Showing papers on "Spironolactone published in 1987"
Journal Article•
TL;DR: It appears that the 9 alpha, 11 alpha-position of the steroid structure is a site of the molecule which can be modified to improve the specificity of aldosterone-antagonists not only in vitro, but also in vivo.
Abstract: The use of spironolactone, the most commonly used antimineralocorticoid compound, is limited by the occurrence of sexual endocrine effects. New antagonists are therefore required which lack these unwanted effects. Three 9 alpha,11 alpha-epoxy-derivatives of known aldosterone antagonists (spironolactone, prorenone and mexrenone) have been characterised in vitro and in vivo. In each experiment spironolactone was run as a reference. The introduction of the epoxy-group only marginally affected the binding affinity of these compounds for the mineralocorticoid receptor, whereas it caused a decrease for the androgen and progesterone receptors of between 10- and 500-fold. In vivo, all three epoxy-derivatives (3 mg/kg) were potent aldosterone antagonists, 1 to 2 times the potency of spironolactone in the rat. Parallel to the decreased affinity for the androgen and progesterone receptor in vitro, there was a 3- to 10-fold decrease of the antiandrogenic and progestagenic effect compared to spironolactone in the rat and in the rabbit, respectively. Virtually no disturbance of the vaginal or ovulatory cycle was observed with either epoxymexrenone or epoxyprorenone, although epoxyspironolactone caused a 20% decrease in ovulation. It appears therefore that the 9 alpha, 11 alpha-position of the steroid structure is a site of the molecule which can be modified to improve the specificity of aldosterone-antagonists not only in vitro, but also in vivo.
315 citations
TL;DR: It is concluded that spironolactone administered in daily practice reduced BP without inducing adverse metabolic adverse effects and that in patients with essential hypertension, doses should be kept below 100 mg.
Abstract: The long-term efficacy and tolerance of spironolactone in essential hypertension was evaluated among 20,812 patients referred to the Broussais and St. Joseph systemic hypertension clinics between 1976 and 1985 by using information prospectively collected in the computerized ARTEMIS data bank. In 182 patients (51 men, 131 women) treated with spironolactone alone during a mean follow-up period of 23 months, a mean dose of 96.5 mg decreased systolic and diastolic blood pressure (BP) by 18 and 10 mm Hg, respectively, below pretherapeutic levels. The BP decrease was greater with doses of 75 to 100 mg (12.4% and 12.2%) than with doses of 25 to 50 mg (5.3 and 6.5%, p less than 0.001), but no additional decrease was found with doses above 150 mg. Plasma creatinine level increased modestly (8.3 mumol/liters), as did plasma potassium level (0.6 mmol/liters) (both p less than 0.001); uric acid level increased, but not significantly (10.5 mumol/liter). Fasting blood glucose and total cholesterol levels did not change, triglyceride levels increased slightly (0.1 mmol/liter, p less than 0.05). These changes were similar in both sexes and were not influenced by length of follow-up. Among the 699 men prescribed spironolactone alone or in association with another antihypertensive treatment, 91 cases of gynecomastia developed (13%). Gynecomastia was reversible and dose-related; at doses of 50 mg or less the incidence was 6.9%, but 52.2% for doses of 150 mg or higher. Despite limitations inherent in the interpretation of data banks, it is concluded that spironolactone administered in daily practice reduced BP without inducing adverse metabolic adverse effects and that in patients with essential hypertension, doses should be kept below 100 mg.
255 citations
TL;DR: It is concluded that serum 3 alpha-diol G measurements are clinically useful in evaluating hirsute women and correlate with the clinical responses to therapy.
Abstract: Serum androstanediol glucuronide (3 alpha-diol G), a metabolite of the active androgens dihydrotestosterone and androstanediol, was elevated in 28 consecutive women with idiopathic hirsutism (IH). The mean 3 alpha-diol G level in the women with IH was 487 +/- 192 (+/- SD) ng/dL compared to 119 +/- 37 ng/dL in normal women (n = 50), and only 1 patient had a value overlapping with the normal range. Since 3 alpha-diol G appears to be formed entirely in target organs and has a long serum half-life, we studied its clinical usefulness by following women with IH during treatment. In 15 of 17 women with IH treated for 1-4 yr with glucocorticoids, contraceptives, or spironolactone, serum 3 alpha-diol G levels changed concordantly with clinical responses, in contrast to the poor concordance of serum testosterone (5 of 17), free testosterone (7 of 17), and androstenedione (7 of 17). Specifically, in IH patients treated with spironolactone, serum testosterone, free testosterone, and androstenedione levels changed little, yet clinical improvement frequently occurred, and this improvement was reflected by concomitantly lowered 3 alpha-diol G levels. Further, in 4 IH patients, discontinuation of effective therapy resulted in prompt increases in serum 3 alpha-diol G as harbingers of worsening hair growth. We, thus, conclude that serum 3 alpha-diol G measurements are clinically useful in evaluating hirsute women and correlate with the clinical responses to therapy.
64 citations
TL;DR: A survey of 54 patients taking spironolactone for hirsutes or acne showed that side‐effects occurred in 91%; in 80% of patients, these were related to the anti‐androgenic mechanism of the drug.
Abstract: A survey of 54 patients taking spironolactone for hirsutes or acne showed that side-effects occurred in 91%; in 80% of patients, these were related to the anti-androgenic mechanism of the drug (menstrual disturbances, and breast enlargement and tenderness). The concomitant use of a contraceptive pill gave a lower incidence of menstrual abnormalities. Only seven patients (13%) had to stop the drug. In a further eight patients, a reduction in dose to between 125 and 175 mg daily achieved a compromise of controlling the disease and the side-effects. Side-effects tended to occur early and so regular review during the initial 3 months of treatment is advised. Two patients in our study developed 'chloasma'--a previously unreported complication of spironolactone. This was the only side-effect which occurred late in treatment.
58 citations
TL;DR: It is suggested that an abnormality in Cortisol action or metabolism results in cortisol behaving as a potent mineralocorticoid and causing the syndrome of AME.
Abstract: We report two female siblings (ages 4 and 9 years) and one 8-year-old male with the syndrome of apparent mineralocorticoid excess (AME) presenting with low renin hypertension and hypoaldosteronism. The deficiency of 11 beta-hydroxysteroid dehydrogenase results in a defect of the peripheral metabolism of cortisol (F) to cortisone (E). As a result, the serum cortisol half-life (T1/2) is prolonged, ACTH is suppressed, and serum F is normal. The specific diagnosis of the disorder was made by the decreased ratio of the urinary metabolites of E (tetrahydrocortisone, THE) and F (tetrahydrocortisol, THF). Continuous i.v. hydrocortisone administration caused an increase in blood pressure and decrease in serum potassium demonstrating the abnormal mineralocorticoid activity of cortisol in these patients. Addition of spironolactone resulted in a decrease in blood pressure, rise in serum potassium and a gradual increase in plasma renin activity. These studies suggest that an abnormality in cortisol action or metabolism results in cortisol behaving as a potent mineralocorticoid and causing the syndrome of AME.
52 citations
TL;DR: It was demonstrated that after a single oral dose of spironolactone, 7 alpha-thiomethylspirolactone is the main metabolite and that unchanged spironlactone reaches maximum serum concentrations which are in the same order of magnitude as canrenone.
Abstract: Spironolactone, a competitive aldosterone antagonist, has been used for almost 30 years in those disorders associated with primary or secondary hyperaldosteronism. This review is confined to its metabolism and biopharmaceutics in man. Spironolactone undergoes extensive metabolism with no unchanged drug appearing in the urine. Its metabolites can be divided into two main categories: those in which the sulfur of the parent molecule is removed and those in which the sulfur is retained. The dethioacetylated metabolite canrenone, belonging to the former category, was long considered to be the major active metabolite of spironolactone. For this reason pharmacokinetic studies have focussed on its kinetic behaviour. However, pharmacodynamic studies indicated that canrenone could only partly explain spironolactone's action. Furthermore, with the advent of modern high-performance liquid chromatographic techniques to measure canrenone concentrations, it was shown that previously employed assay techniques were unspecific and consequently considerably overestimated true canrenone levels. Recently, it was demonstrated that after a single oral dose of spironolactone, 7 alpha-thiomethylspirolactone is the main metabolite and that unchanged spironolactone reaches maximum serum concentrations which are in the same order of magnitude as canrenone. Both spironolactone and 7 alpha-thiomethylspirolactone are known to possess anti-mineralocorticoid activity, and they may be mainly responsible for the activity of spironolactone. It also appears likely that endocrine side effects of spironolactone, such as gynaecomastia, are mediated by these sulfur-containing compounds. The oral absorption of spironolactone is improved by using micronized drug or inclusion complexes of spironolactone with cyclodextrins. Concomitant food intake has also been shown to enhance the bioavailability, by increasing the absorption and decreasing the first-pass effect of spironolactone.
52 citations
TL;DR: No statistically significant changes were observed in blood biochemistry of plasma hormone levels of oestradiol, progesterone or prolactin, though an increase in serum aldosterone levels was seen in the spironolactone-treated group, and no differences were detected in weight, blood pressure or the incidence and severity of complaints following treatment.
Abstract: SummaryThe effect of spironolactone in the alleviation of the symptoms of the Premenstrual syndrome was compared with placebo in a double-blind, parallel group controlled studv. One tablet dailv of 100 mg spironolactone or placebo was given to 63 women from Day 12 of the menstrual cycle until the first day of the next menstrual bleed. This regimen was repeated for two consecutive cycles. Spironolactone was statistically significantly superior in providing relief from bloatedness (p<0.001). No statistically significant changes were observed in blood biochemistry of plasma hormone levels of oestradiol, progesterone or prolactin, though an increase in serum aldosterone levels was seen in the spironolactone-treated group. No differences were detected in weight, blood pressure or the incidence and severity of complaints following treatment.
46 citations
TL;DR: It is concluded from intact DEX-suppressed women that ovarian T, especially when increased, is frequently lowered by spironolactone, and both adrenal and ovarian androgen production may be diminished by this agent.
32 citations
TL;DR: The action of aldosterone on the distal tubule may be important in the pathogenesis of CsA nephrotoxicity, and co-treatment of animals for the 14 day period with enalapril or spironolactone reduced the neph rotoxicity, although PRA remained elevated.
28 citations
Journal Article•
TL;DR: Low-dose spironolactone is safe and effective in the treatment of hirsutism and seems to be useful as an initial or alternative treatment.
Abstract: Twelve women, 11 with hirsutism and one with alopecia areata, were treated with low-dose spironolactone (50 mg daily) from the 4th until the 22nd cycle day over 12 consecutive menstrual cycles. Eight hirsute women observed a favorable effect on hirsutism in 3 to 8 months, and hair loss ceased in the one patient with alopecia areata. No significant side effects occurred. Low-dose spironolactone decreased the concentration of total and free testosterone and elevated the concentration of prolactin on the 10th cycle day, while LH, FSH, estradiol, progesterone, DHEAS, SHBG, and cortisol levels remained unchanged. The plasma aldosterone concentration increased significantly during the treatment, although serum potassium and sodium concentrations remained unchanged. Low-dose spironolactone is, thus, safe and effective in the treatment of hirsutism. It seems to be useful as an initial or alternative treatment.
26 citations
TL;DR: Triiodothyronine enhances the sensitivity of Na-K-ATPase to aldosterone which, in turn, produces a stimulatory action despite the decreased plasma level observed during hypothyroidism.
Abstract: Since thyroid hormones and mineralocorticoids were observed to stimulate kidney Na-K-ATPase in similar sites and with similar time courses, this study was initiated to evaluate whether aldosterone is involved in the stimulation of Na-K-ATPase observed in collecting tubules 3 h after triiodothyronine (T3) administration to thyroidectomized (TX) rabbits. Results indicate that: Plasma aldosterone level decreased markedly in TX rabbits but was not restored 3 h after T3 injection; Early stimulation of Na-K-ATPase by T3 was abolished when plasma aldosterone level was suppressed by adrenalectomy or when aldosterone effects were blocked by spironolactone; Administration of aldosterone to TX rabbits mimicked the action of T3; Sensitivity of Na-K-ATPase to aldosterone markedly decreased after thyroidectomy. These results demonstrate an interaction between aldosterone and T3 in the control of Na-K-ATPase in the collecting tubule. Triiodothyronine enhances the sensitivity of Na-K-ATPase to aldosterone which, in turn, produces a stimulatory action despite the decreased plasma level observed during hypothyroidism.
TL;DR: The data suggest that, at the dosages employed, Aldactone has a better clinical effect on the hair parameters despite a lack of effect on circulating hormone levels.
TL;DR: The data of the urinary sodium excretion showed the escape from sodium-retaining effect of aldosterone, and this escape could be explained by the increase in plasma ANP, which might contribute to the decrease in cortisol and deoxycorticosterone in plasma because of the direct inhibitory action of ANP on steroidogenesis.
Abstract: The withdrawal effect of spironolactone treatment on natriuresis was studied in relation to atrial natriuretic peptide (ANP) in five patients with primary aldosteronism due to adenoma The patients had been treated with spironolactone for 2-3 months before they were admitted After admission, blood pressure, body weight, and urinary excretion of sodium were measured daily Venous samples were obtained twice a week for measurements of plasma levels of ANP, plasma renin activity (PRA), and plasma concentrations of aldosterone (PAC), Cortisol, and deoxycorticosterone The study was performed for 7 days during the treatment with spironolactone and for 18 days after stopping the administration Plasma volume was determined two times, during the control period and on the 13th day after stopping spironolactone Urinary sodium excretion decreased initially and returned to the control levels successively Body weight and plasma volume increased, and blood pressure rose steadily PRA and the plasma concentr
TL;DR: Spironolactone 100 mg daily plus norethindrone and ethinyl estradiol resulted in significant reduction in serum total testosterone, serum free testosterone, and percentage of free testosterone.
Abstract: Sixteen women with hirsutism used spironolactone, 100 mg daily without interruption, plus norethindrone (1 mg) and ethinyl estradiol (35 mg) for 21 of each 28 days. Clinical improvement occurred in 11 of the 16 patients and also in an additional patient when the dose of spironolactone was increased to 200 mg daily. Spironolactone 100 mg daily plus norethindrone and ethinyl estradiol resulted in significant reduction in serum total testosterone, serum free testosterone, and percentage of free testosterone. Side effects were infrequent.
TL;DR: No significant effect of spironolactone could be demonstrated on androgen secretion and the incidence of ovulation, and a slight but statistically insignificant effect on hirsutism when compared with placebo.
Abstract: In a double-blind cross-over study, 24 hyperandrogenic women were treated for three months at a time with either spironolactone 100 mg or placebo daily from the 5th to the 21st days of the menstrual cycle. Spironolactone had a slight but statistically insignificant effect on hirsutism when compared with placebo. Slightly more regular menstruation and better follicular growth was noted during spironolactone treatment. Ovulation (defined as a day 21 serum progesterone level of more than 10 nmol/l) occurred in only 12% of spironolactone cycles, as against 28% of placebo cycles. Spotting occurred in one-third of the spironolactone cycles. No significant differences were found between spironolactone and placebo cycles in serum levels of LH, FSH, prolactin, estradiol, progesterone, androstenedione, total testosterone, sex-hormone binding globulin (SHBG), unbound testosterone, dehydroepiandrosterone sulphate (DHEAS), cortisol, potassium and sodium. The average ovarian volume was 13.0 (5.7-21.8) cm3, and no significant differences were found between treatment and placebo cycles. No significant effect of spironolactone could be demonstrated on androgen secretion and the incidence of ovulation.
TL;DR: Only spironolactone appears to act as an antiandrogen in liver, resulting in a decrease in both AR and male specific estrogen binder content, and (b) neither drug results in elevated hepatic ER content, although spironOLactone-treated animals show an altered subcellular localization.
TL;DR: It is concluded that the pre-operative response of blood pressure to administration of 100 mg per day of spironolactone for 10 days represents a useful indicator of the postoperative prognosis of hypertension in patients with primary aldosteronism owing to adenoma.
Abstract: The prognosis of hypertension was evaluated pre-operatively in 40 patients with primary aldosteronism owing to adenoma by examining the severity of hypertension, family history of hypertension, age of the patients, duration of hypertension, plasma renin activity, plasma aldosterone concentration, and efficacy of spironolactone (100 mg per day for 10 days) on blood pressure. In 30 of the 40 patients, the blood pressure was reduced to below 160/95 mmHg within a year after adrenalectomy (responders). In the other 10 patients, the blood pressure was not markedly reduced and remained above 160/95 mmHg (nonresponders). There were no significant differences in the age of the patients, family history of hypertension, plasma renin activity or plasma aldosterone concentration between these two groups. The severity of hypertension as judged by the WHO classification and the duration of hypertension prior to operation seemed to be of some use in assessing the postoperative prognosis of hypertension, but the efficacy of spironolactone was far more useful. That is to say, a reduction in mean blood pressure of more than 15 mmHg after administration of spironolactone was observed in 29 of the 30 responders. The remaining one patient showed an 11 mmHg reduction in mean blood pressure. On the other hand, none of the nonresponders revealed a reduction in mean blood pressure of more than 15 mmHg after spironolactone administration. From these results it is concluded that the pre-operative response of blood pressure to administration of 100 mg per day of spironolactone for 10 days represents a useful indicator of the postoperative prognosis of hypertension in patients with primary aldosteronism owing to adenoma.
TL;DR: The potential association of spironolactone with granulocytopenia warrants increased awareness of this rare but serious adverse drug reaction and there was concomitant improvement of the leukocyte and neutrophil counts.
Abstract: Agranulocytosis associated with spironolactone administration is described in a 57-year-old man. Four days after initiation of spironolactone, leukocyte counts decreased from 8.2 to 2.3 × 109/L with 6% neutrophils. Spironolactone, domperidone, and prochlorperazine were discontinued. Domperidone and prochlorperazine were reintroduced and there was concomitant improvement of the leukocyte and neutrophil counts. Substitution of triamterene for spironolactone was not associated with recurrent leukopenia. The potential association of spironolactone with granulocytopenia warrants increased awareness of this rare but serious adverse drug reaction.
Journal Article•
TL;DR: It is suggested that it is not impossible to combine an ACE inhibitor with a potassium-sparing diuretic, as long as renal function is normal and serum potassium concentration is monitored closely.
Abstract: Both angiotensin converting enzyme (ACE) inhibitors and potassium-sparing diuretics tend to increase serum potassium levels. This retrospective study was undertaken to assess whether these two types of agents can nevertheless be combined safely. Twelve hypertensive patients were treated for 1-70 months (mean = 17) with an ACE inhibitor together with a potassium-sparing diuretic (spironolactone, n = 10; amiloride, n = 2). In addition, eight patients also took a thiazide or a loop diuretic. Nine patients had a normal and three a slightly impaired renal function. No clinically relevant hyperkalemia was observed during the course of the study. These data suggest that it is not impossible to combine an ACE inhibitor with a potassium-sparing diuretic, as long as renal function is normal and serum potassium concentration is monitored closely.
TL;DR: The results indicate that the liver and kidney are potential sites of 7α-thiomethyl-SL production and that its formation probably does not involve the C-S lyase pathway.
TL;DR: It is strongly suggested that the ambient levels of aldosterone are important in determining potassium excretion following food ingestion, and changes in plasma ald testosterone, with variations in dietary potassium or sodium, suggest a role for a Aldosterone in subsequent potassiumexcretion.
Abstract: To study the role of aldosterone in the short-term control of potassium excretion, rats were gavaged with a liquid diet containing 10-20% of their daily caloric and potassium intake, with a range of sodium intakes. Levels of (effective) aldosterone at the time of gavage were manipulated by administration of spironolactone, aldosterone, and adrenalectomy. Urinary sodium, potassium, and creatinine excretion were measured in conscious unrestrained rats for 2 h after the food load, and then blood was collected for measurement of plasma potassium, aldosterone, and renin activity. Potassium excretion was dependent on both dietary potassium and a minimum dietary sodium content. Potassium excretion was reduced by spironolactone and adrenalectomy and increased by acute aldosterone treatment in most dietary groups. These results strongly suggest that the ambient levels of aldosterone are important in determining potassium excretion following food ingestion. Plasma aldosterone was higher with the higher potassium and lower sodium content diets. Changes in plasma aldosterone, with variations in dietary potassium or sodium, suggest a role for aldosterone in subsequent potassium excretion.
TL;DR: Combination therapy for severe hirsutism in a 13-year-old girl with Kahn type-A syndrome of insulin resistance, acanthosis nigricans, and polycystic ovaries resulted in a marked reduction in facial hair and serum androgen concentrations, which persisted during 18 months of treatment.
01 Jan 1987
TL;DR: Canrenone is the main active metabolite of the diuretic and antihypertensive drugs spironolactone and K-canrenoate and end competes with aldosterone for a common cytosolic receptor in distal and collecting tubules of the nephron.
Abstract: Canrenone is the main active metabolite of the diuretic and antihypertensive drugs spironolactone and K-canrenoate (1), end competes with aldosterone for a common cytosolic receptor in distal and collecting tubules of the nephron (2)
01 Jan 1987
TL;DR: Antimineralocorticoid compounds are widely prescribed for the treatment of essential hypertension and primary or secondary hyper-aldosteronism and their administration however is limited by its anti-androgenic action.
Abstract: Antimineralocorticoid compounds are widely prescribed for the treatment of essential hypertension and primary or secondary hyper-aldosteronism. Spironolactone is the most commonly used drug of this type. Its administration however is limited by its anti-androgenic action.
Journal Article•
TL;DR: An 11 yr old white male with severe hypertension, hypokalemia, and suppressed plasma renin was studied and a left adrenalectomy was performed which revealed macronodular hyperplasia and adrenal vein sampling was the most useful test in determining the etiology of hyperaldosteronism.
Abstract: An 11 yr old white male with severe hypertension (150-170/100-120), hypokalemia (2.6-2.9 mEq/L) and suppressed plasma renin (PRA)(<20 ng/dl/hr) was studied. Initial random serum and urine aldosterone (Aldo) were 19 ug/dl and 11 ng/dl. Antihypertensive therapy and potassium supplementation were begun. Results of dexamethasone (Dex) suppression, ACTH stimulation and adrenal vein sampling are indicated in Table. B, corticosterone; DOC, Deoxycorticosterone; F, Cortisol. The partial suppression of Aldo by Dex and stimulation by ACTH suggested hyperplasia; however, the paradoxical decline in Aldo with upright posture suggested a tumor. Adrenal venography indicated an enlarged left adrenal not confirmed by computed tomography. Because spironolactone failed to correct hypertension, a left adrenalectomy was performed which revealed macronodular hyperplasia. After surgery, hypertension improved along with normalization of biochemical and hormonal abnormalities. Adrenal vein sampling was the most useful test in determining the etiology of hyperaldosteronism.
01 Jan 1987
TL;DR: A patient suffering from non compensated liver cirrhosis and hyperaldosteronism was treated with spironolactone (SP), and severe irreversible hyponatremia developed with severe clinical and symptomatic manifestations documented by laboratory test.
Abstract: A patient suffering from non compensated liver cirrhosis and hyperaldosteronism was treated with spironolactone (SP). Severe irreversible hyponatremia developed with severe clinical and symptomatic manifestations documented by laboratory test. Death of the patient ensued.