Showing papers on "Spironolactone published in 1988"

Side-Effects of Spironolactone Therapy in the Hirsute Woman

Abstract: Spironolactone, an aldosterone antagonist with antiandrogenic activities, is often used to treat hirsute women. Several investigators have reported beneficial effects of such treatment, but the dosages used and side-effects encountered differ in their reports. To clarify this issue, 26 consecutive premenopausal women with idiopathic hirsutism were prospectively evaluated during spironolactone treatment. Sixteen women initially received 100 mg spironolactone twice daily on days 4-21 of their menstrual cycles. In 11 women (68%), the dosage had to be decreased or the medication discontinued due to side-effects. The major side-effect, metrorrhagia with 14-day cycles, occurred in 9 women (56%). This side-effect, while not dangerous, was intolerable to these women. In one woman, spironolactone was discontinued because of urticaria and in another because of scalp hair loss. Ten women initially received 50 mg spironolactone twice daily on days 4-21 of their menstrual cycles. Two developed metrorrhagia, but no other side-effects were noted. Because of the incidence of metrorrhagia at higher dosages, we recommend that spironolactone be administered cyclically at a starting dosage of 50 mg twice daily on days 4-21 of the menstrual cycle. Alternatively, one may consider adding cyclical estrogen/progesterone therapy to continuous spironolactone therapy.

Clinical implications of primary aldosteronism with resistant hypertension.

Abstract: Twenty-eight patients with resistant hypertension were found to have primary aldosteronism; 25 had solitary adenoma and 3 had adrenal hyperplasia. All were severely hypertensive despite receiving three or more antihypertensive agents, including conventional doses of diuretics, sympatholytics, and vasodilators. Hypervolemia (24 patients) or normovolemia (2 patients) despite severe diastolic hypertension was the hallmark in 26 patients. Adequate salt and water depletion alone with spironolactone (200 mg/day) and hydrochlorothiazide (50-100 ng/day) reduced arterial pressure in all. Twenty-two patients had surgical removal of a solitary adenoma. Over 1 to 2 years of follow-up, 13 were normotensive without medication, and six required hydrochlorothiazide and three hydrochlorothiazide plus a beta-blocker to normalize blood pressure. Blood pressure response to surgery had no relation to either duration or severity of hypertension. Six patients (three with hyperplasia, three with adenoma) have continued diuretic therapy and are normokalemic and normotensive. These results indicate that primary aldosteronism can be associated with sever and drug-resistant hypertension, that maintained hypervolemia is the reason for resistance to therapy, that sustained volume depletion is the most important therapeutic goal for these patients, and that cure can be achieved despite prolonged and severe hypertension.

Adrenocorticotropin and cortisol-induced changes in urinary sodium and potassium excretion in man: effects of spironolactone and RU486.

Abstract: The role of the glucocorticoid (type II) receptor in the Na+ retention induced by cortisol is not known. The relative contribution of mineralocorticoid (type I) and type II receptor activation to changes in urinary Na+ and K+ excretion in man was studied using spironolactone and RU486 to inhibit type I and II receptors, respectively. Normal men eating a constant daily diet received either ACTH or cortisol for 5 days. Spironolactone (400 mg/day) inhibited ACTH (80 U/day)-induced kaliuresis, but not the Na+ retention produced by ACTH or cortisol (240 mg/day) and only blunted the modest Na+ retention induced by cortisol (120 mg/day). RU486 (1200 mg/day for the first 2 day) inhibited the first day kaliuresis and carbohydrate intolerance produced by cortisol, but did not affect the Na+ retention. Thus, the kaliuresis produced by cortisol and ACTH can be attributed to type II and type I receptor activation, respectively. The failure of RU486 to inhibit the Na+ retention induced by cortisol with evidence of adequate blockade of type II receptors indicates that the Na+ retention produced by cortisol is not mediated by type II receptor activation, but is, at least in part, mediated by the type I receptor.

Long-term metabolic effects of spironolactone and thiazides combined with potassium-sparing agents for treatment of essential hypertension.

Abstract: By using information prospectively collected in the computerized ARTEMIS databank, the long-term metabolic consequences of spironolactone, hydrochlorothiazide-amiloride combination and cyclothiazide-triamterene combination were evaluated in 100 patients for each group matched according to sex, age and blood pressure (BP). Spironolactone was prescribed at a mean dose of 98 mg, hydrochlorothiazide at 36 mg and cyclothiazide at 2 mg, during a mean follow-up of 20 months. Compared with the pretherapeutic values, BP decreased equally in both treatment groups (18/9 mm Hg on average). Creatinine increased significantly in the 3 groups (9, 8, 14 mumol/liter, p less than 0.001) as did uric acid (18, 31, 42 mumol, p less than 0.001). Plasma potassium increased with spironolactone (0.7 mmol/liter, p less than 0.001) and remained stable with the combinations of the thiazide-potassium-sparing agents. For the 3 groups, the slight and nonsignificant variations of fasting blood glucose and cholesterol were mainly the results of a phenomenon of regression to the mean. However, when both groups of thiazide-treated patients were considered, the reduction of plasma potassium was accompanied by a slight increase in glucose (0.1 mmol/liter) and cholesterol levels (0.2 mmol/liter) compared with when kalemia decreased (-0.1 and -0.1 mmol/liter, respectively, p less than 0.05 and p less than 0.05). It is concluded that in a clinical daily practice of a hypertension clinic low doses of spironolactone or of thiazides combined with potassium-sparing agents reduced BP without alteration in lipid or carbohydrate metabolism on long-term follow-up.

Growth from birth to adulthood in a patient with the neonatal form of bartter syndrome

Abstract: Growth from birth to the age of 19 years was studied in a patient with the neonatal form of Bartter syndrome. The initial modes of therapy (extra fluid, potassium supplements and triamterene) resulted in satisfactory but not optimal growth. Treatment with spironolactone together with potassium led to impressive catch-up growth. When the patient reached the age of 9 years, indomethacin therapy was started, which resulted in a second growth acceleration and was also accompanied by a significant reduction of both polyuria and hypercalciuria. Puberty developed normally, menarche occurred at 12 years 4 months and a normal adult height of 162 cm was reached at the age of 14 years. Treatment with prostaglandin synthetase inhibitors seems to be the best therapy for children with the neonatal form of Bartter syndrome.

Spironolactone and cimetidine in treatment of acne.

Abstract: In an open therapeutic trial, 50 patients with acne vulgaris were randomly allocated to one of two groups. One group received spironolactone 100 mg daily and the other cimetidine 1.6 g daily for 12 weeks. Clinical severity of acne and sebum excretion decreased significantly at the end of the trial with both drugs, but significantly more with spironolactone. Mean serum levels of testosterone, androstenedione and dehydroepiandrosterone-sulfate decreased significantly with spironolactone but showed no change with cimetidine. Our data suggest that spironolactone may be useful as antiandrogen in the short term therapy of acne vulgaris.

The effect of renal and hepatic impairment and of spironolactone on digoxin immunoassays.

Abstract: The effect of renal and/or hepatic dysfunction, and of concomitant spironolactone therapy, on seven commercial digoxin assays was evaluated in 45 patients taking both these drugs, and a comparison made with the digoxin concentrations measured using the same assays in 30 patients taking digoxin in the absence of spironolactone.

Effect of spironolactone on glucocorticoid-induced colonic cation transport.

Abstract: Glucocorticoids stimulate colonic sodium absorption. Whether this stimulation is mediated by crossover binding to the aldosterone receptor has not been established. The effect of the aldosterone receptor antagonist, spironolactone, on dexamethasone-mediated transport was investigated in proximal and distal colon of adrenalectomized rats. In adrenal-intact control rats spironolactone minimally affected sodium absorption but markedly decreased the transmural potential difference (PD). In adrenalectomized, aldosterone-replaced rats spironolactone clearly decreased sodium absorption and transmural PD in both proximal and distal colon. In adrenalectomized rats treated with 5 micrograms/100 g body wt of dexamethasone twice daily spironolactone did not decrease sodium absorption or transmural PD. However, when adrenalectomized rats were treated with 25 micrograms/100 g body wt of dexamethasone, a dose estimated from plasma levels to occupy 80% of colonic aldosterone receptors, spironolactone inhibited 20% of proximal colon and 47% of distal colon sodium absorption. Thus lower doses of glucocorticoid which predominantly occupy glucocorticoid receptors stimulate sodium absorption by a spironolactone independent mechanism. When the levels of glucocorticoid are high enough to also occupy the majority of aldosterone receptors, sodium absorption is stimulated by an aldosterone receptor mediated mechanism.

Experimental studies on the endocrine side effects of new aldosterone antagonists.

Abstract: In the present study, endocrine-pharmacological profiles of new aldosterone antagonists, 15 beta,16 beta-methylenemexrenone (ZK 91587), delta 1-15 beta,16 beta-methylene-spironolactone (mespirenone, ZK 94679) and 7 alpha-thiomethyl analogue of mespirenone (ZK 97894) were characterized in comparing them with those of spironolactone. The results obtained indicate that all three compounds are distinctly less antiandrogenic than spironolactone in inhibiting the testosterone-induced organ growth of seminal vesicles and prostates in orchidectomized rats. The weak antiandrogenic activity of ZK 91587 and mespirenone is also manifested in the intrauterine feminizing effect on rat male foetuses. The in vitro study demonstrates that spironolactone and mespirenone inhibit the human chorionic gonadotropin-stimulated testosterone biosynthesis by rat testis cells, but that ZK 91587 and ZK 97894 have no appreciable effect on it. By contrast, the luteinizing hormone (LH)-dependent testosterone biosynthesis by mouse Leydig's cells is suppressed by ZK 97894, but not by spironolactone, mespirenone or ZK 91587. Mespirenone and spironolactone, given subcutaneously, show the same progestogenic potency in estrogen-primed ovariectomized rabbits. ZK 91587 and ZK 97894 are, however, less progestogenic than spironolactone, when administered subcutaneously. On oral administration, mespirenone and ZK 97894 show 2 to 3 times the progestogenic potency of spironolactone. Mesporenone causes a decrease in the serum testosterone and LH levels in cynomolgus monkeys and is about 2 times as potent as spironolactone. These results suggest that mespirenone seems to be a suitable candidate for development as a clinically useful aldosterone antagonist.

Lack of endocrine systemic side effects after topical application of spironolactone in man.

Abstract: In six healthy male volunteers, the percutaneous absorption of spironolactone was compared with placebo in a double-blind crossover study. The subjects were randomly given either a cream containing 5% spironolactone or placebo to be applied in a randomized sequential way to a well defined skin area equivalent to 55% of body area. During the 72 h following the application of the ointment, blood levels of canrenone, the major metabolite of spironolactone, have been determined. In order to estimate the systemic antiandrogenic effect of spironolactone, plasma levels of 17-α-Hydroxy progesterone (17α-OH-P), Testosterone (pT) and non-conjugated 3α-Androstanediol (3α-diol, metabolite of the active androgen 5α-Dihydrotestosterone or DHT) as well as salivary Testosterone (sT) which relate to the free and active plasma testosterone fraction have also been measured. Urinary levels of canrenone have been determined 48 hours after cream application. No changes in any levels of these hormones have been detected and plasma canrenone levels were undetectable during the 72 hours of topical treatment. Topically administered, spironolactone appears to have only a local skin impregnation.

Bumetanide, spironolactone and a combination of the two, in the treatment of ascites due to liver disease. A prospective, controlled, randomized trial.

Abstract: There are few studies available comparing the efficacy of loop and distal diuretics and a combination of the two groups, in the treatment of ascites due to liver disease. Thirty-seven nonazotemic cirrhotic patients with ascites were randomly allocated to receive for 2 weeks bumetanide (group A, n = 13), spironolactone (group B, n = 12) or a combination of the two drugs (group C, n = 12) after a 5-day stabilization period. The response to the treatment was 69, 42 and 83% in groups A, B and C, respectively; the difference was not significant. Hypokalemia was seen in 4 patients of group A and mild hyperkalemia in 2 patients of group B. Electrolyte disturbances were minimal in patients of group C. The response to diuretic treatment was prompt in groups A and C. It can be concluded that a combination of loop and distal diuretics is superior to a one-drug regimen in achieving a rapid and better diuretic response with fewer side effects.

Successful treatment of hyperkalemic quadriplegia associated with spironolactone.

Abstract: Hyperkalemic flaccid quadriplegia and cardiotoxic disturbances developed during antihypertensive therapy with spironolactone in a 76-year-old woman with chronic renal insufficiency Hyperkalemia was successfully overcome and followed by the disappearance of all cardiac and muscular disorders Progression of the renal disease leading to a decrease of creatinine clearance from 85 ml/min to 45 ml/min, during a three-year observation period per se had apparently no influence on the serum level of potassium Our studies suggested that no primary insufficiency of the renin-aldosterone and glucocorticoid systems had been responsible for the hyperkalemia, therefore, it could be contributed entirely to the effect of spironolactone abolishing the K+ secreting capacity of the already decreased renal mass Further studies revealed that blocking action of the drug on H+ secretion ("renal tubular acidosis") may also have had a role-in addition to the K+ retention-in the development of the spironolactone-induced hyperkalemia

4 Anti-androgens in gynaecological practice

Abstract: Summary Hirsutism and acne in women are common distressing problems Unwanted hair growth, acne and seborrhoea result from the action of androgens on the skin Such effects depend not only on increased androgen production by the ovary or adrenal gland but also on the bioavailability of androgen to peripheral tissues This in turn is related to transport of androgens in plasma by specific binding proteins and to peripheral metabolism of testosterone and androstenedione to their more potent 5α-reduced derivatives An effective anti-androgen is one which blocks the androgen receptor-mediated actions of testosterone and DHT on skin CPA, the treatment of choice in the UK, is a potent androgen receptor-blocking steroid which also has progestational properties When combined with ethinyloestradiol it also suppresses ovarian function, thus reducing androgen production, and provides effective contraception

Influence of spironolactone on urinary prostaglandin E2 and kinin excretion in rats.

Abstract: Spironolactone was administered to spontaneously hypertensive rats (SHRs) in order to examine the urinary excretions of prostaglandin E2 (PGE2) and kinin. Thirteen SHRs were divided into 2 groups: 0.1 ml of sesame oil was administered to one group (the spironolactone-lactone-untreated group, n = 6) and 20 mg of spironolactone in 0.1 ml of sesame oil was administered to the other group (the spironolactone-treated group, n = 7) by the subcutaneous route for 10 days in succession. Determinations were then made of the body weight, blood pressure, urine volume, and excretion levels of Na, K, kinin and PGE2 in the 24-hour urine. After the animals had been killed by decapitation, blood samples were drawn for determination of the plasma renin activity (PRA). The results obtained indicated decreased blood pressure and increased urinary Na excretion in the spironolactone-treated group. On the other hand, the PGE2 excretion level in the 24-hour urine decreased markedly immediately after administration of spironolactone (p<0.05) and was maintained at lower levels up to the end of the experiment. However, the 24-hour urinary kinin levels showed similar changes in both the spironolactone-treated group and the untreated group with no significant difference between them. These findings suggest that spironolactone has a suppressive effect on urinary PGE2 excretion, the activity of which is not mediated by kinin production in the kidneys but is the result of a direct action of spironolactone itself.

Spironolactone therapy in hirsutism and acne

Abstract: Summary Spironolactone has been found to have anti-androgenic properties and to be useful in the treatment of female hirsulism. Benefits have also been noted in the treatment of mature age onset or persistent acne in females. The mechanism of action of this drug is mainly via a peripheral anti-androgenic effect but it may also result in decreased androgen production. The results of a number of clinical studies are discussed with particular reference to the side effects of spironolactone. Guidelines for treatment of hirsutism and female mature age acne are given.

Primary aldosteronism in childhood due to primary adrenal hyperplasia.

Abstract: KIKUTA, Y., SANJO, K., NAKAJIMA, K., ASHIZAWA, I. and OJIMA, M. Primary Aldosteronism in Childhood Due to Primary Adrenal Hyperplasia. Tohoku J. exp. Med., 1988, 155 (1), 57-70-We present an unusual case of primary aldosteronism in childhood. A 9-year-old boy had hypertension, hypokalemia, hyporeninemia and hyperaldosteronism. Dexamethasone administration decreased plasma aldosterone transiently but failed to correct the hyperaldosteronism, excluding dexamethasone-suppressible hyperaldosteronism. Plasma aldosterone decreased with upright posture and showed a circadian rhythm. Spironolactone treatment normalized blood pressure and serum potassium and lowered aldosterone secretion. During the studies, plasma aldosterone correlated with serum cortisol but not with plasma renin. Preoperative results indicated that this patient presented the functional features of aldosteronoma. Adrenal computed tomography, scintigraphy and left venography were not diagnostic of adrenal lesions. The left adrenal venous sampling showed hypersecretion of aldosterone from the left adrenal gland. The left adrenalectomy revealed micronodular hyperplasia but resulted in a prompt and sustained reversal of hypertension and hyperaldosteronism. These findings suggest that primary aldosteronism in this patient resulted from primary adrenal hyperplasia. Thus, adrenal hyperplasia is a heterogenous group of disorders and carefully selected studies allow prospective selection of appropriate treatment.

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

Abstract: 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)

Severe complications during enalapril therapy for heart insufficiency

Abstract: In 3 patients with severe cardiac failure high dose therapy with the ACE inhibitor enalapril was instituted during a state of extracellular volume depletion. Severe arterial hypotension with reversible renal insufficiency developed in all the patients. In two the hypovolemia was induced by diuretic treatment and in one by an acute infection with diarrhea. The latter patient also developed life-threatening hyperkalemia with cardiac arrest since he was also receiving spironolactone and potassium supplements. These cases demonstrate that ACE inhibitors should not be instituted during extracellular volume depletion and their initial dosage should be low. The dangerous combination of ACE inhibitors with spironolactone and potassium supplements should be avoided wherever possible.

Lymphocyte function tests in cirrhotic patients under treatment with spironolactone and potassium canrenoate.

Abstract: This controlled study in cirrhotic patients investigated whether two antialdosteronic steroids, spironolactone (100-200 mg/day; n = 12 patient pairs) and potassium canrenoate (50-100 mg/day, n = 32 patient pairs) which are reported to bind to intracellular membranes and modify cytochrome P-450, could also produce nuclear changes. The model used was the response of peripheral lymphocytes to blastogenic agents by studying lymphocyte sub-populations. No changes occurred in the B- and T-lymphocyte sub-populations or in the helper and suppressor sub-types. The response to the blastogenic agents, phytohaemagglutinin and purified protein derived from mycobacteria, did not change significantly from before entry into the study to the follow-up (18.1 +/- 2.9 months). All control patients (n = 44 patient pairs) had slightly greater mitogenic activity compared with patients treated with spironolactone; no difference was found when control patients were compared with patients given potassium canrenoate. The difference between spironolactone and potassium canrenoate might be due to toxicity caused by the thio group of spironolactone. Overall, however, both drugs may be regarded as safe, in terms of effects on lymphatic tissue, occurring during the course of cirrhosis.

Influence of spironolactone on urinary prostaglandin E2 and kinin excretions in spontaneously hypertensive rats

Abstract: Spironolactone was administered to spontaneously hypertensive rats (SHRs) in order to examine the urinary excretions of prostaglandin E2 (PGE2) and kinin. Thirteen SHRs were divided into 2 groups, and 0.1 ml of sesame oil was administered to one of 2 groups (spironolactone-untreated group) (n = 6) and 20 mg of spironolactone in 0.1 ml of sesame oil was administered to the other group (spironolactone-treated group) (n = 7) by the subcutaneous route for 10 days in succession, followed by the determination of body weight, blood pressure, urine volume, excretion levels of Na, K, kinin and PGE2 in 24-hour urine. Blood samples were drawn after these animals were killed by decapitation for determining plasma renin activity (PRA). In consequence, decreased blood pressure and increased urinary Na excretion were observed in the spironolactone-treated group. On the other hand, PGE2 excretion level in 24-hour urine markedly decreased immediately after administration of spironolactone (p less than 0.05) and was maintained at lower levels up to the end of experiment. However, 24-hour urinary kinin levels showed similar changes in the spironolactone-treated group and the untreated group with no significant difference between the two groups. These results indicate that spironolactone has a suppressive effect on urinary PGE2 excretion, the activity of which is not mediated by kinin production in the kidneys but produced by a direct action of spironolactone itself.