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PubMed1992

Spironolactone, an aldosterone antagonist, acts as an antiglucocorticosteroid on the mouse mammary tumor virus promoter.

The ability of the glucocorticosteroid receptor to bind mineralocorticosteroids suggests that spironolactone, a potent aldosterone antagonist, may also interact with the glucocorticosteroid receptor, resulting in an agonist or antagonist glucocorticosteroid activity. We have investigated the effect of this drug on the activity of the glucocorticosteroid-regulated mouse mammary tumor virus (MMTV) promoter. For these studies we used the mouse fibroblast cell line 1471.1. It contains about 200 copies of a permanently established chimeric DNA construct comprising a transcription unit [MMTV long terminal repeat (LTR)] driving the reporter gene chloramphenicol acetyltransferase linked to the 69% transforming fragment of the bovine papilloma virus genome. This cell line has a high level of glucocorticosteroid receptor (1200 fmol/mg protein) and no detectable mineralocorticosteroid receptor. Competition experiments showed a binding of spironolactone to glucocorticosteroid receptor, with an affinity 50-fold lower than that of dexamethasone. In these cells, spironolactone behaves as an antiglucocorticosteroid, inhibiting in a dose-dependent fashion dexamethasone-induced chloramphenicol acetyltransferase activity, with an ED50 of 8 microM. The absence of agonist activity, even at a high concentration of this compound (10 microM), demonstrates that spironolactone is a pure antiglucocorticosteroid in this cell line. MMTV LTR DNase-I hypersensitivity studies demonstrated that spironolactone, when administered in combination with dexamethasone, inhibits formation of the hormone-induced hypersensitive site located about 160 basepairs up-stream of the MMTV cap site. Furthermore, spironolactone alone failed to induce this DNase-I-hypersensitive site, suggesting that the antagonist-receptor complex does not interact productively with MMTV LTR chromatin.

Animals↗
PubMed1978

Interaction of digitalis and spironolactone with human sex steroid receptors.

Spironolactone and digitoxin have previously been shown to interact with cytosol androgen and estrogen receptors, respectively, in the rat. The interaction of digitoxin with human uterine cytosol estrogen binding protein and spironolactone with human prostate and newborn prepuce cytosol dihydrotestosterone (DHT) binding protein has been analyzed in this study. Specific estradiol binding was found only in premenopausal uteri. The dissociation constant for estradiol binding was 0.6--2.3 X 10(-9) M (n - 12). Digitoxin in concentrations varying between 0.5--2.0 X 10(-6) M inhibited specific estradiol binding with a Ki of 2.0--7.3 X 10(-7) M (n = 9). The dissociation constants for DHT and the human androgen cytosol binding protein in prostate and newborn prepuce were 0.27--3.0 X 10(-8) M (n = 12) and 0.6--2.0 X 10(-8) M (n = 5), respectively. Spironolactone at concentrations of 0.3--2.0 X 10(-6) M competitively inhibited this binding with an affinity about one order of magnitude less than that of DHT. Digitoxin and spironolactone did not displace estradiol and DHT, respectively, from testosterone-estrogen binding globulin in male or female plasma. The interaction of digitoxin with the human uterus estrogen binding protein and spironolactone with the human prostate and prepuce androgen binding protein is similar to our previous observations in the rat, and may explain the weak estrogenic effects of digitoxin and spironolactone in man.

Binding, Competitive↗
PubMed2000

Spironolactone in the treatment of congestive heart failure.

OBJECTIVE: To evaluate evidence supporting the use of spironolactone in managing congestive heart failure. DATA SOURCES: Literature accessed through MEDLINE (January 1966-December 1999) and cross-referencing of selected articles. Search terms included spironolactone and heart failure. DATA SYNTHESIS: Heart failure is a leading cause of morbidity and mortality. Through aldosterone antagonism, spironolactone may be an effective pharmacotherapeutic addition to patients not responding to standard drug therapy for heart failure. RESULTS: Clinical trials have demonstrated that, in patients with heart failure, spironolactone improves laboratory indices, quality of life, and morbidity. Recently, spironolactone has been demonstrated to improve the survival of patients with New York Heart Association (NYHA) III or IV heart failure. CONCLUSIONS: Spironolactone use should be considered in patients with NYHA Class III or IV heart failure.

Clinical Trials as Topic↗
PubMed1989

Dexamethasone and spironolactone in the treatment of non-tumorous hyperandrogenism.

To test the hypothesis that a combination therapy with dexamethasone and spironolactone in hirsute women with menstrual disorders due to non-tumorous hyperandrogenism might yield better results than monotherapy with spironolactone, we evaluated 25 women randomly assigned to dexamethasone-spironolactone (n = 15) and spironolactone (n = 10) groups. The Ferriman-Gallwey score and hormonal levels (LH, FSH, PRL, serum testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol, estrone and salivary testosterone) were determined before and after 6 months of therapy. There were comparable results, with a significant drop in the Ferriman-Gallwey score, in serum androstenedione and estrone concentrations and in salivary testosterone levels in both groups. The only difference between the two groups after therapy was a significant fall in serum dehydroepiandrosterone levels in patients treated with the combination therapy. The results indicate that the combination therapy with spironolactone and dexamethasone presents no real advantage over therapy with spironolactone alone, for the initial treatment of non-tumorous hyperandrogenism.

Adolescent↗
PubMedDate not supplied

Prevalence of primary hyperaldosteronism assessed by aldosterone/renin ratio and spironolactone testing.

Recent studies have suggested that primary hyperaldosteronism may be present in more than 10% of patients with hypertension. We aimed to estimate the prevalence in unselected patients in primary care, and investigate the influence of current drug treatment upon the aldosterone/renin ratio (ARR) and its prediction of blood pressure response to spironolactone. We measured blood pressure, plasma electrolytes, renin activity and aldosterone in 846 patients with hypertension. Spironolactone 50 mg was prescribed for one month to patients with blood pressure > or = 130/85 mmHg and ARR > or = 400. The primary outcome measure was to discover the proportion of patients with plasma aldosterone > or = 400 pmol/l and ARR > or = 800 and either an adrenal adenoma on computed tomography scan or a systolic blood pressure response to spironolactone > or = 20 mmHg. Only one patient had an adenoma, and only 16 (1.8%) had both a plasma aldosterone > or = 400 pmol/l and ARR > or = 800. By contrast, 119 patients (14.1%) had an elevated ARR but normal plasma aldosterone. In 69 patients out of the 119 who received spironolactone, blood pressure fell by 26/11 mmHg. These patients were normokalaemic but had uncontrolled hypertension despite multiple drugs. The response to spironolactone was best predicted by a low plasma renin, < or = 0.5 pmol/ml/h (<10 mU/l), despite treatment with an ACE inhibitor. We concluded that adrenal adenomas are an uncommon cause of hypertension. In the absence of hypokalaemia, a low plasma renin is a sufficient and simple way of detecting spironolactone-responders among patients with resistant hypertension. Only patients with both hypokalaemia and low plasma renin, measured while the patient is off beta blockade, require measurement of aldosterone. A plasma aldosterone >400 pmol/l together with renin activity < or = 0.5 pmol/ml/h should trigger further investigations for an adrenal adenoma.

Adenoma↗
PubMed2001

[Cost-benefit analysis of spironolactone use in the treatment of chronic heart failure].

INTRODUCTION AND OBJECTIVES: Chronic heart failure (CHF) is a disease with a high morbidity and mortality. The addition of spironolactone (25 mg/day) in the treatment of CHF has demonstrated a reduction in the mortality rate by 30% and in the hospitalization rate by 35%. The aim of this study was to perform a cost-benefit analysis of the association of spironolactone with the standard therapy for heart failure. METHODS: This analysis was carried out by assessing all the direct benefits and costs, derived from the association of either spironolactone or placebo with the standard therapy for heart failure in patients with functional degree III and IV. Data of costs and benefits were obtained from RALES. The following costs were included: hospitalisation, complementary tests and medication given. Benefit included avoided hospitalisations, complementary tests not performed and medication saved. The chosen perspective was the National Health Service and the time span chosen was of two years. RESULTS: The cost/patient in the spironolactone group (293,653 pts.) was lower than in placebo group (402,353 pts.). The benefit/patient in the former group (615,690 pts.) was higher than in the latter group (542,014 pts.). The net benefit (benefit-cost) of the spironolactone group (322,037 pts.) was higher than that observed in the placebo group (139,661 pts.). CONCLUSIONS: The association with spironolactone (25 mg/day) with the standard therapy for heart failure produces a remarkable net benefit in monetary terms. This fact will probably generate some resource saving for the National Health Service.

Chronic Disease↗
PubMed2001

[Cost effectiveness of the use of spironolactone in the treatment of chronic heart failure].

BACKGROUND: Chronic heart failure (CHF) is the first cause of hospitalization in elderly patients. The use of spironolactone in patients with CHF (degree III-IV) reduces their mortality and the rate of hospitalization. The aim of this study has been to assess the efficiency of using spironolactone in the treatment of CHF when compared with the use of conventional treatment alone. MATERIAL AND METHODS: The study has been performed through the design of a decision analytic model. A cost-effectiveness analysis was carried out by doing a simulation of 2 hypothetic cohorts of 1000 patients with CHF. It was evaluated the costs of each extra life year gained with each alternative under study. Data included have been obtained from Rales and the mean survival time for these patients has been considered of 4.3 years. Only direct medical costs have been included into this analysis. The chosen perspective has been the society and the time horizon included has been of 4.3 years. RESULTS: The cost/effectiveness ratio has been better in the spironolactone group (1,961,214) than in the standard treatment alone (2,242,912) and each extra life year gained when adding spironolactone to the conventional treatment yielded an additional cost of 591,457 ptas. The sensitivity analysis performed has shown that the option of using spironolactone presents always a better cost/effectiveness ratio even in the worst scenarios. CONCLUSIONS: The association of 25 mg/day of spironolactone to the conventional treatment of CHF is going to get more life years gained for these patients with a reasonable cost and clearly affordable by our National Health Service.

Cost-Benefit Analysis↗
PubMedDate not supplied

Hemodynamic effect of spironolactone in liver cirrhosis and propranolol-resistant portal hypertension.

OBJECTIVE: In a proportion of patients with liver cirrhosis, portal pressure does not decrease adequately with propranolol. These patients may benefit from another drug that may reduce portal pressure. We evaluated the role of spironolactone, alone or with propranolol, in such patients. METHODS: Patients with cirrhosis, with or without ascites, with esophageal varices and with hepatic venous pressure gradient exceeding 12 mmHg, which did not show a 20% reduction after an 80-mg oral dose of propranolol, were studied. They were allocated to receive spironolactone 100 mg orally once daily either alone (group 1, n=10) or with propranolol 40 mg orally twice daily (group 2, n=10), for 7 days, after which the hemodynamic study was repeated. RESULTS: Hepatic venous pressure gradient decreased in those receiving spironolactone and propranolol (p=0.007); 5 patients in group 1 and 7 in group 2 showed a reduction in hepatic venous pressure gradient by more than 20%. However, the reduction produced by spironolactone alone (20.5 [31.3]%) was not significantly different from that produced by combination therapy (30.3 [25.9]%; p=0.46). CONCLUSION: Spironolactone in combination with propranolol achieves adequate reduction (> or = 20%) in hepatic venous pressure gradient in propranolol-resistant portal hypertension in patients with liver cirrhosis. Spironolactone alone was also effective in some patients.

Adrenergic beta-Antagonists↗
PubMed2003

[Effects of aldosterone and spironolactone on the proliferation and collagen synthesis of hepatic stellate cells in rats].

OBJECTIVE: To investigate the effects of aldosterone and spironolactone on the proliferation and collagen synthesis of hepatic stellate cells. METHODS: Rat HSC were incubated with aldosterone or spironolactone, an aldosterone receptor antagonist at different concentrations. The proliferation of HSC was measured by (3)H-thymidine incorporation, and the collagen synthesis by (3)H-Proline. The changes of HSC cycle were analyzed by FCM. RESULTS: At dose of 10(-4) mol/L, ALD increased the incorporation of (3)H-TdR and (3)H-Pro (P < 0.05), but didn't at the lower doses. Spironolactone significantly inhibited HSC proliferation and collagen synthesis. The effective concentration was among 10(-4) mol/L - 10(-6) mol/L, and in dose-dependent manner. The percentage of G(1) phase of the cell cycle was significantly increased, and the cell proliferation suppression of spironolactone is associated with cell arrest in G(1) phase. Co-stimulation with aldosterone and spironolactone did not have significant effects on HSC proliferation and collagen synthesis compared with the control group. CONCLUSION: The proliferation and collagen synthesis of HSC might be enhanced by ALD at higher concentration, but was inhibited by spironolactone.

Aldosterone↗
PubMed1975

Spironolactone bodies in an adrenal adenoma.

Spironolactone bodies were observed in an adrenal cortical adenoma that was removed from a patient with primary hyperaldosteronism (Conn syndrome) treated preoperatively with spironolactone. The electron microscopical evaluation of this adrenal cortical adenoma shows origin of spironolactone bodies from whorls of endoplasmic reticulum in cells with the cytoplasmic features of those from the zona glomerulosa of the adrenal gland. There was no evidence that the bodies were derived from mitochondria, which confirms recent ultrastructural findings in patients treated with spironolactone. These bodies have been described in the adrenal cortex only in patients who have received spironolactone, and the pharmacologic specificity of the bodies strongly suggests a direct mode of action by spironolactone on aldosterone production by cells of the adrenal zona glomerulosa.

Adenoma↗
PubMed1988

Topical spironolactone inhibits dihydrotestosterone receptors in human sebaceous glands: an autoradiographic study in subjects with acne vulgaris.

The interaction between spironolactone and dihydrotestosterone (DHT) receptors was evaluated with an autoradiographic technique. The inhibition of DHT receptors by spironolactone was found to be related to the decrease of tritiated DHT granules in the sebaceous glands of the treated site. 6 male patients affected by acne vulgaris entered the study. The acute study was performed by applying to 25 cm2 of the back a cream containing 5% spironolactone under occlusive dressing. The dosage of spironolactone applied was 4 mg/cm2 for 48 h. The long-term study was performed by applying the same amount to the entire back, without occlusion, twice daily for 1 month. Skin biopsies were taken at the end of the treatment, incubated with tritiated DHT and processed for autoradiography. Both the acute and the long-term study revealed a decrease of the autoradiographic granules in the treated site. This effect is related to the binding of spironolactone with dihydrotestosterone receptors in the sebaceous glands. Our study demonstrates that 5% topical spironolactone cream acts as an antiandrogen in human sebaceous glands, competing with DHT receptors and producing a decrease of labelled DHT. At the concentrations used the effect has been only local. No side-effects were recorded during both studies.

Acne Vulgaris↗
PubMed1988

[Studies of biological availability. A critical assessment based on a study of spironolactone preparations].

Investigations have been performed to determine the relative bioavailability of canrenone from an improved spironolactone preparation, Deverol drgs., in comparison with canrenone from a spironolactone standard preparation on the Austrian market (Osiren drgs.). This was carried out by comparing the areas under the serumconcentration-time-curves under conditions of steady-state after oral application of both preparations. Additionally the contents of spironolactone in the two preparations tested were determined. By intraindividual comparison of the areas under the serum-concentration-time-curves of canrenone a relative bioavailability of 99.37% of canrenone from Deverol drgs. could be calculated versus canrenone from the standard. However a remarkable different content of spironolactone in the preparations was found: in 50 mg of Deverol drgs. 50.5 mg spironolactone and in 100 mg of Osiren drgs. 109.6 mg spironolactone were found. Determination of drug contents in products appears to be necessary to determine their relative bioavailability correctly, because the usual range of +/- 5% may be overshot as demonstrated in our investigation.

Administration, Oral↗
PubMed1986

[Pharmacokinetic studies and bioavailability of bendroflumethiazide in combination with spironolactone].

An intraindividual comparative multiple-dose study (6 days) was carried out under controlled conditions on 10 healthy volunteers in order to establish the bioavailability of bendroflumethiazide (Bft; 3-benzyl-6-trifluoromethyl-7-sulfamyl-3,4-dihydro-1,2,4-benzoth iad iazine-1, 1-oxide), the sum of the fluorogenic metabolites of spironolactone (3-[3-oxo-7-alpha-acetylthio-17 beta-hydroxy-4-androstene-17-alpha-yl]-propionic acid-gamma-lactone) and canrenone, the main spironolactone metabolite from a fixed combination of Bft with spironolactone vs. the commercial preparations of the single drugs. Canrenone was assayed from plasma by high-performance liquid chromatography (HPLC) whereas Bft and the total aldosterone antagonistically acting spironolactone metabolites were determined fluorometrically. Both the fixed and the monosubstance formulation can be considered as bioequivalent for canrenone and the total fluorescence. Bft, in contrast, shows a reduced systemic availability of 61% when administered as the single drug formulation. A 2-compartment model was taken as the basis for the calculation of the steady-state plasma concentration curves and the pharmacokinetic parameters of Bft, canrenone and the sum of the fluorogenic spironolactone metabolites. Following oral multiple administration of 2.5 mg Bft (b.i.d.), the terminal elimination half-life, the steady-state volume of distribution and the total plasma clearance were determined to be 8.6-8.2 h, 0.88 l/kg and 269.4 ml/min, resp. In contrast to Bft, the AUC(120,tlast)-values for post-steady-state elimination, starting with the final spironolactone dose on day 6 were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1979

SC 25152: a potent mineralocorticoid antagonist with decreased antiandrogenic activity relative to spironolactone.

The widely used mineralocorticoid antagonist spironolactone has antiandrogenic activity that may contribute to its side effects of decreased libido, impotence and gynecomastia. We have therefore sought a less antiandrogenic analog of spironolactone that may exhibit reduced endocrine side effects. The analog SC 25152 was chosen for pharmacological testing because of the previous observation that it has considerably reduced affinity for the androgen receptor of both man and rat but exhibits an affinity for the mineralocorticoid receptor similar to that of spironolactone. Bioassays in the rat show that SC 25152 has a 60% decrease in antiandrogenicity, and a 4-fold increase in antimineralocorticoid activity compared to spironolactone, resulting in an overall reduction of antiandrogenic activity to one-tenth that of spironolactone at doses giving equal antimineralocorticoid activity. These studies demonstrate that the antiandrogenic and antimineralocorticoid activities of spironolactone analogs can be dissociated and illustrates the utility of measurements of drug-receptor interaction to identify a compound with desired pharmacological properties.

Adrenalectomy↗
PubMed1979

Effect of spironolactone treatment on the renin-aldosterone system during pregnancy.

Ten pregnant patients were treated with spironolactone (100 mg daily) for two weeks. The patients were on a continuous long-term saluretic therapy for pregnancy edema. In addition, a potassium supplementation (30 mmol/day) was given until the beginning of spironolactone treatment. The patients thus treated had a mean urinary aldosterone excretion (dU-Aldo) of more than ten-fold in comparison to that of non pregnant state. Canrenone, the effective conversion product of spironolactone in plasma, reached its steady state level in three days as in non-pregnant subjects. dU-Aldo decreased in two weeks during the spironolactone by 36% (p less than 0.05). The inhibition of aldosterone secretion is thus evident also after a low clinical dose of spironolactone. Urinary potassium excretion (dU-K) decreased during the 1st day (p less than 0.05) and continued to decrease during one week of spironolactone therapy by a total of 21% (p less than 0.001). The decrease in dU-K reflects the cessation of potassium supplements in the beginning of the study. No changes in urinary sodium excretion were found. Plasma renin activity (PRA) increased in one week by 79 per cent and the changes of PRA and dU-Aldo showed inverse correlation (p less than 0.001). In our study natriuresis, cannot explain the increase of PRA. Our study suggests another feedback effect of aldosterone.

Aldosterone↗
PubMed1977

Spironolactone metabolism in normal subjects and in patients with liver cirrhosis.

The dynamic excretion of aldadiene, the principal metabolite of spironolactone with biological activity, was studied in normal subjects and patients with liver cirrhosis following administration of spironolactone. Aldadiene appeared in the three-days urine collection in around 3% of the dose. There was no significant difference in the biological half-life, calculated from the urinary pattern, and in the rate of excretion in patients with hepatopathy and hospitalized controls. Healthy volunteers without hospitalization exhibited the most rapid elimination of the metabolite. An increase of spironolactone dose enhanced the per cent rate of aldadiene excretion, while the biological half-life did not change. Spironolactone decreased the rate of dehydroepiandrosterone and androsterone excretion even after a single dose. Determination of total 17-ketosteroids is of no value on evaluation of adrenal function during spironolactone therapy, due to a Zimmermann-positivity of spironolactone metabolites.

Administration, Oral↗
PubMed1980

Spironolactone interference with digoxin radioimmunoassay in cirrhotic patients.

The effects of spironolactone and cirrhosis on the measurement of serum digoxin levels by radioimmunoassay were studied in patients not receiving cardiac glycosides. Three groups of 10 patients each were studied. Groups 1 and 2 included patients with alcoholic cirrhosis, with Group 1 patients receiving spironolactone and Group 2 receiving no spironolactone. Group 3, the control group, included patients who were not receiving spironolactone and did not have cirrhosis. Apparent digoxin serum levels were measured by radioimmunoassay, and the mean levels of each group were compared. Group 1 had significantly higher apparent digoxin levels (1.3 +/- 0.62 ng/ml, p 0.05) than Groups 2 or 3. The apparent digoxin level of Group 2 (0.74 +/- 0.44 ng/ml) did not differ significantly from that of Group 3 (0.40 +/- 0.35 ng/ml). Significant correlations were found between apparent serum digoxin levels and daily spironolactone dose (Group 1), SGOT levels (Group 1), and prothrombin time/control ratios (Group 2 and all groups combined). Spironolactone appears to increase digoxin levels measured by radioimmunoassay. The effect of cirrhosis on digoxin radioimmunoassay has not been confirmed.

Digoxin↗
PubMed1997

Analysis of metabolites--a new approach to bioequivalence studies of spironolactone formulations.

The aldosterone antagonist spironolactone undergoes extensive and complex biotransformation. For investigation of bioequivalence of 2 oral spironolactone formulations, Spironolacton 50 Heumann and Aldactone 50, the pharmacokinetics and bioequivalence of the parent drug and 2 predominant active metabolites, canrenone and 7 alpha-thiomethylspirolactone, were determined in a 2-way crossover study in 24 young healthy male volunteers after multiple oral dosing of 100 mg once daily. Plasma samples were measured by a newly developed HPLC assay and individual pharmacokinetic parameters of the 3 compounds were calculated by use of noncompartmental techniques. Statistical analysis was performed by ANOVA and nonparametric methods. Spironolactone was rapidly cleared from plasma. Therefore, only Css,max and tss,max were determined. Concerning Css,max bioequivalence was found with 90% classical shortest confidence interval ranging from 80.7-112.4%. The intrasubject variability for Css,max was determined to be 28.1%. Higher and persisting concentrations were observed for the metabolites. For canrenone 90% classical shortest confidence intervals were calculated as 95.4-105.0% for AUCss,tau, as 92.9-105.8% for Css,max, and as 89.1-106.3% for peak trough fluctuation (PTF). In the case of 7 alpha-thiomethylspirolactone the values were 84.2-103.0% for AUCss,tau, 77.0-98.6% for Css,max, and 85.0-100.4% for PTF. For tss,max nonparametric 90% confidence intervals were determined as 0.00 to 1.50 h for spironolactone and canrenone and as -0.50 to 1.00 h for 7 alpha-thiomethylspirolactone. The intraindividual variability was below 30% for all pharmacokinetic parameters in the case of the metabolites. Thus, bioequivalence of the test and the reference formulation can be concluded. The study suggests the inclusion of parent compound and metabolites for bioequivalence testing of spironolactone formulations. Intraindividual subject variability was clearly diminished by investigating bioequivalence under steady-state conditions.

Administration, Oral↗