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PubMed1976

Antiandrogenic and antirenotropic effect of spironolactone.

Spironolactone given to male mice in dose 1.5 mg for 21 days produced significant changes not only in the highly androgen dependent seminal vesicles but also in the kidneys. Spironolactone blocked the action of endogenous testosterone in intact mice and led to further significant decrease in seminal vesicles and kidney weight in castrated mice. Such an effect could be due to a blocking of androgenic action of adrenal steroids.

Adrenal Glands↗
PubMed1976

Reversal of the suppressed potassium excretion during treatment with combinations of antikaliuretic drugs (spironolactone, canrenone, triamterene, amiloride) in patients with liver cirrhosis.

"Refractory" ascites was drained off by combinations of antialdosterone (spironolactone, canrenone) and pseudoantialdosterone (triamterene, amiloride) drugs inducing as high sodium excretion as 100 mEq per day in two patients with liver cirrhosis kept on a 9 mEq Na diet. Potentiation of the natriuretic effects of the two types of antikaliuretic drugs occurred by real synergism rather than addition. Although natriuretic acitivity showed a typical dose-related pattern, potassium excretion was unpredictable. Significant increase in potassium excretion (reversal of the suppression) occurred when 300 mg triamterene was combined with 200 mg canrenone in one of the two patients and when the dose of spironolactone or canrenone was increased from 200 mg to 600 mg within the combinations with 300 mg triamterene or 20 mg amiloride in the other. Parallel increase in sodium and potassium excretions might be caused by a proximal tubular effect or by inhibition of potassium reabsorption along with sodium in Henle's loop. The vasopressin (DDAVP) refractory distorsion of the relationship between osmolal clearance and free water reabsorpton (induced by pseudo-antialdosterone agents and potentiated by antialdosterone drugs) observed in all the 6 cases of the present patient material favoured the "loop hypothesis".

Amiloride↗
PubMedDate not supplied

Simultaneous determination of chlorthalidone and spironolactone with univariate and multivariate calibration: wavelength range selection.

Chlorthalidone and spironolactone were determined simultaneously with the aid of univariate and multivariate calibration methods. Univariate calibration was performed by the zero-crossing and derivative ratio spectrum methods. Extensive spectral overlap and the scarcity of wavelengths in derivative spectra allowing one analyte to be distinguished and quantitated in the presence of the other gave rise to poor results that called for multivariate calibration. Partial least-squares regression was used in combination with a suitable method for selecting the optimum wavelength range and number of factors for analysis. The ensuing method was applied to simultaneous determination of chlorthalidone and spironolactone in a commercially available pharmaceutical preparation. The results were validated by high-performance liquid chromatography.

Antihypertensive Agents↗
PubMed2001

Preformulation experiences and in vitro model studies with spironolactone-containing suppositories.

The optimal suppository base for the formulation of rectal suppositories containing diuretic spironolactone was selected experimentally. Model studies were carried out about the effect of solubility-increasing additives on the release of the drug from the suppositories. During the in vitro examinations acceptor phases of different pH values were used, and both diffusion time and the number of samplings were changed. Among the lipophilic and hydrophilic suppository bases studied the hydrophilic Macrogolum 1540 was found to be optimal. The release and diffusion of spironolactone was the most favourable from these suppositories. During storage these suppositories remained stable and the values of release did not decrease significantly (p < 0.05).

Algorithms↗
PubMed1975

[Spironolactone combined with chlorthalidone in the treatment of essential arterial hypertension].

The antihypertensive effect and the tolerance of the association of spironolactone and chlorthalidone were evaluated clinically and by numerous laboratory examinations in a group of 18 patients affected with non-complicated essential hypertension. All the patients were treated for 30 consecutive days with chlorthalidone (100 mg/day) and then for another 30 days with the two drugs administered contemporaneously (100 mg/day of spironolactone + 100 mg/day chlorthalidone). The balanced combination of the two drugs showed to be significantly more active than the treatment with just chlorthalidone and the margin of safety wider; the therapeutic activity showed to be independent from the variations of the plasma renin activity.

Aged↗
PubMed2000

Spironolactone in severe heart failure: enhances efficacy of diuretic + ACE inhibitor combinations.

(1) In patients with heart failure who remain symptomatic despite combination therapy with a diuretic and an angiotensin-converting-enzyme (ACE) inhibitor, a strictly conducted trial has shown that adding spironolactone at a mean dose of 25 mg/day reduces overall mortality by approximately 5% per year, and reduces the incidence of hospitalisation for heart disease and disability. (2) There is a risk of gynaecomastia (9%) and potentially severe hyperkalaemia. (3) It is crucial to follow the protocol used in the clinical trial, i.e. this treatment is contraindicated in severe renal failure or hyperkalaemia; creatinine and potassium levels must be monitored strictly; and spironolactone must be combined with a loop diuretic.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Effect of phenobarbital and spironolactone treatment on the oxidative metabolism of antipyrine by rat liver microsomes.

The effects of pretreating rats with the inducers, phenobarbital or spironolactone, on the formation rate of the three major oxidative metabolites of antipyrine in vitro by hepatic microsomal fractions have been investigated. Both inducers reduced the rate of 3-methylhydroxylation of antipyrine by approximately 50%. In contrast, N-demethylation and 4-hydroxylation were enhanced 1.7-fold and 3.4-fold, respectively, in case of phenobarbital induction and 1.4-fold and 2.6-fold, respectively, following spironolactone treatment. To elucidate the role of some cytochrome P450 isoenzymes in the production of the three major metabolites of antipyrine, the effects of form selective enzyme inhibitors on antipyrine oxidation were also studied. Troleandomycin did not alter 3-methylhydroxylation but reduced both N-demethylation and 4-hydroxylation of antipyrine in microsomes from induced rat liver. Cimetidine and chloramphenicol decreased the rate of formation of all three metabolites in microsomes from induced and uninduced animal livers as well. Chloramphenicol seemed to be the most potent inhibitor of in vitro antipyrine oxidation. Alpha-methyldopa significantly enhanced the rate of formation of 4-hydroxyantipyrine and slightly reduced the rate of N-demethylation and 3-methylhydroxylation. According to the data obtained with microsomes from uninduced rat livers, the formation of the three major metabolites of antipyrine is extensively mediated by CYP2C11/C6. In microsomes from induced animal liver, CYP2B and CYP3A may contribute to both N-demethylation and 4-hydroxylation of antipyrine.

Animals↗
PubMed1975

Lack of effect of spironolactone on male genital development.

Spironolactone, which has been shown to have antiandrogen action in mature male rats, was given to pregnant rats from day 14 of pregnancy until delivery in a dose equivalent to the 400-mg adult human regimen. The male members of the resultant litters were then dissected and examined for evidence of pseudohermaphroditism. No evidence of hypospadias, malformation of Wolffian ducts, or narrowing of anogenital distances was found. In the experimental model used, no evidence of an antiandrogen action of spironolactone was found.

Abnormalities, Drug-Induced↗
PubMed2002

[The process of drug development. The "case" of spironolactone].

In the progressive understanding of the heart failure syndrome different models have followed. Current pathophysiology model suggests that heart failure is a neurohormonal disorder: an abnormality in cardiac function and a disturbance in myocardial contractile force is the initiating event in heart failure, and the clinical expression and progression of the disease occurs as a result of subsequent extracardiac alterations. Treatment with drugs capable of antagonizing the effects of neuroendocrine activation, such as angiotensin-converting enzyme inhibitors, beta-blockers and antialdosterone agents have induced a significant reduction in morbidity and mortality in heart failure patients. The progressive understanding of the circulating homeostasis mechanisms moved from the systemic to the paracrine aspects of the neurohormonal systems and contributed to the development of new drugs. Moreover, the analysis of a drug's development can be an important step in the medical knowledge advancement. In this sense, aldosterone and spironolactone became an interesting "case", which is analyzed in this paper, going through the steps that have promoted the spironolactone from a weak diuretic to a neurohormonal drug and, finally, to a "central" drug.

Animals↗
PubMedDate not supplied

Spironolactone metabolism in man studied by gas chromatography-mass spectrometry.

Gas chromatography-mass spectrometry was used to identify metabolites of spironolactone in human blood and urine. In three healthy men about 20% of the radioactivity was excreted in the urine within 24 hr after an oral dose of [20-3H]spironolactone (200 mg + 200 muCi). About half of this radioactivity was extracted with chloroform at pH 3 and from this extract four stable metabolites were isolated by use of column and thin-layer chromatography. Two of these were the previously identified metabolites, canrenone (VII; 2.9% of dose) and the 6beta-hydroxy-sulfoxide (X; 1.8% of the dose). The remaining were the new metabolites, 15alpha-hydroxycanrenone (XI; 0.8% of dose) and the 6beta-hydroxy-thiomethyl derivatives (VI; 0.5% of dose). The principal water-soluble urinary metabolite was canrenoate ester glucuronide (XII; 4.5% of dose). In the 24- to 32-hr pooled serum, canrenone (VII) was the principal metabolite in the organic-extractable fraction; VI was present in appreciable amounts but X and XI were present at extremely low levels.

Canrenone↗
PubMed2005

Life-threatening hyperkalemia during a combined therapy with the angiotensin receptor blocker candesartan and spironolactone.

We describe a hypertensive nephrosclerosis patient presenting with severe hyperkalemia due to a combination therapy of the angiotensin receptor blocker (ARB) candesartan and spironolactone despite mildly decreased renal function. Recently, ARBs are replacing the ACE inhibitors. The combined therapy with ARB and spironolactone will eventually become the standard regimen. The strict attention and close monitoring of serum potassium should be mandatory in combination therapy to prevent hyperkalemia. Assessment of trans-tubular potassium gradient (TTKG) and fractional excretion of potassium (FEK) before starting the therapy would help in identifying the patients at higher risk of developing hyperkalemia. Co-administration of thiazide or loop diuretics is recommended to reduce the risk of hyperkalemia.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

[Normoaldosterone spironolactone sensitive hypertension--a case report].

We report the case of normoaldosterone spironolactone sensitive hypertension. Patients suffering from this recently identified form of arterial hypertension exhibit clinical symptoms resembling the symptoms of primary aldosteronism. The described disturbances may be misdiagnosed as essential hypertension because plasma aldosterone levels and aldosterone/renin ratio in patients are within the normal ranges. In the described state of the examined female, detection of the disease and implementation of spironolactone treatment not only normalised arterial blood pressure but also allowed to avoid unnecessary administration of many antihypertensive agents.

Aged↗
PubMed2006

[Normoaldosterone spironolactone sensitive hypertension].

We report the case of normoaldosterone spironolactone sensitive hypertension. Patients suffering from this recently identified form of arterial hypertension exhibit clinical symptoms resembling the symptoms of primary aldosteronism. The described disturbances may be misdiagnosed as essential hypertension because plasma aldosterone levels and aldosterone/renin ratio in patients are within the normal ranges. In the described state of the examined female, detection of the disease and implementation of spironolactone treatment not only normalised arterial blood pressure but also allowed to avoid unnecessary administration of many antihypertensive agents.

Aged↗
PubMed1990

Reversal of andro-genetic alopecia in a male. A spironolactone effect?

This 73-year-old white male has been bald since the age of 28. He developed nonA-nonB-induced liver cirrhosis and had been treated with spironolactone for the last 6 years. For the last 3 months, his hair had started to regrow over the scalp. This might be related to the antiandrogenic effect of spironolactone.

Aged↗
PubMed1986

[Efficacy and tolerability of enalapril compared to altizide combined with spironolactone in patients with moderate arterial hypertension].

The aim of this study was to compare the efficacy and safety of enalapril and a combination of a thiazide diuretic (altizide) and a diuretic that reduce potassium excretion (spironolactone), in patients presenting moderate essential hypertension. The four-month, double-blind study of two parallel groups involved 20 patients (12 males, 8 females) of mean age 54 years. All patients first received placebo for 15 days. Subsequently, 10 patients received 20 mg enalapril per day and 10 patients 15 mg altizide combined with 25 mg spironolactone in the same tablet. Blood pressure was measured every five minutes for 30 minutes with an automatic apparatus (Dynamap 845), before administration of placebo, before treatment and one, two and three months after treatment. There was no significant change of pulse rate with enalapril or with the diuretic combination. Both treatments produced an identical significant drop in systolic pressure. On the other hand enalapril seemed more efficacious in reducing diastolic pressure at the fourth month: respective pressures 98.2 +/- 13.3 mmHg and 81.0 +/- 8.5 mmHg (p less than 0.005) with enalapril, 98.6 +/- 7.4 mmHg and 86.0 +/- 6.1 mmHg (p less than 0.001) with the diuretic association (17% versus 12%, p less than 0.05). Safety was good with both medicinal preparations and the few side-effects noted did not necessitate withdrawal of treatment.

Adult↗
PubMed1987

[Effects of ovarian wedge resection (WR) and spironolactone administration on pulsatile LH release and serum steroid hormone levels in women with polycystic ovarian disease].

The exact mechanism(s) by which WR induces ovulation in women with PCOD is still uncertain. The aim of this study is to observe the change in sex steroids and pulsatile LH release (pul-LH-R) after WR. Before and either 7-8 days after the surgery (n = 8) or after 30 days of spironolactone treatment (n = 4), serum LH levels were measured every 15 min for 2-4 hours in PCOD women. Sex steroids were radioimmunoassayed before, and 3-4 and 7-8 days after WR. Testosterone (T) and androstenedione (A) in 7 women in whom spontaneous ovulation occurred after WR decreased significantly either 3-4 or 7-8 days after the surgery (p less than 0.001). Estrone decreased significantly (p less than 0.001) 7-8 days after the operation. The mean level of LH after WR in the 7 women decreased significantly (p less than 0.001). Furthermore, significant decreases both in the mean values of LH pulse amplitude (p less than 0.001) and frequency (p less than 0.01) were observed after WR. Ovulation occurred after 45 and 58 days of spironolactone administration in 2 PCOD women who showed changes in pul-LH-R and a drop in serum testosterone levels after 30 days of treatment. The data suggested that changes in pul-LH-R and decreased sex steroids after WR seemed to play key roles in the mechanism(s) by which WR induces ovulation.

Adult↗
PubMed1986

A fixed-dose combination of furosemide and spironolactone in digitalized congestive heart failure patients.

Twenty-three optimally digitalized patients with congestive heart failure completed a 4-week treatment period with a fixed-drug association of 20 mg furosemide plus 50 mg spironolactone. Eleven patients responded with a 75% decrease in cardiac failure score on a daily dose of 1 capsule of the combination. The remaining 12 patients were initiated on the same dose, but needed, at the end of the first 14 days, an additional capsule (making a daily total of 40 mg furosemide and 100 mg spironolactone) over the next 2 weeks. On this dose, the patients achieved an average reduction of 52% in their cardiac failure score. There were no treatment failures. Electrolyte abnormalities and side-effects were not observed. The combination product, in a daily dose of 1 or 2 capsules, was found useful and well tolerated in the management of congestive heart failure.

Aged↗