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Biomedical subjects

P Jaillon

Publications and source records attributed to P Jaillon.

At least 181 records · Page 10Linked to original sources
PubMedDate not supplied

Low levels of lymphocyte MDR1 gene expression during early renal transplantation in patients treated with tacrolimus.

P-glycoprotein (P-gp) is a membrane efflux pump increasing the transport of drugs such as tacrolimus out of the cells. The aim of the study was to determine the kinetics of lymphocyte P-gp expression in patients treated with tacrolimus during the first 3 months following renal transplantation. Lymphocyte MDR1 gene expression was measured by semi-quantitative RT-PCR a few hours before transplantation, 3 weeks and 3 months after the graft. Lymphocyte MDR1 gene expression was low in all the 10 patients compared to 10 healthy volunteers: 0.30 +/- 0.07 arbitrary units (patients) vs. 1.74 +/- 0. 55 (healthy volunteers) (P = 0.0002). MDR1 gene expression decreased among the patients during the study: 0.28 +/- 0.12 (3 weeks later) and 0.12 +/- 0.09 (3 months later) (P = 0.006). We can conclude that lymphocyte MDR1 gene expression among patients before renal transplantation is low and remains low during the first 3 months following the graft.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Lymphocyte P-glycoprotein expression and activity before and after rifampicin in man.

It has recently been shown that P-glycoprotein (P-gp) is inducible by rifampicin in the human gut as shown in intestinal biopsies. The present study was performed in order to test the hypothesis that human peripheral lymphocytes can be used to assess such an inducibility. We also assessed inter- and intra-individual variability of P-gp expression and activity in peripheral lymphocytes. Blood samples from 13 healthy volunteers were collected 1.7, 14 and 19 days after inclusion. Rifampicin treatment (600 mg/day) was administered from day 15 to day 18. Lymphocyte P-gp expression was measured at the messenger RNA level by semi-quantitative RT-PCR and at the protein level by immunostaining flow cytometry. P-gp activity was determined by flow cytometry with rhodamine 123 efflux. Cytochrome P4503A4 (CYP3A4) inducibility was measured by comparing the urinary metabolic ratio of 6beta-hydroxycortisol/cortisol on day 14 and 19, Lymphocyte P-gp expression and activity was not induced by rifampicin, while it increased CYP3A4 activity from 5.0 +/- 4.0 to 22.9 +/- 16.6 (P < 0.001). There was a 3 - 4-fold inter-individual variability and a 3 - 44 % intra-individual variability of lymphocyte P-gp expression and activity. Peripheral lymphocytes are not an appropriate material to assess P-gp inducibility in humans. P-gp shows significant inter- and intra-individual variability in human lymphocytes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Clinical pharmacokinetics of prazosin.

Prazosin, a quinazoline derivative, is a peripheral vasodilator used in the treatment of arterial hypertension and more recently, congestive heart failure (CHF). Prazosin is extensively metabolised by the liver and has high first-pass metabolism and low oral bioavailability. In normal healthy volunteers, the time of peak concentration occurs between 1 and 3 hours after oral administration, with wide interindividual variations. The extent of oral absorption seems to be similar for different pharmaceutical forms and is not influenced by the presence of food in the digestive tract. Oral bioavailability of prazosin ranges from 43.5 to 69.3% (mean 56.9%). Prazosin is highly (92 to 97%) bound to human plasma proteins (albumin and alpha 1-acid glycoprotein) and the extent of binding is independent of the plasma concentration of the drug in the range of 20 to 150 ng/ml. Preliminary studies in humans indicate that pathways for biotransformation of prazosin are similar to those observed in the rat and dog. Only 6% of prazosin is excreted unchanged, mainly in the urine. The two main metabolites (0-demethylated) are almost completely excreted in bile. The time course of disappearance of prazosin from plasma after intravenous injecton indicates that prazosin disposition should be described by a model containing at least 2 kinetically distinct compartments. The mean elimination half-life is about 2.5 hours. After intravenous administration, the steady-state volume of distribution has been calculated to be 42.2 +/- 8.9L and the total body clearance 12.7 +/- 1.3L/h. In hypertensive patients with normal renal function, prazosin kinetics do not differ significantly from normals. However, prazosin disposition is modified in chronic renal failure and in congestive heart failure. In both cases, the plasma free fraction of prazosin is increased and plasma elimination half-life is longer. Prazosin kinetics may be expected to be altered in patients with liver diseases. Pharmacokinetic data do not suggest a mechanism to explain the disappearance of the first-dose effect during continued administration of prazosin. Although more investigation is needed to define prazosin kinetics in congestive heart failure and chronic renal failure, the available information about prolongation of elimination half-life, decreased protein binding and increased peak plasma concentrations suggest that prazosin dosage should be titrated cautiously in such patients.

Biological Availability↗
PubMedDate not supplied

[Phase I clinical trials].

OBJECTIVE: Phase I clinical trials consist in studying tolerance to new drugs administered for the first time to humans, the pharmacodynamics of these drugs in order to describing as clearly as possible their pharmacological mechanism of action, and their pharmacokinetics in order to determine the metabolic and excretory pathways involved in the human organism. IMPLEMENTATION: Phase I trials are conducted in healthy volunteer men and women. An exception is made for drugs with predictable toxic effects, for example anti-cancer drugs, which cannot be tested in healthy subjects. These trials are controlled by legal regulations clearly defined in the French law of December 20, 1988. CONTRIBUTION: Data collected from Phase I trails in humans are crucial for initiating phase II and III drug development trials to be conducted in patients and designed to obtain a satisfactory assessment of the new drug's risk/benefit ratio.

Antineoplastic Agents↗
PubMedDate not supplied

[Pharmaco-epidemiology: identification of needs, databases, and study quality criteria].

Reference data on pathologies, their management, risk factors and the use of drugs in real life is necessary. In France, there are no existing databases of a set of systematically recorded data which associate information on drugs and morbidity/mortality. In contrast, there are a great number of studies focused on pathologies, their management or on drugs. A directory that could identify these databases and a means of accessing them would be desirable. Pharmaco-epidemiology studies must answer epidemiologically specific quality criteria, which must be planned at study conception. The protocol must be developed with a scientific committee on which there are epidemiologically experienced people. It is a prerequisite that a committee of experts with epidemiological competence should give advice on the 'acceptability' of the protocol, that is on the aim and the methodology. Data collection must be the subject of specific quality control of both the study and its aims. Cross-checking with other sources of data is recommended when possible. The coordinator of each study must send a final report to investigators and publish the results.

Clinical Protocols↗
PubMedDate not supplied

[Good clinical practice in clinical trials: training clinicians,incentives to apply good clinical practice and assessment of compliance].

Fourteen years after the concept was created, it seemed important to assess how well investigators actually apply Good Clinical Practice. Various sources of information have revealed a general deficiency in their application: "investigation by the working group, Afssaps (French Agency for the Safety of Health-Care Products) inspections, industrial data". The deficiencies identified stem from different factors: lack of professionalization, lack of training, lack of motivation, the large numbers of poorly conducted studies. The working group drew up proposals intended to improve the training of investigators, to dissuade investigators from pursuing inadequate procedure and to verify the level of compliance. However in this respect, the investigator is not the only one at fault. Improved practice unavoidably requires better assistance on the part of the sponsors, more consistent supervision of monitoring, and greater vigilence by the authorities involved in the control and use of trials.

Clinical Trials as Topic↗
PubMedDate not supplied

[A new, rapid and robust genotyping method for CYP2C9 and MDR1].

Single nucleotide polymorphisms (SNPs) can significantly affect human phenotypes. Detection of allelic variant carriers has become a major goal for clinical pharmacologists in order to study phenotype-genotype relationships. However, there is a crucial need for rapid, and validated pharmacogenetic tests. The aim of the study was to validate a new fluorescence PCR strategy for cytochrome P450 2C9 (CYP2C9) and multidrug resistance gene (MDR1) genotyping. Results of CYP2C9 and MDR1 genotypes determined with reference techniques were compared to those obtained by allelic discrimination assays employing fluorescent TaqMan probes. Sixteen subjects carrying CYP2C9*2 and CYP2C9*3 allelic variants (heterozygous and homozygous) previously identified by sequencing and 55 subjects previously genotyped for MDR1 exon 26 (C3435T) SNP by conventional PCR-RFLP were genotyped with fluorescent PCR. Fluorescent PCR gave 100 % accuracy with the results obtained with reference genotyping strategies for each of the 3 SNPs. Genotyping results with fluorescent PCR repeated on three consecutive occasions remained constant over time for each of the 3 SNPs. Allelic discrimination assays based on fluorescent PCR gave entire satisfaction for CYP2C9 and MDR1 genotyping. This reliable genotyping strategy can be easily used in clinical practice and should be further developed for additional SNPs identification.

Alleles↗
PubMedDate not supplied

[Ventricular pro-arrhythmic effects of anti-arrhythmia drugs].

Ventricular pro-arrhythmic effects of antiarrhythmic drugs correspond either to an aggravation of a pre-existing arrhythmia or to the development of a new arrhythmia not yet observed for a patient. More easily inducible ventricular tachycardias (VT) take part in this latter category. The incidence of ventricular pro-arrhythmias is difficult to evaluate but should be close to 3 to 10% during antiarrhythmic treatments. Two main mechanisms can be involved in pro-arrhythmia: 1) reentry can cause sustained VT complicating a pre-existing cardiopathy when a sodium channel blocker is prescribed, 2) early post depolarizations can result in the occurrence of torsades de pointes complicating an antiarrhythmic treatment which prolongs ventricular repolarization and QT interval. The main risk factors of pro-arrhythmia are in the first case the existence of antecedents of VT or V fibrillation with an altered ventricular function and in the second case an important prolongation of QT with bradycardia and hypokalemia. The incidence of pro-arrhythmia should decrease when these risk factors are taken into consideration. However the diagnosis of pro-arrhythmia should be systematically evoked by clinicians since these unwanted side-effects can occur with any class Ia, Ic and III antiarrhythmic drug and any drug which prolongs QT. If this diagnosis is confirmed, the need for an antiarrhythmic treatment should then be systematically evaluated in any patient taking into consideration the benefit/risk ratio of the treatment.

Anti-Arrhythmia Agents↗
PubMedDate not supplied

[Pharmacokinetics of oral propafenone in patients with supraventricular arrhythmia].

The efficacy of propafenone (P), a class IC antiarrhythmic drug with weak beta-blocking properties was studied over a four day period in 10 patients with supraventricular arrhythmias (atrial fibrillation 7, flutter 1 and tachycardia 2). Group 1 included five patients (3M, 2F) who received 300 mg of P on days 1 and 4. Group 2 included five patients (4M, 1F) who received 600 mg on days 1 and 4. All the patients received 1200 mg/day on days 2 and 3. Pharmacokinetics parameters were calculated for the first and the final dosing. Half of the patients were converted to sinus rythm after a delay ranging from 12 to 55 h after the first dosing. The duration of arrhythmia was shorter and the left atrial diameter was significantly lower in the responder group than in the non-responders. No relationship was observed between clinical efficacy and dose or plasma concentration of P. After the first administration of P, major interindividual variability in pharmacokinetic parameters was observed. Seven patients correspond to the extensive metabolizer phenotype with t1/2 el less than 10 h (mean: 5.4 +/- 2.2 SD). In this group t1/2 el increased from day 1 to day 4 and the AUC final/AUC initial ratio ranged between 4 to 17.5. Three patients showed the non-extensive metabolizer phenotype with t1/2 el ranging from 12.4 to 13.7 h and a moderate increase in AUC over chronic dosing. Adverse effects (cardiac conduction abnormalities, visual and digestive disturbances) were observed in the 3 oldest patients (70-73 yrs).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗