficiency profiles between the four treatments. Therefore, the urinary excretion profile of a formulation of furosemide may be more important for the cumulated drug effect than the amount absorbed.

Adult↗
PubMed1995

Limitations of the maximum entropy principle in devising drug input rate.

A computer program applying the principle of maximum entropy to the analysis of drug absorption rate has been developed. Plasma concentrations of amoxicillin obtained after oral and intravenous dosing have been analysed, together with simulated data corresponding to a complex input. Amoxicillin absorption rates devised by the program were similar to those obtained by a standard deconvolution method, although they were displayed as an almost continuous profile. However, improbable fluctuations were obtained with some data sets and the fraction absorbed was underestimated by 13%. With the simulated data, the maximum entropy program did not provide a better solution than the standard deconvolution procedure, and it was sensitive to the addition of random error and to the number of samples. The maximum entropy principle, as implemented in our computer program, may not have a better performance than standard deconvolution procedures, especially in human experiments where the number of blood samples is usually limited.

Administration, Oral↗
PubMed1995

Stability of debrisoquine (CYP2D6) phenotype in liver transplant patients.

Liver metabolism may be modified after liver transplantation according to the phenotype of the donor and may be influenced by posttransplantation complications. The CYP2D6 phenotype was assessed in 13 patients (group I) before and after liver transplantation using debrisoquine. CYP2D6 activity was also assessed in vitro on microsomes from the liver of the recipients and the donors, using dextromethorphan. Twelve patients were extensive metabolizers both before and after transplantation. One apparently poor metabolizer was transplanted with the liver of another poor metabolizer. The intrinsic clearance of dextromethorphan (CL(int)) measured on recipient liver microsomes was significantly lower than that on donor liver microsomes (p < 0.05). In extensive metabolizers, the debrisoquine metabolic ratio was correlated with CL(int) before (r = 0.78, p < 0.05) and after (r = 0.89, p < 0.0005) transplantation. Debrisoquine phenotype was measured repeatedly in nine additional patients (group II) up to 3 years after liver transplantation. Their phenotype was stable during the follow-up observation, although the variations observed may be clinically relevant. Therefore, no change in CYP2D6 phenotype (extensive/poor metabolizer) was observed because of the liver transplantation, and the debrisoquine log metabolic ratio was largely unaffected by the liver complications observed during the posttransplantation follow-up observation.

Cytochrome P-450 CYP2D6↗
PubMed1995

Pharmacokinetics of a more reliable Chloraminophene formulation.

The pharmacokinetics of two formulations of chlorambucil, Chloraminophene capsules and Chloraminophene tablets, were compared in 12 patients in a randomized cross-over study. Chlorambucil concentrations in plasma were measured by HPLC over a period of 24 h after drug intake. The peak concentration (Cmax) occurred earlier after administration of capsules than after administration of tablets [median (range)]: 0.50 (0.33-0.66) h vs 2.00 (0.66-4.00) h (p < 0.01). Although values of Cmax and the area under the plasma concentration versus time curve (AUC) were not significantly different, the two formulations were not bioequivalent. Tolerance was in both cases acceptable, with only a transient decrease in haemoglobin one day after last drug intake. The variability of chlorambucil pharmacokinetics tended to be less important for capsules than for tablets: 38% vs 71% and 35% vs 113% for Cmax and AUC respectively. Capsules are therefore likely to be more reliable than tablets for clinical use.

Aged↗
PubMed1994

Separation of fifteen non-steroidal anti-inflammatory drugs using micellar electrokinetic capillary chromatography.

Micellar electrokinetic capillary chromatography with sodium dodecylsulfate as anionic surfactant was used to separate simultaneously fifteen non-steroidal anti-inflammatory drugs. UV detection was performed at 254 nm. The electroosmotic flow was carefully adjusted for optimal separation. Resolution of the drugs was obtained using a buffer containing 40 mmol l-1 NaH2PO4, 0.104 mol l-1 sodium dodecylsulfate and 3% (v/v) methanol, adjusted to pH 8 with sodium hydroxide. Lack of interference was checked with a number of drugs and metabolites. Between-day coefficients of variation ranged between 2 to 10%.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

Modeling of the saturable time-constrained amoxicillin absorption in humans.

Amoxicillin pharmacokinetics was modeled using a two-compartment disposition model and a saturable time-constrained absorption model with a storage compartment. The absorption model parameters estimated by the nonlinear regression are: a rate constant of the systemic input, ksys, (median: 1.31 h-1, range: 0.79-7.01 h-1), a maximal absorption rate, Vmax (median: 1407 mg/h, range: 703-4181 mg/h), an account corresponding to the half maximal rate, Kma, (median: 1077 mg, range: 235-4376 mg), time of the absorption cessation, Tabs, (median: 1.72 h, range: 0.82-4.53 h) and absorption lag time. Tlag, (median: 0.085 h, range: 0-0.123 h). It was shown, that the first-order absorption parallel to the saturable process is negligible in the dose range studied. The model described well the dependence of areas under concentration-time curves on the dose determined in several earlier studies. It was used also to predict the fraction of the amoxicillin dose absorbed for different doses. Simulations performed over a wide dose range (50-10000 mg) demonstrated that the fraction absorbed decreases nonlinearly from 90% at 50 mg to 22% at 10000 mg and strongly depends on the duration of the absorption period.

Absorption↗
PubMed1994

The concentration-effect relationship of quinine-induced hearing impairment.

Quinine-induced reversible hearing impairment at the frequencies of 1000 and 2000 Hz was investigated in healthy volunteers to analyze the plasma concentration-effect relationship of the drug. Six subjects were given two identical oral doses of quinine and a constant rate infusion of quinine over 6 hours (15 mg.kg-1) on three separate occasions. A simple pharmacodynamic model, E = k.C gamma (in which E is effect, k is a proportionality constant, C is drug concentration, and the exponent gamma is a fitting parameter), was found to describe well the relationship between hearing impairment and quinine concentrations in a hypothetical effect compartment. No statistical differences were found in the estimated parameters when the three dosings were compared, indicating that quinine-induced hearing impairment is independent of route of administration. The first-order rate constant (keo), linking plasma concentrations to the concentrations in the effect compartment, was (mean +/- SD) 0.71 +/- 0.19 and 0.99 +/- 0.37 hr-1 for 1000 and 2000 Hz, respectively. The corresponding values of k were 0.15 +/- 0.10 and 0.12 +/- 0.19 and the values of gamma were 2.13 +/- 0.57 and 3.44 +/- 1.04 for 1000 and 2000 Hz, respectively. Effect was also analyzed by semiparametric pharmacodynamic modeling, which gave results comparable to those obtained with the link model. We conclude that a simple power function is a reliable pharmacodynamic model for describing quinine-induced hearing impairment in healthy subjects.

Administration, Oral↗
PubMed1994

Is debrisoquine hydroxylation modified during acute viral hepatitis?

Drug metabolism in the liver may be decreased during liver diseases. However, the extent of impairment of specific isozymes of cytochrome P450 is largely unknown. We have studied the debrisoquine hydroxylation capacity of 17 patients with acute viral hepatitis and 106 unrelated healthy subjects. Debrisoquine metabolic ratio was increased in extensive metabolizers (EM) with acute viral hepatitis as compared with healthy EMs (median metabolic ratio: 1.20 vs 0.84, P < 0.05). However, there was no difference in phenotype prevalence between patients and controls. Our results suggest that acute viral hepatitis only has a marginal effect on the activity of CYP2D6 and that substrates of this enzyme may be given in normal therapeutic doses to this category of patients.

Acute Disease↗
PubMed1993

Dose proportional absorption of 25-150 mg atenolol.

We investigated the dose proportionality after the intake of oral atenolol 25, 50, 100 and 150 mg. Standard tablets were taken by 8 healthy volunteers in randomised order of doses. The area under the curve divided by dose did not differ between the doses, indicating that the absorption of this hydrophilic compound, with known incomplete bioavailability, was constant over the range tested.

Administration, Oral↗