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Biomedical subjects

J L Pinquier

Publications and source records attributed to J L Pinquier.

At least 19 recordsLinked to original sources
PubMed2000

The acute effects of amisulpride (50 mg and 200 mg) and haloperidol (2 mg) on cognitive function in healthy elderly volunteers.

In this double-blind, placebo controlled, four-way cross-over trial in 16 healthy elderly volunteers, the acute effects of haloperidol 2 mg, amisulpride 50 mg and 200 mg, were assessed on a range of tests of cognitive function. On each study day, cognitive performance was assessed prior to dosing and at 2, 4, 6, 9, 12 and 24 h after dosing with the following tests from the Cognitive Drug Research computerized assessment system: simple reaction time, digit vigilance task, choice reaction time, visual tracking, Critical Flicker Fusion, body sway, numeric working memory, immediate and delayed word recall, word recognition and self-ratings of mood and alertness. Haloperidol showed a general tendency to impair performance, and although this did not reach significance compared to placebo, for two tasks there were significant impairments with haloperidol compared to amisulpride. Amisulpride 50 mg and 200 mg, was not associated with impairment. In fact, there was some suggestion of improvement over placebo on three measures. The timings of assessment were appropriate for the study compounds. Furthermore, in a recent study in which a smaller number of elderly volunteers was tested on the same cognitive assessment system, a clear profile of acute impairments of haloperidol 3 mg, was identified. This indicates that haloperidol 2 mg, is not a sufficient dose to affect cognitive function in the elderly, supporting the general absence of effects with this dose in the young. Thus, the general absence of cognitive impairments with amisulpride at the doses used in this study suggests that this compound does not impair cognitive function in the elderly.

Aged↗
PubMed1996

Inhibition of histamine-induced skin wheal and flare after 5 days of mizolastine.

Mizolastine is a new, nonsedating antihistamine providing satisfactory symptomatic relief in allergic rhinitis and urticaria. The purpose of this study was to use inhibition of wheal and flare formation after 2-mu g intradermal histamine injections as a measure of the antihistamine effect of repeated doses of mizolastine. Eight volunteers were enrolled in this four-arm, double-blind, cross-over, randomized study. Three dose levels of once-daily mizolastine (5 mg, 10 mg, and 15 mg) were compared with placebo during 5-day dose periods. Histamine tests were performed before drug intake on days 1 and 5, and then 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours after drug intake on day 5. All 3 doses of mizolastine were more effective than placebo in suppressing wheal and flare reactions, and the antihistamine activity was highest at both the 10- and 15-mg dose levels. The effect on the flare reaction appeared within 1 hour, reached a maximum effect 4 hours after administration, and persisted for as long as 24 hours. The relative changes in wheal and flare areas were correlated with mizolastine trough plasma levels on day 5. Safety was satisfactory in all groups. This study confirms that mizolastine is a rapid and potent antihistamine; and its long-lasting effectiveness indicates that a once-daily regimen is acceptable for clinical use.

Adult↗
PubMed1994

Administration of RU 486 for 8 days in normal volunteers: antiglucocorticoid effect with no evidence of peripheral cortisol deprivation.

New therapeutic indications based on the antiprogesterone action of RU 486 (Mifepristone) are emerging which require long term administration and raise the question of its safety because of the antiglucocorticoid action of the drug. A trial was designed to assess the antiglucocorticoid effect of RU 486, possible manifestations of peripheral cortisol deprivation, and the adrenocortical and corticotroph reserves. Ten normal male volunteers (aged 21-29 yr) were given RU 486 (200 mg/day) or placebo between 0800-0900 h for 8 consecutive days in a randomized, double blind, cross-over design, with a 1-month interval between the two periods. RU 486 induced overactivation of the pituitary-adrenal axis; baseline values (mean +/- SEM) before and at end of treatment were, respectively: 0800 h plasma cortisol, 147.3 +/- 15.5 and 257.6 +/- 8.8 ng/mL; 0800 h salivary cortisol, 5.8 +/- 1.2 and 15.2 +/- 0.8 ng/mL; nocturnal (2200-0800 h) urinary cortisol, 8.4 +/- 1.5 and 33.7 +/- 11.1 micrograms; and 0800 h plasma ACTH, 29.2 +/- 3.7 and 60.2 +/- 8.4 pg/mL. All of these variations were significantly different from those during placebo treatment (0.0001 < P < 0.03) and disappeared within 4 days after the end of treatment. A daily record of subjective clinical symptoms, body weight and temperature, blood pressure, and heart rate showed neither side-effects nor any significant variation during treatment. Blood electrolyte and eosinophil counts were unchanged; fasting blood glucose was slightly higher at the end of treatment (5.0 +/- 0.2 vs. 4.7 +/- 0.1 mmol/L; P = 0.04). The adrenocortical response to Cortrosyn (0.25 mg, im) was exaggerated during RU 486 treatment (P < 0.006): peak values before and at the end of treatment were, respectively: plasma cortisol, 272.5 +/- 15.2 and 347.1 +/- 20.6 ng/mL; and salivary cortisol, 17.0 +/- 2.2 and 31.1 +/- 3.1 ng/mL. Direct pituitary stimulation (100 micrograms ovine CRH, followed by 1 IU lysine vasopressin over 15 min) also induced exaggerated corticotroph and adrenocortical responses (P < 0.005); peak values before and at the end of treatment were, respectively: plasma ACTH, 147.7 +/- 24.6 and 254.0 +/- 41.3 pg/mL; and plasma cortisol, 231.6 +/- 7.3 and 319.2 +/- 12.3 ng/mL. These data show that 8-day treatment with 200 mg RU 486 daily induces a hormonally detectable antiglucocorticoid effect without clinical symptoms. This state results from reversible cortisol overproduction with preservation of adrenocortical and pituitary reserves.

Adrenocorticotropic Hormone↗
PubMed1993

[Behaviors at risk of the intravenous drug addicts and prevention of HIV infection].

Needle sharing and sexual behaviour were studied in 396 intraveinous drug addicts (IVDA). Only 20% stopped needle sharing and used condoms. They were 6% before 1990 and 23% after. Both preventive measures were adopted by 32 of 78 HIV positive and only 25 of 210 HIV negative IVDA. Attention is drawn on the need for specific measures for prevention of heterosexual transmission of HIV infection by IVDA.

Female↗
PubMed1993

Lack of effect of phenobarbital on ex vivo leukocyte oxidative metabolism in healthy volunteers.

Oxidative metabolism in activated human polymorphonuclears catabolizes leukotriene B4 by a cytochrome P450 omega-hydroxylase and procainamide by a myeloperoxidase. The percentage of leukotriene B4 metabolized by activated human polymorphonuclears and the apparent enzymatic parameters of procainamide metabolism were studied ex vivo in six healthy volunteers before and after phenobarbital intake (100 mg/day) for 10 days and in six healthy control volunteers. No differences were found between groups for the difference in percentage of leukotriene B4 metabolized between day 11 and day 1. The apparent enzymatic parameters, Km and Vm, of procainamide oxidation did not differ significantly between the groups both on day 1 and day 11. These results do not show any evidence of inducibility of leukotriene B4 and procainamide metabolism in human polymorphonuclears. However, a positive correlation between 6 beta OH-cortisol excretion and percentage of leukotriene B4 metabolized was observed on day 11. This study suggests that human polymorphonuclears cytochrome P450 leukotriene B4 omega-hydroxylase and procainamide metabolism is not a useful method to study cytochrome P450 induction in clinical pharmacology.

17-Hydroxycorticosteroids↗
PubMed1991

Inhibition of ex-vivo PAF-induced platelet aggregation by the PAF-antagonist RP 48740: relationship to plasma concentrations in healthy volunteers.

RP 48740, 3-(3-pyridyl)-1H,3H-pyrrolo [1,2-c] thiazole-7-carboxamide, a specific competitive PAF-receptor antagonist in vitro, was given to 29 healthy male volunteers for 7 days. Plasma drug concentrations and ex-vivo PAF-induced platelet aggregation were assessed on Days 1, 4, and 7. RP 48740 had linear pharmacokinetics after single and repeated doses. It caused stable inhibition of PAF-induced platelet aggregation in a dose-dependent manner. The effect disappeared within 24 h, even after 7 days of repeated doses. The effect of RP 48740 displayed a sigmoidal relation to the plasma drug concentration; I50 2.3 (0.3) mg.l-1. There were no clinical or biological adverse reactions to RP 48740 during the study.

Administration, Oral↗
PubMed1990

[Diagnosis of cerebral toxoplasmosis in AIDS patients. Value of antibodies evaluation in cerebrospinal fluid].

The purpose of this study was to evaluate the diagnostic value of search for intrathecally synthesized specific antibodies in cerebral toxoplasmosis. Intrathecal synthesis of antibodies was measured by calculating the immunity load coefficient (ILC) in both serum and cerebrospinal fluid. In this retrospective study the records of 42 AIDS patients with clinically on the basis of computerized tomography and therapeutic results, and was excluded in 31 patients (control group). Specific immunoglobulins G were found in the cerebrospinal fluid of 9 out of the 11 patients with toxoplasmosis, but also in 14 of the 31 controls. Since ILC measurements in serum and cerebrospinal fluid identified 7/11 cases other hand, since the ILC value was higher than the positivity threshold in controls, the specificity of the test was assessed at 68 percent.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Pharmacodynamic without pharmacokinetic interaction between cicloprolol, a partial beta 1-adrenoceptor agonist, and digoxin in healthy subjects.

1. Cicloprolol is a partial beta 1-adrenoceptor agonist considered for the treatment of patients with coronary artery disease and impaired left ventricular function. In such patients, digoxin remains in widespread use. 2. We assessed the pharmacokinetic and pharmacodynamic interaction between oral cicloprolol 50 mg day-1 and oral digoxin 0.25 mg day-1 in 10 healthy male volunteers, using a double-blind, randomised protocol, during three 8 day periods. Digoxin was given alone during the first period to reach steady state; then digoxin was given with cicloprolol or placebo during the second and third periods, according to a cross-over design. 3. No significant adverse effects were observed. 4. The pharmacokinetics of digoxin were not different significantly at the end of the placebo-digoxin and cicloprolol-digoxin periods. 5. A significant increase in minimum heart rate and mean nocturnal heart rate, assessed by 24 h Holter recordings, was observed at the end of the cicloprolol-digoxin period as compared with the placebo-digoxin period (means +/- s.e. mean, 57.1 +/- 3.2 beats min-1 vs 52.2 +/- 3.1 beats min-1, P less than 0.01; and 65.6 +/- 3.8 beats min-1 vs 59.9 +/- 3.9 beats min-1, P less than 0.01, respectively). 6. A significant increase in left ventricular ejection fraction and shortening fraction, assessed by echocardiography, was noted at the end of the cicloprolol-digoxin period as compared with the placebo-digoxin period (means +/- s.e. mean, 66.4 +/- 1.4% vs 61.3 +/- 1.2%, P less than 0.05; and 37.0 +/- 1.1% vs 33.3 +/- 0.9%, P less than 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Establishing a phase I unit: organisation.

The organisation of a phase I unit must take into account the safety, quality and scientific requirements of such studies. The clinical pharmacology unit demands a highly qualified staff, as well as intensive care equipment. The investigator, generally a clinical pharmacologist who coordinates the different tasks as a project leader, has often to initiate a fruitful collaboration with a specialised consultant staff in order to implement the studies.

Drug Evaluation↗
PubMed1989

Differences in the serum binding determinants of isradipine and darodipine--consequences for serum protein binding in various diseases.

1. Serum protein binding of isradipine and darodipine, and serum concentrations of alpha 1-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids (NEFA) were measured in three groups of patients, I: healthy subjects (n = 20); II: patients with inflammatory disorders (n = 15) and III: patients with hepatic insufficiency (n = 17). 2. AAG was increased significantly in group II patients (P less than 0.001) and decreased in group III patients (P less than 0.001); HSA was decreased significantly in group II and group III patients (P less than 0.001). 3. The free percentage of isradipine was decreased significantly in group II patients (P less than 0.05) and increased in group III patients (P less than 0.05) and multivariate analysis showed that these variations were inversely related to changes in AAG concentration. 4. The free percentage of darodipine was increased significantly in group II and III patients (P less than 0.05) due to a decrease in HSA concentration, as shown by multivariate analysis. 5. The changes in free serum percentages of isradipine and darodipine were inversely related to concomitant changes in the concentration of the serum protein for which they showed the highest affinity, AAG for isradipine and HSA for darodipine, respectively. 6. The unexplained variability in the binding data was greater when AAG was the major determinant of binding (isradipine).

Adult↗
PubMed1988

Binding of [3H]isradipine (PN 200-110) on smooth muscle cell membranes from different bovine arteries.

The binding of [3H]isradipine [( 3H]PN 200-110), a new dihydropyridine (DHP) calcium blocker on smooth muscle cell (SMC) membranes from different bovine arteries was saturable with comparable high affinities but different binding site densities (Bmax). The data were fitted to a model that provided a common estimation for the dissociation constant (Kd = 0.46 nM, SD = 0.03) but different Bmax values. Two groups of arteries could be distinguished, large-sized with high Bmax (aorta, 149 fmol/mg, SD = 4; intrapulmonary, 134 fmol/mg, SD = 4) and medium-sized with lower Bmax (mesenteric, 67 fmol/mg, SD = 2; internal carotid, 50 fmol/mg, SD = 2; renal artery, 29 fmol/mg, SD = 2). The Kd values were similar to those previously reported, but the Bmax value on aorta SMC was higher than usually reported with other DHPs, showing that isradipine was a high full antagonist of calcium channel. Our results also suggest that the increase in arterial compliance induced by DHPs will probably be more important on large-sized arteries than on medium-sized arteries because of higher DHP binding.

Animals↗
PubMed1988

Comparative binding of two closely related dihydropyridines (isradipine and darodipine) to serum proteins and erythrocytes.

The binding of the two drugs isradipine and darodipine, chemically related to dihydropyridines and potent calcium channel blockers, was studied in vitro to isolated plasma proteins, erythrocytes and human serum. The two drugs were strongly bound to serum proteins (up to 97%), mainly to human serum albumin (HSA), alpha 1-glycoprotein (AAG) and lipoproteins (VLDL, LDL and HDL). Their bindings to AAG were saturable with high affinity constants (isradipine 498,000 M-1, darodipine = 155,000 M-1; n = 1). The binding of these drugs to HSA, VLDL and HDL was unsaturable, but it was saturable on LDL. In blood the drugs partitioned in erythrocytes, 16% for isradipine and 14.8% for darodipine.

Binding, Competitive↗
PubMed1988

Pharmacological criteria for risk-benefit evaluation of NSAIDs.

Evaluation of new non-steroidal anti-inflammatory drugs (NSAIDs) must compare efficacy and toxicity with existing compounds. Real progress involves maintaining effectiveness while decreasing toxicity. It is relatively easy to assess the effects of NSAIDs in animal models, and to determine gastrointestinal toxicity. However, although the ratio of active and toxic doses in animals can be extrapolated to man, the approach is limited and the NSAID needs to be assessed in a clinical setting as early as possible. In France, a national survey system has reported a wide range of adverse effects related to NSAIDs and shown important differences between compounds. Overdosage may be one of the factors responsible for toxicity, therefore pharmacokinetic evaluation is useful. In some disease states e.g. rheumatoid arthritis, there is a higher possibility of saturation pharmacokinetics with some drugs. Other pharmacokinetic parameters of interest are half-life, functions limiting activity, and hepatotoxicity. Furthermore, different pharmacokinetic parameters are required for different forms of disease. In acute states, the NSAID should have a short half-life and low protein binding and vice versa in chronic states. An important goal is to develop more selective NSAIDs regarding mechanisms of action or distribution into diseased tissues.

Animals↗
PubMed1987

Effect of the binding of isradipine and darodipine to different plasma proteins on their transfer through the rat blood-brain barrier. Drug binding to lipoproteins does not limit the transfer of drug.

Brain extraction of two calcium channel antagonists, isradipine (PN 200-110) and darodipine (PY 108-068) was investigated using the carotid injection technique in rats. An inhibitor effect of binding to plasma proteins on the brain extraction was also investigated. Equilibrium dialysis at 37 degrees C showed that both drugs were highly bound to human serum proteins, including albumin, alpha-1 acid glycoprotein and lipoproteins. The free dialyzable drug fraction was inversely related to the protein concentration. The brain extraction of the drugs in the presence of either albumin or alpha-1 acid glycoprotein was inversely related to the protein concentrations in the presence of either albumin or alpha-1 acid glycoprotein, but it was higher than expected from the in vitro measurement of the dialyzable fraction. Despite a significant degree of binding to lipoproteins, no significant reduction in the brain extraction of the drugs was observed, regardless of the class or the concentration of lipoproteins. These data indicate that the amount of circulating darodipine or isradipine available for entry in a peripheral tissue such as brain exceeds the dialyzable fraction of drug. However, the in vivo exchangeable drug fraction still parallels the dialyzable fraction, except if the drug is lipoprotein bound.

Animals↗
PubMed1986

Role of alpha-1 acid glycoprotein, albumin, and nonesterified fatty acids in serum binding of apazone and warfarin.

Altered concentrations of serum proteins and nonesterified fatty acids (NEFAs) often accompany malignant diseases. Free fractions (fu) of apazone and warfarin were measured by equilibrium dialysis in serum samples obtained from 31 patients with cancer and 18 control subjects. Mean fu values of both drugs were significantly higher in the patient group. Multivariate analysis showed albumin, NEFA, and AAG for apazone and albumin, NEFA, and age for warfarin accounted for 60% and 63%, respectively, of interpatient variation in bound/free drug concentration ratios in the group of patients with cancer. The interactions of apazone and warfarin with AAG were further characterized; the more avid site had association constants of 4.5 X 10(5) and 2.3 X 10(5) L/mol, respectively. Finally, it is strongly suggested that when hypoalbuminemia is present and a drug binds to AAG with an affinity constant comparable to or higher than that to albumin, then fu will become dependent on the concentration of AAG.

Adult↗