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PubMed1993

Low dose spironolactone in the treatment of female hyperandrogenemia and hirsutism.

Thirty one women with hyperandrogenism, clinically divided into polycystic ovary syndrome (PCOS)--28 women and idiopathic hirsutism (I.H.)--3 women, were treated with low dose spironolactone (50 mg or 75 mg daily) for average five months. There was an excellent clinical response in 19 (61%), incomplete response in 8 (26%), no response in 5 women. Six of 18 patients with sterility became pregnant during the one year after treatment and delivered a healthy infant at term. Two patients dropped out of the trial because of intolerance of the therapy. Remarkable change of the menstrual pattern characterised as polymenorrhea was major side effect of the therapy. Other side effects were not problem. Spironolactone caused statistically significant reduction in testosterone, luteinizing hormone and prolactin values at the end of the treatment. Our results demonstrate that low-dose spironolactone is effective in the treatment of hyperandrogenism in women.

Adolescent↗

PubMed1977

[Correlations between blood pressure, blood volume and plasma renin during therapy with diuretics in essential hypertension. Comparison between the mineralocorticoid antagonist spironolactone and the "loop" diuretic mefruside].

35 patients with benign essential hypertension were treated for 6 weeks with high doses of the mineralocorticoid-antagonist spironolactone (400 mg/day), or with the "loop-diuretic" mefruside (mean maximal dose 110 mg/day). Spironolactone caused greater reductions in blood pressure and blood volume and a more marked increase in plasma renin activity (PRA) than mefruside (p less than 0.05). It appears possible that he weaker antihypertensive effect of mefruside may relate partly to its lesser influence on circulatory volume. With both diuretics, mean decreases in blood pressure were greater in patients with low pre-therapeutic PRA than in patients with normal or high PRA. However, the diuretic-induced changes in blood pressure did not correlate with the associated variations in blood volume or PRA. Thus, the increased blood pressure sensitivity to diuretics in patients with low-renin essential hypertension did not appear to be volume or renin-dependent. Under normal conditions, the maintenance of a constant blood pressure during volume depletion may partly depend on compensatory activation of the sympathetic nervous system. Moreover, patients with low-renin essential hypertension have been found to have decreased adrenergic activity. It seems possible, therefore, that the marked blood pressure sensitivity to diuretic treatment in such patients may be the result of an impaired compensatory sympathetic response to sodium and volume depletion. Analysis of the literature suggests that the diuretic furosemide, a structural relative of mefruside, may also have less blood pressure lowering efficacy in patients with essential hypertension than the distally-acting thiazides, chlorthalidone or spironolactone. Consideration of possible differences in the blood pressure reducing potential of certain diuretics thus appears to be necessary in planning the pharmacotherapy of essential hypertension.

Blood Pressure↗

PubMed1998

[Effect of combined captopril-spironolactone therapy of cardiac insufficiency on kidney function and serum electrolyte values].

Author investigated the safety of combined ACE inhibitor (captopril) and spironolacton therapy on 237 pts with severe heart failure (NYHA III-IV.) treated with digitalis and loop diuretic during on average 65.4 months follow-up period. Incidence of clinically significant increase in serum urea, creatinine and potassium level was evaluated and compared with those of in group treated 47 pts with the same standard therapy captopril, digitalis, furosemide, without spironolacton. There was no significant difference between the incidence of azotemia and hyperkalemia in the two groups. The author emphasizes on the base of their results the safety of combined captopril and low dose spironolactone therapy in heart failure.

Captopril↗

PubMedDate not supplied

Optimal use of spironolactone for treatment of heart failure.

Spironolactone has recently been shown to have a favorable impact on the prognosis and functional status of patients with left ventricular systolic dysfunction and severe symptoms who are receiving standard therapy. However, participants in clinical studies of spironolactone represent a selected group. Clinicians managing a less selected group must be mindful of selection criteria and appropriate methods to monitor patients who are initiated on these medications. In this review, two case studies are described that demonstrate the importance of careful selection of candidates for spironolactone, the need for close laboratory and symptom monitoring, and the need for patients' active participation in reporting changes in their clinical status. (c)2001 CHF, Inc.

Journal Article↗

PubMed1976

Spironolactone. II. Bioavailability.

The bioavailability of commercial 25-mg spironolactone tablets and a new tablet preparation containing 100 mg of the drug has been determined in 12 healthy male subjects. After a 200-mg oral dose of the drug given in a solution of polyethylene glycol-400, the peak plasma level of the dethioacetylated metabolite canrenone was 633 +/- 154 ng/ml (mean +/- SD) and was reached at 1.4 +/- 0.43 hr. This peak was higher and was achieved earlier than after either eight 25-mg tablets (480 +/- 155 ng/ml at 2.9 +/- 1.03 hr) or two 100-mg tablets (474 +/- 182 ng/ml at 3.0 +/- 1.37 hr). From the ratio of the 24-hr area under the plasma concentration-time curves, the bioavailabilities of the two tablet preparations relative to the solution were 99.6 +/- 18.2% and 92.1 +/- 22.9%, respectively. The amount of canrenone excreted in the urine by 48 hr was 4.48 +/- 1.26 mg (solution), 6.36 +/- 2.02 mg (eight 25-mg tablets), and 7.81 +/- 1.87 mg (two 100-mg tablets), representing 2% to 4% of the administered dose. It is concluded that urinary excretion of canrenone alone is not a reliable method for determining the bioavailability of spironolactone.

Administration, Oral↗

PubMed1977

Influence of probenecid and spironolactone on furosemide kinetics and dynamics in man.

The pharmacokinetics and pharmacodynamics following administration of furosemide (40 mg intravenously) have been studied before and after treatment with probenecid (0.5 gm orally every 6 hr for 3 days) and spironolactone (200-mg initial oral dose followed by 50 mg every 6 hr for 3 days) in 6 normal male subjects. Urine losses during each study period were replaced with saline-dextrose-KCl intravenously. The study was performed with the use of a Latin-square design. Probenecid pretreatment induced significant reductions in renal clearance of furosemide by 78%, the extrarenal clearance by 56%, and the volume of distribution by 52%. As a consequence, furosemide half-life was increased by 54%. Probenecid significantly reduced the rate of sodium excretion at all plasma concentrations of furosemide, but the ratio between urinary furosemide concentration and urinary sodium concentration was not altered. Since the proportion of furosemide excreted unchanged in the urine was not markedly changed, total diuretic response was not influenced by probenecid. There was no evidence of any pharmacokinetic interaction between spironolactone and furosemide. The relationship of furosemide kinetics to dynamics observed in these studies confirms that, in man, the diuretic response is determined by drug that reaches the renal tubule rather than the drug level in plasma.

Adult↗

PubMedDate not supplied

A randomized comparison of metoclopramide and domperidone on plasma aldosterone concentration and on spironolactone-induced diuresis in ascitic cirrhotic patients.

The effect of metoclopramide and domperidone, two dopamine antagonists, administered to cirrhotic patients with ascites and secondary hyperaldosteronism, was examined to evaluate the changes in plasma aldosterone levels and in spironolactone-induced diuresis. In 15 patients with ascites and secondary hyperaldosteronism, the intravenous administration of 10 mg metoclopramide significantly increased plasma aldosterone levels (23%, p less than 0.01). This effect was observed when an equivalent dose of domperidone was administered. In 20 ascitic patients treated with spironolactone (300 mg per day), the administration of metoclopramide (20 mg) significantly reduced urinary output (24%, p less than 0.001) and urinary sodium (35%, p less than 0.001) while simultaneously increasing urinary potassium (24%, p less than 0.001) and plasma aldosterone (40%, p less than 0.001). This effect was not observed with domperidone in an equivalent dose. Therefore, it is recommended that metoclopramide should be avoided during diuretic therapy in cirrhotic patients with ascites. In these circumstances, domperidone is preferred.

Adult↗

PubMed1991

Polymorphism of spironolactone.

Single crystals of two polymorphic and four solvated crystalline forms of spironolactone (C24H32O4S) were obtained using different solvents. The morphology, symmetry, and crystallographic parameters were determined for all crystal forms except for the one obtained from methanol. The stability and transformation of each type of crystal were studied by DSC, TGA, and X-ray diffraction analysis. The structural data of three forms allowed the observation of the change of conformation of the molecules of spironolactone in the three different lattices.

Crystallization↗

PubMed1993

Renal sodium handling and neurohumoral systems in patients with cirrhosis in sitting posture: effects of spironolactone and water immersion.

Renal sodium handling, neurohumoral systems, and systemic hemodynamics were investigated under baseline conditions in sitting posture in 10 healthy subjects, 11 patients with cirrhosis without, and 10 patients with cirrhosis with ascites. Furthermore, the effects of head-out water immersion, 1-week spironolactone administration, or their combination was assessed in the two groups of patients. Patients without ascites exhibited a significant increase in plasma norepinephrine concentration and a tendency toward an increase in plasma aldosterone concentration. Patients with ascites had a significantly lower mean arterial blood pressure despite significant reduction of urinary sodium excretion and fractional sodium excretion as well as an increase of plasma renin activity, plasma aldosterone, and norepinephrine concentration. In patients with ascites, the increase in renal sodium excretion and fractional sodium excretion following water immersion or spironolactone was clearly augmented by the combination of the two maneuvers. The same pattern was observed in patients without ascites. Our findings (a) underscore the importance of studying hemodynamics, renal function, and neurohumoral systems also in upright posture, (b) suggest a role of sympatico-adrenergic activation and proximal sodium retention in preascitic patients, and (c) are compatible with the vasodilation hypothesis of ascites formation.

Adult↗

PubMed1982

Adrenal scintigraphy in primary aldosteronism. Spironolactone as a cause of incorrect classification between adenoma and hyperplasia.

In primary aldosteronism the type of adrenal lesion was correctly identified in 28 of 40 patients (70%) by standard adrenal scintigraphy. Suppression scintigraphy did not improve the validity of the method. In all patients the diagnosis was confirmed by surgery (unilateral adenoma n = 32; bilateral adrenal hyperplasia n = 11). False classification of the adrenal lesion(s) by standard scintigraphy was mostly due to a bilateral adrenal isotopic uptake in patients with an unilateral aldosteronoma. However, a substantial number of these patients (6 of 11 patients) received long-term spironolactone treatment prior to the examination. Thus, in primary aldosteronism adrenal changes induced by chronic spironolactone administration are probably a major cause for incorrect differentiation between adenoma and hyperplasia by adrenal scintigraphy.

19-Iodocholesterol↗

PubMed1984

Pharmacokinetics of canrenone and metabolites after base hydrolysis following single and multiple dose oral administration of spironolactone.

The pharmacokinetics of canrenone and 'total metabolites' after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and 'total metabolites' were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t1/2 alpha) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t1/2 beta) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of 'total metabolites' after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of 'total metabolites' was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and 'total metabolites' were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.

Administration, Oral↗

PubMed1993

Effect of spironolactone on cytosolic free sodium concentration in platelets from hypertensive patients with primary aldosteronism.

Cytosolic free sodium concentration ([Na+]i) was investigated in intact platelets from 5 hypertensive patients with primary aldosteronism (unilateral adenoma in 3 patients, and adrenal hyperplasia in 2 patients) and 21 normotensive control subjects. [Na+]i was measured using a novel sodium-sensitive fluorescent dye technique. [Na+]i was significantly decreased in platelets from patients with primary aldosteronism compared to control subjects (21.9 +/- 4.1 mM vs 35.8 +/- 2.2 mM, mean +/- SEM, P < 0.05). After administration of the mineralocorticoid antagonist spironolactone in 4 patients [Na+]i tended to be higher in platelets although the differences did not reach statistical significance (26.3 +/- 7.2 mM vs 18.2 +/- 2.4 mM, P = 0.125). From the present results it may be concluded that intracellular sodium is decreased by aldosterone-induced activation of Na-K-ATPase. That activation may be partly blocked by spironolactone.

Aged↗

PubMed1985

Colorimetric analysis of some diuretic drugs: hydrochlorothiazide and spironolactone.

Two convenient spectrophotometric methods were developed for the determination of hydrochlorothiazide and spironolactone. A specific colour reaction for the determination of hydrochlorothiazide is reported. One method is based on the reaction of hydrochlorothiazide with n-butylamine and cobaltous chloride in anhydrous methanol. A blue-violet colour is produced and is measured at 570 nm. A highly selective colorimetric method was adopted for the analysis of spironolactone by reacting with isoniazid forming a coloured hydrazone derivative and subsequent measurement of the coloured product at 405 nm.

Chemical Phenomena↗

PubMed1987

Spironolactone in the treatment of hirsutism.

Spironolactone was used in 90 hirsute women because of its antiandrogenic effect. The drug was administered twice daily from the 4th to the 22nd day of six cycles (total dosage was 200 mg per day). The results suggest that spironolactone is suitable for the treatment of hirsutism.

17-Ketosteroids↗

PubMed2002

Spironolactone for the treatment of hypercalciuric hypocalcemia.

A patient with hypocalcemia and hypomagnesemia, and renal wasting of both cations, is presented. This patient had a dramatic calcium response to treatment with spironolactone. The possible diagnoses and mechanisms of response are discussed. It is concluded that the patient had a calcium-sensing receptor mutation, and that treatment with spironolactone induced an effect on renal handling of calcium in this condition. It is suggested that this treatment be tried in other similar patients.

Calcium↗

PubMed2004

Acquired hemophilia as first manifestation of breast carcinoma in a man under long-term spironolactone therapy.

A 69-year-old man under long-term spironolactone therapy (16 years) was hospitalized with spontaneous hematoma on the trunk and extremities. Coagulation studies disclosed an acquired hemophilia that was successfully treated with human factor VIII for a few days and immunosuppressive agents for several months. Physical examination revealed bilateral gynecomastia and an upper left quadrant breast nodule. Complete staging was unremarkable. Complete left mastectomy was performed. Histopathology showed invasive ductal carcinoma, expressing positivity for estrogen and progesterone receptors. The acquired hemophilia was considered to be a paraneoplasic syndrome. The question of a linkage between long-term spironolactone therapy and breast carcinoma is discussed.

Aged↗

PubMed2006

Spironolactone induces apoptosis and inhibits NF-kappaB independent of the mineralocorticoid receptor.

Spironolactone (SPIR) binds to cytoplasmic mineralocorticoid receptors (MR) and functions as an aldosterone (ALDO) antagonist. Recently, however, the drug was shown to have an early MR independent, suppressive effect on immunoactive and inflammatory cytokines as well as an apoptotic effect on blood mononuclear cells (MNC). To elucidate the mechanism behind SPIR's apoptotic effect, we investigated the relation between apoptosis and cytokine suppression for SPIR along with the apoptosis-inducing and antiinflammatory drug sulfasalazine (SFZ). Using human MNC, we found that SPIR and SFZ, at concentrations 10 and 1000 muM, respectively, significantly increased both apoptosis and cell death. Production of inflammatory cytokines was significantly reduced by 3 to 30 muM SPIR and by 300 to 1000 muM SFZ. We also found that 0.4 muM SPIR and 300 muM SFZ significantly reduced the activity of NF-kappaB, a transcription factor involved in both apoptosis and immunoinflammation. ALDO, the MR antagonist, eplerenone, and the SPIR metabolite, 7alpha-thiomethyl-spironolactone, slightly reduced NF-kappaB activity, but they did not interfere with SPIR's effect, showing that MR binding is not involved in SPIR-induced suppression of NF-kappaB activity. Finally, phosphorylation of IkappaBalpha was also significantly reduced by SPIR. These results provide new insight into the apoptotic and anti-inflammatory effects of SPIR.

Apoptosis↗

PubMed2000

Spironolactone in congestive heart failure.

When a large multicenter research trial is abruptly terminated, it is usually a consequence of significant adverse events. In contrast, when the Randomized Aldactone Evaluation Study (RALES) mortality trial was discontinued 18 months early, it was because of the prominent salutary effect of spironolactone, added to standard multidrug therapy consisting of an angiotensin converting enzyme (ACE) inhibitor and loop diuretic (with or without digoxin), in reducing the incidence of death and hospitalization in patients with severe congestive heart failure (CHF). Therapies directed toward suppression of neurohormonal activation have contributed to significant reductions in morbidity and mortality. ACE inhibitors, in particular, have had the largest impact on adverse outcome measures in CHF. Yet despite combined therapy with an ACE inhibitor and loop diuretic, patients on these agents still have an unacceptably high incidence of progressive ventricular failure and death. In the years that followed its discovery in 1954, aldosterone was considered a target for therapy in CHF because of its role in sodium retention. It is now clear that chronic elevations in plasma aldosterone are responsible for many other adverse effects (Fig. 1), including enhanced potassium and magnesium excretion, myocardial fibrosis, inhibition of catecholamine reuptake, endothelial cell and baroreceptor dysfunction, and ventricular arrhythmias. Blockade of aldosterone action is a desirable pharmacologic approach to treating both the underlying pathophysiology of CHF and its clinical consequences. Spironolactone promotes magnesium and potassium retention, increases uptake of myocardial norepinephrine, attenuates formation of myocardial fibrosis, and decreases mortality associated with both progressive ventricular dysfunction and malignant ventricular arrhythmias. Despite the encouraging results seen in the recent RALES mortality trial, a diagnosis of CHF still carries 30% to 40% mortality at 2 years. We need to continue the trend of evaluating newer therapies directed at the pathophysiologic mechanisms of this syndrome, with a goal toward delaying and eventually reversing long-term consequences.

Aldosterone↗