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PubMed1981

Spironolactone inhibits vascular reactivity by a prostaglandin related mechanism unconnected with aldosterone.

Effects of aldosterone and spironolactone on the vascular responses to noradrenaline and potassium were studied in the perfused rat mesenteric vascular bed. Aldosterone did not modify the response to either vascular agent. Spironolactone inhibited the vascular response to both pressor agents in a dose-dependent manner. The inhibitory effect of spironolactone was not altered by various concentrations of aldosterone and ouabain. However it was not apparent in preparations in which endogenous prostaglandin synthesis had been abolished in indomethacin. The observations suggest that spironolactone has actions on vascular reactivity which are not related to aldosterone or to sodium/potassium pumping. They may depend on modification of prostaglandin biosynthesis.

Aldosterone↗
PubMed2004

Effects of ACE gene insertion/deletion polymorphism on response to spironolactone in patients with chronic heart failure.

BACKGROUND: Angiotensin-converting enzyme (ACE) is involved in the pathophysiology of chronic heart failure, and its activity is determined in part by a polymorphism of the ACE gene. We hypothesized that the benefits of spironolactone, which inhibits downstream elements of ACE-mediated abnormalities, may depend on ACE genotype. METHODS: We randomly assigned 93 chronic heart failure patients to treatment with spironolactone (n = 47) or to a control group (n = 46) and followed them for 12 months. Genotype for the insertion/deletion polymorphism of the ACE gene was determined by polymerase chain reaction. An echocardiographic examination was performed at baseline and at the end of the 12 months. RESULTS: The mean (+/- SD) age of the 93 patients was 62 +/- 9 years, and the mean New York Heart Association class was 2 +/- 1. The genotype was DD in 26 patients (28%). Forty-seven patients were assigned to spironolactone treatment (mean dose, 32 +/- 16 mg). In the treated group, only patients with a non-DD genotype showed significant improvement in left ventricular ejection fraction (3.0%; 95% confidence interval [CI]: 1.2% to 4.8%; P = 0.002), end-systolic volume (-23 mL; 95% CI: -36 to -11; P = 0.0005), and end-diastolic volume (-27 mL; 95% CI: -43 to -12; P = 0.001). In the multivariate analysis, the estimated net effect of treatment was 29 mL better (95% CI: -20 to 78 mL) for end-diastolic volume, 20 mL better (95% CI: -18 to 58 mL) for end-systolic volume, but 1.4% worse (95% CI: -3.4% to 6.2%) for left ventricular ejection fraction in patients with non-DD versus DD genotypes. CONCLUSION: The effects of spironolactone treatment on left ventricular systolic function and remodeling may in part depend on ACE genotype.

Diuretics↗
PubMed2005

Influence of aminoglutethimide and spironolactone on the efficacy of carbamazepine and diphenylhydantoin against amygdala-kindled seizures in rats.

Antagonists of steroid receptors may interfere with seizure phenomena. The present study deals with effects of aminoglutethimide and spironolactone on the action of carbamazepine and diphenylhydantoin in amygdala-kindled rats of both genders. Co-administration of the antimineralocorticoid with carbamazepine at their ineffective doses (50 and 15 mg/kg, respectively) led to significant reduction of the seizure and afterdischarge durations. No anticonvulsant effect was observed when spironolactone was combined with diphenylhydantoin. The concomitant treatment of aminoglutethimide and carbamazepine (both drugs at their subprotective doses of 5 and 15 mg/kg, respectively) resulted in antiseizure activity in respect of all measured parameters, including the afterdischarge threshold, seizure severity, seizure duration and afterdischarge duration. The similar combination of aminoglutethimide with diphenylhydantoin (2.5 mg/kg) significantly shortened the seizure and afterdischarge durations. The antiseizure effect of tested combinations was not sex-dependent and not reversed by hydrocortisone pretreatment. Pharmacokinetic events may be involved only in the interaction between spironolactone and carbamazepine. Among various chemoconvulsants, bicuculline reversed the action of aminoglutethimide on carbamazepine and diphenylhydantoin. The effect of aminoglutethimide on diphenylhydantoin was also abolished by N-methyl-d-aspartic acid and aminophylline. In conclusion, our results suggest that doses of carbamazepine and diphenylhydantoin should be modified in epileptic patients concomitantly treated with aminoglutethimide or spironolactone.

Aminoglutethimide↗
PubMed2005

Comparison of the clinical efficacy of flutamide and spironolactone plus Diane 35 in the treatment of idiopathic hirsutism: a randomized controlled study.

OBJECTIVE: To compare the effectiveness of flutamide and spironolactone plus Diane 35 in the treatment of idiopathic hirsutism (IH). DESIGN: Prospective randomized clinical study. SETTING: Social Security Agency, Aegean Obstetrics and Gynecology Teaching Hospital, Department of Reproductive Endocrinology and Infertility, a tertiary referral center. PATIENT(S): Eighty women with IH who had been admitted to our center. INTERVENTION(S): Patients were randomly and equally assigned to receive flutamide (250 mg/d for the first 10 days of the cycle) and spironolactone plus Diane 35 (spironolactone 100 mg/d; Diane 35 is a combination tablet of 2 mg cyproterone acetate and 35 microg ethinylestradiol/d) for 9 months. MAIN OUTCOME MEASURE(S): Modified Ferriman-Gallwey (F-G) score and hormonal profile before treatment and at the end of treatment. RESULT(S): In spite of the fact that there were no statistically significant differences in modified F-G scores in between the two groups, a significant decrease in modified F-G scores was observed in the flutamide (from 19.93 +/- 4.31 to 15.58 +/- 4.28) and spironolactone plus Diane 35 (from 18.77 +/- 3.76 to 14.54 +/- 3.29) groups. There were also no differences between the two groups with respect to hormonal profiles including serum FSH, LH, free T, 17-OH-progesterone, and DHEAS levels. No major side effect, including liver toxicity, was observed in either group. CONCLUSION(S): Our data suggest that both therapies have similar effectiveness in the treatment of IH.

Adult↗
PubMed2006

Development and validation of an HPLC method for the determination of spironolactone and its metabolites in paediatric plasma samples.

An HPLC method has been developed and validated for the determination of spironolactone, 7 alpha-thiomethylspirolactone and canrenone in paediatric plasma samples. The method utilises 200 microl of plasma and sample preparation involves protein precipitation followed by Solid Phase Extraction (SPE). Determination of standard curves of peak height ratio (PHR) against concentration was performed by weighted least squares linear regression using a weighting factor of 1/concentration2. The developed method was found to be linear over concentration ranges of 30-1000 ng/ml for spironolactone and 25-1000 ng/ml for 7 alpha-thiomethylspirolactone and canrenone. The lower limit of quantification for spironolactone, 7 alpha-thiomethylspirolactone and canrenone were calculated as 28, 20 and 25 ng/ml, respectively. The method was shown to be applicable to the determination of spironolactone, 7 alpha-thiomethylspirolactone and canrenone in paediatric plasma samples and also plasma from healthy human volunteers.

Canrenone↗
PubMed2004

Additive effects of combined valsartan and spironolactone on cardiac aldosterone escape in spontaneously hypertensive rats.

The additive effects of combined valsartan and spironolactone on plasma and cardiac aldosterone escape were evaluated in spontaneously hypertensive rats (SHRs). Twenty-four SHRs were treated with valsartan (30 mg/kg body weight per day), spironolactone (20 mg/kg body weight per day) and a combination of both for 4 months. Blood was collected and plasma aldosterone (PA) was estimated with radioimmunoassay (RIA). Ex vivo heart perfusion was performed, the ex vivo cardiac aldosterone (EXCA) was assessed by RIA after high-performance liquid chromatography separation. PA and EXCA were significantly decreased after one month but increased after 4 months in valsartan administration group. The combined valsartan and spironolactone therapy normalized cardiac aldosterone levels. This study provides the first evidence that the long-term treatment with Angiotensin II type 1 receptor antagonist (AT1A) induces local aldosterone escape in cardiovascular tissue, whereas the combined AT1A and spironolactone therapy inhibits the escape in hypertensive rats.

Aldosterone↗
PubMed2006

Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders.

Multiple studies now demonstrate that autism is medically characterized, in part, by immune system dysregulation, including evidence of neuroglial activation and gastrointestinal inflammation. This neuroglial process has further been characterized as neuroinflammation. In addition, a subset of autistic children exhibit higher than average levels of androgens. Spironolactone is an aldosterone antagonist and potassium-sparing diuretic with a desirable safety profile. It possesses potent anti-inflammatory and immune modifying properties that might make it an excellent medical intervention for autism spectrum disorders. Furthermore, spironolactone demonstrates substantial anti-androgen properties that might further enhance its appeal in autism, particularly in a definable subset of hyperandrogenic autistic children. One case report is briefly reviewed demonstrating objective clinical improvements in an autistic child after spironolactone administration. Additional research in controlled trials is now needed to further define the risks and benefits of spironolactone use in children with autism.

Androgen Antagonists↗
PubMed2005

Spironolactone improves carotid artery fibrosis and distensibility in rat post-ischaemic heart failure.

Myocardial infarction causes neurohormonal activation involving aldosterone and angiotensin II (AngII). These hormones may increase arterial stiffness, an independent cardiovascular risk factor contributing to progression of congestive heart failure (CHF). This study aimed to determine the effect of aldosterone and AngII blockade on carotid artery distensibility and collagen density in adult Wistar rats with MI-induced CHF. Five groups were studied: Sham-operated, CHF, CHF + spironolactone, CHF + lisinopril, CHF + Spironolactone + Lisinopril. After echocardiography, in vitro isobaric carotid distensibility (echo-tracking technique) and collagen density were measured, and the incremental elastic modulus (Einc) calculated. In the CHF group, intra-ventricular pressure and cardiac weight were increased; carotid distensibility was reduced (CHF: 0.42 +/- 0.30 per mmHg(3) versus sham: 1.75 +/- 0.50 per mmHg(3); P < 0.001), and collagen content increased by 87% when compared to sham. All treatments reduced intra-ventricular pressure, carotid distensibility and fibrosis when compared to CHF but did not change cardiac weight. However, carotid distensibility and intra-ventricular pressure were not completely restored towards sham values and were significantly and inversely related. Spironolactone, which did not decrease significantly blood pressure, was the only drug reducing Einc independently of wall stress (WS). Thus, MI-induced CHF was associated with carotid artery remodeling. This vascular change, which may contribute to maintain cardiac hypertrophy and CHF, is largely prevented by AngII and aldosterone blockade. Only spironolactone reduced the stiffness of carotid wall material independently of blood pressure and WS.

Animals↗
PubMed2000

Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy.

Epidemiologic studies have shown an important increase in the high mortality of patients with congestive heart failure (CHF) despite optimal medical management. Ventricular arrhythmia was recognized as the most common cause of death in this population. Electrolyte imbalance, myocardial fibrosis, left ventricular dysfunction, and inappropriate neurohumoral activation are presumed responsible for sudden cardiac death. In this study, we focused on the deleterious effects of the overproduction of aldosterone that occurs in patients with CHF. Secondary hyperaldersteronism can be part of several factors thought to be responsible for sudden cardiac death. We randomized 35 patients (32 men, aged 48 +/- 9 years) with systolic dysfunction (ejection fraction 33 +/- 5%) and New York Heart Association class III CHF secondary to dilated or ischemic cardiomyopathy into 2 groups. The treatment group received spironolactone, an aldosterone receptor antagonist, along with standard medical management using furosemide, angiotensin-converting enzyme inhibitors, and digoxin. The control group received only the standard medical treatment. Holter monitoring was used to assess the severity of ventricular arrhythmia. After 20 weeks, patients who received spironolactone had a reduced hourly frequency of ventricular premature complexes (VPCs) (65 +/- 18 VPCs/hour at week 0 and 17 +/- 9 VPCs/hour at week 16) and episodes of nonsustained ventricular tachycardia (VT) (3.0 +/- 0.8 episodes of VT/24-hour period at week 0, and 0.6 +/- 0.3 VT/24-hour period at week 16). During monitored treadmill exercise, a significant improvement in ventricular arrhythmia was found in the group receiving spironolactone (39 +/- 10 VPCs at week 0, and 6 +/- 2 VPCs at week 16). These findings suggest that aldosterone may contribute to the incidence of ventricular arrhythmia in patients with CHF, and spironolactone helps reduce this complication.

Analysis of Variance↗
PubMed1996

Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]).

The present study enrolled 214 patients, aged 26 to 83 years, with symptomatic New York Heart Association class II through IV congestive heart failure. Patients were continued on their previous therapeutic regimens, which included an angiotensin-converting enzyme (ACE) inhibitor and a loop diuretic with or without digitalis. Patients were randomized to 1 of 5 parallel treatment groups: placebo or spironolactone at a single daily dose of 12.5, 25, 50, or 75 mg for 12 weeks. Serum levels of creatinine, urea nitrogen, potassium, plasma renin activity, and N-terminal proatrial natriuretic factor (pro-ANF), as well as urinary aldosterone levels, were measured periodically. Measurements at 12 weeks versus baseline values indicated significant increases in plasma renin activity and aldosterone excretion and significant decreases in systolic and diastolic blood pressure and pro-ANF. Hypokalemia (serum potassium < 3.4 mmol/L) occurred in 10% of placebo-treated patients and in 0.5% of the spironolactone group. The incidence of hyperkalemia (serum potassium > or = 5.5 mmol/L) was 5% for the placebo group, whereas it was 5%, 13%, 20%, and 24% for the 12.5-, 25-, 50- and 75-mg spironolactone treatment groups, respectively. Predictors of hyperkalemia included the use of ACE inhibitors other than captopril, ACE inhibitor dose, and baseline elevation of serum creatinine or potassium levels. Thus, daily doses of 12.5 to 25 mg of spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics, and digitalis are relatively safe (provided that serum potassium levels are monitored) and effective in blocking the effects of aldosterone, while reducing the potential for hypokalemia in patients with heart failure.

Adult↗
PubMed1991

Predictors of clinical response in hirsute women treated with spironolactone.

OBJECTIVE: To examine the clinical efficacy of low dose spironolactone in hirsute women. DESIGN: Retrospective. SETTING: Outpatient endocrinology clinic. PATIENTS: One hundred nine consecutive women prescribed 75 to 100 mg/d spironolactone for at least 4 months in whom adequate follow-up data were available. RESULTS: Hirsutism improved in 72% of the women. Women with regular menses, whether or not they used oral contraceptives (OCs), had the highest response rate to spironolactone (78%), whereas women with irregular menses who did not use an OC had the lowest response rate (55%). Favorable responses were associated with increased severity of hirsutism (P = 0.04) and lower serum dehydroepiandrosterone sulfate levels (P = 0.05). Responders and nonresponders did not differ significantly in age (P = 0.10), duration of hirsutism (P = 0.14), pretreatment serum testosterone (T) (P = 0.48), or body mass index (P = 0.11). However, when each parameter was divided into subsets, trends toward decreasing response were observed with increasing age, duration of hirsutism over 15 years, and increasing serum T level. CONCLUSION: Low-dose spironolactone improves hirsutism in a majority of hirsute women, irrespective of age, severity or duration of hirsutism, menstrual status, or serum hormone levels.

Adolescent↗
PubMed1996

Comparison of spironolactone-oral contraceptive versus cyproterone acetate-estrogen regimens in the treatment of hirsutism.

OBJECTIVE: To compare the efficacy of two antiandrogens, cyproterone acetate (CPA) and spironolactone, in the treatment of hirsutism. DESIGN: Prospective randomized single-blinded study. SETTING: A tertiary hirsutism clinic. PATIENTS: Forty-two premenopausal patients with hirsutism were selected. INTERVENTIONS: Subjects were randomized to receive either 100 mg spironolactone and an oral contraceptive (OC) containing 150 microg desogestrel and 30 microg ethinyl E2 or 50 mg CPA daily on days 1 to 10 of the menstrual cycle, which was administered with 35 microg ethinyl E2 daily on days 1 to 21. MAIN OUTCOME MEASURES: Hirsutism scores were measured according to Ferriman-Gallwey scoring system and side effects were monitored for 9 months of treatment. Blood samples were taken at each visit for assessment of endocrine, biochemical, and hematologic parameters. RESULTS: Hirsutism scores were decreaded significantly in both groups at the end of 9 months. The percent of change in hirsutism scores in CPA and spironolactone group were as follows: 19.23% +/- 14.77% and 24.48% +/- 14.27% at 3 months; 39.01% +/- 19.77% and 37.46% +/- 16.90% at 6 months; and 51.89% +/- 20.87% and 46.39% +/- 16.10% at 9 months, respectively. There was a trend toward a better response with CPA treatment, which did not achieve significance. None of the patients stopped treatment because of side effects. CONCLUSION: The present data suggest that both spironolactone and CPA were similarly effective in treatment of hirsutism.

17-alpha-Hydroxyprogesterone↗
PubMed1998

Comparison of Diane 35 and Diane 35 plus spironolactone in the treatment of hirsutism.

OBJECTIVE: To compare the clinical efficacy and safety of Diane 35 (cyproterone acetate [2] mg and ethinyl estradiol [35 microg]) plus spironolactone [100 mg] combination and Diane 35 alone in the treatment of hirsutism. DESIGN: Prospective clinical study. SETTING: Outpatients in Erciyes University Medical School. PATIENT(S): Fifty women with hirsutism. INTERVENTION(S): Group I patients (n = 22) were treated with Diane 35 alone and group II patients (n = 28) with Diane 35 plus spironolactone [100 mg]. MAIN OUTCOME MEASURE(S): The basal hormone levels total and free T, androstenedione, DHEAS, sex hormone-binding globulin (SHBG), and prolactin (PRL) were measured by RIA before the study. Free T, SHBG, and DHEAS were also measured at 6-month intervals for 12 months. Hirsutism was graded at 6-month intervals. RESULT(S): The basal hormone levels were similar between the groups. Hirsutism score significantly decreased at the end of the therapy in both groups. The reduction in hirsutism score in group II at 12 months was greater than in group I. But the scores before the treatment, at 6 and 12 months were similar between the groups. CONCLUSION(S): Although the actual hirsutism score and free T concentration are not significantly different between the two groups at 12 months, percentage change in the hirsutism score at 12 months was higher in the Diane 35 plus spironolactone group. Therefore, the addition of spironolactone to Diane 35 may have a synergistic effect on hirsutism score.

Adolescent↗
PubMed1998

Differential induction of glutathione S-transferase subunits by spironolactone in rat liver, jejunum and colon.

The effect of spironolactone pretreatment on glutathione S-transferase activity and on the relative content of the principal subunits (Ya, Yc, Yb1, Yb2 and Yp or 1, 2, 3, 4 and 7 respectively) was studied in rat liver, jejunum and colon. Male Wistar rats were injected with spironolactone i.p. at daily doses of 50, 100 and 200 micromol/kg body wt for 3 consecutive days. Glutathione S-transferase activities were assayed using 1-chloro-2,4-dinitrobenzene as substrate. Changes in subunit composition were evaluated by Western blot analysis in rats treated with the highest dose of spironolactone. The results demonstrated a dose-dependent increase in enzyme activity in liver, while in jejunum the three tested doses exhibited the same magnitude of induction. No significant difference in glutathione S-transferase activity was observed between control and treated rats for the colon. Immunoblot analysis revealed more Ya and Yp protein in liver (140 and 118% increase respectively) and jejunum (45 and 145% increase respectively) from treated rats. While Ya and Yp relative contents were similar in jejunum, the latter subunit slightly contributed to total GST in liver, even in SL-treated animals. The inducer produced no change in subunit composition in colon. In conclusion, spironolactone was able to increase glutathione S-transferase activity mainly by induction of Ya subunit in liver and Yp subunit in jejunal mucosa, without affecting colonic enzyme.

Animals↗
PubMed1978

The effect of the administration of spironolactone on the concentration of plasma testosterone, estradiol and cortisol in male dogs (1).

The effect of the administration of spironolactone, deacetylspironolactone, aldadiene or soldactone on the concentration of plasma testosterone, estradiol, and cortisol was examined in male dogs. Decreases of 60 to 75% in plasma testosterone and estrodiol occur only at high doses (100 mg/kg) of spironolactone or deacetylspironolactone but not at low doses of spironolactone (5 to 10 mg/kg); they occur concomitantly with similar decreases of androgen formation by the testis. No decreases were detected with aldadiene or soldactone. Treatment of dogs with spironolactone (100 mg/kg) also lowered by 50 to 65% the concentration of cortisol in adrenal venous plasma.

Animals↗
PubMed1986

Treatment of hirsutism with spironolactone.

The discovery of compounds possessing antiandrogenic activities has led to their utilization in the treatment of hirsutism of various aetiologies. Spironolactone generally lowers the plasma testosterone by altering its formation and metabolism as well as by decreasing its blood production rate; the medication also contributes to increase the peripheral conversion of testosterone to oestradiol. A major action is that spironolactone inhibits androgen binding to receptor molecules in the cytosol or the nucleus of target tissues such as the skin. During the last five years, we have studied over 450 cases of hirsutism. Approximately 80% of these women were treated with spironolactone alone or in association with dexamethasone (2.5%) or an oral contraceptive (15%). Hirsutism was classified according to Lorenzo (1970). Good to very good clinical results were observed in 80% of the patients who were under study for a minimum of 3 to 4 years. Adverse side-effects were recorded in less than 5% of our group of patients. On the basis of our data and our clinical experience, we conclude that spironolactone is an effective drug in the treatment of female hirsutism.

17-alpha-Hydroxyprogesterone↗
PubMed1997

Spironolactone prevents Na+/H+ exchange enhancement in primary aldosteronism.

The study was undertaken to determine the possible effect of an aldosterone antagonist, spironolactone (SP), on red blood cell sodium-hydrogen exchange (NHE) enhancement in primary aldosteronism (PA) and essential hypertension (EH). NHE was measured as the amiloride-inhibited fraction of H+ efflux (V max) from erythrocytes (pHi 6.40 +/- 0.05) into a Na+-containing medium (pHo 8.00 +/- 0.05). Subjects were 12 hypertensive patients with aldosterone-producing adrenal adenoma (six treated with 200 mg/day spironolactone for an least 5 days and six drug-free), 20 essential hypertensives (10 treated with the same regimen of spironolactone and 10 drug-free), and 20 healthy controls. Treatment with spironolactone decreased NHE in PA patients but did not change the mean NHE in essential hypertensives. It is concluded that SP may be useful to differentiate between elevated NHE in PA and essential hypertension.

Adult↗
PubMed2001

Direct estimation of the in vivo dissolution of spironolactone, in two particle size ranges, using the single-pass perfusion technique (Loc-I-Gut) in humans.

AIM: The objective of this in vivo dissolution study was to investigate the usefulness of the Loc-I-Gut technique for differentiating between the in vivo dissolution rate of two particle sizes of spironolactone, and to compare these in vivo results with corresponding in vitro data. METHODS: The study included six volunteers, and consisted of three sequential parts (I, II, III). In parts I and III the in vivo dissolution was measured directly by perfusing a semi-open segment in the proximal jejunum. In part II, a solution of spironolactone was administered orally, and the plasma concentration time profile was followed for 48 h. The in vitro dissolution was measured using flow-through cells and different dissolution media simulating human gastrointestinal fluids. RESULTS: A difference in in vivo dissolution rate of the two different particle sizes was observed, based on perfusion data. This difference was not pronounced in the relative bioavailability of spironolactone administered in two different particle sizes. The relative bioavailability was dependent on the bile acid concentration in vivo. In vitro, dissolution rate of the smaller particles was improved at fasted state bile acid concentrations, while the larger particles were only significantly affected at fed state bile acid concentrations. CONCLUSION: In vivo dissolution studies discriminated between the dissolution rate of the two different particle sizes of spironolactone, based on the perfusate samples. The lack of difference in relative bioavailability, might be explained by the insufficient wash-out of particles after ending the perfusion, reabsorption of surface active ingredients along the GI tract, relatively small difference in particle size and the large inter- and intra-individual differences in pharmacokinetic variables.

Adsorption↗