Dose-response curve for torasemide in healthy volunteers

The safety and diuretic activity of torasemide (1-isopropyl-3- ([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea) were investigated in a phase I single-blind clinical study. After a pretreatment control day on placebo, a single dose of torasemide was administered orally according to an escalating dosage of 2.5, 5, 10 and 20 mg, respectively, in 4 groups of 3 healthy young male volunteers, after an overnight fast and 1 h before breakfast. The peak stimulatory effect on urinary volume was observed within 1 to 2 h and was followed by a gradual decline at the 3rd or 4th h back to or even slightly below the corresponding control values. Thus, the duration of action averaged 3-4 h and only moderate rebound effects were detected. This time-related diuretic activity perfectly fitted with the pharmacokinetics data since torasemide plasma levels peaked at the 1st h after drug administration and thereafter rapidly fell to less than 10% of the maximal plasma concentrations after the 4th h. While 2.5 mg torasemide showed only minor diuretic action, urinary volume and urinary excretion of sodium, chloride and calcium increased linearly with the logarithm of the dose during the first 4 h as well as during the whole 24 h period with 5, 10 and 20 mg torasemide. Conversely, the urinary density and osmolality fell progressively as the dose of torasemide increased. There was a trend towards a moderate decrease in urinary excretion of uric acid which seemed independent of the dose given. Finally, only minimal potassium urinary losses were observed without clear tendency towards an increase with increasing drug doses.(ABSTRACT TRUNCATED AT 250 WORDS)