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PubMed2003

Transcardiac gradient of aldosterone before and after spironolactone in patients with congestive heart failure.

To evaluate the transcardiac extraction of aldosterone before and after spironolactone administration to patients with congestive heart failure, we measured the plasma aldosterone in the aortic root and the coronary sinus in eight congestive heart failure patients with dilated cardiomyopathy. The plasma aldosterone level was significantly lower in the coronary sinus than in the aortic root before spironolactone administration (87.5 +/- 16 versus 62.2 +/- 11 pg/ml, p = 0.01). After chronic treatment with spironolactone, there was no significant difference in the aldosterone level between the aortic root and the coronary sinus (151 +/- 49 versus 148 +/- 48 pg/ml), and the transcardiac gradient of aldosterone (aortic root to coronary sinus) was significantly decreased (25.3 +/- 7.3 versus 3.1 +/- 4.5 pg/ml, p = 0.046). These results indicate that plasma aldosterone is extracted through the heart in congestive heart failure patients with dilated cardiomyopathy, and that spironolactone inhibits the transcardiac extraction of aldosterone in congestive heart failure patients. This suggests that spironolactone blocks the effects of aldosterone on the failing heart in congestive heart failure patients with dilated cardiomyopathy.

Adult↗
PubMed1979

Cutaneous reaction to spironolactone resembling lupus erythematosus.

A cirrhotic male patient was admitted with a skin eruption. He had been taking spironolactone and hydrochlorothiazide for two months prior to admission. The morphology and distribution of skin lesions resembled that of systemic lupus erythematosus (SLE). Histologic changes in the skin biopsy specimen were consistent with SLE. Biopsy specimens of normal and affected skin were reported to show weak focal deposition of IgM and complement at the dermal-epidermal junction. However, there was a striking absence of serologic evidence of SLE. The rash disappeared when all medications were discontinued and reappeared when the patient was given spironolactone. The character and distribution of the rash after spironolactone administration was identical to the previous lesions. It disappeared again when spironolactone was withdrawn. This response to spironolactone is good evidence that it and not chlorothiazide was responsible for the rash. The latter drug has been reported to cause SLE-like skin changes.

Diagnosis, Differential↗
PubMedDate not supplied

[Pharmacokinetics in healthy subjects of althiazide and spironolactone in a fixed combination for 2 doses].

Pharmacokinetic plasma curves of altizide (ALT), spironolactone (SPI) and two of the main metabolites of spironolactone, 7 alpha-thiomethyl-spirolactone (7TM) and canrenone (CAN) have been established in 12 healthy human volunteers (6 men and 6 women) after unique oral administration of 1 or 2 tablets of a combination of the two diuretic compounds: altizide (15 mg per tablet) and spironolactone (25 mg per tablets). Main pharmacokinetic parameters have been calculated using a biexponential (ALT and SPI) or a triexponential model (7TM and CAN). Spironolactone is rapidly absorbed. Plasma curves show Tmax respectively equal to 1.19 +/- 0.47 hours (1 tablet) or 1.21 +/- 0.46 (2 tablets). Spironolactone is rapidly metabolized as it is shown by the mean Tmax of metabolites: 7TM and CAN Tmax are respectively 1.56 +/- 0.45 hours and 2.54 +/- 1.06 hours after administration of 1 tablet, or 1.58 +/- 0.42 hours and 2.67 +/- 1.13 hours after administration of 2 tablets. The mean residence time (MRT) of ALT [4.94 +/- 1.14 hours (1 tablet) or 5.31 +/- 1.06 hours (2 tablets)] and SPI [1.81 +/- 0.45 hours (1 tablet) or 1.88 +/- 0.50 hours (2 tablets)] shows a rapid elimination of both drugs. SPI metabolites present higher MRT than the unchanged drug. 7TM MRT after administration of 1 or 2 tablets, are 24.51 +/- 15.35 hours and 18.11 +/- 11.87 hours, respectively. CAN MRT are 39.65 +/- 23.58 hours (1 tablet) and 38.93 +/- 24.58 (2 tablets). Statistical analysis shows no significant administration order effect on the different parametres. Student' t test shows a significant sex effect on CAN AUC, for both formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Stability of extemporaneously compounded spironolactone suspensions.

The short-term stability of spironolactone in liquid formulations prepared from spironolactone tablets was studied at three temperatures. Suspensions of spironolactone at concentrations of 2.5, 5.0, and 10.0 mg/mL were prepared by grinding film-coated tablets to a fine powder, adding Purified Water, USP, triturating the mixture to form a fine paste, adding Cherry Syrup, NF, and homogenizing the suspension. Drug concentrations were immediately measured by a stability-indicating high-performance liquid chromatographic (HPLC) method. Samples were stored in amber glass prescription bottles at 5 and 30 degrees C in controlled environmental cabinets and at ambient room temperature (20 to 24 degrees C) under intense fluorescent light. After two and four weeks of storage the bottles were shaken, and samples were removed and assayed by HPLC. There was no appreciable loss of spironolactone from the cherry syrup formulations stored for two weeks under the conditions studied. Degradation was less than 5% for samples stored for four weeks. Color and odor of the samples did not change appreciably, and counts of bacteria and fungi remained within acceptable limits. Extemporaneously prepared suspensions of spironolactone in Cherry Syrup, NF, are stable for four weeks under the conditions studied.

Biological Availability↗
PubMed1988

Comparative clinical study of spironolactone and potassium canrenoate. A randomized evaluation with double cross-over.

In the present study 54 cirrhotic patients were investigated in order to compare the clinical effects of spironolactone (100-200 mg/d) and potassium canrenoate (50-200 mg/d). Diagnosis was established on clinical and laboratory findings for at least 12 months and/or on liver biopsy: no patients had signs of hepatic decompensation. Patients entering the study without previous treatment, after a basal period of observation, were randomly allocated to one of the spirolactones (spironolactone or potassium canrenoate); those already under antialdosteronic treatment underwent a first observation period and were then all shifted to the other drug. After completing a second observation all patients underwent a second cross-over and a new assessment of clinical and laboratory parameters after the third period of observation. 31 patients completed all observations (3.5 months each, overall mean). No differences in liver function tests were present during follow-up. Maintenance of body weight was achieved with a dose of potassium canrenoate half that of spironolactone. Serum K+ was increased in each patient after spironolactone and potassium canrenoate as compared to the basal period. The 24-h urinary excretion of K+ was significantly decreased in each patient after both drugs. No significant changes were observed in both Na+ and Cl- plasmatic concentration and urinary excretion. Gynaecomastia was present in 3/11 patients during the basal observation, in 13/30 patients under spironolactone and in 5/25 patients under potassium canrenoate; this finding, however, was not correlated to changes in the basal serum concentration of prolactin.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1985

Antiandrogenic effects of topically applied spironolactone on the hamster flank organ.

The effects of topically applied spironolactone on the sebaceous glands of flank organs in adult male golden hamsters were investigated. Daily treatment with spironolactone (0.3 mg and 3 mg) on one side only significantly reduced the size of the treated flank organs, while the contralateral flank organs remained unchanged. Lower doses of spironolactone and the vehicle had no effect. Cyproterone acetate therapy resulted in the bilateral reduction of flank organ sizes. In vivo measurement of the palpable bulk of the flank organs correlated with flank organ volumes as determined by computer-assisted planimetry of serial histologic sections. Dry weights of seminal vesicles in animals treated with spironolactone did not differ significantly from those of the control group, while topically applied cyproterone acetate significantly reduced seminal vesicle weight. Topically administered spironolactone appears to have only local antiandrogenic effects, as indicated by the lack of changes in the untreated contralateral flank organs and in the weights of seminal vesicles.

Administration, Topical↗
PubMed1986

Spironolactone therapy for hyperandrogenic anovulatory women--clinical and endocrinological study.

Seventeen patients with irregular menstrual periods and androgenic symptoms such as excessive hair growth, acne, and oily skin were treated with spironolactone. The basal levels of serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and luteinizing hormone (LH) were significantly higher in the patients than in the controls. After a 4-week treatment with spironolactone, serum T and DHT showed significant decreases. Before treatment, the serum sex hormone binding globulin (SHBG) levels were significantly lower in the patients than in the controls. After initiation of the spironolactone treatment, the SHBG levels tended to increase but not significantly. Spironolactone treatment resulted in the improvement or disappearance of acne in 4 of 5 patients who suffered from this ailment. Improvement of hirsutism was obtained in 2 of 10 patients. Although 4 oligomenorrheic patients and 6 amenorrheic patients showed anovulatory bleeding but did not ovulate, 2 patients in the amenorrheic group ovulated. Two patients complained of tiredness and weakness, and 2 others of polyuria and polydipsia. Both groups showed only temporary symptoms, so treatment was not interrupted. Spironolactone has beneficial effects on ovarian function and few side effects, so it may prove to be an effective anti-androgen, especially for hyperandrogenic anovulatory patients.

Adult↗
PubMed1979

Effect of neomycin on the bioavailability of spironolactone: a single-dose study.

The effect of oral neomycin sulfate on the bioavailability of oral spironolactone in humans was studied. A 100-mg spironolactone tablet was administered alone or with two 500-mg neomycin sulfate tablets to 12 healthy, fasting men in a randomized crossover fashion. Levels of canrenone (an active spironolactone metabolite) in plasma and urine samples collected for 32 and 48 hours after dosing, respectively, were measured fluorimetrically. Neomycin significantly decreased the peak plasma canrenone concentration, significantly increased the time to reach peak concentration of canrenone, and significantly decreased the urinary excretion of canrenone over the first four hours (p less than 0.05). There were no significant differences between treatment groups in elimination half-life, area under the plasma curves or 48-hour urinary excretion of canrenone. Single doses of neomycin appear to delay the rate but not reduce the extent of spironolactone absorption. Thus, neomycin may not interfere with the clinical efficacy of spironolactone.

Adult↗
PubMed1981

[Bioavailability studies of two spironolactone-preparations (author's transl)].

In a preliminary open bioequivalence investigation of orientating character (n =4) a single 100 mg dose of spironolactone (study I) led to maximum canrenone plasma levels (determined by HPLC) of 126.5 +/- 28.4 ng/ml (standard formulation 1) and 130 +/- 13.1 ng/ml (test formulation 2). The corresponding values for the sum of the fluorogenic metabolites were 418.9 +/- 43.5 ng (eq)/ml formulation 1 and 469.9 +/- 80.3 ng (eq)/ml formulation 2. A comparison of AUCs for both total fluorogenic metabolites and canrenone showed no marked differences. In a 2nd cross-over bioequivalence study with multiple dosing, mean minimum steady-state levels of 102.5 +/- 14 ng/ml (formulation 1) and 98.1 +/- 14.1 ng/ml (formulation 2) were obtained for canrenone, and 389 +/- 35.8 ng (eq)/ml (formulation 1) and 391.4 +/- 18.9 ng (eq)/ml (formulation 2) for total fluorescence. The AUCs for post-steady-state elimination, starting with the final spironolactone dose on day 10, were comparable. They were calculated to be 13226 +/-828 ng (eq)/ml . h (formulation 1) and 13858 +/- 651 ng (eq)/ml . h (formulation 2) for total fluorescence, and 3222 +/- 217 ng/ml (formulation 1) and 3167 +/- 195 ng/ml (formulation 2) for canrenone. Both spironolactone formulations can be considered as bioequivalent. The elimination half-lives (t 1/2) after a single 100 mg dose of spironolactone are (Study I) 16.4--19.1 h for canrenone and 13.6--14.0 h for the sum of the active (i.e., antagonistic to aldosterone) metabolites. Certain therapeutic conditions (e.g. multiple dosing of 100 mg spironolactone with tau = 12 h, Study II) can lead to slightly increased t 1/2 values for both canrenone (18.6--21.4 (h)) and total fluorogenic metabolites (15.8--16.9 (h)). The steady-state level for both formulations is reached by the third day of treatment.

Adolescent↗
PubMed1979

Spironolactone-associated digoxin radioimmunoassay interference.

Apparent digoxin was measured in the serum of 21 patients receiving spironolactone and in 21 controls, by use of a sequential-saturation 3H-radioimmunoassay (RIA) and an equilibrium 125I-RIA. No patient had been given digoxin for at least four weeks. "Digoxin" values in the former group were significantly (p less than 0.05) higher than in the control group, and often were in or near the "therapeutic" range by the equilibrium 125I-RIA, but not by the sequential-saturation 3H-RIA. Canrenone (a major active metabolite of spironolactone) in the serum of the former group was measured by a newly developed liquid-chromatographic technique and correlated (r = 0.73) with "digoxin" concentrations by the 125I-RIA. However, external addition of canrenone to control serum in comparable concentrations did not cause appreciable "digoxin" values by the 125I-RIA. These findings suggest that other metabolites of spironolactone are responsible for the assay interference, the degree of which appears to depend on antibody specificity. Therefore, assay specificity should be established in clinical laboratories by using digoxin-free serum from patients ingesting spironolactone, and not by using spironolactone- or canrenone-fortified digoxin-free serum.

Digoxin↗
PubMed1995

Neointimal thickening after balloon denudation is enhanced by aldosterone and inhibited by spironolactone, and aldosterone antagonist.

OBJECTIVE: The aim was to examine the effects of aldosterone and of an aldosterone antagonist, spironolactone, on neointimal thickening in a rabbit model of balloon injury. METHODS: Eighteen rabbits underwent aortic and iliac balloon injury and were randomised to subcutaneous infusion of aldosterone (70 micrograms.kg-1.d-1) or vehicle solution for 28 d. Eighteen other rabbits were randomised to receive daily subcutaneous injections of spironolactone (50 mg.kg-1.d-1) or of vehicle for 7 d before injury and for 28 d after the procedure. All animals were then killed just after measurement of plasma renin activity and of arterial pressure. Vessels were fixed and five cross sections were analysed per rabbit (three aortic; two from iliac artery). Mean values of neointimal area and of the neointimal area/medial area ratio were calculated. RESULTS: Aldosterone treatment was associated with a decrease in renin activity and a non-significant increase in mean arterial pressure. Aldosterone significantly augmented the neointimal thickening in the iliac artery [0.42(SEM 0.07) v 0.24(0.03) mm2, P < 0.05] but not in the aorta [0.63(0.08) v 0.59(0.12) mm2, NS]. Spironolactone significantly inhibited intimal thickening, both in the iliac artery [0.09(0.02) v 0.29(0.01) mm2, P < 0.001] and in the aorta [0.31(0.03) v 0.59(0.06) mm2, P < 0.001]. Spironolactone administration was associated with an increase in renin activity and a decrease in mean arterial blood pressure. CONCLUSIONS: Aldosterone administration enhances neointimal thickening after injury and spironolactone, an aldosterone antagonist, is a potent inhibitor of neointimal thickening in the same model. This suggests a role for aldosterone in the pathophysiology of neointimal proliferation after balloon injury and for aldosterone antagonists in its prevention.

Aldosterone↗
PubMed1997

[Effects of ramipril and spironolactone on ventricular remodeling after acute myocardial infarction: randomized and double-blind study].

BACKGROUND: Studies have shown that angiotensin converting enzyme (ACE) inhibition prevents left ventricular remodeling and cardiovascular events after an acute myocardial infarction. The role of aldosterone in ventricular remodeling after a myocardial infarction has not been addressed. AIM: To compare the effects of an ACE inhibitor, an aldosterone receptor antagonist and placebo on left ventricular remodeling after a first episode of transmural acute myocardial infarction. PATIENTS AND METHODS: Patients hospitalized for a first episode of acute myocardial infarction were blindly and randomly assigned to receive ramipril (2.5 mg bid), spironolactone (25 mg tid) or placebo. Ejection fraction, left ventricular end diastolic and end systolic volumes were measured by multigated radionuclide angiography, at baseline and after six months of treatment. RESULTS: Twenty four patients were assigned to placebo, 31 to ramipril and 23 to spironolactone. Age, gender, Killip class, treatment with thrombolytics, revascularization procedures and use of additional medications were similar in the three groups. After six months of treatment, ejection fraction increased from 34.5 +/- 2.3 to 40.2 +/- 2.4% in patients on ramipril, from 32.6 +/- 2.9 to 36.6 +/- 2.7% in patients on spironolactone, and decreased from 37 +/- 3 to 31 +/- 3% in patients on placebo (ANOVA between groups p < 0.05). Basal end systolic volume was similar in all three groups, increased from 43.4 +/- 3.4 to 61.4 +/- 6.0 ml/m2 in patients on placebo and did not change in patients on spironolactone or ramipril (ANOVA p < 0.05). End diastolic volume was also similar in the three groups, increased from 70.6 +/- 4.3 to 92.8 +/- 6.4 ml/m2 in patients on placebo and did not change with the other treatments. CONCLUSIONS: Ramipril and spironolactone had similar effects on ventricular remodeling after acute myocardial infarction, suggesting that aldosterone contributes to this phenomenon and that inhibition of its receptor may be as effective as ACE inhibition in its prevention.

Analysis of Variance↗
PubMed1997

[Spironolactone-induced pemphigoid].

BACKGROUND: Sporadic observations would suggest that certain drugs play a role in the development of pemphigoid. A recent case-control study on long-term drug use associated with pemphigoid was unable to confirm the suspected role of these drugs, but did demonstrate a significant association between the development of pemphigoid and use of spironolactone. CASE REPORT: An 82-year-old patient had bullous erythematous lesions on the left thigh suggestive of pemphigoid. Histology and direct cutaneous immunofluorescence confirmed the diagnosis. The patient had been taking alimemazine, adrafinil, flunarizine, spironolactone and furosemide as long-term treatment. Spironolactone alone was withdrawn. The cutaneous lesions regressed and have not recurred during the 18-month follow-up. DISCUSSION: The causal effect of spironolactone in this case of pemphigoid is quite plausible. This hypothesis is favored by the agreement with epidemiological data. Other observations are however required before the causal role of spironolactone in development of pemphigoid can be confirmed.

Aged↗
PubMed1977

Metolazone and spironolactone in cirrhosis and the nephrotic syndrome.

Eighteen patients with hepatic cirrhosis or nephrotic syndrome and having edema and/or ascites were treated during successive periods with metolazone 5 to 40 mg/day, spironolactone 100 mg/day, and with both diuretics concurrently. Metolazone alone produced a marked diuresis, natriuresis, and weight loss in 8 patients. Spironolactone alone had little effect, but the addition of metolazone renewed diuresis and natriuresis and resulted in additional substantial weight losses in all patients responsive to metolazone alone. Concurrent spironolactone and metolazone also induced moderate diuretic effects in some patients who failed to respond to either drug alone. The drugs were well tolerated; the administration of spironolactone with metolazone prevented decreases in serum potassium, which had occurred during treatment with metolazone alone.

Adult↗
PubMed1978

Spironolactone-induced changes in digoxin kinetics.

Plasma clearance, volumes of distribution, and renal and extrarenal clearances of digoxin were calculated from plasma digoxin concentrations and urinary excretion of digoxin after intravenous injection of digoxin in 8 subjects. The investigation was repeated in the same subjects during long-term treatment with spironolactone. Increased plasma concentration of digoxin was detected during spironolactone treatment. Calculated plasma and renal clearances of digoxin and the volumes of distribution decreased statistically significant. Near maximal capacity for the tubular secretion of digoxin was found when normal digoxin dosage was used. It is suggested that unless spironolactone decreases the myocardial sensitivity for digoxin, the loading dose as well as the maintenance dose of digoxin should be reduced during treatment with spironolactone.

Adult↗
PubMed1978

Antihypertensive responses to spironolactone in normal renin hypertension.

The antihypertensive effect of spironolactone was studied in 20 patients with essential hypertension and normal stimulated peripheral renin activity (PRA). Single-blind 8-wk treatment periods of placebo, 100, 200, and 400 mg spironolactone were used in consecutive order. Average supine and erect blood pressures were lower than placebo values at the end of each treatment. A prominent orthostatic effect was observed. Changes in blood pressure were not related to changes in body weight, PRA, or blood urea nitrogen. A larger proportion (50%) of patients had a more normal erect diastolic pressure at the end of 400 mg/day than at the end of 100 mg/day (20%), but the response to 400 mg/day could not be predicted from the responses to lower doses. Larger doses of spironolactone were predictably associated with rises in serum potassium, PRA, and aldosterone excretion. Adverse effects were absent during therapy with 100 mg/day but were frequent during 200--400 mg/day. Although there are no apparent advantages in increasing spironolactone from 100 to 200 mg/day in this group of patients with normal renin hypertension, increasing the dose to 400 mg/day resulted in better blood pressure control with more frequent adverse effects.

Adult↗
PubMedDate not supplied

Correlation between the biliary excretion of ouabain and the lateral mobility of hepatocyte plasma membrane proteins in the rat--the effects of age and spironolactone pretreatment.

The biliary excretion of intravenously injected ouabain and the diffusion constant of the lateral mobility of hepatocyte plasma membrane proteins were examined in control (saline-treated) and spironolactone-treated Wistar male rats of different ages (4, 14 to 15 and 24 months old). The biliary excretion of ouabain progressively decreased with age in control rats, the first 10-min biliary recovery in 24-month-old animals being one-third that of the youngest rats (4-month-old). The oral administration of spironolactone for 4 days (10 mg per 100 gm body weight on the first day and 20 mg per 100 gm body weight for the successive 3 days) caused a marked increase in the biliary recovery of ouabain in all age groups. Similarly, the average lateral diffusion constant of hepatocyte plasma membrane proteins as measured by fluorescence recovery after photobleaching showed a linear decrease with age, as was previously observed with F-344 rats of both sexes. Markedly and significantly (30 to 40%) higher diffusion constants were observed in rats pretreated with spironolactone for all three age groups, compared with the respective control values of corresponding ages. The parallelism between ouabain excretion and protein diffusion (i.e., a decrease with age and an increase with spironolactone pretreatment) suggests that the lateral mobility of proteins in the hepatocyte plasma membrane is a candidate mechanism for regulating ouabain excretion through the liver into the bile, most probably by regulating the hepatic uptake process for ouabain.

Aging↗
PubMed2002

Bidirectional (positive/negative) interference of spironolactone, canrenone, and potassium canrenoate on serum digoxin measurement: elimination of interference by measuring free digoxin or using a chemiluminescent assay for digoxin.

Spironolactone and potassium canrenoate (aldosterone antagonist diuretics) are often used with digoxin in clinical practice. Spironolactone, potassium canrenoate, and their common metabolite canrenone cross-react with the fluorescence polarization immunoassay (FPIA) for digoxin, and can falsely elevate serum digoxin concentrations. Serum digoxin concentrations were falsely lowered when the microparticle enzyme immunoassay (MEIA) was used. Aliquots of drug-free serum were supplemented with therapeutic and above-therapeutic concentrations of spironolactone, canrenone, and potassium canrenoate, and apparent digoxin activities were measured. We observed digoxin-like activities in the FPIA, but observed no activity with the MEIA or the chemiluminescent assay (CLIA). However, when serum digoxin pools prepared from patients receiving digoxin were supplemented with these compounds, we observed suppression of total digoxin levels with the MEIA. In contrast, no interference was observed in the presence of these compounds when CLIA was used for digoxin measurement. These compounds are strongly protein-bound, and no apparent digoxin activity was observed in the protein-free ultrafiltrate when drug-free sera were spiked with high levels of these compounds. Taking advantage of strong protein binding of these compounds and weak protein binding of digoxin (25%), interference of spironolactone, canrenone, and potassium canrenoate in FPIA and MEIA digoxin assays can be mostly eliminated by monitoring free digoxin concentration. Another approach to avoid this interference is to use the CLIA digoxin assay.

Canrenoic Acid↗