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Biomedical subjects

B Diquet

Publications and source records attributed to B Diquet.

At least 37 records · Page 2Linked to original sources
PubMed2000

Dehydroepiandrosterone replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects.

Dehydroepiandrosterone (DHEA; 50 and 25 mg) and placebo tablets were orally administered daily to 24 healthy aging men and women (67.8 +/- 4.3 yr) for 8 days according to a balanced incomplete block design. Nine blood tests on both the first and eighth days allowed the measurement of DHEA, its sulfate DHEAS, and metabolites: testosterone, 5alpha-androstan-3alpha,17beta-diol glucuronide, estradiol, and estrone. Relatively low background levels of DHEA(S) were observed, and with the reestablishment of "young" levels, four important results were obtained. 1) Blood DHEA had an apparent terminal half-life of more than 20 h, the same order of magnitude as that of blood DHEAS, a result explainable by back-hydrolysis of the large amount of DHEAS formed after oral administration of DHEA, a mechanism providing long-lived unconjugated DHEA and metabolites. 2) The metabolic conversion of DHEAS to DHEA was significantly greater in women than in men. 3) No accumulation of steroids was observed. 4) No worrying transformation to androgen and estrogen was recorded; indeed, the limited increased estradiol in aged women could be predicted to be beneficial. These results suggested that daily oral administration of DHEA (25/50 mg) is safe in elderly subjects. The 50-mg dose was chosen for a 1 yr, double blind, placebo-controlled trial of daily oral administration of DHEA in 60- to 80-yr-old individuals (DHEAge).

Aged↗
PubMed2000

Influence of Ramadan on the pharmacokinetics of a single oral dose of valproic acid administered at two different times.

This study was carried out in healthy volunteers in order to examine the influence of changes in eating and rest/activity rhythms during Ramadan on the pharmacokinetics of valproic acid (VPA; Depakine). A single oral dose of 800 mg was administered to the first group of subjects (n = 7) at 8:00 PM and to the second group (n = 5) at 5:00 AM. Each group was submitted to three treatment phases: the first was carried out 3 weeks prior to Ramadan (PR), the second one at the end of the first week of Ramadan (R1) and the last at the end of the third week of Ramadan (R3). The plasma kinetics of VPA were determined for each treatment schedule throughout the 50 h following drug intake. During Ramadan, a significant decrease was observed in the Cmax (56.22 +/- 5.32 mg/l in PR vs. 48.35 +/- 5.07 mg/l in R3; p < 0.05) and in the AUC(0.50 h) (1429.92 +/- 284.23 in PR vs. 1090.26 +/- 277.73 mg.h/l in R3; p < 0.05) for the 8:00 PM intake. For the 5:00 AM intake, a significant decrease was observed in the t1/2 (12.15 +/- 1.45 h in PR vs. 9.55 +/- 1.97 h in R3; p < 0.05) and AUC(0.50 h) values (1241.29 +/- 239.01 mg.h/l in PR vs. 1019.21 +/- 256.86 mg.h/l in R3; p < 0.05). These parameters showed a significant decrease at the end of the third week of Ramadan (R3), compared to the control period (PR).

Administration, Oral↗
PubMed1999

Liposomal encapsulation of ganciclovir enhances the efficacy of herpes simplex virus type 1 thymidine kinase suicide gene therapy against hepatic tumors in rats.

Suicide gene therapy based on ganciclovir (GCV) metabolism by transgene herpes simplex thymidine kinase (HSV-1 TK) has been used to selectively kill proliferating cells in clinical settings such as cancer, vascular restenosis, and immunological disorders. We investigated whether encapsulation of ganciclovir (GCV) into liposomes would improve its efficacy, especially against hepatic tumors. Large unilamellar liposomes containing GCV were prepared by reversed-phase evaporation. Pharmacokinetic studies in rats showed that, compared with free GCV, the intravenous injection of liposome-encapsulated GCV (lip-GCV) led to a faster decrease in GCV plasma concentrations, but higher liver-blood ratios. After treatment of syngeneic HSV-1 TK+ liver metastases in rats, histologically active tumors were found in 95% of the transplanted lesions when physiological saline had been given and in 50% when free GCV had been given at 90.2 microM/kg twice daily. This dose is known to be insufficient for the eradication of HSV-1 TK+ tumors. In contrast, only 5% viable tumors were found in rats receiving lip-GCV at this same concentration. Average tumor volumes were 19 +/- 15, 7 +/- 9, and <1 mm3 for the control, free GCV, and lip-GCV groups, respectively. GCV-related toxicity was no longer observed. The results demonstrate that liposomal encapsulation of GCV is feasible and significantly enhances its efficacy against HSV-1 TK+ hepatic tumors.

Animals↗
PubMed1998

A phase I/II study of herpes simplex virus type 1 thymidine kinase "suicide" gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma.

Despite extensive surgery for glioblastoma, residual tumor cells always lead to relapse. Gene therapy based on retrovirus-mediated gene transfer of herpes simplex virus type 1 thymidine kinase (HSV-1 TK), which specifically sensitizes dividing cells to ganciclovir (GCV) toxicity, may help eradicate such cells. During glioblastoma surgery, HSV-1 TK retroviral vector-producing cells (M11) were injected into the surgical cavity margins after tumor debulking. After a 7-day transduction period, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by MRI-based relapse-free survival at month 4 and by overall survival. Twelve patients with recurrent glioblastoma were treated without serious adverse events related to M11 cell administration or GCV. Quality of life was not negatively influenced by this treatment. Overall median survival was 206 days, with 25% of the patients surviving longer than 12 months. At 4 months after treatment, 4 of 12 patients had no recurrence; their median overall survival was 528 days, compared with 194 days for patients with recurrence (p=0.03 by the log rank test). One patient is still free of detectable recurrence, steroid free and independent, 2.8 years after treatment. Thus, brain injections of M11 retroviral vector-producing cells for glioblastoma HSV-1 TK gene therapy were well tolerated and associated with significant therapeutic responses. These results warrant further development of this therapeutic strategy in brain tumor, including recurrent glioblastoma.

Adult↗
PubMed1998

Rapid and simple micromethod for the quantification of fluindione in human plasma using high-performance liquid chromatography.

A new high-performance liquid chromatographic (HPLC) assay without any extraction procedure was developed for the quantification of fluindione in plasma using a 100-microl sample volume and coumarin as the internal standard. A deproteinization procedure was coupled with a reversed-phase HPLC separation using a 250x4.6 mm I.D. C18 column and a UV detector set at 280 nm. Peak height ratios were linear over the range 0.05 to 10 microg/ml (correlation coefficient >0.998). The method was found to be highly reproducible, as indicated by the low value obtained for the coefficient of variation: C.V. < or = 6.1% (n = 10). The limit of quantification, estimated under the described conditions at a signal-to-noise ratio of three and with a C.V. lower than 20% for precision and accuracy, was 0.025 microg/ml. The total turnaround time was 25 min. After storage of blood samples at concentrations of 0.1, 0.5 and 2.5 microg/ml at room temperature and exposition to light for 120 h, no degradation of fluindione occurred. This micromethod is simple (no extraction step), fast and currently is being used for drug monitoring.

Anticoagulants↗
PubMed1998

Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients.

OBJECTIVE: Fluindione is a vitamin K antagonist with a long half-life. This study was designed to investigate the pharmacokinetics and pharmacodynamics of multiple doses of fluindione in patients. METHODS: In a learning group of 49 patients who began fluindione treatment, blood samples were taken 12, 18, or 24 hours after one, three, and five doses. Concentration of fluindione, activity of clotting factors II, VII, IX and X, prothrombin complex activity (PCA), and international normalized ratio (INR) were measured. An indirect-response pharmacodynamic model was used for each effect. A comprehensive analysis was performed with a nonparametric population approach. The model was evaluated in 24 other patients: blood samples were taken 24 hours after two, three, four, and six doses; and PCA and INR were observed. RESULTS: Analysis of concentrations and clotting factor activities showed notably that (1) fluindione has a long half-life (median, 69 hours), and (2) concentration that inhibits the synthesis of the clotting factors by 50% varied for each factor, with a median ranging from 0.25 to 2.05 mg.L-1 for factors VII and II, respectively. The results obtained for INR and PCA were validated in the 24 subsequent patients. CONCLUSION: The population approach allowed the comparison of several pharmacodynamic submodels. This first application of the indirect-response model to multiple oral anticoagulant doses in patients confirmed that both the pharmacokinetics and the pharmacodynamics of fluindione show substantial interindividual variability.

Anticoagulants↗
PubMed1998

High-performance liquid chromatography with ultraviolet and fluorimetric detection for the simultaneous determination of tacrine, nimodipine, and their respective metabolites in the plasma of patients with Alzheimer disease.

A new high-performance liquid chromatography (HPLC) assay was developed for the simultaneous determination of tacrine (THA), nimodipine, and their three metabolites (MI, MII, and MIII) using a 1-ml plasma sample volume. A liquid-liquid extraction procedure was coupled with a reverse-phase HPLC separation. Quantification was performed by fluorometric detection for THA and metabolites and by ultraviolet detection for nimodipine and metabolites. Peak-height ratios were linear across the ranges 0.5 to 100 micro/l for THA and its three metabolites; 2 to 500 microg/l for nimodipine, MII, and MIII; and 4 to 500 microg/l for MI. Correlation coefficients were better than 0.998 for all compounds. Accuracy and precision were less than 12% for the entire concentration range for each substance. This method is sensitive and selective. Analysis of plasma samples collected from patients with Alzheimer disease demonstrated that the assay is suitable for clinical and pharmacokinetic trials including drug-drug interactions studies.

Alzheimer Disease↗
PubMed1998

Modeling INR data to predict maintenance fluindione dosage.

This study was designed to construct a pharmacokinetic/pharmacodynamic model describing the evolution of International Normalized Ratio (INR) under oral anticoagulation treatment by fluindione in patients and to develop a method for individualization of fluindione dosage. Three indirect response models describing the concentration-INR relationship were tested using a nonparametric estimation method. INR was modelled as a quantity being produced and eliminated. According to a log-likelihood ratio test, the evolution of INR was best modelled as an inhibition of its elimination by fluindione. The selected model was evaluated in 24 additional patients with INR measurements (after 2, 3, 4, 6, and 10 doses). Using a Bayesian method with data until day 4, INR was correctly predicted for days 6 and 10. The population characteristics of fluindione were estimated, pooling the two groups of patients. A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state. Prescription rules for fluindione were derived using this method retrospectively on the 73 patients in this study.

Anticoagulants↗
PubMed1997

Sensitive and rapid method for the simultaneous quantification of five antidepressants with their respective metabolites in plasma using high-performance liquid chromatography with diode-array detection.

A high-performance liquid chromatographic method with diode array detection (HPLC-DAD) has been developed for the simultaneous separation and quantification of imipramine, amitriptyline, maprotiline, fluoxetine, clomipramine and their respective metabolites using a 500-microl plasma sample and clovoxamine as the internal standard. The substances were eluted on a Symmetry C18 5-microm column (250x4.6 mm, I.D.). Full UV spectra from 200 to 450 nm were recorded on-line during the entire analysis and were automatically compared to spectra stored in a library. The quantification was performed at 226, 254, and 400 nm. Peak height ratios were linear over a concentration range of 10-3000 ng/ml: the correlation coefficient (r) was better than 0.998 for all substances at each wavelength. Acceptable coefficients of variation are demonstrated for both within-run and day-to-day assays. The method is simple, highly specific and currently being used for drug monitoring and toxicological studies in children and adult patients.

Amitriptyline↗
PubMed1995

Evaluation of cardiac beta 1-adrenergic sensitivity with dobutamine in healthy volunteers.

1. Evaluation of cardiac beta 1-adrenergic sensitivity in heart failure should provide instructive therapeutic as well as prognostic information. We set up a non-invasive test in healthy volunteers to evaluate beta 1-adrenergic reactivity using dobutamine as a preferential agonist. 2. The range of i.v. bolus doses was 3.2 to 12.2 micrograms kg-1. The test was well tolerated. The parameters that were most sensitive and best correlated to dobutamine doses were systolic blood pressure and the rate-corrected electromechanical systole (QS2i). The reproducibility of the test over 48 h and over 1 month was satisfactory for most parameters, with a mean variation coefficient ranging from 9 to 26%, and was better for QS2i than for heart rate. 3. Slope of log dose-response for heart rate and QS2i was similar with dobutamine and with isoprenaline, corresponding to stimulation of the same type of beta-adrenergic receptors (beta 1-subtype). This result was obtained despite a higher vagal stimulation with dobutamine. We conclude that the left ventricular contractile response assessed by QS2i provided the best parameter for evaluation of beta 1-adrenergic cardiac effects either with dobutamine or with isoprenaline. 4. In heart failure patients such a dobutamine test should allow separation of altered contractility and beta-adrenergic desensitization, since alteration of inotropic response to dobutamine should depend on both altered contractile function and adrenergic desensitization but heart rate response should only depend on the latter phenomenon.

Adult↗
PubMed1995

Is there a relationship between antipsychotic blood levels and their clinical efficacy? An analysis of studies design and methodology.

There are now more than 50 studies concerning neuroleptic blood levels and clinical outcome relationships. Haloperidol, the most studied, is the only antipsychotic permitting some conclusions. A number of authors suggest that the striking lack of agreement between different studies results from heterogeneity of their quality. Here, we have used a scoring system for assessing the quality of those studies. According to this system, none (0/14) of the studies having a score < 0.60 was able to show a therapeutic window, as compared to 53% (10/19) of those having a score > or = 0.60 (p = 0.002, Fisher exact test). Also, the studies able to identify the presence of a therapeutic window during haloperidol treatment were those having sample size > 20 (p = 0.06) and those whose patients were treated with fixed doses (p = 0.02). The diagnosis of schizophrenia in the studies seems not to be an exclusive condition, as compared with those also including schizophreniform and schizoaffective disorders (p = 0.12). Our qualitative analysis of haloperidol blood level publications seem to indicate that an upper limit may exist for haloperidol efficacy; values above this limit seem not to provide any supplementary clinical improvement and may even reduce therapeutic effect.

Antipsychotic Agents↗
PubMed1994

The pharmacokinetics and electrocardiographic effects of chloroquine in healthy subjects.

Chloroquine prophylaxis was administered to 3 healthy male volunteers at 100 mg base/day for 25 days, followed by the curative dose at 25 mg base/kg for 3 days. Subjects attained effective chloroquine (mean = 50 micrograms/l) and desethylchloroquine (mean = 17 micrograms/l) concentrations by the 3rd week of prophylaxis, underlining the need to start chloroquine prophylaxis two weeks before travel. On the second day of the treatment period, hourly electrocardiographic monitoring showed a diminution of the T wave and prolongation of the QTc interval, manifesting cumulatively during the 3 days' curative dose, but with no cardiac symptoms. A dose-dependent cumulative effect of chloroquine was demonstrated with higher blood concentrations during the treatment period. Electrocardiographic readings spontaneously normalized after the treatment period as drug concentrations diminished progressively.

Adult↗
PubMed1994

In-vitro tests on Philippine isolates of Plasmodium falciparum against four standard antimalarials and four qinghaosu derivatives.

In-vitro drug sensitivity tests were performed on Philippine isolates of Plasmodium falciparum between 1991 and 1993, using the radioisotope microdilution method. The success of the tests varied significantly with the level of parasitaemia, the source of the strains, the period that elapsed before culturing, and the detectable concentrations of antimalarials in the blood. There was a significant positive correlation between the IC50 values for chloroquine and artesunate and the level of chloroquine in the blood before testing. In the Philippines the sensitivity profiles of the standard antimalarials (chloroquine, quinine, mefloquine, and halofantrine) were less severe than those in other south-east Asian countries. Fairly low IC50 values were obtained for the qinghaosu derivatives artemisinin, artemether, arteether and artesunate. There was a positive correlation between quinine, mefloquine, halofantrine and some of the qinghaosu derivatives, and between the qinghaosu compounds themselves, raising the possibility of either cross-resistance or possible drug associations.

Adolescent↗