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PubMed1985

Pharmacokinetics of spironolactone and potassium canrenoate in humans.

Plasma concentrations and urinary excretion of canrenone (III), canrenoic acid (IV) and canrenoic acid glucuronide (V) were determined by means of high performance liquid chromatography (HPLC) and fluorometry after oral administration of spironolactone (I) and potassium canrenoate (II) to human subjects. Comparison of both assays for III in plasma as well as in urine after administration of I showed marked differences. Plasma concentrations of III were significantly higher after administration of II than I, Cmax and AUC from II being 3--5 times larger than those from I by means of HPLC assay, while the fluorometrically determined values for III in plasma after administration of I and II did not differ as much from each other. On the other hand, in contrast to plasma, the amount of III excreted in urine after administration of I was much larger than that after II, i.e. 3--4 times greater by means of HPLC and over 10 times greater by means of fluorometry. These results strongly suggest that precursors of III are formed which have a higher renal clearance than that for III alone after oral administration of I. Considering the relative biological potency ratio of I and II, it is presumed that their pharmacological activities may relate to the urinary excretion of III. Plasma concentrations of IV were definitely higher after administration of II compared to those after I. Canrenoic acid (IV) was excreted mainly as glucuronide (V) in urine.

Adult↗
PubMed2006

Effects of spironolactone during an angiotensin II receptor blocker treatment on the left ventricular mass reduction in hypertensive patients with concentric left ventricular hypertrophy.

BACKGROUND: Angiotensin II receptor blockers (ARB) are now commonly used to treat hypertension because of their beneficial effects on cardiovascular remodeling. However, ARB treatment can not inhibit the left ventricular (LV) remodeling sufficiently, which may be related with aldosterone secretion. To inhibit the action of aldosterone during ARB treatment, the additional effects of an aldosterone blocker and spironolactone (SPRL) on LV hypertrophy in patients with essential hypertension was studied. METHODS AND RESULTS: The patients with essential hypertension were randomly divided into 2 groups; 1 group was treated with an ARB, candesartan (8 mg/day), for 1 year (ARB group) and other group was treated with the ARB for the first 6 months and with the ARB plus SPRL (25 mg/day) for the next 6 months (combination group). Seventy patients who underwent echocardiography every 6 months were analyzed and were also classified into 4 subgroups of LV geometric pattern according to the LV mass index (LVMI) and the relative wall thickness (RWT). The ARB treatment and the addition of SPRL significantly reduced the blood pressure, however, both treatments did not affect the LV geometry in both groups. The ARB treatment in the subgroups of concentric LV remodeling (RWT>or=0.45 and LVMI<125) and concentric LV hypertrophy (RWT>or=0.45 and LVMI>or=125) significantly reduced RWT. However, ARB treatment in all subgroups did not affect LVMI. The addition of SPRL only in the concentric LV hypertrophy subgroup significantly reduced the LVMI, despite similar changes in blood pressure. CONCLUSIONS: These results indicated that the addition of SPRL treatment during the ARB treatment and conventional treatments is clinically useful to reduce the LVMI in hypertensive patients with concentric LV hypertrophy; however, does not improve the eccentric LV hypertrophy.

Aged↗
PubMed2004

Mineralocorticoid receptor antagonist spironolactone improves left ventricular remodeling in patients with congestive heart failure and acute myocardial infarction.

Randomized aldactone evolution study (RALES) and eplerenone post-AMI heart failure efficacy and survival study (EPHESUS) had shown that aldosterone blockade (AB) with standard therapy resulted in a reduction in mortality in patients with congestive heart failure (CHF) and acute myocardial infarction (AMI). However, the mechanism for the beneficial effect of AB remains unknown. To evaluate the effect of spironolactone (Spi) on left ventricular (LV) remodeling, 34 CHF patients with DCM were randomly divided into the Spi (+) or Spi (-) groups. Four months of treatment with Spi improved the LV volume and mass. To evaluate the effect of Spi on post-infarct LV remodeling, 134 patients with first anterior AMI were randomly divided into the Spi (+) or Spi (-) groups after revascularization. LV ejection fraction was significantly improved after 1 month in the Spi (+) group compared with that in the Spi (-) group. LV end-diastolic volume index was significantly suppressed in the Spi (+) group compared with that in the Spi (-) group. Transcardiac extraction of aldosterone through the heart was significantly suppressed in the Spi (+) group and was significant lower in the Spi (+) group compared with the Spi (-) group. These findings indicate that AB combined with standard therapy can prevent LV remodeling in patients with CHF and AMI, suggesting that the failing heart is the target organ of the aldosterone.

Adolescent↗
PubMed2000

Thyroid hyperactivity induced by methimazole, spironolactone and phenobarbital in marmosets (Callithrix jacchus): histopathology, plasma thyroid hormone levels and hepatic T4 metabolism.

To determine drug-induced hyperfunction of marmoset thyroids due to inhibition of synthesis or enhancement of metabolic elimination of thyroid hormones, males were orally administered 10 and 30 mg/kg/day methimazole (MMI), 30 and 100 mg/kg/day spironolactone (SPL), or 50 mg/kg/day phenobarbital (PB) for 4 weeks. MMI caused marked hypertrophy of follicular epithelial cells in accordance with a significant decrease in the plasma thyroxin (T4) level. Hypertrophied epithelial cells were filled with dilated rough endoplasmic reticulum and reabsorbed intracellular colloids, and the luminal surface was covered with abundant microvilli. The colloid included vacuoles positive to anti T4 immuno-staining. SPL and PB also caused similar histomorphological changes, although they were less severe than those due to MMI and were not clearly associated with decrease in the plasma T4 levels. Hepatic T4 UDPGT activities tended to increase due to SPL and PB treatment, however, which were not so significant as increases in microsomal cytochrome P-450 contents. Some animals treated with SPL and PB showed marked increases in thyroid weights due to inactive dilated follicles. In conclusion, hyperactivity of thyroid follicles was induced in marmosets not only due to inhibition of T4 synthesis produced by MMI but also because of enhancement of hepatic T4 elimination produced by SPL and PB. However, hypertrophic effects of SPL and PB were less severe than MMI, because plasma T4 levels were maintained at almost pretreatment or control levels after SPL or PB treatment.

Animals↗
PubMed1980

Disturbances in sexual differentiation of rat foetuses following spironolactone treatment.

Pregnant rats were treated with 40 mg spironolactone (sp) po from the 13th to the 21st day p.c. The foetuses were prepared and histologically examined on day 22. The male foetuses showed distinct signs of feminization especially of the external genitalia. The anogenital distance was nearly 48% shorter than that of the controls. The prostatic utricle persisted more distinctly, and the number and size of the prostatic buds were significantly reduced. The degree of feminization of the male foetuses which is achieved under the influence of sp (40 mg/day) is the same as that which can be induced by 1--3 mg cyproterone acetate.

Animals↗
PubMed1986

Use of spironolactone to investigate the role of testosterone secretion during luteolysis in the goat.

In non-pregnant goats, appreciable amounts of testosterone (2.1 ng/g) and 5 alpha-dihydrotestosterone (DHT, 0.8 ng/g) were present in the corpus luteum on Day 12 of the oestrous cycle. Significant (P less than 0.01, N = 18) veno-arterial concentration differences of testosterone were found across ovaries bearing corpora lutea. No such difference in testosterone concentration occurred across ovaries without corpora lutea (P greater than 0.5, N = 12). Increased peripheral plasma concentrations of testosterone and DHT occurred at the start of luteal regression, as monitored by progesterone concentration, and before the day of oestrus. Subcutaneous injections of spironolactone (10 mg/kg/day) in peanut oil between Days 10 and 20 of the oestrous cycle inhibited the increase in testosterone and DHT concentrations and delayed luteolysis and oestrus. It is suggested that aromatization of testosterone to oestrogens is needed for luteal regression and expression of oestrus in goats.

Animals↗
PubMed1998

An improved high-performance liquid chromatography assay for spironolactone analysis.

This study prepared an extemporaneously formulated liquid suspension dosage form (5 mg/ml) from commercially available 25 mg tablets. Stability-indicating HPLC assay procedures were established and utilized to analyze the concentration of the drug. The method proved to be a simple model since it does not contain a buffer system. The mobile phase used was the same as that suggested by the manufacturer for the storage of the column. Therefore, the solvent system saves analytical processing time, since it does not require a change in the mobile phase before or after the analysis. The analytical method has been shown to be stability-indicating. The results have shown that there is no interference from any of the degradation products obtained from stressing spironolactone by heat and extremes in pH or with the internal standard, hydrocortisone 21-acetate.

Chemistry, Pharmaceutical↗
PubMed1982

Plasma active and inactive renin and urinary kallikrein in normal subjects in response to hydrochlorothiazide, spironolactone or aldosterone administration.

The aim of this study has been to see whether acute variations in the proportions of circulating active and inactive renin in normal subjects were related to concurrent changes in the excretion of urinary kallikrein. Hydrochlorothiazide (50 mg/day) was given to 6 normal volunteers for 6 days; another group of 6 normal subjects received spironolactone (300 mg/day) for 6 days whereas synthetic aldosterone (0.5 mg/day) was administered i.m. for three days to 3 normal subjects. Both diuretics induced a sharp rise in active and total renin and a significant transient decrease in inactive renin so that the active: total renin proportion significantly increased. Urinary kallikrein excretion did not significantly change in either group. Parenteral administration of aldosterone induced a striking fall in all renin components without changing the proportions of active and inactive renin whereas urinary kallikrein excretion increased. These results indicate that changes in active: total renin proportions can occur without parallel variations in urinary kallikrein excretion. The latter cannot be used, therefore, as a reliable index of the possible role of renal kallikrein as activator in-vivo of inactive renin in man.

Adult↗
PubMed2005

[Severe hyperkalemia associated to the use of losartan and spironolactone: case report].

Hyperkalemia is a complications of the use of angiotensin converting enzyme inhibitors, angiotensin receptor antagonists and aldosterone antagonists. These drugs are commonly used for the treatment of hypertension and cardiac failure. We report a 84 year-old female treated with losartan 50 mg/day and spironolactone 25 mg/day that presented with a hyperkalemia of 8.4 mEq/l and bradicardia, drowsiness and respiratory depression. She required hemodialysis and ventilatory assistance. She was discharged in good conditions five days after admission.

Aged, 80 and over↗
PubMed1980

Comparison of a single-dose and twice-a-day spironolactone therapy in mild hypertension.

Once-a-day therapy with spironolactone has been compared with a twice-a-day regimen in an open crossover trial in patients with essential hypertension. When compared with placebo, both treatments significantly lowered blood pressure. Twice-a-day therapy provided slightly better blood pressure control than the once-a-day dosing schedule. There were only minor differences in biochemical findings between the two regimens. Three of the 17 patients developed reversible gynaecomastia.

Adult↗
PubMed1976

[The efficacy of spironolacton in cardiopulmonary insufficiency (author's transl)].

In 17 patients with cardiopulmonary insufficiency the authors found a significant positive inotropic heart effect and a moderate improvement of ventilation after one injection of 400 mg Spirolacton. 2. The positive inotropic effect is experimentally confirmed in 8 dwarf pigs. 3. In 13 patients with severe cardiac and cardiopulmonary insufficiency a tendency to normalization of arterial blood gases, of actual bicarbonate and of vital capacity was found. There may be an indirect effect on the respiratory center by alteration of acid-base-status and by diuresis causing diminuation of pulmonary compliance. Spironolacton seems to be a valuable therpeutical completion in cardiac and cardiopulmonary insufficency in its intravenous quick application and its oral time application.

Animals↗
PubMed1976

Spironolactone-associated aggravation of renal functional impairment.

Five patients in whom deterioration in renal function was associated with the use of the aldosterone antagonist, spironolactone, are reported. Care in the use of this drug is urged, especially in the elderly. Patients with known renal functional impairment should not receive this agent.

Aged↗
PubMed1975

Negligible interference by spironolactone and prednisone in digoxin radioimmunoassay.

Spironolactone and prednisone reportedly cause measurable values for apparent digoxin, even when none is present. Effects of these medications were evaluated with 125I-labeled digoxin kits from five different manufacturers. Values obtained for apparent digoxin were either negligible or not sufficiently great to be clinically significant, regardless of kit methodology or manufacturer.

Digoxin↗
PubMed2002

[Significance of combining spironolactone during long-term administration of ARB].

Blocking aldosterone action has been of clinical interest in the treatment of hypertension and related target organ damage. Although we have previously demonstrated aldosterone escape during long term administration of AT1 antagonist, pathological significance of aldosterone remains unknown. We investigated the effects of co-administration of spironolactone(SPRL) on the cardioprotective effects of AT1A in SHR-SP. Administration of AT1A alone resulted in a significant decrease in cardiac weight, cardiac transverse section area, cardiac fibrosis, and mRNA expression of BNP, type I and type III collagen, while cardiac ET-1 mRNA showed a significant increase. Co-administration of AT1A with SPRL resulted in a significant decrease in all the parameters including ET-1 mRNA expression. These results provide theoretical rationale for combination therapy of AT1A and SPRL in hypertension.

Angiotensin Receptor Antagonists↗
PubMed2004

[Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction].

BACKGROUND: Aldosterone has been shown to stimulate cardiac collagen synthesis and fibroblast proliferation via activation of local mineralocorticoid receptors. In patients with acute myocardial infarction, we demonstrated that aldosterone was extracted through the infarct-heart and extracting aldosterone stimulated post-infarct left ventricular remodeling. METHODS AND RESULTS: To evaluate the effect of mineralocorticoid receptor antagonist (MRA) spironolactone on post-infarct left ventricular remodeling. 134 patients with first anterior acute myocardial infarction were randomly divided into the MRA (n=65) or non MRA (n=69) group after revascularization. All patients were administrated angiotensin converting enzyme inhibitor (ACEI) and study drug just after revascularization. Left ventriculography with contrast medium was performed at acute and after 1 month to evaluate left ventricular remodeling. Aldosterone was measured at aortic root and coronary sinus. There was no difference in the baseline characteristics including infarct size and left ventricular performance between the two groups. However, left ventricular ejection fraction was significantly improved in MRA group compared with that in non MRA group (46.0 +/- 0.6% to 53.2 +/- 0.8% vs 46.5 +/- 0.8% to 51.0 +/- 0.8%, P interaction = 0.012). Left ventricular end-diastolic volume index was significantly suppressed in MRA group compared with that in non-MRA group (86.5 +/- 1.0 to 90.6 +/- 2.4 vs 87.5 +/- 1.3 to 106.8 +/- 3.5 ml/m2, P interaction = 0.002). Transcardiac extraction of aldosterone through the heart was significantly suppressed in MRA group (P interaction = 0.001) and plasma procollagen type III aminoterminal peptide, a biochemical marker of fibrosis, level was significant lower in MRA group compared with those in non-MRA group (P interaction + 0.002). CONCLUSIONS: These findings indicate that MRA combined with ACEI can prevent post-infarct left ventricular remodeling better than ACEI alone in association with the suppression of a marker collagen synthesis.

Biomarkers↗
PubMed2006

[Chronic effects of spironolactone in conjunction with an angiotensin-converting enzyme inhibitor enalapril on circulating procollagen marker P III NP and vascular resistance in patients with essential hypertension].

OBJECTIVE: Disturbances of the synthesis and breakdown of the extracellular matrix of arterial walls have emerged as key features of the atherosclerotic process. We observed the changes of circulating procollagen marker for type III collagen turnover rate, the N-terminal propeptide P III NP and vascular resistance in hypertensive patients treated with various antihypertensive regimens. METHOD: A total of 130 light to moderate hypertensive patients were randomly assigned to receive enalapril (group B, n = 43), enalapril + spirolactone (20 mg/d, group A, n = 44) and anti-hypertensive drugs not directly affecting RAAS (calcium antagonist, beta-blocker, group C, n = 43) for 1 year. Target blood pressure is < 130/80 mm Hg. RESULTS: Target blood pressure was reached in all treated patients and was similar among various groups. Under the same blood pressure controlling precondition, serum P III NP were similar at baseline among various groups and remained unchanged in group B [(3.4 +/- 0.3) microg/L vs. (3.7 +/- 0.3) microg/L, P > 0.05] and significantly decreased in group A [(2.3 +/- 0.2) microg/L vs. (3.8 +/- 0.2) microg/L, P < 0.05] while significantly increased in group C [(3.9 +/- 2.0) microg/L vs. (3.2 +/- 1.5) microg/L, P < 0.05]. Vascular resistance was similar among groups before therapy and all significantly decreased after 1 year antihypertensive therapy and the decrease was more significant in group A [(1064.3 +/- 158.6) dyn.s(-1).cm(-5)] than that in group B [(1200.8 +/- 298.7) dyn.s(-1).cm(-5)] and group C [(1205.1 +/- 206.4) dyn.s(-1).cm(-5)]. CONCLUSION: Spironolactone in conjunction with enalapril is a more favorable antihypertensive regimen in decreasing P III NP and improving vascular resistance than enalapril alone or antihypertensive drug regimens not directly affecting RAAS.

Adult↗
PubMed1976

[Sexual side-effects of spironolactones. Possible mechanisms of their anti-androgen action].

Spirolactones (spironolactone, potassium canrenoate) may produce secundary sexual effects such as gynecomastia in man and menstrual disturbances in women. The mechanism of action of the antiandrogenic effects has been studied in man and rat. Acute i.v. injection of potassium canrenoate into man results in a decrease of plasma testosterone, without any change of gonadotropins. This decrease might be due to an impaired testicular steroidogenesis. On the other hand, spirolactones have an antiandrogenic effect at the target cells level. They do not modify the prostate 5alpha-reductase activity; however, they do inhibit the binding of androgens to their receptors. Thus the spirolactones interact with both biosynthesis and peripheral action of androgens.

Adult↗