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PubMed1997

Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation.

AIMS/METHODS: Our aim was to study the antifibrotic and hemodynamic effects of simvastatin (SMV), pentoxifylline (PTX) and spironolactone (SPN), three drugs which may have antifibrotic and/or portal hypotensive properties, in a model of hepatic fibrosis and portal hypertension induced in rats by bile duct ligation. A blind study was performed in five groups of 53 Sprague-Dawley rats: sham, placebo (PL), SMV (2.5 mg x kg(-1) x J(-1)), PTX (50 mg x kg(-1) x J(-1)) and SPN (100 mg x kg(-1) x J(-1)). Drugs were administered by daily gavage over a 4-week period as soon as bile duct ligation was performed. At day 28, the following parameters were evaluated: area of hepatic fibrosis by image analysis after staining collagen with picrosirius and plasma concentrations of hyaluronate, splanchnic and systemic hemodynamics (radiolabeled microspheres). RESULTS: Portal venous pressure (PL: 15.5+/-1.5, SMV: 15.8+/-2.5, PTX: 15.9+/-1.8, SPN: 13.5+/-2.1 mmHg, p<0.05) and porto-systemic shunts (PL: 30+/-31, SMV: 18+/-27, PTX: 25+/-24, SPN: 5+/-4%, p<0.05) were significantly reduced in the SPN group; other hemodynamic parameters were not significantly altered. There was a significant correlation between portosystemic shunts and portal pressure (r(s)=0.47, p<0.01). The area of fibrosis was not significantly different among the four groups of bile duct ligated rats (PL: 8.7+/-3.9, SMV: 7.1+/-3.6, PTX: 7.8+/-2.7, SPN: 6.6+/-3.3%) but was higher than in sham rats (1.5+/-0.5%, p<0.001). Hyaluronate was significantly higher in bile duct ligated rats (from 374+/-162 to 420+/-131 microg/l, among the four groups) than in sham rats (52+/-16 microg/l, p<0.0001). CONCLUSIONS: In this model, none of the drugs prevented hepatic fibrosis. On the other hand, spironolactone decreased portal pressure and prevented porto-systemic shunts. Therefore, this drug may have beneficial effects in patients with early portal hypertension.

Animals↗
PubMed1985

Determination of the serum concentration of spironolactone and its metabolites by high-performance liquid chromatography.

A simple and rapid high-performance liquid chromatographic assay is described for the simultaneous determination in serum of the aldosterone antagonist spironolactone and its metabolites 7 alpha-thiomethylspirolactone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone and canrenone. Ultraviolet absorption at 240 nm was used to detect the different compounds after elution on a normal-phase column. Endogenous serum substances did not interfere with the assay. This method provides a convenient tool in pharmacokinetic studies of spironolactone, in contrast to previously reported aspecific fluorimetric assays or time-consuming thin-layer chromatographic analyses of radioactive biological material.

Canrenone↗
PubMed1983

Determination of canrenone, the major metabolite of spironolactone, in plasma and urine by high-performance liquid chromatography.

An assay procedure for measuring plasma and urine levels of canrenone is described. The drug is extracted with n-hexane-toluene (1:1, v/v) after adding spirorenone as internal standard, and is then separated from plasma constituents and metabolites by high-performance liquid chromatography followed by UV detection at 285 nm. The limit of detection is less than 5 ng/ml. Interference with a series of spironolactone and canrenone metabolites was not observed. Plasma levels and renal excretion of canrenone after oral administration of 200 mg of spironolactone and intravenous injection of 200 mg of potassium canrenoate to a healthy male volunteer were measured.

Administration, Oral↗
PubMed2002

Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure.

OBJECTIVES: This study was designed to assess the effects of spironolactone (SP) on left ventricular (LV) function and exercise tolerance in patients with chronic heart failure (CHF). BACKGROUND: In severe heart failure (HF), SP improves survival, but the underlying mechanisms are not clear. METHODS: We randomized 106 outpatients with HF to SP (12.5 to 50 mg/day) (group 1) or control (group 2). Complete echocardiography and cardiopulmonary exercise testing were performed at baseline and 12 months after randomization. RESULTS: Left ventricular end-systolic volume at baseline and at follow-up was 188 +/- 94 ml and 171 +/- 97 ml in group 1 and 173 +/- 71 ml and 168 +/- 79 ml in group 2 (treatment group-by-time interaction, p = 0.03). Left ventricular ejection fraction at baseline and at follow-up was 33 +/- 7% and 36 +/- 9% in group 1 and 34 +/- 7% and 34 +/- 9% in group 2 (treatment group-by-time interaction, p = 0.02). At baseline, 9 patients in group 1 and 3 patients in group 2 had a restrictive mitral filling pattern, a marker of severe diastolic dysfunction; at follow-up, 3 patients in group 1 and no patient in group 2 improved their pattern. No patient in group 1 and 4 patients in group 2 worsened their pattern (chi-square, p = 0.02). Peak oxygen consumption increased significantly in patients treated with 50 mg of SP and decreased in group 2 (17.7 +/- 5.2 vs. 18.5 +/- 5.9 and 19.1 +/- 5.6 vs. 17.9 +/- 5.3, respectively; analysis of variance, p = 0.01). CONCLUSIONS: Spironolactone improves LV volumes and function; furthermore, it improves exercise tolerance at the highest administered dose. Our data might explain the mortality reduction during aldosterone antagonism in patients with HF.

Aged↗
PubMed1999

Spironolactone-related inhibitors of type II 17beta-hydroxysteroid dehydrogenase: chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities.

The family of 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyzes the formation and inactivation of testosterone (T), dihydrotestosterone (DHT), and estradiol (E2), thus playing a crucial role in the regulation of active steroid hormones in target tissues. Among the five known 17beta-HSD enzymes, type II catalyzes the oxidation of E2 into estrone (E1), T into androstenedione, DHT into androstanedione, and 20alpha-dihydroprogesterone into progesterone. Specific inhibitors are thus an interesting means to study the regulation and to probe the structure of type II 17beta-HSD. In this context, we have efficiently synthesized a series of 7alpha-thioalkyl and 7alpha-thioaryl derivatives of spironolactone that inhibit type II 17beta-HSD. These new C19-steroidal inhibitors possess two important pharmacophores, namely 17-spiro-gamma-lactone and a bulky side-chain at the 7alpha-position. It was found that a para-substituted benzylthio group at the 7alpha-position enhances the inhibitory potency of spironolactone derivatives on type II 17beta-HSD. In fact, the compound with a para-hydroxy-benzylthio group showed an IC50 value of 0.5 microM against type II 17beta-HSD, whereas the compound with a para-[2-(1-piperidinyl)-ethoxy]-benzylthio group inhibited this enzyme with an IC50 value of 0.7 microM. The latter inhibitor is more selective than the former because it did not show any inhibitory potency against P450 aromatase as well as any affinity towards four steroid receptors (AR, PR, GR, ER). As a result, this inhibitor did not show any proliferative effect on androgen-sensitive Shionogi cells and estrogen-sensitive ZR-75-1 cells. These findings contribute to a better knowledge of the structure of type II 17beta-HSD and offer an interesting tool to study the regulation of this enzyme in several biological systems.

17-Hydroxysteroid Dehydrogenases↗
PubMed1977

Ring D oxygenated Spirolactones. Characterization of human metabolic product of spironolactone.

15alpha-Hydroxycanrenone (1b) was prepared from canrenone (1a) by microbiological oxidation with a penicillium species. The product was identical with one obtained from the metabolism of spironolactone(3) in human. Oxidation of 1b with Jones regent furnished the corresponding 15-oxocanrenone (1d) which underwent base-catalyzed beta elimination to generate an alpha,beta-unsaturated cyclopentenone system. 15alpha-Hydroxycanrenone (1b) failed to show antimineralocorticoid activity at the screening dose of 2.4 mg while the oxo derivative 1d exhibited approximately 15% the activity of 3. Since the activity of canrenone is 38% that of spironolactone, introduction of the carbonyl group at the 15 position of canrenone resulted in a reduction in activity. This effect is opposite to that observed with 6-dehydroprogesterone.

Animals↗
PubMed2000

[Diuretic therapy in congestive heart failure--new views on spironolactone therapy].

Cardiac pump failure leads to a reduction of the effective arterial volume. This is sensed by the kidney via afferent sympathetic fibres. The renal response to the perceived lack of volume is the retention of sodium and water. Although initially homeostatic, this renal counterregulation is maladaptive later on and may contribute to further cardiac compromise by increasing preload (volume retention) and afterload (hyperreninism). The renal sodium retention in congestive heart failure is a consequence of the activation of the sympathetic nervous system and of the renin-angiotensin-aldosterone system. The retention of osmotically free water is partly caused by the nonosmotic secretion of antidiuretic hormone from the posterior pituitary and partly by a diminished osmoregulatory capacity of the kidney due to diuretic therapy and/or (pre-)renal insufficiency. In the near future specific blocking drugs of vasopressin receptors should become available which could make a significant contribution to the management of hyponatremia in this setting. For the management of extracellular volume overload a negative sodium balance is the central objective. A moderate reduction of sodium intake is helpful to achieve this goal and has the additional benefit of reducing thirst and renal potassium loss. However, the majority of patients require (loop) diuretics in addition. Patients who are refractory to high and repeated doses of loop diuretics may respond to a combination of diuretics which act on different nephron segments. Diuretics increase the risk of hypokalemia which can trigger life-threatening tachyarrhythmia, particularly in patients with cardiac dysfunction. Hypokalemia is therefore an indicator of an adverse outcome. Secondary hyperaldosteronism--which can persist despite effective therapy with ACE-inhibitors--is the major cause of hypokalemia in this setting. The randomized aldactone evaluation study (RALES) has shown that spironolactone (25 mg/day) reduced the risk of hypokalemia and decreased morbidity, mortality and clinical symptoms in patients with heart failure. The recent encouraging results with vasopressin receptor antagonists and spironolactone point to the fact that the therapeutic modification of maladaptive homeostatic renal mechanisms plays an increasingly important role in the modern diuretic management of heart failure beyond symptomatic relief from volume overload.

Antidiuretic Hormone Receptor Antagonists↗
PubMed1980

Spironolactone and triamterene in volume-dependent essential hypertension.

The effects of 2 potassium-retaining diuretics on arterial pressure, intravascular volume, responses of the renin-angiotensin-aldosterone system, serum electrolytes, and renal function were compared by means of an 8-wk double-blind, crossover trial in 13 patients with "volume-dependent" essential hypertension. The fall in systolic, diastolic, and mean arterial pressures in the supine and erect positions (all p less than 0.005) induced by spironolactone was greater than that by triamterene. The pressure fall induced by spironolactone was also associated with a persistent contraction in plasma volume (p less than 0.05) and a secondary hyperaldosteronism that was not accompanied by hypokalemic alkalosis. The pressure fall induced by triamterene was not associated with reduced plasma volume, effect on plasma renin activity, or aldosterone excretion. Both drugs produced significant rises in blood urea nitrogen and creatinine levels that never exceeded normal limits.

Adult↗
PubMed2006

Effects of spironolactone on human blood mononuclear cells: mineralocorticoid receptor independent effects on gene expression and late apoptosis induction.

1 Spironolactone (SPIR) binds to cytoplasmic mineralocorticoid receptors (MR) and functions as an aldosterone antagonist. Recently, the drug was shown to have an early suppressive effect on several immunoactive and proinflammatory cytokines. 2 To elucidate the mechanism behind this, the four MR-binding steroids SPIR, canrenone, 7alpha-thiomethyl-spironolactone and aldosterone (ALDO) were investigated for effects on lipopolysaccharide- and phytohemagglutinin-A-activated human blood mononuclear cells. Gene expression was examined after 4 h using microarrays, and SPIR affected 1018 transcripts of the (=) 22,000 probed. In contrast, the SPIR-related steroids affected 17 or fewer transcripts. Combining SPIR and ALDO resulted in 940 affected transcripts, indicating that SPIR has an early gene-regulatory effect independent of MR. 3 The affected genes encode a large number of signalling proteins and receptors, including immunoinflammatory response genes and apoptosis and antiapoptosis genes. Apoptosis was evident in CD3-, CD14- and CD19-positive cells, but only after 18 h of exposure to SPIR. 4 The transcriptional network involving the differentially regulated genes was examined and the results indicate that SPIR affects genes controlled by the transcription factors NF-kappaB, CEBPbeta and MYC. 5 These observations provide new insight into the non-MR-mediated effects of SPIR.

Adult↗
PubMed1976

Effects of aldosterone and spironolactone on arterial renin in rats.

1. The metabolic role of arterial angiotensin I-forming enzyme (i.e. renin activity) was studied in total homogenates and in subcellular fractions of the aorta of normotensive and hypertensive rats. 2. Angiotensin I-forming enzyme was measured in (a) uninephrectomized rats rendered hypertensive with D-aldosterone and sodium chloride (10 g/l drinking solution, (b) rats treated in the same manner but with the addition of spironolactone, and (c) control rats. 3. Hypertension developed in aldosterone-treated rats within 3-6 weeks and was associated with decreased plasma and renal renin values. Total aortic renin activity was up to sixfold higher in the hypertensive animals than in control animals and there was an increased ratio of supernatant to microsomal renin activity in the aorta. 4. In spironolactone-treated rats blood pressure and total aortic renin concentrations were comparable with those in the control rats. 5. The results support the hypothesis that renin generated at local vascular sites, which is independent of circulating renin levels, contributes to regulation of blood pressure.

Aldosterone↗
PubMed1979

[Biological availability of spironolactone in two different galenic forms (author's transl)].

The biological availability of spironolactone in two different galenic preparations (Spiro-Tablinen and Aldactone-100 Caps) was investigated in a single-blind, randomised, cross-over study in six healthy probands. The serum concentration of canrenone after oral intake of spironolactone (100 mg) was investigated in the steady state as well as the renal excretion of canrenone. There were no statistically significant differences between the two preparations either in the course of the serum concentration of canrenone or in the cumulative renal excretion.

Adult↗
PubMed2001

Ovarian cyst in a premature infant treated with spironolactone.

We describe the late occurrence of an ovarian cyst in a premature infant, the second of a set of monochorionic diamnionic twins, during treatment with spironolactone. Spironolactone is commonly used in the management of neonatal chronic lung disease in combination with other diuretics because of its potassium-sparing effect. It has progestational activity and has been reported to cause gynecomastia. It is used widely for its antiandrogenic properties in the treatment of female hirsutism and hyperandrogenism and it has a role in the management of familial male-limited precocious puberty. However, the estrogenic influence induced during therapy may significantly alter the hormonal milieu in newborn females, resulting in the formation of ovarian cysts. Simple ovarian lesions <5 cm merit close ultrasonographic surveillance for resolution while larger complex masses may warrant surgical intervention.

Diseases in Twins↗
PubMed1979

Haemodynamic effects of treatment and withdrawal of spironolactone in essential hypertension.

The effect of spironolactone (50 mg b.i.d.) in essential hypertension was studied by measurement of effective renal plasma flow (ERPF), blood urea nitrogen (Ur+), serum creatinine (Cr), cardiac index (CI), plasma volume (PV), body weight (BW), mean arterial blood pressure (MAP), total peripheral resistance index (TPRI), plasma renin activity (PRA) and plasma aldosterone (PA) in two groups of patients. Ten cases had determinations before, after 5 weeks and 4 months of treatment; fourteen cases who had been treated at an average of 18 months, had measurements while on treatment and 5 weeks after cessation of the drug. Among the ten patients ERPF fell in six and increased in four patients during treatment, but was statistically unchanged in the total group. Ur + and Cr were also unchanged by treatment. ERPF was unchanged after withdrawal of the drug. During treatment BW decreased 3.5%, PV decreased in nine and increased in one patient, while PRA and PA increased 426% and 202%, respectively. After cessation of the aldosterone blockade, BW increased 1.9%, PV 10.5% while PRA and PA fell 60% and 48.9%, respectively. MAP fell in eight out of ten patients during treatment. This fall was associated with a fall in CI or TPRI, or both. After withdrawal of the drug, MAP increased in nine and decreased in five of the patients. The data shows that this dosage of spironolactone gave minor adjustments of the systemic and renal circulation in spite of the consistent changes in BW, PV, PRA and PA.

Adult↗
PubMed1990

HPLC-photolysis-electrochemical detection in pharmaceutical analysis: application to the determination of spironolactone and hydrochlorothiazide in tablets.

To extend the applicability of electrochemical detection in pharmaceutical analysis, an on-line postcolumn photochemical reactor is used to produce electroactive photoderivatives of selected cardiovascular drugs. This system is applied to the analysis of dosage forms containing spironolactone in both single-component formulation and in combination with hydrochlorothiazide. The pH of the mobile phase and irradiation time within the reactor are optimized to produce maximum amperometric response. Spironolactone, hydrochlorothiazide, and 4-amino-6-chloro-1,3-benzenedisulfonamide, the synthetic precursor and hydrolysis product of hydrochlorothiazide, are separated by reversed-phase chromatography on a 5-microns cyano bonded phase column within nine minutes by using a methanol-phosphate buffer mobile phase. Minimum detectable levels are in the low ng range.

Chromatography, High Pressure Liquid↗
PubMed1994

Interference by spironolactone on adrenocortical scintigraphy and other pitfalls in the location of adrenal abnormalities in primary aldosteronism.

A case of primary aldosteronism is presented in which the CT scan was initially misleading, adrenocortical scintigraphy was rendered inaccurate by pharmacological interference of spironolactone, and selective adrenal venous sampling of aldosterone was technically difficult. When dexamethasone suppression adrenocortical scintigraphy was performed with attention to technical detail and exclusion of interference by spironolactone, the causative lesion was scintigraphically demonstrated. This finding was confirmed by the results of venous sampling and the correctly located tumor removed.

Adosterol↗
PubMed1978

Spironolactone prophylaxis in manic-depressive disease.

Lithium is now recognized as the drug of choice for the prophylactic control of manic-depressive disease, but its mechanism of action is the nonspecific inhibition of adenyl cyclase and subsequent cAMP formation which produces many undesirable side effects. However, the effect that lithium has on the central nervous system is compatible with all three theories regarding the basis of affective disorders, i.e., the biogenic amine theory, the electrolyte theory, and the membrane theory. Fluctuations of the hormone aldosterone during the various stages of manic-depressive disease could account for an etiological mechanism, that also is compatible with all three theories. Both spironolactone and lithium can inhibit the action of aldosterone. Therefore, when six manic-depressive patients, who had been well maintained on lithium, requested discontinuance of this drug because of side effects, spironolactone was substituted. On a minimum 1-year follow-up study, five of the six patients were well maintained on this new drug regimen.

Adult↗
PubMed1981

The interaction of spironolactone and digoxin: a review and evaluation.

A review of the literature describing the interaction of digoxin and spironolactone is presented. Two mechanisms of possible interaction are discussed. Spironolactone and its metabolites may interfere with digoxin radioimmunoassay or alter the pharmacokinetics of digoxin. The occurrence of either or both of these processes may make interpretation of serum digoxin levels difficult.

Digoxin↗
PubMed1979

Effects on muscle electrolytes of potassium and magnesium infusions, spironolactone medication and operation in a case of primary aldosteronism.

Serum and muscle electrolytes were determined in a case of primary aldosteronism before and after potassium and magnesium infusions as well as spironolactone treatment and following surgery. Repeated potassium infusions resulted in a transient normalization of the muscle potassium (K/m), followed within 3-4 days by a return to the previously low K/m. Magnesium infusions did not give any increase in muscle magnesium (Mg/m). On the contrary, there was a decrease in Mg/m concomitant with a decrease in K/m. Treatment with spironolactone for one month was followed by a normalization of both serum and muscle electrolytes. Following surgery the serum potassium and K/m remained normal, but the serum magnesium (Mg/s) and Mg/m showed a decrease to subnormal values. Despite the initial findings of normal Mg/s and Mg/m as well as excretion of more than 80% of the i.v. magnesium dose, this may indicate that there was a magnesium deficiency in the skeletal pool.

Female↗