Showing papers on "Spironolactone published in 1980"

A Novel Use of Spironolactone: Treatment of Hirsutism

Abstract: An excess of androgens is the recognized cause of hirsutism in women. In this study, the antiandrogenic properties of spironolactone were tested clinically in 30 hirsute women. The drug was administered from the 4th to the 22nd day of each menstrual cycle. The moderate side effects in no case forced interruption of the treatment. Hair growth diminished substantially in 23 of the patients, the effect becoming evident 3-5 months after the commencement of treatment. Serum testosterone concentrations decreased in all patients, and estradiol increased in 25 women. Our data suggest that the antiandrogenic properties of spironolactone render it a suitable agent in the treatment of hirsutism.

Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patents

Abstract: Dose-response curves for amiloride and spironolactone were defined in 15 hypertensive patients treated with bendroflumethiazide (bendrofluazide). The relative potency amiloride:spironolactone in correcting hypokalemia was 2.8:1, an estimate significantly lower than the 5:1 potency currently accepted. The relative potency for reduction of plasma sodium was 3.9:1 (amiloride:spironolactone). Amiloride was disproportionately potent in lowering serum bicarbonate, and the data do not suggest that these drugs elevate plasma potassium simply by correcting metabolic alkalosis. Changes in blood pressure were confounded by the presence of carryover effect between treatment phases. Both drugs increased plasma angiotension II and aldosterone, but the rise in aldosterone with spironolactone was smaller than expected from concurrent plasma angiotension II and potassium concentrations. This was consistent with a partial block of aldosterone biosynthesis by spironolactone. The activity of spironolactone did not require the presence of hyperaldosteronism. In a smaller study potassium chloride induced a significant log dose-response on plasma potassium, but the effect was small in absolute terms. At least 64 mmole potassium chloride was needed to match the effect of 20 mg amiloride or 56 mg spironolactone.

Hypertension in a Four-Year-Old Child: Gas Chromatographic and Mass Spectrometric Evidence for Deficient Hepatic Metabolism of Steroids

Abstract: A 4-yr-old boy with hypertension and hypokalaemic alkalosis had low plasma aldosterone levels and renin activity. The hypertension and hypokalemia responded to spironolactone and triamterene therapy. A partial response to dexamethasone was observed. Analysis of urinary steroid metabolites by gas chromatography-mass spectrometry showed that the excretion of metabolites of deoxycorticosterone and aldosterone was subnormal, and there was no evidence for sizeable excretion of unusual steroids with potential mineralocorticoid activity. The cortisol excretion rate, however, was subnormal, and the relative excretions of individual metabolites of this hormone were not typical. In particular, the excretion of tetrahydrocortisone was markedly reduced, and the excretions of allotetrahydrocortisol and free cortisol and metabolites were elevated. These findings suggest that modified or deficient metabolism of adrenal steroids could give rise to elevated blood pressure. It is not known whether the inappropriate production of unusual cortisol metabolites were responsbile for the high blood pressure or whether the altered metabolism is indicative of similar abnormality in the metabolism of other adrenal steroids, resulting in hyperproduction or extended half-life of minor but highly active mineralocorticoids of unknown structures.

Role of glucocorticoids and aldosterone in maintenance of colonic cation transport

Abstract: Adrenalectomized rats were maintained on physiologic replacement doses of aldosterone or dexamethasone for 24 h after adrenalectomy. Net cation movement and transmural potential difference were determined during in vivo perfusion of the colon. Adrenalectomy without replacement steroids resulted in marked reduction of sodium and water absorption, potassium secretion, and transmural potential difference (PD). Aldosterone 10 microgram . 100 g body wt-1 . 24 h-1 significantly increased net potassium secretion above adrenalectomized levels but did not restore transport to control levels. Sodium and water absorption and transmural PD were not affected. Aldosterone 30 microgram . 100 g body wt-1 . 24 h-1 increased but did not restore net movement of sodium or potassium to control levels. In contrast to aldosterone, physiologic amounts of dexamethasone, 10 microgram . 100 g body wt-1 . 24 h-1, preserved normal electrolyte movement and electrical properties in adrenalectomized rats. In additional experiments the aldosterone antagonist spironolactone was administered for 3 days to rats with intact adrenal function. Net sodium absorption fell only 22% below control with insigificant decreases in potassium secretion and transmural PD. These data suggest that glucocorticoid hormones exert regulatory control of basal colonic fluid and electrolyte function.

Familial, dexamethasone-suppressible, normokalemic hyperaldosteronism.

Abstract: An 8-year-old boy was found to be hypertensive on routine exam (144/88). His brother (age 6) and father (age 31) were also found to have elevated blood pressure. Detailed investigations first revealed a low renin level without hypokalemia. Further study revealed that all three patients had low plasma renin activity and nonsuppresible plasma aldosterone levels after saline infusion. Serum potassium was almost always normal. A trial of dexamethasone therapy normalized blood pressure, and plasma and urinary aldosterone decreased to low levels and renin levels increased. Therapy with spironolactone and prednisone also normalized blood pressure. However, the amount of prednisone required to maintain normotension resulted in Cushingoid features and has been discontinued. Studies in the father suggest that the aldosterone production by his adrenals is hyperresponsive to adrenocorticotropic hormone (ACTH). Renin levels should be determined in all hypertensive children and their hypertensive parents. If renin is low and plasma aldosterone fails to be suppressed by saline infusion, a trial of dexamethasone would seem indicated before other investigations are carried out.

Interaction of conventional and antikaliuretic diuretics with the renal prostaglandin system.

Abstract: 1. The effects of frusemide, hydrochlorothiazide and spironolactone on the renal prostaglandin system, and the interference with their diuretic and natriuretic effects by inhibition of prostaglandin synthase, were investigated in healthy human subjects. 2. Urinary excretion of prostaglandin E2 was increased by the administration of frusemide ( P < 0.05), hydrochlorothiazide and particularly by spironolactone, the least potent natriuretic agent ( P < 0.05). A qualitatively similar but statistically insignificant rise in excretion of prostaglandin F2α was observed with hydrochlorothiazide. 3. The rise in urinary excretion of sodium after frusemide and hydrochlorothiazide was significantly reduced by indomethacin, which also abolished the potassium-sparing effect of spironolactone and partially suppressed the diuretic-induced rise in plasma renin activity. 4. Indomethacin had no significant effect on urinary osmolality or free water absorption in the presence of frusemide or hydrochlorothiazide, but markedly enhanced urinary osmolality ( P < 0.05) and free water absorption ( P < 0.05) in the presence of spironolactone. 5. Increased renal prostaglandin activity after frusemide, hydrochlorothiazide and spironolactone may contribute to their natriuretic action which, in addition to the antikaliuretic effect of spironolactone, may be partially abolished by the presence of non-steroidal antiphlogistic agents.

Clinical and biochemical effects of spironolactone administered once daily in primary hypertension. Multicenter Sweden study.

Abstract: In a prospective, double-blind, intraindividual, cross-over, placebo-controlled multicenter study, clinical and biochemical effects of once daily postprandial dose regimens of 50, 100, and 200 mg spironolactone were investigated in 45 outpatients with primary hypertension, WHO (World Health Organization) Stage I-II. Each of the three active therapy periods, which were randomly allocated to patients, were of 2 months' duration, with intervening placebo periods, Clinical and biochemical parameters, including furosemide-stimulated plasma renin activity (PRA), were recorded at regular intervals. All three spironolactone doses resulted in statistically significant blood pressure (BP) reductions independent of initial pretreatment levels and yielded satisfactory BP control in more than half of the patients. The 200 mg daily dose of spironolactone was found to be more effective than 50 but not 100 mg. When, correlating blood pressure response (delta MAP) to PRA, the profiling for positive spironolactone responders was characterized by high age and low PRA, irrespective of sex. Spironolactone therapy resulted in decreased serum sodium and magnesium values; potassium, creatinine, urate, and triglyceride levels were increased. However, all treatment values were within normal ranges. Side effects were infrequent and mainly of endocrine nature.

Treatment of refractory congestive heart failure and normokalemic hypochloremic alkalosis with acetazolamide and spironolactone

Abstract: Combination therapy with a loop diuretic and an aldosterone antagonist can produce normokalemic hypochloremic alkalosis, a complication not previously documented in the literature. This report describes 74 patients who had severe congestive heart failure treated with a combination of furosemide and spironolactone in whom this complication developed. Acetazolamide corrected the metabolic abnormality. The combination of furosemide and spironolactone with intermittent courses of acetazolamide was very effective in the treatment of severe congestive heart failure complicated by normokalemic hypochloremic alkalosis.

Hyperaldosteronism, Hyperparathyroidism, Medullary Sponge Kidneys, and Hypertension

Abstract: Hyperparathyroidism and hyperaldosteronism coexisted in association with medullary sponge kidneys in a 27-year-old woman with severe hypertension. A modest fall in systolic and diastolic pressure followed removal of a parathyroid adenoma. Blood pressure was controlled with spironolactone therapy and restored to normal after removal of an aldosterone-secreting adrenal tumor. Elevated levels of aldosterone may have been responsible for the severe hypertension, while hypercalcemia may have had a synergistic effect on the arteriolar response to circulating vasoactive peptides. (JAMA244:1351-1353, 1980)

Diuretic treatment of resistant hypertension.

Abstract: In patients with hypertension resistant to three or four drugs including a thiazide diuretic substitution of frusemide for the thiazide, or the addition of spironolactone, produced significant reductions in blood pressure and body weight. The response did not depend on the presence of overt fluid retention, renal impairment, or the use of antihypertensive drugs of high potency. Women had larger responses than men. Expansion of the plasma or extracellular fluid volume is an important cause of resistance to treatment even when a thiazide diuretic is used. An increase in diuretic treatment should be tried before using the postganglionic adrenergic blockers or minoxidil in resistant hypertension.

The occurrence of hyperaldosteronism in infants with congestive heart failure

Abstract: Serum aldosterone and plasma renin were measured in 20 normal infants and 15 infants with congestive cardiac failure. Serum aldosterone was significantly increased (151 ± 38 ng/dl mean ± standard error of the mean) in patients before treatment when compared with aldosterone in normal infants (29 ± 7 ng/dl). Increasing serum aldosterone was related to increasing plasma renin. The response to furosemide appeared to be inversely related to serum aldosterone concentrations. In four infants, administration of an aldosterone antagonist (spironolactone) resulted in improved diuresis and decreased serum aldosterone. Hyperaldosteronism is an important factor contributing to fluid and sodium retention in infants with heart failure.

Spironolactone and amiloride in hypertensive patients with and without aldosterone excess

Abstract: The antihypertensive action of spironolactone has been ascribed to both a nonspecific diuretic and a specific antimineralocorticoid effect. To better evaluate the relative importance of these effects, we compared its effects with the mineralocorticoid-independent drug amiloride. Spironolactone (400 mg/day) and amiloride (40 mg/day) were given to 10 patients with essential hypertension (EH) and to 10 patients with hypertension and supranormal aldosterone secretion (SNA). After 6 wk, blood pressure responded better to spironolactone (−20.5%) than to amiloride (− 10.4%) in patients with SNA, but the response was similar in patients with EH (−7.4% and −6.5%). The decrease in body weight—as a measure of volume depletion—was greater after spironolactone (−4.6%) than after amiloride both in patients with SNA (−4.6% and −0.8%) and in patients with EH (−3.7% and −0.6%). After both drugs, plasma sodium decreased (−3.4% and −2.6%) and plasma potassium increased (+37.2% and +32.6%) to the same extent in patients with SNA, reflecting a similar degree of antimineralocorticoid-like activity. After spironolactone patients with SNA showed a greater rise in PRA than after amiloride (412% and 82%). Despite the greater rise in PRA, the rise in aldosterone excretion was in the same range after both drugs (113% and 195%), pointing to inappropriately low aldosterone excretion after treatment with spironolactone. We conclude that differences in volume depletion or antimineralocorticoid-like activity cannot explain the better response in blood pressure of patients with SNA after spironolactone than after amiloride. Our data provide evidence for a specific antialdosterone effect of spironolactone in lowering the blood pressure, especially in patients with aldosterone excess. Clinical Pharmacology and Therapeutics (1980) 27, 317–323; doi:10.1038/clpt.1980.42

Spironolactone in the long-term management of patients with congestive heart failure

Abstract: The therapeutic efficacy of 100 mg spironolactone once daily in patients with congestive heart failure was evaluated in a multi-centre study in general practice. One hundred and fifteen patients were admitted to the study. Clinical and haemotological assessments were made at entry and at regular intervals throughout the 48-week study period. Body weight decreased and the incidence of both pitting and pulmonary oedema was reduced during spironolactone treatment. Plasma sodium level was consistently reduced and plasma potassium increased to accepted normal levels. Seventy-nine patients remained free of side-effects throughout the treatment period.

Effect of spironolactone on aldosterone regulation in man.

Abstract: 1. The action of spironolactone, a well-known antagonist of mineralocorticoids, on aldosterone regulation was investigated in normal young men to see whether it also acted as an inhibitor of biosynthesis in the adrenal gland. 2. The action of spironolactone was studied under three different conditions: (a) during 3 days of treatment with spironolactone; (b) during 1 day of combined administration with long acting adrenocorticotropic hormone (ACTH); (c) in the course of a continuous infusion of angiotensin II. 3. Spironolactone did not alter the metabolism of aldosterone or cortisol. 4. Spironolactone administration produced: (a) a marked increase in both aldosterone secretion and plasma renin activity, but no change in the plasma aldosterone/plasma renin activity ratio, the cortisol secretion rate or the plasma corticosterone concentration; (b) no blunting in the response of aldosterone to stimulation by ACTH; (c) no decrease in plasma aldosterone concentration when changes of the endogenous renin activity were prevented by an infusion of angiotensin II. 5. These results do not confirm the considerable inhibition of aldosterone excretion found by others after spironolactone administration to normal men. We observed no inhibition of aldosterone biosynthesis by spironolactone. However, a minimal, short-lived inhibition of biosynthesis cannot be excluded, but this possible action of spironolactone plays at best a minor role in the action of this drug.

Activity of sulfur‐containing intermediate metabolites of spironolactone

Abstract: The renal antimineralocorticoid activity of single administration of 2 sulfur-containing compounds, which are thought to be intermediate metabolites of spironolactone, was assessed in healthy subjects. They were each active in reversing the urinary electrolyte changes indiced by fludrocortisone for 2 to 10 hr after dosing, but only the 7 alpha-thiomethyl derivative exhibited activity in the period 12 to 16 hr after treatment. The activity of both drugs was less than of spironolactone. Taking urinary log 10 Na/K as the best index of antimineralocorticoid activity, the potencies of the intermediates relative to spironolactone were 0.26 (95% confidence limits, 0.12 to 0.49) for 7 alpha-thio-spirolactone and 0.33 (95% confidence limits, 0.15 to 0.62) for 7 alpha-thiomethyl-spirolactone in the period 2 to 10 hr after medication. We conclude that these minor sulfur-containing intermediate metabolites of spironolactone are unlikely to contribute significantly to the renal antimineralocorticoid activity of spironolactone.

Effect of spironolactone on androgen-dependent proteins in the ventral prostate of the rat.

Abstract: The effect of spironolactone on five androgen-dependent proteins in the ventral prostate of the rat was investigated by two-dimensional gel electrophoresis. Spironolactone was given to intact male, castrated and androgen-stimulated castrated rats. It has been shown that spironolactone had no influence on the synthesis or accumulation of the androgen-dependent proteins in intact animals. However, spironolactone suppressed the restoration of the major androgen-dependent protein of low molecular weight in castrated rats given testosterone. The mechanism by which spironolactone exerts its anti-androgenic activity was shown to be unrelated to its capacity to inhibit the synthesis or accumulation of the five androgen-dependent proteins studied in this investigation.

Hypokalemia during the treatment of arterial hypertension with diuretics

Abstract: In a study of 50 patients with uncomplicated arterial hypertension the administration of hydrochlorothiazide, 50 to 100 mg daily or every other day, with or without reserpine, 0.25 mg daily, resulted in a fall in the mean blood pressure from 182/113 to 144/92 mm Hg. The mean duration of therapy was 19 months. The mean serum potassium concentration was 4.3 mmol/l before the onset of therapy. It fell during the first 6 weeks of treatment, but seldom below 3.5 mmol/l, then rose gradually and spontaneously to 4.1 mmol/l after 19 months of therapy. All the patients remained asymptomatic. These findings bring into question the routine use of potassium supplements or a potassium-sparing diuretic, such as spironolactone or triamterene, during the treatment of hypertension with diuretics such as the thiazides. The use of potassium supplements or a potassium-sparing agent may induce hyperkalemia in spite of the simultaneous administration of a diuretic that acts more proximally. Since hyperkalemia is potentially lethal, the serum potassium concentration should be carefully monitored in any patient receiving potassium supplements or a potassium-sparing agent.

Nephropathologic Characteristics of a Woman with Bartter’s Syndrome after Prolonged Treatment with Spironolactone

Abstract: A study was made of two renal biopsy specimens obtained from a 22-year-old woman with Bartter’s syndrome, the first to substantiate the diagnosis, the second 2 years later after the treatment with spi

Bartter's Syndrome: Effect of Indomethacin on Prostaglandins, Urinary Kallikrein, Renin-Angiotensin-Aldosterone System, and the Response to Angiotensin II Antagonist

Abstract: In two patients with Bartter's syndrome, significant increases in serum immunoreactive prostaglandin E like-material (iPGE) and urinary kallikrein excretion were observed during the control period. Urinary PGE excretion was not always increased as serum iPGE. After an administration of indomethacin, an inhibitor of prostaglandins (PG's) synthetase, their clinical symptoms, hyperactivity of renin-angiotensinaldosterone (R-A-A) system and resistence to the pressor effects of angiotensin II and norepinephrine were apparently eliminated, but hypokalemia was not corrected completely. Indomethacin caused a remarkable decline in urinary kallikrein excretion and in serum and urinary PG's values. Spironolactone also produced a significant fall in urinary kallikrein excretion in spite of an extreme increase in the R-A-A system activity. However, spironolactone did not suppress the urinary PGE excretion. After an administration of aminoglutethimide, the urinary kallikrein excretion decreased gradually, followed by a decline in aldosterone production.Short-term administration of aspirin, ibuprofen, aminoglutethimide and dexamethasone did not improve hypokalemia despite the normalization of aldosterone production.An angiotensin II antagonist, [Sar1, Ile8] angiotensin II, lowered the blood pressure of hyperreninemic patients. After indomethacin, a significant improvement in blood pressure response to this antagonist was observed. These results indicate that angiotenin II receptors of arteriolar smooth muscle in patients with Bartter's syndrome are still responsive to endogenous angiotensin II, andthat the R-A-A system plays a considerable role in the regulation of blood pressure. Moreover, our observations suggest that a more “proximal” cause of Bartter's syndrome is renal potassium wasting i. e., hypokalemia which causes an inappropriate production of PG's in the kidney and vascular walls, resulting in vasocontrictor insensitivity and hyperactivity of the R-A-A system. Likewise, it appears that hyperactivity of the renal kallikrein-kinin system does not stimulate the production of PG's in this syndrome, but rather is secondary to increased PG's synthesis

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

Abstract: 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.

Bartter's syndrome with normal urinary excretion of prostaglandin E: therapeutic effects of propranolol, spironolactone, indomethacin and potassium chloride

Abstract: Urinary excretion of prostaglandin E (PGE) in 8 patients with Bartter's syndrome measured by the radioimmunoassay method was not augmented over the normal values. In one of them, urinary excretion of sodium, potassium, chloride and PGE, serum sodium, potassium and chloride, plasma renin activity and plasma aldosterone concentration were studied before and after the administration of propranolol, spironolactone, indomethacin and potassium chloride. Neither propranolol nor spironolactone affected any of these parameters. Indomethacin promptly reduced urinary excretion of sodium, potassium, chloride and PGE, and markedly suppressed the renin-aldosterone system. Serum potassium was elevated, but remained still in hypokalemic range. Potassium chloride was most effective in raising the serum potassium level during the first 4 weeks of administration. These results suggest that overproduction of renal PGs is not the primary cause of Bartter's syndrome, and that the renal potassium wastage is one of the etiological factors in this syndrome. It has also been suggested that hyperreninemia in this syndrome was associated in some way with renal PGs, not PGE but other series of PGs.

Spironolactone and triamterene in volume-dependent essential hypertension

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

Long term spironolactone and the adrenal cortex in essential hypertension

Abstract: SUMMARY In view of recent evidence that spironolactone may inhibit synthesis of corticosteroids by a direct effect on the adrenal cortex, adrenocortical function was studied in eight patients with essential hypertension who had been treated with spironolactone from 3 months to 14 years. Their 24 h renal excretion of adrenocorticoid metabolites and the responses of cortisol, aldosterone and 18-hydroxy-1 l-deoxycorticosterone (18-OH-DOC) to an incremental infusion of tetracosactrin (1–24 ACTH) were compared with those in eight patients with recently diagnosed essential hypertension who had received no spironolactone. The spironolactone-treated group had a significantly higher excretion of aldosterone, whilst the excretion of other adrenocorticoid metabolites did not differ. The same group also required less tetracosactrin to stimulate a detectable rise of plasma cortisol and 18-OH-DOC, they had greater plasma 18-OH-DOC responses at all infusion rates and, at the lowest infusion rates, had greater aldosterone responses. These results indicate that long-term spironolactone therapy does not inhibit adrenocortical function and may have some stimulatory effects.

Modifications of bile secretion and liver microsomal enzymes by aldosterone and spironolactone.

Abstract: During a period of two weeks male adult albino rabbits received a daily subcutaneous injection of: Group I: 0.1 ml of 0.9% sodium chloride solution/kg b. wt (control); Group II: 150 micrograms spironolactone/kg b. wt. Twenty-four hours after the final injection, the animals were anesthesized, the bile duct was cannulated (after ligation of the cystic duct) and bile was collected for two hours. At the end of the experiment, the liver was removed, weighed and submitted for cytochrome P-450 measurement and microscopic analyses. Red blood cell sodium content was measured in the aldosterone group before and after treatment. Compared with control animals, we found the following: (I) The bile flow, the biliary sodium and bile acid excretion were significantly decreased (P less than 0.01) in aldosterone-treated animals and significantly increased (P less than 0.01) in spironolactone treated ones. (II) In animals treated with aldosterone and in those treated with spironolactone, liver cytochrome P-450 was significantly increased (P less than 0.001). (III) In livers of both aldosterone and spironolactone-treated animals, there were hyaline changes in the hepatocytes without necrosis or steatosis. Electron microscope studies revealed a proliferation of smooth endoplasmic reticulum in livers of both groups. (IV) Red blood cell sodium content was significantly increased (P less than 0.001) after treatment with aldosterone. In conclusion, aldosterone and spironolactone have the opposite effect on bile secretion. Both are liver microsomal enzyme inducers. A correlation between bile secretion and liver enzyme induction seems improbable.

Effect of spironolactone on intraocular pressure in glaucoma patients

Abstract: In order to eliminate a previously reported stimulation of aqueous humor production by aldosterone, 22 glaucoma patients were treated for two weeks with 200 mg Spironolactone daily. The intra-ocular pressure decreased significantly and was still distinctly below the original values 14 days after termination of treatment.