No abstract

Sibutramine HCl, a monoamine reuptake inhibitor type of antidepressant, was administered to healthy male volunteers as either a single dose (12.5 or 50 mg) or repeated treatment (5-20 mg once daily or 15 mg twice daily). Plasma, obtained at regular intervals during and after sibutramine HCl or placebo treatment, was assayed in vitro for its ability to inhibit the uptake of [3H]-noradrenaline (NA) by rat cortical synaptosomes, [3H]-5-hydroxytryptamine (5HT) by human platelets and [14C]-dopamine (DA) by rat striatal synaptosomes. After both single and repeated sibutramine HCl administration, the rank order of uptake inhibition was [3H]-NA greater than [3H]-5HT greater than [14C]-DA. The level of monoamine uptake inhibition increased on daily administration to a plateau 4-6 days after initiation of treatment, for example, approximately 60% and 40% inhibition of [3H]-NA and [3H]-5HT, respectively, following 15 mg sibutramine HCl twice daily. The pattern of monoamine uptake inhibition following sibutramine HCl administration to man is similar to that observed in sibutramine HCl-treated rats, and probably at least partly reflects inhibition of uptake by drug metabolites in both species. The inhibition of monoamine uptake following sibutramine HCl administration to man is consistent with an antidepressant effect.

The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49 465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49 465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49 465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49 465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60 degrees head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49 465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.

No abstract

The responses of urine and urinary solute outputs and flows to single doses of 80 mg furosemide, 25 mg hydrochlorothiazide, and 100 or 200 mg flosequinan were investigated in healthy subjects using a double-blind, randomized, crossover design. Treatment days were separated by 7 days. Volumes of urine passed between 0 and 3, 3 and 6, 6 and 9, 9 and 12, and 12 and 24 h after drug administration were determined and urinary concentrations of chloride, sodium, potassium, calcium, magnesium, phosphate, zinc, urate, urea and creatinine were measured. Venous blood was taken before and 6 and 24 h after dosing and the serum was analysed for the same solutes as urine. Excretions of urine and urinary solutes accumulated at the end of each collection period after each formulation were fitted by the UY function, whose derivative provided corresponding flows as functions of time. Instantaneous renal clearances of solutes 6 and 24 h after dosing were evaluated from the flows. This approach showed that 80 mg furosemide and 25 mg hydrochlorothiazide were equipotent 24-h natriuretics. Rapid urinary responses which then rebounded compared with the control responses were produced by 80 mg furosemide, whereas changes after 25 mg hydrochlorothiazide were smooth. Neither 100 or 200 mg flosequinan showed any important effect on urinary excretion.