Enhancement of uricosuric properties of indacrinone by manipulation of the enantiomer ratio

Abstract

Racemic indacrinone is a high-ceiling, relatively long-acting diuretic. Both enantiomers have uricosuric activity, but the diuretic activity resides predominantly in the (-) enantiomer. Usual therapeutic doses of racemic indacrinone have only transient uricosuric activity, so that, as with other diuretics, hyperuricemia occurs. Sixty-five healthy men participated in a multicenter, double-blind, randomized, balanced, incomplete-block study comparing the effects on plasma urate and urate clearance of indacrinone (-) enantiomer 10 mg given concomitantly with 0, 10, 20, 40, and 80 mg (+) enantiomer (10/0, 10/10, 10/20, 10/40, 10/80), as single daily doses for 7 days. Hydrochlorothiazide (HCTZ) 50 mg daily and ticrynafen (T) 250 mg daily were controls. Each subject received two of the seven treatments, so that there were 18 subjects per treatment. On days 7 to 8, morning (mean of 0-hr values on days 7 and 8), HCTZ, 10/0, 10/10, and 10/20 elevated plasma urate by 8% to 16%. 10/40 was approximately isouricemic, and 10/80 and T lowered plasma urate by 13% and 41%. There were corresponding changes in urate clearance.

A new uricosuric diuretic, S-8666, in rats and chimpanzees.

“…Although the causes for the different responses among the tested animals are not clear, these differences sug gest that S-8666 should be classified as a different type of diuretic from indacrinone and furosemide. As reported by Tobert et al (20), the markedly diuretic effect of indacrinone made its uricosuric activity ineffective for preventing the incidence of hyperuricemia.…”

Enantiomeric drug development: Issues, considerations, and regulatory requirements

“…A good example is that of indacrinone. 33,34 The dextroenantiomer of indacrinone exhibits a strong diuretic action and also causes a retention of uric acid. However, the levo-enantiomer, completely negates the side effects of the eutomer because of its uricosuric properties.…”

A new diuretic that does not reduce renal handling of uric acid in rats, S-8666.

“…Uricosuric diuretics such as tienilic acid (3) and indacrinone (4) have recently been studied as such candidates. However, the results have shown the need for careful testing (5,6). In particular, the` fact that potent activity for hyperuricosuria does not always produce an iso or hypouricemic effect during use as medication, as found with indacrinone, has necessitated the more direct measurement of the hyperuricemic effect of diuretics.…”