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PubMed1982

Comparison of prorenoate potassium and spironolactone after repeated doses and steady state plasma levels of active metabolites.

1 After repeated single daily doses, the aldosterone antagonists prorenoate potassium and spironolactone were compared with regard to renal antimineralocorticoid activity, plasma potassium concentration and steady state plasma levels of their active metabolites, prorenone and canrenone respectively, in a balanced crossover study of twelve healthy subjects. 2 Following challenge with the mineralocorticoid, fludrocortisone, best estimates of the potency of prorenoate potassium relative to spironolactone were 3.6 (95% confidence limits 1.6-10.4) for urinary sodium excretion and 3.4 (95% confidence limits 2.0-6.5) for urinary log10 10Na/K. Estimates with respect to urinary potassium excretion and plasma potassium concentration were imprecise, confirming the limitations of the fludrocortisone model in the evaluation of aldosterone antagonists at steady state. 3 Both compounds exhibited directly proportional relationships between daily dose and steady state plasma levels of active metabolites. The approximate mean terminal elimination half-life of prorenone at steady state was 32.6 h (range 18-80 h).

Adolescent↗
PubMed1984

Relative potency of prorenoate potassium and spironolactone in attenuating diuretic induced hypokalaemia.

The plasma potassium responses to the aldosterone antagonists prorenoate K (10 mg/day and 40 mg/day) and spironolactone (25 mg/day and 100 mg/day) were compared following treatment for 11 days in combination with the diuretic metolazone (2.5 mg/day) in a double-blind crossover study in twelve healthy men. The best estimate of the potency of prorenoate K relative to spironolactone in attenuating metolazone induced hypokalaemia was 5.6 with 95% confidence limits 2.4-35.2. The method employed allowed a statistically valid quantitative comparison of the potassium sparing properties of the mineralocorticoid antagonists after repeated doses and may be useful in the preclinical evaluation of these drugs.

Adult↗
PubMed1988

Tolerance of spironolactone.

A survey of 54 patients taking spironolactone for hirsutes or acne showed that side-effects occurred in 91%; in 80% of patients, these were related to the anti-androgenic mechanism of the drug (menstrual disturbances, and breast enlargement and tenderness). The concomitant use of a contraceptive pill gave a lower incidence of menstrual abnormalities. Only seven patients (13%) had to stop the drug. In a further eight patients, a reduction in dose to between 125 and 175 mg daily achieved a compromise of controlling the disease and the side-effects. Side-effects tended to occur early and so regular review during the initial 3 months of treatment is advised. Two patients in our study developed 'chloasma'--a previously unreported complication of spironolactone. This was the only side-effect which occurred late in treatment.

Acne Vulgaris↗
PubMed1981

Combined captopril and spironolactone treatment in Conn's syndrome with renal impairment and refractory hypertension.

Spironolactone alone in full dosage failed to correct hypertension in a patient with Conn's syndrome and renal impairment, although the previously increased total exchangeable sodium fell to normal and the previously suppressed plasma angiotensin II did not rise above the normal range. Addition of the converting enzyme inhibitor captopril reduced plasma angiotensin II to very low levels, with a slight further fall in exchangeable sodium. Blood pressure was well controlled. Because hypertension in Conn's syndrome resistant to spironolactone usually also responds poorly to removal of the adenoma, and is difficult to treat with conventional hypotensive agents, the combination of a converting enzyme inhibitor with a potassium conserving diuretic is worthy of trial in such cases.

Adult↗
PubMed1985

The effect of spironolactone on hirsutism and female androgen metabolism.

An objective evaluation of the anti-androgen effects of spironolactone was performed in a consecutive series of 12 hirsute patients receiving a daily dose of 150 mg; nine completed the study. Using a computer assisted image analyser, hair diameter on two weekly shavings decreased significantly over a 12 month period in three of the patients, although growth rate and mean diameter did not change in the group as a whole. Plasma testosterone fell significantly to a mean of 53% of basal levels. The mean free testosterone (derived) fell significantly to 64% of basal by the sixth month (P = less than 0.005) and remained significantly depressed the remainder of the study. There was subjective benefit in hair growth and greasiness and a significant reduction in the semi-objective Ferriman-Gallwey index in nine of 10 subjects assessed for at least 9 months. We conclude that although spironolactone was not consistently successful, it may represent effective therapy for a sub group of patients with hirsutism.

Adolescent↗
PubMed1976

Renin unresponsiveness and the effects of oxprenolol, methyldopa and spironolactone in pateints with essential hypertension.

Plasma renin activity (PRA), supine, erect and post-frusemide (1 mg/kg IV) was studied in 51 patients with previously untreated essential hypertension and their age- and sex-matched normotensive controls. Supine PRA, and the rise in PRA in response to the erect posture and frusemide, were significantly less in hypertensives compared to controls. When the hypertensives were arbitrarily divided into lower, mid, and upper subgroups according to supine PRA, the renin responsiveness was similar in each subgroup but significantly less in hypertensives compared to controls, subdivided in the same way. This does not support the existence of a separate "low renin" subgroup. The low supine PRA and reduced response to stimulation appears to be a feature of patients with essential hypertension. Thirty-nine of these hypertensives entered a double-blind cross-over drug trial of oxprenolol, methyldopa and spironolactone. All three drugs were equally effective in lowering the systolic and diastolic blood pressures in all three renin subgroups. Spironolactone caused a greater fall in systolic pressure in the lower renin group than in the other groups. Oxprenolol was the best tolerated drug, with only 5% of patients withdrawing due to side-effects compared to 13% on spironolacone and 29% on methyldopa.

Adult↗
PubMed1997

Intestinal safety of water-soluble beta-cyclodextrins in paediatric oral solutions of spironolactone: effects on human intestinal epithelial Caco-2 cells.

Effects of water-soluble beta-cyclodextrins (beta CDs) on intestinal epithelial integrity were investigated, to establish the safe use of these beta CDs as solubilizers of spironolactone in paediatric enteral solutions. Mannitol permeability and transepithelial resistance (TER) of human intestinal epithelial Caco-2 cell monolayers during exposure to dimethyl-beta-cyclodextrin (DM beta CD), hydroxypropyl-beta-cyclodextrin (HP beta CD) and sulphobutyl ether beta-cyclodextrin (SBE beta CD) were followed. Staining methods were used to discern cells with damaged membranes and to study the integrity of cytoskeletal actin and tight junctions. Cytotoxicity of the beta CDs was tested by effects on intracellular dehydrogenase activity. Exposure to HP beta CD and SBE beta CD solutions had only minor effects on the integrity of Caco-2 cell monolayers. In contrast, DM beta CD clearly increased the epithelial permeability for the hydrophilic marker [14C]mannitol across Caco-2 monolayers, decreased TER and showed a dose-dependent cytotoxicity. According to staining, DM beta CD increased the permeability of the apical cell membrane without discernable effects on cytoskeletal actin. HP beta CD and SBE beta CD appear to be safe additives for use in enteral spironolactone preparations with respect to their acute local effects on epithelial integrity.

Administration, Oral↗
PubMed1975

Stimulation by aldosterone of the sodium efflux in barnacle muscle fibres: effects of RNA inhibitors and spironolactone.

1. Single muscle fibres from the barnacle Balanus nubilus have been studied to provide information about the mode of action of aldosterone on Na transport in a symmetric cell. 2. Neither internal nor external application of aldosterone modified the course of the Na efflux. However, fibres pre-exposed overnight to a dose of aldosterone showed a biphasic response to external aldosterone. The first phase was prompt in onset and consisted of a falling rate constant for Na efflux becoming a constant. This has been interpreted as indicating that aldosterone acts by releasing sequestered or bound Na. The second phase was delayed in onset with the average latent period being 68 min. It consisted of a step-up in the rate of Na efflux, followed by a transitory rise in the efflux rate constant. This second phase was dose-dependent, the minimum concentration being 10(-9) M. 3. Internal application of aldosterone in a concentration as low as 10(-10) M promptly stopped the rate constant for Na efflux from further falling but failed to cause delayed stimulation. 4. The response of the Na efflux into Li-ASW following external application of aldosterone was bi-phasic. The magnitude of the delayed stimulation was comparable to that found in controls. 5. No correlation between latent period or size of the internal Na bound fraction, and the magnitude of the delayed stimulation could be established. 6. Internal application of actinomycin-D, alpha-amanitin or cordycepin shortly before application of external aldosterone caused complete abolition of the delayed stimulation. 7. Overnight pre-exposure of the barnacle to actinomycin-D caused complete abolition of the falling rate constant for Na efflux, as well as the delayed stimulation caused by external aldosterone. 8. Internal application of spironolactone SC-14266 shortly before external application of aldosterone caused complete abolition of the biphasic response to the steroid. 9. It is concluded that (i) barnacle fibres can be made sensitive to aldosterone, (ii) the biphasic effects on the Na efflux depend on prior induction of RNA, (iii) the first effect caused by internal or external aldosterone involves mobilization of sequestered Na, (iv) the results obtained with spironolactone are in keeping with the current view that aldosterone interacts with a receptor system before causing de-repression. 10. The implications of the finding that aldosterone releases sequestered Na are briefly touched upon.

Aldosterone↗
PubMed1973

Preparation of metabolites of spironolactone by microbial oxygenation.

It has been postulated that 3-(3-oxo-7alpha-methylthio-4-androsten-17alpha-yl)propionic acid gamma-lactone (I) is a key intermediate in the metabolism of the anti-aldosterone agent, spironolactone (3-[3-oxo-7alpha-acetylthio-17beta-hydroxy-4-androsten-17alpha-yl] propionic acid gamma-lactone). In the present study it was found that microbial oxygenation of I by Chaetomium cochloides QM 624 gave three metabolites which retained sulfur in their molecules and were found to be identical to the human metabolites of spironolactone.

Ascomycota↗
PubMed1975

Potassium metabolism in patients with rheumatoid arthritis. Effects of treatment with depot tetracosactrin, spironolactone, and oral supplements of potassium chloride.

(1) Plasma and urine electrolytes and whole body potassium have measured before and after a 2-week administration of depot tetracosactrin 0.5 mg on alternate days to eight patients with rheumatoid arthritis (RA.) The effects of adding supplements of potassium chloride (48 mmol/d) and spironolactone 200 mg daily have been investigated. (2) Acute changes in red blood cell water and potassium content, plasma electrolyte concentration, and plasma 11-hydroxycorticosteroid levels were measured for 48 hours after a single intramuscular injection of 0.5 mg depot tetracosactrin in six patients with RA. (3) The measured total body potassium was significantly less than that predicted from the height, weight, and age formula in patients with RA. (4) Treatment with depot tetracosactrin resulted in an acute fall in plasma and red cell potassium independent of external potassium loss. (5) Two weeks of treatment with depot tetracosactrin resulted in hypokalaemia and a rise in plasma sodium and bicarbonate. There was no associated electrocardiogram changes or a rise in blood pressure. (6) Neither oral potassium supplements nor spironolactone altered total body potassium. (7) The significance of the findings and the physiological mechanisms underlying them are discussed.

Adult↗
PubMed1979

Comparison of natriuretic, uricosuric, and antihypertensive properties of tienilic acid, bendrofluazide, and spironolactone.

The antihypertensive properties of the new diuretic tienilic acid were investigated. Thirteen previously untreated hypertensive patients took part in a double-blind crossover study in which 30 days' treatment with tienilic acid 250 mg, bendrofluazide 5 mg, and spironolactone 100 mg were compared. Bendrofluazide caused the greatest natriuresis on the first treatment day and the most rapid fall in blood pressure. The ultimate antihypertensive effect of all three drugs was similar. Tienilic acid caused a noticeable reduction in serum urate concentrations and a rise in urate clearance, in contrast to the other two agents, which caused slight urate retention. Tienilic acid and bendrofluazide caused falls and spironolactone a rise in plasma potassium concentrations. No untoward effects were seen from any of the drugs. It is concluded that tienilic acid is a moderately potent diuretic that lowers plasma urate concentrations. It may be the drug of first choice for hypertensive patients who already have gout or are likely to develop it when taking thiazide diuretics.

Bendroflumethiazide↗
PubMed1993

Type IV renal tubular acidosis and spironolactone therapy in the elderly.

Spironolactone therapy is a well-known cause of hyperkalaemia, but in susceptible patient, it may also be associated with metabolic acidosis. We report a case of severe renal tubular acidosis (Type IV) with life-threatening hyperkalaemia caused by spironolactone, and discuss the mechanisms by which this may occur.

Acidosis, Renal Tubular↗
PubMed2001

Effects of spironolactone and fosinopril on the spontaneous and chronic ventricular arrhythmias in a rat model of myocardial infarction.

We documented chronic ventricular arrhythmias in a first group of 58 rats after myocardial infarction (MI), then assessed the effects of spironolactone and fosinopril on morphological indexes and arrhythmias in a second group (n = 33). Rats underwent Holter monitoring at 2 months after MI. Treatment was randomly given from 1 until 4 months after MI: placebo in 12 rats (P), fosinopril in 9 (F) and spironolactone + fosinopril in 12 (SF). The score of ventricular premature beats (VPBs) was related to the MI size and the delay from MI (p < 0.01). VPB's reduction/increase required to demonstrate anti/pro-arrhythmic effects were 55 and 59%. Mass indexes were lower in F and SF (p = 0.01). VPB's difference (4 months vs. 1) was positive in P, significantly lower in F and negative in SF (p = 0.04). In this relevant model of spontaneous and chronic ventricular arrhythmias, SF association did not increase mortality but lowered the arrhythmic score.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Effect of chronic treatment with clonidine and spironolactone on cold-induced elevation of blood pressure.

The present study was designed to determine whether antihypertensive agents known to affect the renin-angiotensin-aldosterone (RAA) system might affect the elevation of blood pressure induced by chronic exposure to cold. Spironolactone, a mineralocorticoid receptor blocker, was added to the food and administered to rats chronically exposed to cold. In addition, clonidine, and alpha 2-adrenergic agonist and inhibitor of renin secretion, was administered to another group of cold-exposed rats by daily intraperitoneal injection. A warm-adapted and a cold-treated control group were also used. Chronic administration of spironolactone prevented the development of hypertension but failed to prevent other adaptive physiological changes characteristically occurring during exposure to cold and seen in the cold-treated control rats. Thus, increased weight of the heart, kidneys, adrenals and brown adipose tissue, increased dipsogenic responsiveness to angiotensin II, increased urinary outputs of norepinephrine and epinephrine, and increased food and water consumption were observed in all rats, treated and untreated, during exposure to cold. Similarly, daily injection of clonidine attenuated the elevation of blood pressure but also failed to prevent the other adaptive physiological changes characteristic of cold. These results are consistent with the hypothesis that the RAA system plays a role in the development of the cold-induced elevation of blood pressure.

Aldosterone↗
PubMed1985

Importance of plasma aldosterone concentration on the natriuretic effect of spironolactone in patients with liver cirrhosis and ascites.

23 cirrhotics with ascites and sodium retention, whose aldosteronemia had been evaluated after an equilibration period at controlled sodium intake at the occasion of previous studies, were retrospectively investigated. The dosage of spironolactone needed to induce a negative sodium balance correlated significantly with plasma aldosterone concentration: r = 0.64; p less than 0.001. However, in cases with plasma albumin concentration less than 3 g/dl, glomerular filtration rate less than 80 ml/min, and plasma sodium concentration less than 136 mmol/l such a relationship was no longer significant. The diuretic response to spironolactone is mainly linked to plasma aldosterone concentration. Factors affecting the removal of ascites from the peritoneal cavity and renal sodium handling can influence the expected diuretic response to the drug.

Aldosterone↗
PubMed1995

Left ventricular fibrosis in renovascular hypertensive rats. Effect of losartan and spironolactone.

Myocardial fibrosis resulting from arterial hypertension alters myocardial structure and function. Myocardial fibrosis is characterized by a pathological accumulation of types I and III collagens. We used an aldosterone antagonist (spironolactone) and an angiotensin II antagonist (losartan) to elucidate the respective role of these hormones and hypertension in the development of myocardial fibrosis in the Goldblatt model of two-kidney, one clip hypertension in the rat. Fibrosis was assessed by computer-assisted morphometry in the interstitial space, around coronary arteries, in microscar areas, and on left ventricular sections stained with Sirius red and by biochemical techniques. Morphometry was performed with both standard light and polarization microscopy; this latter method was used to quantify yellow-red and green collagen fibers. Concurrently, type I and type III collagen mRNAs were evaluated by a semiquantitative polymerase chain reaction method. The collagen content of the untreated two-kidney, one clip hypertensive rats increased mainly around the coronary arteries; the number and surface area of microscars also increased in chronic hypertension. Losartan treatment decreased systolic pressure and yellow-red collagen fiber content in all areas, whereas spironolactone treatment decreased green collagen fiber content without decreasing systolic pressure. mRNA levels for types I and III collagens showed profiles similar to those of yellow-red and green collagen fiber contents, respectively, suggesting that yellow-red collagen fibers are mainly type I collagen fibers and green collagen fibers are mainly type III collagen fibers. These results suggest that angiotensin II, possibly together with hypertension, and aldosterone, independently of hypertension, have a major influence on myocardial fibrosis, inducing type I and type III collagen deposits, respectively, mainly around coronary arteries.

Angiotensin II↗
PubMed1986

Spironolactone in the treatment of idiopathic hirsutism and the polycystic ovary syndrome.

Forty-eight hirsute women were treated with spironolactone 100 mg twice daily for 3 to 12 months. Both facial and body hirsuties improved by 30-40%, and there was a threefold reduction in frequency of local treatments such as waxing or shaving. Plasma testosterone fell by 30%, though the improvement in hirsuties grading did not correlate with the fall in plasma testosterone. Six subjects discontinued treatment because of lack of effect, and 4 because of menstrual disturbance. Spironolactone was equally effective in the treatment of idiopathic hirsutism and of the polycystic ovary syndrome.

Adolescent↗