N. Ferry

Increased serotonin platelet uptake after tianeptine administration in depressed patients

Tianeptine is a new antidepressant drug reported to enhance serotonin (5-hydroxytryptamine [5-HT]) uptake in rat brain. The effect of tianeptine on 5-HT platelet uptake was studied in 10 depressed patients treated for 28 days. Tianeptine increases Vmax of 5-HT platelet uptake during treatment without inducing any change in Km. As early as 2 hr after the first administration, Vmax increased significantly (+23%, alpha = 0.01). Although of a lesser magnitude, 5-HT platelet uptake remains increased after chronic administration (+14% on day 10 and +13% on day 28). This suggests that tianeptine affects 5-HT platelet uptake sites, either directly or via an action on modulators of 5-HT uptake. These results, in contrast with the action of other tricyclic antidepressants, confirm the original action of tianeptine on 5-HT platelet metabolism.

Determination of nalidixic acid and its two major metabolites in human plasma and urine by reversed-phase high-performance liquid chromatography

This paper describes a precise and sensitive method for analysis of nalidixic acid and its two major metabolites in plasma and urine following the oral administration of a therapeutic dose in humans. After addition of an internal standard (oxolinic acid), 1-ml samples of plasma or urine are extracted at acidic pH with chloroform. The extracts are purified by re-extraction with sodium hydroxide solution and then chloroform. The final extracts are evaporated to dryness, reconstituted in mobile phase and injected into a high-performance liquid chromatograph equipped with RP-8 column and UV detector operating at 254 nm. The limit of sensitivity of the method is lower than 0.5 micrograms/ml of plasma or urine for each compound. The applicability of the method to pharmacokinetic studies of nalidixic acid in humans is demonstrated.

Influence of hepatic impairment on the pharmacokinetics of nefazodone and two of its metabolites after single and multiple oral doses

Summary— The pharmacokinetics of nefazodone, a new antidepressant, and two of its active metabolites, hydroxynefazodone and m‐chlorophenylpiperazine, were determined after single and repeated oral escalating doses of 50, 100 and 200 mg, in healthy volunteers (n = 13) and patients with mild (n = 13) or severe (n = 6) hepatic impairment. All subjects were classified according to their dextromethorphan oxidation capacity. In healthy volunteers, nefazodone was rapidly absorbed after which the plasma concentrations declined with an apparent elimination half‐life ranging from 2.7 ± 1.7 h to 10.2 ± 4.4 h according to the dosage. Hydroxynefazodone appeared rapidly in plasma and its time‐course (half‐life ranging 1.4 ± 0.9 h to 6.5 ± 1.6 h) paralleled that of nefazodone, while mCPP showed low and variable concentrations. The disproportionately longer half‐life and more markedly increased Cmax and AUC0–48 which was observed with dosage and treatment duration, and moreover AUC0–12 at steady state significantly higher (P < 0.05) than AUC0–∞ after single dose demonstrated the non‐linearity of the pharmacokinetics of nefazodone and hydroxynefazodone. The constant molar AUC0–48 hydroxy‐nefazodone/nefazodone ratio (0.32 ± 0.04) and the close correlation (r2 = 0.95) between kinetic parameters of nefazodone and hydroxynefazodone suggest that nefazodone hydroxylation is not a saturable process. The kinetics of nefazodone and metabolites were significantly affected by severe but not by mild liver insufficiency. As a consequence, on a pharmacokinetic basis nefazodone should be used with caution in severely hepatic impaired patients.

Determination of piroximone in Plasma and urine by high performance liquid chromatography

Abstract A reversed-phase high-performance liquid chromatographic (HPLC) method with UV detection was developed for quantifying piroximone (PI) in plasma and urine. A solid phase extraction of PI simultaneously with an internal standard with an average recovery higher than 86% was needed to avoid endogenous interferences especially in urines from patients with reduced renal functions. The sensitivity limit was 2 ng/ml in plasma and 100 ng/ml in urine. The method was reproducible with intra- and inter-assay coefficients of variations below 7 %. This method was applied to the determination of plasma and urine levels during a pharmacokinetic study in healthy subjects and renally impaired patients. It was found suitable to follow the concentrations until 24 h after a single intravenous infusion of 0.5 mg/kg body weight of piroximone.

High-performance liquid chromatographic determination of cicletanide, a new diuretic, in plasma, red blood cells, urine and saliva

A sensitive, selective and easy to use high-performance liquid chromatographic method for the determination of cicletanide, a new diuretic, in plasma, red blood cells, urine and saliva is described. After extraction of cicletanide together with an internal standard with diethyl ether, or diethyl ether-n-hexane (20:80) for urine, the sample extracts are chromatographed with water-methanol-acetic acid (50:50:0.3) as eluent on to a Nucleosil C18 column. Both compounds are detected by their ultraviolet absorption at 280 nm. The calibration graph was linear between 0.2 and 20 micrograms/ml for plasma and between 0.2 and 5 micrograms/ml for the other biological fluids. The sensitivity limit was 20 ng/ml for plasma, red blood cells and saliva and 30 ng/ml for urine. The coefficients of variation of the between-day assays did not exceed 4.6% in plasma, 8.3% in red blood cells, 7.8% in urine and 4.2% in saliva for the lowest concentrations studied. The application of the method to a pharmacokinetic study of cicletanide after a single oral therapeutic dose in humans is reported.

Determination of Chlormezanone in Plasma and Urine by High Performance Liquid Chromatography

Abstract A reversed-phase high-performance liquid chromatographic (HPLC) method with UV detection was developed for quantifying chlormezanone in plasma and urine. an extraction step was needed to avoid endogenous interferences especially in urines and led to an average recovery of 90%. the sensitivity limit was 20 ng/ml in both plasma and urine. the method was reproducible with intra- and inter-assay coefficients of variations below 5%. This method was applied to the determination of plasma and urine levels during a pharmacokinetic study in the elderly. It was found suitable to follow the concentrations as long as 120 h after a single oral administration of 400 mg chlormezanone.

Predictive value of phase I studies: relevant criteria

Summary— Phase I studies cannot predict the therapeutic efficacy of a new drug. However, they can lead to important information concerning: i), the undesirable effects and their mechanisms of occurrence; and ii), the pharmacokinetics and the metabolism of the drug as well as their possible alterations in renal or hepatic diseases. When considering the therapeutic effects, 3 cases have to be considered which are, in order of decreasing predictive value: i), when a direct relationship is expected between the drug concentration in the body and its therapeutic effects (eg, antibiotics); ii), when the drug has a known molecular or cellular target which is directly involved in the pathophysiology of the disease (eg, renin inhibitors); and iii), when the drug does not have a known target or is directed toward a precise target which is not directly involved in the disease. In all these cases, a phase I study in healthy volunteers should be able to describe, at least qualitatively, the pharmacodynamic effects of the drug which are relevant to its therapeutic goal.

Influence of Renal Insufficiency on the Pharmacokinetics and the Renal Effects of Cicletanine

Cicletanide is a new antihypertensive agent with diuretic properties which have been postulated to rely partly upon the stimulation of the renal synthesis of prostacycline (1–2). In the present work, the kinetics as well as the effects of a single oral dose of cicletanine on the urinary excretion of electrolytes and of the metabolites of prostacycline and thromboxane A2 were determined in patients with varying degrees of renal function.