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At least 19 recordsLinked to original sources
PubMed1977

Renin levels and spironolactone treatment in general practice: similar blood pressure lowering effect of spironolactone in low and normal renin patients.

We examined the predictive value of plasma renin activity (PRA) in ambulatory patients in the selection of hypertensive patients for treatment with spironolactone. The patients were classified as frusemide responders or non-responders according to their PRA response to 80 mg frusemide orally. After an initial 4 weeks placebo period forty-five patients with the clinical diagnosis of benign hypertension (WHO stage I-II) entered a 4 X 4 week double blind treatment period during which they received spironolactone (Aldactone) 400, 300, 200 and 100 mg/day, respectively. Five out of the forty-five patients who started the trial were withdrawn on account of side-effects and five patients for other reasons. Of the thirty-five patients who completed the study eighteen belonged to the group of non-responders to frusemide, seventeen to the responders. A gradual and significant decrease in mean blood pressure occurred during the period with the high doses of spironolactone, without any significant difference between the groups. The blood pressure lowering effect obtained with the initial high doses was maintained during the consecutive periods when the doses was reduced to a half or even a fourth, in both groups. We conclude that PRA measurement in ambulatory patients is of little, if any, value for the selection of hypertensives for spironolactone treatment; this in contrast to similar selections performed on hospitalized patients.

Adult↗
PubMed1976

A comparison of the dissolution and bioavailability characteristics of three spironolactone tablet formulations, including preliminary data on two spironolactone metabolites.

The bioavailabilities of three spironolactone tablet formulations specially selected for major differences in in vitro dissolution tests were compared in normal male volunteers by measuring plasma and urinary levels of the pharmacologically active spironolactone metabolite canrenone. It was possible to demonstrate small but statistically significant differences in plasma canrenone concentration-time curves derived from the three formulations together with significant differences in the time course of urinary canrenone excretion. The bioavailabilities of the three formulations did not differ significantly although the tablet with the poorest in vitro dissolution produced a significant delayed peak canrenone concentration. The dissolution rate methodology and results are described and an approach to the development of improved in vitro dissolution tests for spironolactone is suggested. The use of a new method for canrenone estimation resulted in the incidental detection of two other quantitatively significant spironolactone metabolites and preliminary information is given on these.

Adolescent↗
PubMed1976

Mechanism of action of spironolactone on adrenocortical function in guinea pigs.

Spironolactone administration (50 mg/kg/day for 3 days) to make guinea pigs decreased cortisol production by adrenal slices in vitro. Adrenal microsomal and mitochondrial cytochrome P-450 levels were also decreased after treatment with spironolactone. The decline in adrenal cytochrome P-450 content was accompanied by decreases in microsomal 21-hydroxylase and mitochondrial cholesterol side-chain cleavage and 11beta-hydroxylase activities. Activities of other adrenal enzymes, such as delta4-hydrogenase and NADPH-cytochrome c reductase, were unaffected by spironolactone treatment. Cortisone administration to guinea pigs failed to mimic the effects of spironolactone on adrenal function, which indicates specificity of spironolactone action and excludes inhibition of adrenocorticotropin secretion as a mode of action. Addition of spironolactone to isolated adrenal mitochondria or microsomes produced type I spectral changes with spectral dissociation constants similar to those for endogenous steroid substrates. Spironolactone, in vitro, inhibited 11beta- but not 21-hydroxylase activity. The results indicate that spironolactone administration diminishes the activity of adrenal mitochondrial as well as microsomal cytochrome P-450-containing enzymes, resulting in a fall in corticosteroid output.

Adrenal Cortex↗
PubMed1976

In vitro and in vivo availability of spironolactone from oral dosage forms.

Tablet formulations of spironolactone with hydrochlorothiazide were studied in vitro and in vivo to evaluate the effect of formulation parameters on the bioavailability of spironolactone. The time required for 50% tablet dissolution (T50) in simulated gastric fluid was linearly correlated with the disintegration times of four experimental formulations and one commercial tablet of spironolactone and hydrochlorothiazide. Bioavailability studies were conducted in four healthy, female beagle dogs. The mean time to peak concentration of canrenone,f cancrenone, the major metabolite of spironolactone, was proportional to the T50 dissolution parameter. A study of spironolactone administered orally with and without hydrochlorothiazide showed that the bioavailability of spironolactone is not affected by hydrochlorothiazide. No significant difference in the bioavailability of spironolactone from one 100-mg and four 25-mg tablets were observed. Estimates of some pharmacokinetic parameters for canrenone closely agreed with those previously reported.

Animals↗
PubMed1992

Interaction of spironolactone with mercury. A possible molecular mechanism.

The protective activity of spironolactone (CAS 52-01-7) against mercuric acetate intoxication and the action of a spironolactone-mercuric acetate complex were studied on female Sprague-Dawley rats. Spironolactone was given 30 min after the toxic agent. It was found that spironolactone reversed the toxic effects of mercury, the mercury-spironolactone complex was much less toxic than mercuric acetate and its toxicity disappeared with the administration of spironolactone. A molecular mechanism for the protective action of spironolactone against mercury intoxication is proposed. The presence of both the steroidal skeleton and the thioacetyl group in the same molecule is necessary for the protection against mercury intoxication.

Animals↗
PubMed1977

Validation of plasma and urinary canrenone for determination of bioavailability of spironolactone--comparison of tablets with solution/suspension.

Data showing a linear relationship between spironolactone dose and the levels of canrenone in plasma and urine are presented to support the use of canrenone levels as a measure of the bioavailability of spironolactone. The bioavailability of a selected batch of spironolactone 25 mg tablets was compared to that of an oral aqueous suspension of spironolactone in a separate balanced cross-over study involving 10 healthy subjects. The tablets were equivalent to suspension as regards area under the plasma concentration-time curve and total urinary excretion of canrenone, the prinicipal unconjugated metabolite of spironolactone. Peak plasma concentrations of canrenone were higher, and were attained significantly earlier, after treatment with spironolactone in suspension. The results indicate that spironolactone was absorbed more rapidly from the suspension, but that the total absorption did not differ between the two formulations.

Administration, Oral↗
PubMed1975

[Spironolactone and thiabutazide in the treatment of essential hypertension (author's transl)].

The anti-hypertensive effect of spironolactone and thiabutazide was tested on 47 unselected patients with primary hypertension. They were divided into two groups according to the change in plasma-renin activity in response to furosemide administration: those with and those without response to stimulation, and sub-groups with low, normal or high plasma-renin activity (low renin hypertension; normal renin hypertension; high renin hypertension). During both 4-week treatment periods there was a distinct fall in systolic blood pressure, most marked in the patients without plasma renin stimulation (after spironolactone of about 26.2 mm Hg, after thiabutazide 29 mm Hg), the diastolic pressure fall being only slight in all groups (about 5-10 mm Hg). The plasma-renin activity and plasma-aldosterone concentration increased in all groups, after both spironolactone and thiabutazide three-to fourfold compared with the basal value, even in patients without change in plasma-renin activity after furosemide injections. Serum sodium content decreased after administration of spironolactone, increasing again after subsequent thiabutazide administration. Serum potassium content increased after spironolactone, decreasing after thiabutazide. There was no significant difference between either individual groups or different treatment periods with spironolactone or thiabutazide as far as weight, urine volume or electrolyte excretion in 24-hour urine was concerned.

Aldosterone↗
PubMed1992

Absence of hepatic p-nitrophenol UDP-glucuronosyltransferase induction by spironolactone in male rats: possible involvement of testosterone.

This study was performed to determine whether the lack of spironolactone induction of hepatic p-nitrophenol UDP-glucuronosyltransferase in male rats could be attributed to a presumed interaction between spironolactone and testosterone. The effect of spironolactone was evaluated in four experimental groups: normal females, normal males, castrated males, and castrated males that received testosterone. Enzyme activity was measured in native microsomes and in microsomes activated with UDP-N-acetylglucosamine or Triton X-100. When the nucleotide was included in the incubations, it was observed that enzyme activity in castrated male rats decreased to values approaching those obtained in normal females. Treatment of castrated animals with testosterone enhanced enzyme activity so that no significant difference existed between this group and normal males. This suggests that testosterone may act as an endogenous inducer of hepatic p-nitrophenol glucuronidation. It was also found that only females and castrated males showed an increase in enzyme activity in response to spironolactone treatment. Thus, the absence of an additive effect of endogenous or exogenous testosterone and spironolactone on UDP-glucuronosyltransferase activity suggests that these compounds could share a common induction mechanism, which appears to reach its maximal capacity in male rats. Possible explanations of this observation are discussed. From the analysis of enzyme activity in native and Triton X-100 activated microsomes, it can be postulated that spironolactone enzyme induction in female and castrated male rats could be attributed to an enhancement in the transferase synthesis rather than to an alteration of the membrane environment.

Animals↗
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↗
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↗
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↗
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↗