On the clinical evaluation of diuretics with particular reference to a new phthalimidine diuretic, clorexolone

Abstract

A standardized technique suitable for clinical evaluation of diuretic drugs in hospitalized patients with fiuid retention is described. The sensitivity and reliability of the method have been explored. Urinary excretion of sodium, potassum, and fiuid, as well as acute weight loss have been employed as response parameters. The assay has been applied to yield data on the absolute and comparative efficacies of a newly introduced phthalimidine diuretic, clorexolone, in a group of fifty patients. Clorexolone was found to be a potent diuretic producing a pattern of water and electrolyte excretion similar to that caused by the benzothiadiazine group of diuretics. Its natriuretic action persisted for at least 48 hours after oral administration. A comparison of maximally effective doses of clorexolone and a standard benzothiadiazine derivative, hydrofiumethiazide, showed the two drugs to be essentially eqUipotent. Except for a rise in serum uric acid levels, no potentially adverse effects were observed during prolonged therapy with clorexolone and potassium supplements.

A single dose comparison of piretanide and bumetanide in congestive cardiac failure.

“…The early techniques of evaluating diuretics as described by Gold, Kwit, Messeloff, Kramer, Golfins, Greiner, Goessel, Hughes & Warshaw (1960) gave the test drug and a standard drug daily or every other day and assessed weight loss. This technique has been modified by Lant, Baba & Wilson (1966) to assess biochemical variables as well as weight. However only one day was allowed between treatments.…”

Effects of piretanide, bumetanide and frusemide on electrolyte and urate excretion in normal subjects.

“…Physiological homeostatic mechanisms are known to be stimulated in response to diuresis (Lant, Baba & Wilson, 1966). These mechanisms comprise increased tubular reabsorption of sodium ions in the proximal tubule of the nephron (Brenner & Berliner, 1969;De Wardener, 1969) and increased aldosterone secretion (Nicholls, Espiner, Donald & Hughes, 1974).…”

Bioassay of aldosterone antagonists in normal human subjects: a relationship between the level of plasma uric acid before treatment and apparent drug responses.

“…Steady state levels of spironolactone metabolites in plasma are achieved only after several days administration (Sadee, Schroder, Leitner & Dagcioglu, 1974), and in the clinical situation there is a similar delay in observing the peak pharmacological effect of spironolactone. The latter observation led to the suggestion that single dose bioassay methods are inappropriate for testing aldosterone antagonists (Lant et aL., 1966).…”

“…These workers used repeated doses of aldosterone antagonists over a three to five day period, and it has been suggested that the methods of bioassay using single doses of drug which are * approved name prorenoate potassium. commonly utilized in diuretic evaluation is inappropriate for the study of aldosterone antagonists (Lant, Baba & Wilson, 1966 (1) SC-23992, 50 mg (5 x 10 mg tablets) plps placebo spironolactone. (2) spironolactone, 125 mg (5 x 25 mg Aldactone A tablets) plus placebo SC-23992.…”