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PubMed1998

Investigation on the bioequivalence of 2 oral preparations containing spironolactone and furosemide.

The bioequivalence of 2 formulations containing spironolactone and furosemide was determined. The test preparation was Spironolacton 50 plus Heumann tablets, a new generic spironolactone preparation, developed by Heumann Pharma GmbH, the reference preparation was Osyrol 50-Lasix capsules, Hoechst AG. The study was designed as a randomized 2-period, 2-sequence, crossover study. A daily dose of 50 mg spironolactone and 20 mg furosemide was administered over 5 days to 24 healthy volunteers in the fasting state. Plasma samples were assayed for spironolactone, its 2 active metabolites canrenone and 7alpha-thiomethylspirolactone, and furosemide by HPLC. Statistical analysis was performed by ANOVA and by nonparametric methods. Because spironolactone was rapidly eliminated from plasma, its pharmacokinetics could only be evaluated with regard to maximum plasma levels. This parameter did slightly miss the criteria for bioequivalence. For canrenone and 7alpha-thiomethylspirolactone bioequivalence was given. For furosemide the test formulation was found to be equivalent concerning the extent of bioavailability. Bioequivalence with regard to maximum concentrations could not be shown. However, from the point of view of pharmacodynamics, this finding may not necessarily be of clinical relevance.

Adult↗

PubMed1998

[Spironolactone protection from hydralazine-induced stress in the rat myocardium].

OBJECTIVES: We wished to verify the possible protective action of spironolactone (SPIRO), through its blocking action of slow calcium channels, in what concerns behavioural, morphologic, histochemical and ultrastructural alterations caused by experimental exposure to hydralazine (HZ), due to the excess release of catecholamines and the cellular influx of calcium. MATERIAL AND METHODS: Forty-eight adult male Wistar rats [correction of mice] were divided into 4 groups. The control group (CON) was administered olive oil for 4 days and distilled water i.v. on the last day, the hydralazine group (HZ) was administered olive oil for 4 days and 40 mg/kg i.v. of hydralazine on the last day; the spironolactone group (SPIRO) was administered 20 mg/kg of spironolactone diluted in olive oil for 4 days and distilled water on the last day; and the hydralazine with spironolactone group (HZ + SPIRO) was administered 20 mg/kg of spironolactone diluted in olive oil for 4 days and 40 mg/kg i.v. of hydralazine on the last day. The rats [correction of mice] were dissected and fragments of the myocardium removed for electron microscopy, and suprarenal fragments removed for light microscopy. Mitochondrial alterations characterised by ridge edema, lysis and vacuolisation (Cristolysis rate = damaged mitochondria/total mitochondria) were considered in the ultrastructural study. RESULTS: Light microscopy of the HZ group showed intense depletion of lipids in the cortical region of the suprarenals. The HZ + SPIRO group did not present significant alterations and was similar in appearance to the CON group. The ultrastructural study of the myocardium revealed the following rates of Cristolysis: CON group = 5.8%, HZ group = 91.9%, SPIRO group = 10.9%, HZ + SPIRO group = 10.2%*. (* = p < 0.001 chi-square test). CONCLUSION: The use of spironolactone in a model of stress induced by hydralazine caused: 1. Myocardial protection shown by reduced lesion of cardiomyocytes; 2. Protection of the suprarenals.

Adrenal Glands↗

PubMedDate not supplied

Spironolactone therapy in older patients--the impact of renal dysfunction.

Low dose spironolactone reduces the risk of death from heart failure. We examined the effects of spironolactone on potassium homeostasis in a cohort of elderly patients with congestive heart failure (CHF). Eighteen patients >70 years, mean 80.5 (+/- SD 6.3) with New York Heart Association CHF Grade II-IV were enrolled. All patients were commenced on 25 mg spironolactone daily. The dose was reduced to 12.5 mg daily when hyperkalemia (potassium>5.0) occurred. A serum creatinine of >150 micromol/l was defined as indicating renal impairment (RI). Blood pressure, pulse rate, urea, creatinine, Na+ and K+ were measured at baseline, day 2-5, day 28 and more often if clinically indicated. Nine of those recruited had RI. Baseline serum potassium was significantly higher in those with RI, mean 4.56 (+/- 0.30) vs. 4.04 (+/- 0.30) mmol/l (P<0.01). Six patients with RI developed hyperkalemia versus one of those with serum creatinine <150 micromol/l (P<0.05). Serum K+ returned to normal in all patients when the dose of spironolactone was reduced to 12.5 mg daily with one exception in whom the medication was withdrawn. When spironolactone is prescribed to older patients with CHF, hyperkalemia appears more likely in those with RI. Halving the dose to 12.5 mg daily results in normalisation of serum potassium. Older patients commencing spironolactone therapy should have serum potassium monitored frequently, particularly in the presence of RI.

Journal Article↗

PubMed2003

Factors predicting hyperkalemia in patients with cirrhosis receiving spironolactone.

OBJECTIVE: To evaluate the factors leading to hyperkalemia in patients with cirrhosis receiving spironolactone. DESIGN: An observational, analytical, case control study. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital. Six months. SUBJECTS AND METHODS: One hundred and fifty consecutive patients (100 males, 50 females) with cirrhosis of liver, hospitalized for decompensated disease and receiving spironolactone for at least two weeks before admission, were included in this study. Patients with hyperkalemia (n=67) having potassium level >5 mmol/l were compared with patients who had normal potassium level 5 mmol/l (n=83). The parameters taken into account were age, gender of the patients, type and dose of diuretics along with concomitant medicines, diastolic blood pressure, edema, ascites, blood urea nitrogen, serum creatinine, electrolytes, bilirubin, albumin, prothrombin time, Child class, and Child Pugh score. RESULTS: Patients with hyperkalemia (K > 5 mmol/l) had higher blood urea nitrogen, serum creatinine and bilirubin levels (p= 0.004, 0.001 and 0.044 respectively). Their serum sodium and albumin levels were lower (p= 0.000 and 0.017 respectively). They had advanced cirrhosis with high Pugh score (p= 0.003). These patients were on higher dose of spironolactone (p =0.001). Multivariate analysis showed that dose of spironolactone >100 mg /day, serum creatinine >1.3 mg/dl, persistence of ascites and edema, and female gender were important predictors of development of hyperkalemia. CONCLUSION: Patients with cirrhosis receiving high dose of the diuretic, having edema, ascites and high serum creatinine are at the greater risk of developing hyperkalemia during spironolactone therapy.

Female↗

PubMed2006

Use and side-effect profile of spironolactone in a private cardiologist's practice.

BACKGROUND: The beneficial effects of spironolactone on the treatment of cardiovascular diseases are well known, but translating these benefits into private practice can be difficult because of the drug's side-effect profile. HYPOTHESIS: When patients are monitored over the long term, spironolactone can be used safely with an acceptable side-effect profile. METHODS: We retrospectively studied 762 patients taking spironolactone over a 7-year period in a cardiologist's referral-based practice and monitored them for side effects from the medication. RESULTS: Data were available on 762 patients. The average age of our patients when started on the medication was 67.2 +/- 0.5 years. Of these, 585 (76.8%) patients were treated for heart failure and 155 (20.3%) for hypertension. An average dose of 38.4 +/- 1.4 mg of spironolactone was used for treatment of all conditions. Of the 762 patients, 81 (10.6%) experienced side effects while using the medication; 40 had hyperkalemia (5.3%), 14 had gynecomastia (1.8%), and 15 had gastritis (2%). Of the patients with hyperkalemia, average creatinine clearance decreased from 64.6 +/- 5.8 ml/min at therapy start to 50.3 +/- 5.5 ml/min at the time of onset of side effects. CONCLUSION: Spironolactone can be used with an acceptable side-effect profile as long as patients are monitored long-term while receiving the medication.

Aged↗

PubMed1976

Spironolactone and potassium canrenoate in normal man.

The pharmacological activity of single doses of the two aldosterone antagonists, potassium canrenoate and spironolactone, was examined in two studies in healthy volunteers. Both drugs were active in reversing urinary electrolyte changes induced by fludrocortisone in periods 2 to 16 hr after treatment. Potassium canrenoate was significantly less potent that spironolactone on a weight or molar basis, with best estimates of the relative potency potassium canrenoate: spironolactone of approximately 0.3:1. On a weight basis the two drugs yielded plasma levels of the metabolite canrenone which were approximately equivalent. The results indicate that canrenone is not the principal pharmacologically active metabolite of spironolactone. Our study suggests that a major part of the renal antimineralocorticoid activity of spironolactone may be attributable to minor sulfur-containing metabolites or their precursors having a high renal clearance that affords access to their site of activity via the renal tubular fluid.

Canrenoic Acid↗

PubMed1977

Spironolactone and canrenoate-K: relative potency at steady state.

Relative dose ratios of the mineralocorticoid antagonists spironolactone (100 mg and 200 mg daily) and canrenoate-K (200 mg daily) at steady state were defined in six healthy subjects with fludrecortisone as the mineralocorticoid agonist. The urine log 10 Na/K responses during spironolactone treatments were consistent with the law of mass action. The potency of canrenoate-K was 0.68 (95% C.L. 0.53 to 0.89) that of spironolactone on a weight basis. Approximately 72% of the renal antimineralocorticoid activity of spironolactone could attributed to the metabolite canrenone. The results at steady state are contrasted with those of a previously study comparing single doses of spironolactone and canrenoate-K.

Administration, Oral↗

PubMed1978

Role of aldosterone in the antihypertensive effect of spironolactone in essential hypertension.

In order to evaluate the relationship between aldosterone status and the blood pressure-lowering effect of spironolactone, 38 patients with essential hypertension were treated with spironolactone (400 mg/day) during one week in hospital on a rigidly sodium-restricted diet. The degree of hyperaldosteronism was assessed by the aldosterone secretory rate after 5 days of salt loading (315 mmol Na+/day). The mean arterial pressure decreased 5.6% (range, -21 to +8%). When the patients were divided into subgroups with low and normal renin activity, there was no difference in the change in mean arterial pressure (-5.0% and -6.1%). When the patients were divided into three groups with low, normal, and supranormal aldosterone secretory rates, the last group had a significantly greater fall in blood pressure after the spironolactone than the other groups (-1.0, -7.1, -11.1%). Thus there was a correlation between the aldosterone secretory rate after sodium loading and the blood pressure-lowering effect of spironolactone (r = -0.53, p less than 0.01). The blood pressure-lowering effect was not related to changes in body weight, kidney function, or plasma electrolytes. Our findings do not provide solid arguments for the view that the blood pressure-lowering effect of high dose spironolactone is due to its antimineralocorticoid activity, but the correlation between the degree of hyperaldosteronism and the blood pressure-lowering effect strongly suggests that aldosterone does play a role in the genesis or maintenance of the hypertension in these patients.

Adult↗

PubMed1979

Hydrochlorothiazide and spironolactone in hypertension.

A double-blind study of hydrochlorothiazide and spironolactone, alone and in combination, was conducted in 49 patients with mild-to-moderate essential hypertension after a 4-wk placebo washout period. In the whole group mean arterial blood pressure fell to levels of less than or equal to 107 mm Hg or declined by more than 15 mm Hg in 78% of the patients after twelve weeks of treatment. Sixty-nine percent of patients receiving hydrochlorothiazide alone developed serum potassium levels lower than 3.5 mEq/L; serum potassium levels were above 5.5 mEq/L in 2 patients (5.5%) receiving spironolactone 400 mg/day. Uric acid levels rose in all patients, more in those on hydrochlorothiazide, but clinical gout did not develop in any subject. Hydrochlorothiazide, spironolactone, and the combination of the two are effective antihypertensives. Spironolactone in doses of 200 and 400 mg/day was associated with side effects but did not induce a greater antihypertensive effect than doses of 100 mg/day. Our data suggest that when hydrochlorothiazide is associated with potassium loss, when gout or elevated uric acid levels are of concern, or when carbohydrate tolerance is abnormal, supplementation or replacement with spironolactone (up to 100 mg/day) may be useful in controlling blood pressure while reducing side effects.

Adult↗

PubMed1977

Disposition kinetics of spironolactone in hepatic failure after single doses and prolonged treatment.

Six male patients withhistologically characterised, decompensated liver disease who had not previously received spironolactone, were given orally Aldactone 7 mg/kg with 3H-spironolactone 100muCi. The kinetics of the drug were studied in plasma and urine for 6 days. Then, Aldactone 7 mg/kg was given daily for 12 consecutive days, and the pharmacokinetics of a single dose of 3H-spironolactone were re-examined. The kinetics of total radioactivity, as well as of fluorigenic metabolites in plasma, after the first single dose of spironolactone did not differ in patients and normal test subjects; similar percentages of the dose given were excreted within 6 days in urine from patients (47.47 +- 4.88%) and from controls (53.68 +- 2.04%). The kinetics of CH2CI2/H2O distribution coefficients of labelled material in plasma and urine, as well as TLC analysis of the CH2CI2 soluble fraction, revealed no significant differences from controls. After treatment for 12 days with spironolactone, 4 out of 6 patients showed marked acceleration in the rate of elimination of radioactivity from plasma and a corresponding increase in excretion of labelled compounds in urine. Analysis of the excretion products in urine revealed proportionally increased excretion and no evidence of selective induction of a single degradation step. In contrast, delayed elimination was observed in the 2 other patients after 12 days' treatment. However, this was due to dehydration and oliguria caused by over-treatment with the diuretic.

Adult↗

PubMed1976

Metabolism of digitoxin in man and its modification by spironolactone.

The effect of spironolactone on the metabolism of intravenously administered 3H-digitoxin (80 muCi) was investigated in eight patients. In three of them the labelled glycoside was given on a second occasion after spironolactone treatment had been discontinued for at least 65 days. Of total urinary radioactivity 79% was unaltered drug and 12% consisted of water soluble compounds. No digitoxigenin or digoxigenin and only trace amounts (less than 2 %) of digoxin and the bis- and monoglycosides of digoxigenin were found. After spironolactone total urinary radioactivity was unchanged but the fraction eliminated as unchanged digitoxin fell from 79 to 66 % and the water soluble compounds increased from 12 to 26 % (p less than 0.05). In addition spironolactone caused a 20 ( reduction in the half-life of serum radioactivity (p less than 0.01) and a 16 % reduction in the volume of distribution (p less than 0.05). Induction of hepatic enzymes by spironolactone is proposed to explain the alteration in the metabolism of digitoxin in man. Both the altered metabolic pattern and the reduction in the volume of distribution appear to contribute to the reduction in half-life.

Aged↗

PubMed1975

Effect of phenobarbital, spironolactone and pregnenolone-16 alpha-carbonitrile on bile formation in the rat.

The effects of pretreatment for 4 days with the hepatic microsomal enzyme inducers phenobarbital (8 mg/100 g body weight), spironolactone (20 mg/100 g body weight) and pregnenolone-16alpha-carbonitrile (7 mg/100 g body weight) on bile flow and bile pipid secretion have been compared in rats. Similar to phenobarbital, spironolactone and pregnenolone-16alph-carbonitrile increased bile flow but did not alter bile salt excretion, indicating that these agents increased bile salt independent bile formation. This finding could be substantiated for spironolactone by studies of the relationship between bile salt excretion and bile flow during bile salt infusions. Whereas phenobarbital decreased cholesterol and phospholipid secretion to 39 and 49 per cent, respectively, spironolactone and pregnenolone-16alpha-carbonitrile more than doubled cholesterol excretion without influencing phospholipid output. As a consequence, marked differences in the effect on cholesterol saturation were observed: a decrease by phenobarbital and an increase following spironolactone and pregnenolone-16alpha-carbonitrile. The present studies demonstrate that different types of enzyme inducers may share certain effects on bile formation and differ in others.

Animals↗

PubMed1975

Changes of fractional renal clearance of magnesium after spironolactone administration in normal subjects.

Spironolactone, 200 mg/24 hours, was administered for 4 days to 18 clinically healthy subjects and 10 hospitalised patients with normal renal function. Changes of fractional renal clearance of magnesium before and after spironolactone administration were studied in the first group. Corresponding changes of the ratio of renal clearance of potassium to renal clearance of magnesium were studied in the second group. After spironolactone administration, fractional clearance of magnesium showed a statistically significant decrease in relation to its values before spironolactone administration, while the ratio clearance of potassium/clearance of magnesium showed no statistically significant change. The results suggest that spironolactone administration decreases the renal excretion of magnesium and potassium in an equivalent manner.

Adolescent↗

PubMed1983

The bioavailability of two new preparations of spironolactone tablets.

Two new preparations of spironolactone tablets containing 25 and 100 mg of spironolactone have been characterized by their disintegration time, tablet spironolactone content, dissolution profile and bioavailability in comparison with two known spironolactone preparations as reference material. The preparations were found to possess almost identical characteristics, assuring a proper clinical use of the new tablet preparations. For spironolactone, a positive outcome of the in vitro dissolution test coincides with an excellent bioavailability.

Adult↗

PubMed2005

Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity and lipid profile.

This prospective clinical trial was designed to assess the effects of a long-term therapy with spironolactone, with and without dietary-induced weight-loss, on clinical features, lipid profile and insulin levels in women with polycystic ovary syndrome (PCOS). Twenty-five patients (range of age 16-32 yr; 13 lean and 12 overweight) fulfilling formal diagnostic criteria for PCOS (oligomenorrhea and/or amenorrhea, biochemical and/or clinical evidence of hyperadrogenism) were studied at baseline and then received oral spironolactone (100 mg/die) for 12 months; association with lifestyle modifications was recommended to all over-weight patients. Clinical, endocrine and metabolic parameters [oral glucose tolerance test (OGTT), lipid profile] were measured at baseline and at the end of the antiandrogen treatment. The therapy was associated with a significant average decline of triglycerides in overweight subjects and with increased HDL-cholesterol levels in lean patients. The insulin levels at 60 min during OGTT, homeostasis model assessment-insulin resistance and area under curve of insulin were significantly lowered in overweight women after 12 months of spironolactone and weight loss and no negative changes in insulin secretion and sensitivity were observed in PCOS women after pharmacological treatment alone. The efficacy of spironolactone on the androgenic clinical aspects of PCOS has been confirmed in this study. Furthermore, our data show that long-term treatment with spironolactone exerts no negative effects on lipoprotein profile and glucose metabolism; more relevant beneficial effects on glucose and lipid metabolism were observed when the antiandrogen was associated with weight loss in overweight PCOS women.

Adolescent↗

PubMed1988

Lack of endocrine systemic side effects after topical application of spironolactone in man.

In six healthy male volunteers, the percutaneous absorption of spironolactone was compared with placebo in a double-blind crossover study. The subjects were randomly given either a cream containing 5% spironolactone or placebo to be applied in a randomized sequential way to a well defined skin area equivalent to 55% of body area. During the 72 h following the application of the ointment, blood levels of canrenone, the major metabolite of spironolactone, have been determined. In order to estimate the systemic antiandrogenic effect of spironolactone, plasma levels of 17-alpha-Hydroxy progesterone (17 alpha-OH-P), Testosterone (pT) and non-conjugated 3 alpha-Androstanediol (3 alpha-diol, metabolite of the active androgen 5 alpha-Dihydrotestosterone or DHT) as well as salivary Testosterone (sT) which relate to the free and active plasma testosterone fraction have also been measured. Urinary levels of canrenone have been determined 48 hours after cream application. No changes in any levels of these hormones have been detected and plasma canrenone levels were undetectable during the 72 hours of topical treatment. Topically administered, spironolactone appears to have only a local skin impregnation.

17-alpha-Hydroxyprogesterone↗

PubMedDate not supplied

Anti-androgenic therapy using oral spironolactone for acne vulgaris in Asians.

BACKGROUND: Few studies have addressed anti-androgenic therapy using oral spironolactone for acne in Asians. Obtaining this race-specific information is important because Westerners and Asians respond differently to hormone therapy. This study aimed to examine the efficacy and safety of oral spironolactone used to treat acne in Asians. METHODS: Spironolactone (initial dose, 200 mg/day) was administered orally to 139 Japanese patients (116 females and 23 males) with acne. Serum laboratory data, including various hormones and electrolytes, were examined for 25 of the subjects. RESULTS: Most of the female patients who completed the 20-week regimen exhibited excellent improvement (evaluated by a photographic grading scale), although some discontinued treatment because of menstrual disturbances or other reasons. The treatment was less efficacious for the males than for the females, and because gynecomastia developed in three male patients, spironolactone treatment for males was stopped. Examination of the serum of 25 patients did not identify any toxicity associated with the treatment. Drug eruptions and edema in the lower extremities were each seen in three patients. CONCLUSION: Oral spironolactone is effective and safe for the treatment of acne in Asian females, and can be a good option for severe, recurring, and widespread types of the condition.

Acne Vulgaris↗

PubMed1976

Controlled treatment of primary hypertension with propranolol and spironolactone. A crossover study with special reference to initial plasma renin activity.

Twenty-seven patients with hypertension were randomly allocated to a 10 month crossover study. Treatment consisted of spironolactone (200 mg/day for 2 months), propranolol (320 mg/day for 2 months) and combined administration of both drugs at half the dosage. Between treatment periods placebo was given for 2 months. Fourteen patients were previously untreated. The average pretreatment blood pressure for the entire group was 188/114 +/- 16/7(mean +/- standard deviation) mm Hg supine and 188/118 +/- 20/9 mm Hg standing. Both spironolactone and propranolol reduced blood pressure significantly in both the supine and standing positions. Upright plasma renin activity was determined by radioimmunoassay of angiotensin I. The average initial level was 1.9 +/- 1.2 (range 0.4 to 5.0) ng/ml/hr. There was a close correlation between plasma renin activity and the effects of the drugs: With increasing renin level the response to propranolol was better whereas the opposite was true for spironolactone. The combination of spironolactone and propranolol decreased the blood pressure still further in the supine and standing positions, irrespective of initial plasma renin activity. All patients achieved a normal supine pressure. Blood pressure and plasma renin activity returned toward pretreatment values during placebo administration. It is concluded that pretreatment levels of plasma renin activity can predict the antihypertensive response to propranolol and spironolactone. The combination of the two drugs, which have different modes of action, will effectively reduce blood pressure in hypertension. The results support the concept that the renin-angiotensin-aldo-sterone system may be involved in primary hypertension.

Adult↗