Dose-Response Relationship of a Uricosuric Diuretic

Emmerson, B. T.; Thompson, L.; Mitchell, Keith

doi:10.1007/978-1-4684-3285-5_48

Cited by 4 publications

(8 citation statements)

References 1 publication

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“…The uricosuric response increased with increasing doses of indacrinone, up to a maximum at 40 mg (Figure 2b). These results differ from those of Emmerson et al (1977) who, whilst demonstrating a pronounced uricosuria in the 0-6 h post drug period, could only find an increase in urate excretion during 24 h at doses above 60 mg. Such contrasts may reflect differences in subject responsiveness, since Emmerson's study was carried out in Australia.…”

Section: Single Dose Metabolic Studycontrasting

confidence: 99%

“…Results are expressed as mean absolute excretion/period + s.e.mean (n = 4). (Figure 2a and 2b) (Baba, Lant & findings in this study, Emmerson et al (1977Emmerson et al ( ) 1965Fuchs, Bodi & Mallis, 1959 Changes in handling of uric acid after a single equivocal ( Table 1). The effect of loop diuretics on ose of indacrinone (10 mg).…”

Section: Single Dose Metabolic Studysupporting

confidence: 51%

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Studies on the mechanism and characteristics of action of a uricosuric diuretic, indacrinone (MK‐196).

Brooks¹,

Blair²,

Finch³

et al. 1980

Brit J Clinical Pharma

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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.

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Section: Single Dose Metabolic Studycontrasting

confidence: 99%

Section: Single Dose Metabolic Studysupporting

confidence: 51%

Studies on the mechanism and characteristics of action of a uricosuric diuretic, indacrinone (MK‐196).

Brooks¹,

Blair²,

Finch³

et al. 1980

Brit J Clinical Pharma

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“…Diuresis and saluresis were more marked and prolonged with MK-196 than with frusemide, and increased as the dose of MK-196 was increased from 20 mg daily to 80 mg daily (Emmerson, Thompson & Mitchell, 1977).…”

mentioning

confidence: 92%

“…However, the uricosuria was followed by urate retention, so that the overall 24-h renal excretion of urate was unchanged from baseline control (Emmerson et al, 1977). In a multiple-dose, metabolic balance trial in healthy volunteers, MK-196 (10 mg daily for 14 days) did not increase serum uric acid levels, but frusemide (40 mg daily for 14 days) did (Dziewanowska, Tempero, Perret, Hitzenberger & Besselaar, 1976 acid, creatinine, blood urea nitrogen, and fasting glucose.…”

mentioning

confidence: 96%

A double‐blind comparison of a novel indanone diuretic (MK‐196) with hydrochlorothiazide in the treatment of essential hypertension.

Ce¹,

Ja²,

Moerlin³

et al. 1979

Brit J Clinical Pharma

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1 The antihypertensive effect and tolerability of MK‐196 (10 mg and 15 mg daily) was compared to hydrochlorothiazide (HCT; 50 mg daily) in a 4‐ week multiclinic, double‐blind study involving 42 patients with mild to moderate, essential hypertension. 2 Both doses of MK‐196 were as effective and sometimes more effective than HCT in lowering standing and supine systolic and diastolic blood pressures. 3 HCT consistently brought about significant increases in serum uric acid and significant decreases in serum potassium; both doses of MK‐196 produced similar but less frequent and smaller changes in both of these parameters. 4 Both doses of MK‐196 brought about significant decreases in body weight at Weeks 3 and 4 of drug treatment. 5 Patients taking MK‐196 reported fewer adverse clinical reactions (10 mg = 15%; 15 mg = 13% than those taking HCT (21%). 6 MK‐196 may offer a therapeutic advantage over HCT as an antihypertensive agent for use in the treatment of mild to moderate, essential hypertension.

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“…has been shown to be both diuretic and significantly uricosuric in the chimpanzee [2] and thus had the potential of not causing the hyperuricemia so common ly seen with other diuretics. Initial studies with healthy human volunteers showed that the 10 mg dose was diuretic but had no overall effect on the plasma urate concentration [1], Accordingly, the question of whether there would be any dissociation between the uricosuric and the diuretic action with larger doses was an important question for human therapy.…”

mentioning

confidence: 99%

Uricosuric Response to Increasing Doses of the Indanone Diuretic MK-196 in Healthy Volunteers

Emmerson

Thompson

Mitchell

1979

Nephron

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Doses of 20,40,60 and 80 mg of the indanone diuretic MK-196 and 40 mg of frusemide were administered in random order to 5 healthy volunteers in a stable metabolic state, on the same day for 5 consecutive weeks. Diuresis, natriuresis and kaluresis increased with increasing doses, the natriuresis lasting for about 12 h and the kaluresis for about 24 h. Uricosuria increased with increasing doses of MK-196 and lasted for about 6 h. The uricosuria was followed by urate retention, so that there was little net change in the renal excretion of urate. Significant weight loss occurred, so that there was probably some associated plasma volume contraction, which would promote urate retention. By contrast, frusemide caused a reduction in renal excretion of urate at all times.

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Dose-Response Relationship of a Uricosuric Diuretic

Cited by 4 publications

References 1 publication

Studies on the mechanism and characteristics of action of a uricosuric diuretic, indacrinone (MK‐196).

Studies on the mechanism and characteristics of action of a uricosuric diuretic, indacrinone (MK‐196).

A double‐blind comparison of a novel indanone diuretic (MK‐196) with hydrochlorothiazide in the treatment of essential hypertension.

Uricosuric Response to Increasing Doses of the Indanone Diuretic MK-196 in Healthy Volunteers

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