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Biomedical subjects

A Mignot

Publications and source records attributed to A Mignot.

34 records · Page 2Linked to original sources
PubMed1992

Pharmacokinetics of 2-(alpha-thenoylthio)-propionylglycine (TTPG) in healthy volunteers--an oral dose-proportionality investigation.

The dose linearity of 2-(alpha-thenoylthio)-propionylglycine (TTPG) pharmacokinetics after a single oral administration at three different TTPG doses (180, 540 and 1080 mg) was evaluated in 12 healthy volunteers according to an open, randomized, cross-over study with a 1-week wash-out period between each administration. The duration of the study, for each subject, was 4 weeks. Plasma concentration and urinary excretion of TTPG and its two systemic metabolites, namely propionylglycine (tiopronin) and thiophenecarboxylic acid (TCA) were assayed by a previously well validated HPLC method. Due to differences in the physical and chemical properties of these compounds, two assays were needed, one to measure TTPG and TCA as such, and one to measure derivatized tiopronin. Both used UV detection. TTPG, tiopronin and TCA were quickly detected in plasma, suggesting that the drug administered is rapidly absorbed and biotransformed, in part, in the systemic circulation into the two metabolites noted above. Time-to-peak for all three analytes showed a trend to increase with increasing doses of TTPG, being: 0.42, 0.40 and 0.67 h (P < 0.01) with TTPG; 0.53, 0.47 and 0.73 h (P < 0.05) with TCA; and 1.33, 2.13 and 2.58 h (P < 0.01) with tiopronin. Cmax showed the opposite behaviour with values (ng ml-1) normalized to the dose of 540 mg: 1235, 905 and 513 (P < 0.001) with TTPG; 888, 547 and 383 (P < 0.001) with TCA; and 7290, 6950 and 5170 (P < 0.01) with tiopronin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

High-performance liquid chromatographic evaluation of 2-(alpha-thenoylthio)propionylglycine and its two metabolites in biological fluids.

A high-performance liquid chromatographic (HPLC) method for determining 2-(alpha-thenoylthio)propionylglycine (TTPG) and its two main metabolites, thiophenecarboxylic acid and thiopronine, in biological samples was developed. TTPG and its metabolites were extracted by solvent partition and then determined by reversed-phase HPLC with UV detection at 245, 295 and 360 nm. This procedure was validated in order to allow the assay of these compounds in plasma and urine samples with sufficiently low detection limits (50 ng/ml for TTPG and TCA and 100 ng/ml for thiopronine) and with good linearity within the concentration range investigated. It was applied to a comprehensive pharmacokinetic investigation of TTPG in healthy volunteers.

Chromatography, High Pressure Liquid↗
PubMed1991

Alteration of the inner surface of venous catheters by antineoplastic drugs.

Septic complications and thrombosis are frequent causes of long-term venous catheter implantation failure and tend to occur more frequently in oncology than in patients using catheters for hyperalimentation only. The purpose of this in vitro study was to study extensively the inner surface behaviour and the possible changes in their mechanical properties of various silicone and polyurethane catheters after exposure to a flow of the most common antineoplastic drugs. Silicone catheters appeared to be the best choice for cytostatic drug infusions because of their chemical stability, but the addition of an opacifier imposes a protective inner and outer layer to improve their surface properties for biocompatibility.

Antineoplastic Agents↗
PubMed1989

Mechanisms of chronotropic cardiac effects of alinidine and plasma concentration-response relationships in the conscious dog with chronic atrioventricular block.

The chronotropic cardiac effects of alinidine were studied in the conscious dog with chronic atrioventricular block. Alinidine at 0.5 - 4 mg/kg, i.e., at plasma concentrations between 42 +/- 2 and 1625 +/- 371 ng/ml, initially increased atrial rate dose-dependently. This effect fell off rapidly, but atrial bradycardia was never observed. After atropine and pindolol, which raised basal atrial rate, alinidine (2 mg/kg) decreased atrial rate, whereas after phenoxy-benzamine, yohimbine or phentolamine, it produced atrial effects identical to those observed under basal conditions, i.e., initial tachycardia and no bradycardia. Alinidine dose-relatedly decreased ventricular rate. None of the pretreatments modified the maximal ventricular bradycardia, but interestingly after pindolol or yohimbine this effect developed more rapidly (maximal bradycardia between 3 and 5 against 30 min) and then declined progressively. Alinidine did not modify mean blood pressure at any dose. After atropine, phenoxybenzamine or phentolamine, alinidine remained without effect on mean blood pressure, but after pindolol or yohimbine, a hypotensive effect appeared concomitantly with the reduction of the ventricular bradycardia. These results show that the initial atrial cardioacceleration due to alinidine results from a direct vagolytic action of this drug and that the absence of atrial bradycardia results from buffering by the vagolytic effect and/or a relatively low basal atrial rate. They also suggest that the ventricular bradycardia does not involve either the muscarinic cholinoceptors or the alpha- or beta-adrenoceptors, though the results obtained after pindolol or yohimbine suggest possible involvement of a fall in sympathetic tone by stimulation of presynaptic or central alpha2-adrenoceptors, particularly in the persistence of the bradycardic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1988

Pharmacokinetics of rilmenidine in healthy subjects.

Rilmenidine is a novel alpha 2-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once or twice daily. The pharmacokinetic parameters were investigated after single or repeated administration in healthy subjects, using labeled and unlabeled compounds. Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability factor close to 1 and a maximal plasma concentration achieved within 2 hours. Rilmenidine was not subject to presystemic metabolism. Distribution was independent of the free fraction because rilmenidine was weakly bound to plasma proteins (less than 10%). The volume of distribution was approximately 5 l.kg-1 (315 liters). Elimination was rapid with a total body plasma clearance of approximately 450 ml.min-1 and an elimination half-life of approximately 8 hours. Renal excretion was the major elimination process (two-thirds of the total clearance). Metabolism was very poor, with a renal elimination of rilmenidine as the parent drug (urinary fraction of rilmenidine was about 65% and no metabolite plasma levels were detected). Linear pharmacokinetics were demonstrated for rilmenidine from 0.5 to 2 mg but, at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linear disposition of rilmenidine with dose was confirmed.

Absorption↗
PubMed1987

Quantitative analysis of S3341 in human plasma and urine by combined gas chromatography-negative ion chemical ionization mass spectrometry: 15 month inter-day precision and accuracy validation.

A new quantitative assay for the determination of S3341, an alpha-2 agonist antihypertensive drug, has been developed using combined gas chromatography-negative ion chemical ionization mass spectrometry. The [M]-. ions from TFA derivatives of S3341 (m/z 276) and the internal standard (2H4)S3341 (m/z 280) are monitored simultaneously by selected ion monitoring. For S3341 concentrations ranging from the limit of detection (0.2 ng ml-1 using 1 ml of plasma) to 5 ng ml-1, the average assay precision (CV) is approximately 7% while the average assay accuracy (percentage of error) is 4%. Validation of the day-to-day precision and accuracy was realized after analysing control plasma samples (n = 295) concurrently with the biological samples collected during the pharmacokinetic studies conducted over 15 months. The average day-to-day precision (CV) and accuracy (percentage of error) are 10% and 6% respectively, thus indicating that this assay procedure routinely provides reliable analytical data.

Adrenergic alpha-Agonists↗
PubMed1986

[Comparative pharmacokinetics of piperacillin in young and elderly subjects].

One single 4 g dose of piperacillin was administered by intravenous infusion over 30 min to 15 patients aged from 66 to 90 years (mean +/- s.e.m.: 79.8 +/- 2.0 years); the patients mean weight was 53 +/- 4 kg. Fifteen samples of blood were withdrawn from each subject. Plasma piperacillin levels were measured by high performance liquid chromatography with detection in ultraviolet light at 214 nm. Mean plasma piperacillin concentrations in elderly subjects, measured 0.5, 2 and 12 h after dosing, were 168.5 +/- 15.7, 79.9 +/- 11.5 and 1.72 +/- 0.69 microgram.ml-1, as against 146.8 +/- 10.6, 35.5 +/- 3.9 and 0.212 +/- 0.040 microgram.ml-1 in healthy young adults. Plasma piperacillin concentrations versus time curves obtained after the infusion was discontinued were bi-exponential, with half-lives T1/2 (lambda 1) and T1/2 (lambda 2) of 0.65 +/- 0.11 and 1.72 +/- 0.09 h respectively; the corresponding figures in young adults were 0.59 +/- 0.03 and 1.81 +/- 0.13 h respectively). In elderly subjects the mean total clearance of piperacillin (ClT = 2.90 +/- 0.25 ml.min-1.kg-1) was reduced by 15% (NS) and the volume of distribution during steady state (Vdss = 0.337 +/- 0.027 L.kg-1) was increased by 43% (P less than 0.001). As a result, the mean time of piperacillin stay in the body (MRS = Vdss/Cl) was practically doubled in elderly subjects (2.09 +/- 0.15 h as against 1.15 +/- 0.04 h in young adults (P less than 0.01).

Adult↗
PubMed1984

Pharmacokinetic study of cefmenoxime (SCE 1365-CMX) in healthy adults.

Cefmenoxime pharmacokinetics were investigated in six healthy volunteers after intravenous and intramuscular administration of 0.5, 1, and 2 g. Blood and urine samples were analyzed by reversed-phase high-pressure liquid chromatography using ultraviolet detection at 275 nm. The assay is precise and linear up to 200 micrograms/ml-1, with 0.02 micrograms/ml-1 as the limit of detection. Linearity of cefmenoxime kinetics was demonstrated because the area under the plasma concentrations is proportional to studied doses. Eight hours after 1 g of cefmenoxime intramuscularly, mean plasma concentrations are, respectively, 0.6 +/- 0.1 and 0.3 +/- 0.1 microgram/ml-1. Intramuscular cefmenoxime is rapidly absorbed (Ka = 7.28 hours-1) with complete bioavailability (F = 0.99); apparent volume of distribution is 0.35 liters/kg-1 and elimination half-life 1.5 hours. The fraction of cefmenoxime excreted unchanged in the urine after intramuscular administration is 0.72, indicating a major contribution of renal clearance in total clearance. Experimental data after intramuscular administration were well fitted with a two-compartment model.

Adult↗
PubMedDate not supplied

Which bioequivalence study for a racemic drug? Application to milnacipran.

Milnacipran, a new non tricyclic antidepressant drug, is a racemic mixture (F2207) composed of two enantiomers: F2695 and F2696, both demonstrated to be active. A randomized open label, single-dose latin square study was undertaken in 24 healthy volunteers to compare, based on racemate data, the relative bioavailability of two new formulations to that of a reference formulation. Later on, as suggested by actual regulatory trend, analysis was carried out on enantiomer data, although in a supportive way. Bioequivalence was assessed on calculation of 90% confidence intervals for log-transformed Cmax and AUC(0-infinity) and on Wilcoxon test for Tmax with a 5% level of significance. Based on racemate data, both test formulations were demonstrated to be equivalent to the reference capsule in terms of Cmax and AUC-(0-infinity). Differences in Tmax reached statistical significance, although their mean magnitude was small, and probably not relevant when related to antidepressant long-term therapy. When considering the test capsule - reference capsule comparison, the equivalence demonstrated for the racemate reflect that of each enantiomer. On the contrary, equivalence between the test tablet and the reference capsule demonstrated for the racemate, is not supported by both enantiomers as Cmax of F2696 fails to reach bioequivalence criteria, making more uncertain the conclusion of bioequivalence. From this experience, it seems than when equivalence is demonstrated close to the limits for the racemate, it is difficult, especially for a low variability drug such as milnacipran, to comply with equivalence criteria for both enantiomers.

Adult↗
PubMedDate not supplied

[Pharmacokinetics of sulindac in aged patients presenting with inflammatory joint disease].

The kinetic of sulindac and its two metabolites (sulfide and sulfone) was investigated in twelve elderly patients, following multiple oral dose administration of 400 mg/d. Data were compared to those obtained previously in ten healthy volunteers who received the same dosage regimen. Following multiple dose administration, accumulation ratios indicate that sulindac do not accumulate either in elderly patients (R = 1.35; R = AUC0-24 J8/AUC0-24 J1) or in healthy young subjects (R = 1.38; R = U0-24 J1). No significant modification of sulindac and sulfide kinetic parameters was observed. The apparent bioavailability of the inactive metabolite, sulfone, was found to be doubled in elderly patients (p less than 0.05). We conclude that there is no need to modify the dosage regimen of Arthrocine (400 mg once a day) in elderly patients.

Administration, Oral↗