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Ten healthy subjects received 10 mg oral enalapril (MK 421) daily for a period of 8 days. Renal clearances of electrolytes, urate and phosphate were monitored and factored for glomerular filtration rate, as measured by creatinine clearance, with particular emphasis on the first and eighth day of treatment. Apart from a fall of around 10% in creatinine clearance between 1-2 h on both days 1 and 8, GFR remained unchanged throughout the study. Fractional sodium excretion increased in a biphasic manner by approximately 50% over control between 1-2 h and 4-8 h on day 1. Significant chloruresis (+39.0 +/- 12.9%) and kaluresis (+26.5 +/- 10.3%) occurred between 4-8 h. Urinary pH increased between 0-1 h (+0.29 +/- 0.12; P less than 0.05), and between 4-8 h (+0.50 +/- 0.08; P less than 0.01). The biphasic saluretic effect was also seen between 1-2 h and 4-8 h on day 8. Enalapril caused significant increases in urate and phosphate excretion on day 8 of therapy. There was a biphasic increase in fractional urate excretion at 1-2 h (+28.1 +/- 6.9%; P less than 0.05) and at 4-8 h (+21.0 +/- 6.0% P less than 0.01). Significant phosphaturia (+36.8 +/- 5.2%; P less than 0.05) was also observed at 4-8 h on day 8. Urinary drug excretion was also biphasic; over the first 2 h the predominant drug form was unchanged enalapril, whilst the peak excretion of the diacid metabolite, enalaprilat, occurred at 4-8 h.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The effects of indacrinone (IND) have been investigated in a two part study. First, a total of 36 clearance studies have been performed in 14 healthy volunteers, under conditions of either maximal hydration or hydropenia, to compare the renal sites of action of single oral doses of IND, 20 mg, ethacrynic acid (EA), 100 mg, and hydrochorothiazide (HCTZ), 100 mg. Under conditions of maximal water hydration, IND increased fractional Na+ excretion from a mean of 1.19 +/- 0.05 to 4.93 +/- 0.67% of GFR. This was similar to the response seen with HCTZ, which increased fractional Na+ clearance up to 3.16 +/- 0.17% of GFR; EA increased fractional Na+ excretion up to 14.5 +/- 2.5% of GFR. The mean reduction in fractional free-water clearance (CH2O/GFR X 100%) invoked by IND, (delta = −34.8% of control) was similar to that produced by EA, (delta = −27.2% of control), and by HCTZ, (delta = - 26.6% of control). During hydropenia with superimposed mannitol diuresis, both IND and EA caused a fall in fractional free-water reabsorption (TcH2O/GFR X 100%), delta IND = −20.3% of control, delta EA = −70.1% of control. HCTZ produced a significant increase in fractional free-water reabsorption, delta HCTZ = −20.7% of control. In all studies, single doses of IND were both uricosuric and hypouricaemic. Fractional urate excretion increased from a mean 6.7 +/- 0.1 to 15.2 +/- 2.1% of GFR whilst plasma urate concentration fell from a mean of 0.36 +/- 0.03 to 0.34 +/- 0.03 mM (P less than 0.05) within 2- 3 h post drug. HCTZ and EA, in single doses, had little effect on urate excretion. In the second part of the study, a total of 16 healthy volunteers received either IND, 10 mg, or HCTZ 50 mg, orally for 8 days, whilst on a diet of controlled electrolyte content. Both drugs were well tolerated by both sets of subjects with no adverse clinical or pathological findings. Both IND and HCTZ caused a significant reduction in weight and standing systolic blood-pressure during the first 48 h of therapy. At the doses administered, IND and HCTZ displayed similar diuretic responses with respect to water, Na+, Cl-, Ca2+ and PO4(3-) excretion. IND produced less kaliuresis than HCTZ during the first treatment day but cumulative K+ loss was similar for both drugs over the eight days of therapy. Fractional urate excretion after IND remained elevated throughout the 8 days of therapy and the subjects remained isouricaemic for 7 days.(ABSTRACT TRUNCATED AT 400 WORDS) [ABSTRACT FROM AUTHOR]

1 The renal action of indacrinone (MK-196), a phenoxyacetic acid derivative with diuretic and uricosuric properties, has been studied in fifteen male subjects. 2 Increasing single doses of up to 60 mg of oral indacrinone produced a linear increase in urinary volume and excretion of Na+ and Cl-, whilst the responses of urinary K+, Ca2+, Mg2+ and uric acid excretion, rose to a plateau at the 40 mg dose. 3 Indacrinone evoked a rapid diuretic response which reached a maximum of 2-4 h and was largely complete at 8-12 h after administration. 4 During maximal hydration, indacrinone produced a substantial fall in fractional free water clearance (CH2O), from 8.89% to 5.83% of the filtered load of water, associated with an increase in osmolal clearance, from 1.38% to 5.78% of the filtered load of solute. The reduction in CH2O was of the same order as that produced by a dose of ethacrynic acid with comparable saluretic activity and significantly greater than that produced by an equi-saluretic dose of hydrochlorothiazide. These findings imply an action of indacrinone upon solute transport in the diluting segments of the distal tubule. 5 At the time of maximal indacrinone-induced saluresis, which amounted to an increase from 0.48% to 4.61% of the filtered load of NaCl, fractional urate clearance increased from 5.16% to 12.24% of the filtered load of uric acid. 6 Indacrinone is a long acting diuretic, sharing some properties in common with both loop diuretics and benzothiadiazines. The results are discussed in relation to structure-activity amongst derivatives of phenoxyacetic acid. [ABSTRACT FROM AUTHOR]

Twelve healthy male volunteers received single daily oral doses of enalapril (EN) 10 mg for 8 consecutive days. Serum samples for prolactin (PRL) assay were taken on day 0 (baseline) at 12.00 h and 16.00 h, and on days 1 and 8 at 08.00 h (pre-drug), 12.00 h and 16.00 h. The 08.00 h values on day 1 served as the pre-drug baseline. There were no significant changes from baseline in serum PRL levels on days 1 and 8. All mean serum PRL levels on day 8 were significantly (P less than 0.01) lower than the upper limit of the normal range (2-15 ng/ml) found for healthy males in this laboratory. It is concluded that therapeutic doses of EN (10 mg/day, p.o.) for 8 consecutive days do not raise mean serum PRL levels above the normal range in healthy male volunteers. [ABSTRACT FROM AUTHOR]