Showing papers on "Spironolactone published in 1979"

A Syndrome of Apparent Mineralocorticoid Excess Associated with Defects in the Peripheral Metabolism of Cortisol

Abstract: A syndrome is described whose features, suggestive of primary mineralcorticoid excess, included hypertension, hypokalemia, low PRA, and responsiveness to spironolactone. Aldosterone levels were subnormal but as yet there has been no evidence of overproduction of other mineralocorticoids by chemical analysis or by bioassay of plasma and urinary extracts. The steroidal abnormalities that were observed involved peripheral matabolism rather than secretion. One patient exhibited a transient delay in reduction of the 3-keto group in the A ring, and both patients exhibited a decrease in the metabolism of cortisol to biologically inactive cortisone. This was shown by the marked decrease in the excretion of urinary metabolites bearing an 11-keto group and a decrease in the oxidation of 11 alpha-[3H]cortisol to tritiated water. The defect appeared not to be a deficiency of the 11 beta-oxidoreductase system itself, since the reverse reaction of conversion of cortisone to cortisol proceeded normally, but, rater, an alteration in the equilibrium position of 11 beta-oxidoreduction in favor of the reduced form. This was also expressed by a prolongation of the half-time of disappearance of cortisol. The decrease in the MCR permitted the maintenance of normal cortisol plasma levels and normal glucocorticoid function at a diminished rate of secretion. The decreased rate of conversion of cortisol to cortisone serves as a biochemical marker of this hypertensive syndrome.

Androgen Biosynthesis in Leydig Cells after Testicular Desensitization by Luteinizing Hormone-Releasing ormone and Human Chorionic Gonadotropin

Abstract: LHRH-induced elevation of endogenous LH in adult male rats was followed by dose-dependent loss of testicular LH receptors and cAMP responses to hCG stimulation in vitro. Leydig cells from animals treated with 10-100 jtxg LHRH to induce over 50% receptor loss showed reduced testosterone responses to hCG, dibutyryl cAMP, and choleragen. However, prognenolone formation (measured in the presence of 17β-hydroxy- 4,4,17-trimethyl-3-oxoandrost-5-ene-2a-carbonitrile and spironolactone) was normal or increased after LHRH treatment. When LHRH-desensitized cells were stimulated with hCG in vitro, the marked decrease in testosterone production was accompanied by accumulation of 17a-hydroxyprogesterone, either alone or with progesterone. These findings localized the major steroidogenic block in LHRH-desensitized cells at the site of conversion of the 17a-hydroxylated steroid to androgen, similar to the lesion observed in Leydig cells from animals treated with iv hCG. In the latter, the steroidogenic defects were more ...

Spironolactone-Induced Hyperchloremic Acidosis in Cirrhosis

Abstract: Six patients with alcoholic cirrhosis developed a reversible metabolic acidosis during treatment with the aldosterone antagonist spironolactone. Mean serum bicarbonate concentration decreased significantly with spironolactone therapy (100 to 200 mg/day) from 18.2 +/- 4.5 to 10.9 +/- 3.2 meq/litre (P less than 0.001). Upon withdrawal of spironolactone, serum bicarbonate concentration increased from 10.9 +/- 3.2 to 18.1 +/- 3.5 meq/litre (P less than 0.001). During the development of this hyperchloremic metabolic acidosis, serum potassium concentration rose from 3.7 +/- 0.5 to 5.0 +/- 0.8 meq/litre (P less than 0.005); this reversed after cessation of spironolactone therapy. These effects of spironolactone treatment were not associated with significant alterations in serum creatinine or sodium concentration. Thus, even though an aldosterone antagonist in the treatment of sodium and water retention in cirrhotic patients may prevent hypokalemia and rapid diuresis, it may also induce or worsen another complication: hyperchloremic metabolic acidosis.

Hydrochlorothiazide and spironolactone in hypertension

Abstract: A double-blind study of hydrochlorothiazide and spironolactone, alone and in combination, was conducted in 49 patients with mild-to-moderate essential hypertension after a 4-wk placebo washout period. In the whole group mean arterial blood pressure fell to levels of less than or equal to 107 mm Hg or declined by more than 15 mm Hg in 78% of the patients after twelve weeks of treatment. Sixty-nine percent of patients receiving hydrochlorothiazide alone developed serum potassium levels lower than 3.5 mEq/L; serum potassium levels were above 5.5 mEq/L in 2 patients (5.5%) receiving spironolactone 400 mg/day. Uric acid levels rose in all patients, more in those on hydrochlorothiazide, but clinical gout did not develop in any subject. Hydrochlorothiazide, spironolactone, and the combination of the two are effective antihypertensives. Spironolactone in doses of 200 and 400 mg/day was associated with side effects but did not induce a greater antihypertensive effect than doses of 100 mg/day. Our data suggest that when hydrochlorothiazide is associated with potassium loss, when gout or elevated uric acid levels are of concern, or when carbohydrate tolerance is abnormal, supplementation or replacement with spironolactone (up to 100 mg/day) may be useful in controlling blood pressure while reducing side effects.

Spironolactone-associated digoxin radioimmunoassay interference.

Abstract: 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.

Role of Renin Classification for Diuretic Treatment of Black Hypertensive Patients

Abstract: Previous studies in white and mixed-race hypertensive patient populations have generally found patients with low renin activity more responsive to diuretic therapy than patients with normal renin activity. Twenty-nine black patients (26 women and three men) with placebo diastolic blood pressure of 90 to 115 mm Hg were treated with spironolactone (100 to 400 mg/day) and hydrochlorothiazide (100/mg/day). Renin status was categorized by (1) the intravenous furosemide test, (2) ambulation during placebo, and (3) ambulation during spironolactone and hydrochlorothiazide treatment. Only seven patients were categorized identically with all methods. No method identified a low renin subgroup that was more responsive to either spironolactone or hydrochlorothiazide. Diastolic blood pressure fall with hydrochlorothiazide (18 mm Hg) and 400 mg/day of spironolactone (15 mm Hg) was similar. Thus, since black women with both low and normal renin activity are quite responsive to diuretics, renin classification to guide initial antihypertensive selection is not warranted. ( Arch Intern Med 139:1365-1370, 1979)

Mineralocorticoid-induced blood pressure, electrolyte, and hormone changes, and reversal with spironolactone, in healthy men

Abstract: The pathophysiology of mineralocorticoid-induced hypertension is not clear, and the factors determining renal "escape" remain to be defined. In an attempt to clarify these unknowns, the effect of 9-alpha-fludrocortisone on blood pressure was studied in six healthy males on fixed sodium and potassium intakes. Systolic blood pressure increased by 10 mm Hg after 10 days of fludrocortisone therapy, and supine mean pressure rose by 6 mm Hg. During fludrocortisone administration, the increments of systolic blood pressure in individual subjects were negatively correlated with weight gained, the amount of sodium retained, and the degree of hypokalemia. Renal "escape" from the sodium-retaining influence of fludrocortisone was not determined by the amount of sodium retained, but was closely related to the rise in systolic blood pressure during the first 48 hr of treatment. A more pronounced rise in blood pressure was associated with earlier renal "escape". Spironolactone therapy reversed the mineralocorticoid-induced abnormalities (increased body weight, rise in systolic blood pressure, fall in total body potassium, and decline in plasma renin concentration) in a dose-response manner. The results show that the hypertension resulting from fludrocortisone administration in normal man is not a function of expansion of the total body sodium content, and the renal "escape" appears to relate to the early development of hypertension rather than to the amount of sodium retained.

Interaction of spironolactone with rat skin androgen receptor.

Abstract: Some characteristics of the dorsal skin cytoplasmic androgen receptor (AR) have been studied in male rats. The affinity constant, the binding specificity, and the sedimentation profile of the receptor have been found to be similar to the rat prostate AR. The measurement of the number of binding sites in various hormonal conditions (deprivation) led to the conclusion that this receptor was largely occupied by endogeneous hormones from gonadal and (or) adrenal sources. Administration of spironolactone or canrenone to 7-day-castrated rats was accompanied by a rapid and drastic decrease of available binding sites. This diminution was ascribed to the competitive inhibition of canrenone, the active in vivo metabolite of spironolactone. It is postulated that the antiandrogenic action of spironolactone, at the skin level, is mediated by canrenone which inhibits the formation of specific testosterone and (or) 5 alpha-dihydrotestosterone receptor complex in cytoplasm and consequently in nuclei.

Long-term use of propranolol, ibuprofen, and spironolactone in the management of Bartter's syndrome.

Abstract: This report concerns two patients with Bartter's syndrome who were treated with propranolol, spironolactone, and potassium supplements. When ibuprofen was added to this regimen, potassium supplements were no longer required. In both patients, plasma renin activity decreased, plasma volumes increased, and a "catch-up" in linear growth ensued. This report confirms others that indicate prostaglandin synthetase inhibitors are a useful adjunct in the therapy of Bartter's syndrome.

Diuretic-induced renal impairment without volume depletion in cirrhosis: changes in the renin-angiotensin system and the effect of β-adrenergic blockade

Abstract: In 4 patients with cirrhosis and ascites, diuretic therapy resulted in an impairment of renal function that was associated with a rise in plasma renin activity (PRA). In 3, this occurred in the absence of volume depletion. When diuretics were discontinued, renal function returned to normal. β-adrenergic blocking drugs were then given to suppress renin secretion and diurectics restarted. On this occasion, impairment of renal function did not occur. In 2 further patients, administration of β-adrenergic blockers during a period of diuretic-induced renal impairment resulted in an improvement in renal function. Although these findings may indicate that diuretic-induced renal impairment in cirrhosis is at least partly due to activation of the renin-angiotensin system, in another group of patients a diuretic-induced rise in PRA was not associated with a deterioration in renal function.

Enhancement by L-dopa of the renal action of aldosterone in the rat.

Abstract: Summary 1. The administration of aldosterone to adrenalectomized rats produces an increase in K+ and decrease in Na+ excretion in the urine. The relationship of the post-aid osterone to the pre-aldosterone urinary sodium and potassium excretion is termed the renal response to aldosterone. 2. The administration of L-dopa enhances the renal response to aldosterone. This enhanced renal response does not appear to be due to the enhanced urinary creatinine and sodium excretion also seen with L-dopa. 3. The enhanced response to aldosterone seen in the L-dopa loaded rat is inhibited by spironolactone (an aldosterone antagonist), carbidopa (an inhibitor of the enzyme producing dopamine from L-dopa in the periphery), and haloperidol (a putative dopamine receptor blocker). The action of L-dopa in enhancing the renal response to aldosterone would thus appear to be mediated by dopamine within the kidney. 4. Modification of the renal response to aldosterone may be one role of the high levels of dopamine produced within the kidney.

SC 25152: a potent mineralocorticoid antagonist with decreased antiandrogenic activity relative to spironolactone.

Abstract: The widely used mineralocorticoid antagonist spironolactone has antiandrogenic activity that may contribute to its side effects of decreased libido, impotence and gynecomastia. We have therefore sought a less antiandrogenic analog of spironolactone that may exhibit reduced endocrine side effects. The analog SC 25152 was chosen for pharmacological testing because of the previous observation that it has considerably reduced affinity for the androgen receptor of both man and rat but exhibits an affinity for the mineralocorticoid receptor similar to that of spironolactone. Bioassays in the rat show that SC 25152 has a 60% decrease in antiandrogenicity, and a 4-fold increase in antimineralocorticoid activity compared to spironolactone, resulting in an overall reduction of antiandrogenic activity to one-tenth that of spironolactone at doses giving equal antimineralocorticoid activity. These studies demonstrate that the antiandrogenic and antimineralocorticoid activities of spironolactone analogs can be dissociated and illustrates the utility of measurements of drug-receptor interaction to identify a compound with desired pharmacological properties.

Pituitary-thyroid function in spironolactone treated hypertensive women.

Abstract: Four weeks high dose spironolactone treatment (Aldactone Searle, 100 mg q. i. d.) significantly enhanced the TSH (delta max. 8.5 +/- 4.1 vs. 4.6 +/- 3.1 microunits/ml, P less than 0.05) and T3 (delta max. 32 +/- 27 vs. 11 +/- 16 ng/100 ml, P less than 0.05) responses to an intravenous TRH/LH-RH bolus injection in 6 eumenorrhoeic euthyroid hypertensive women, without affecting basal serum TSH, T3 or T4 levels or the basal and stimulated LH, FSH and prolactin values (P greater than 0.10). The mean serum testosterone, 17-hydroxyprogesterone and oestradiol levels were also similar before and during therapy. Spironolactone, possibly by virtue of its antiandrogenic action, may exert its enhancing effect on pituitary-thyroid function by modulating the levels of receptors for TRH in the thyrotrophs or by altering the T3 receptor in the pituitary permitting a greater response to TRH.

Fixed‐Dose Combination Diuretics in Congestive Heart Failure: An Evaluation

Abstract: Thirty-two patients with congestive heart failure were studied for their clinical and biochemical responses to the administration of two combination diuretic products (hydrochlorothiazide/spironolactone and hydrochlorothiazide/triamterene) and the single entity diuretic furosemide. Data from these studies revealed the following: 1. Comparison of the patients on furosemide with those receiving the combination products showed no difference in serum potassium or 24-hour potassium excretion. 2. Significant changes in blood urea nitrogen, plasma renin activity, and urinary aldosterone excretion were noted with both fixed-combination medications but not with furosemide. 3. The combination diuretics offered no clinical benefits over the single agent furosemide. 4. Therapy is best served by the use of a single effective diuretic agent for the treatment of most patients with congestive heart failure.

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

Abstract: 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.

Reduced response of plasma aldosterone to acute ACTH stimulation during long-term treatment with spironolactone in essential hypertension.

Abstract: The response of plasma aldosterone (PA) to ACTH administration (250 µg α1-24 ACTH i.m.) before and during treatment with spironolactone (Sp, 75-100 mg/day) for at least 8 months was studied in 11 patients with essential hypertension. These responses were compared with those before and during prolonged treatment with hydrochlorothiazide (Th, 50-75 mg/day), with or without potassium supplement, in 14 hypertensives. PA and plasma cortisol (PC) were determined by radioimmunoassay in which Sp showed minimal cross-reactivity. Both Sp and Th treatments caused similar increases in plasma renin activity accompanied by nearly identical decreases in blood pressure and body weight. PA was also increased by both treatments, but to a significantly greater extent in the Sp-treated group. Serum potassium concentration was increased only by Sp treatment. The response of PA, but not of PC, to acute ACTH stimulation was blunted in the Sp-treated group. That is, the maximal increment of PA above the baseline level was significantly lower during Sp treatment than either before Sp treatment or during Th treatment. These results demonstrate that long-term treatment with Sp can inhibit aldosterone production by acute ACTH stimulation in patients with essential hypertension.

Influence of spironolactone on serum corticosteroids in primary hyperaldosteronism.

Abstract: 5 male patients with primary hyperaldosteronism (2 due to adenomata, 3 due to idiopathic hyperplasia) were treated with 100 mg spironolactone t.i.d. while on a diet containing 135 meq sodium daily. Serum levels of drug metabolites, of 8 adrenal steroids, of sodium and potassium, plasma renin activity (PRA) and angiotensin II (AT II) in plasma as well as sodium excretion in urine were measured before and during 5 (7) days of treatment. Spironolactone caused sodium excretion and potassium retention as it was shown by the changes in electrolytes in the serum and urine. Whereas PRA remained suppressed in 4 patients during the period of observation, a significant increase of PRA occurred 3 days after starting the spironolactone medication in another patient. In this patient also, a prompt and considerable increase of 11-deoxycorticosol, 11-deoxycorticosterone, corticosterone and a terminal increase of 18-OH-deoxycorticosterone was seen, which points at an inhibition of adrenal 11- and 18-hydroxylases by metabolites of spironolactone. Serum aldosterone, however, did not fall, but rose slightly within the first 3 days and — in accordance with the kinetics of PRA — significantly during the following days under spironolactone. In the other 4 patients, the mean concentrations of aldosterone in serum decreased slightly within the first day of spironolactone medication and oscillated around the control levels on the following days. A moderate but significant increase of 11-deoxycorticosterone as well as of corticosterone was also observed under the influence of spironolactone in these patients. These alterations, which are also consistent with the hypothesis of an inhibition of 11- and especially 18-hydroxylases, were however, less pronounced than was expected from previous studies with diet-induced hyperaldosteronism. While patients suffering from adenoma tended to show a decrease in their serum aldosterone, those suffering from idiopathic hyperplasia tended to show an increase in response to spironolactone. There slight differences in the mean values, however, were neither significant nor consistent in the individual cases. It was concluded that the inhibitory action of spironolactone on aldosterone biosynthesis is variable and thus of less significance than its inhibition of the aldosterone effects at the receptor sites.

Opposing effects of deoxycorticosterone and spironolactone on isoprenaline-induced myocardial infarction.

Abstract: Adult, male, Sprague-Dawley rats were subjected to massive myocardial infarction with isoprenaline. Some of the animals were treated with the potent mineralocorticoid, deoxycorticosterone, or the anti-mineralocorticoid, spironolactone. Autopsies spaced at sequential time intervals demonstrated that circulating levels of enzymes, eg, CPK, SGOT, SGPT and LDH, lipids, eg, triglycerides, free fatty acids, and cholesterol, glucose, BUN, and corticosterone rose in conjunction with on-going necrosis and became lowered in conjunction with myocardial repair. Body and organ weights, ie, adrenal, thymus, heart, and kidney, underwent dynamic changes commensurate with necrosis and repair. Animals given isoprenaline alone died (52 % survival) during the height of their massive infarct and congestive heart failure (Days 3 and 4). Animals treated with DOC showed the most severe congestion but died (36% survival) during the late repair phase (Days 7 and 8). Animals treated with spironolactone showed the most effective clearance of thoracic fluid and also died (18% survival) during the late repair phase (Days 7 and 8). These spironolactone-treated animals had large, left ventricular aneurysms with organised, adherent thrombi. It is believed that alterations in electrolyte balance induced by DOC or spironolactone caused changes in adrenocortical function which greatly modified the usual pathophysiological response to myocardial infarction.

Effect of spironolactone treatment on the renin-aldosterone system during pregnancy.

Abstract: Ten pregnant patients were treated with spironolactone (100 mg daily) for two weeks. The patients were on a continuous long-term saluretic therapy for pregnancy edema. In addition, a potassium supplementation (30 mmol/day) was given until the beginning of spironolactone treatment. The patients thus treated had a mean urinary aldosterone excretion (dU-Aldo) of more than ten-fold in comparison to that of non pregnant state. Canrenone, the effective conversion product of spironolactone in plasma, reached its steady state level in three days as in non-pregnant subjects. dU-Aldo decreased in two weeks during the spironolactone by 36% (p less than 0.05). The inhibition of aldosterone secretion is thus evident also after a low clinical dose of spironolactone. Urinary potassium excretion (dU-K) decreased during the 1st day (p less than 0.05) and continued to decrease during one week of spironolactone therapy by a total of 21% (p less than 0.001). The decrease in dU-K reflects the cessation of potassium supplements in the beginning of the study. No changes in urinary sodium excretion were found. Plasma renin activity (PRA) increased in one week by 79 per cent and the changes of PRA and dU-Aldo showed inverse correlation (p less than 0.001). In our study natriuresis, cannot explain the increase of PRA. Our study suggests another feedback effect of aldosterone.

Escape from sodium and potassium retaining actions of aspirin-like drugs used in a patient with bartter's syndrome

Abstract: Escape from sodium and potassium retaining actions of aspirin-like drugs used in a patient with Bartter's syndrome. AN analysis was done with regard to the mode of escapes from sodium and potassium retaining actions of aspirin-like drugs in a patient with Bartter's syndrome. In the indomethacin therapy of the syndrome, there was a delay in the initiation of potassium escape as compared to sodium escape, whereas no delay was seen in the ibuprofen therapy. This delay was probably related to the direct or indirect inhibition of sodium-potassium exchange in the distal nephrons. The course of aspirin therapy went midway between the above two. In the spironolactone therapy, the mode of escape was a mirror image of the one in the indomethacin therapy. Also, in a patient with rheumatoid arthritis, but without Bartter's syndrome, the escapes from the effects of indomethacin were seen. In order to understand the effect of these drugs on potassium excretion in Bartter's syndrome, some other intrarenal events, such as the influence on chloride transport in the loop of Henle leading to potassium conservation, may have to be considered.

Modification of D-galactosamine-induced liver injury in the rat by spironolactone.

Abstract: Spironolactone, a competitive inhibitor of mineralocorticoid effects on the distal tubule of the kidney, has recently been found to have other metabolic effects. In these studies, spironolactone (200mg/kg intraperitoneally) for 3 days was found to have a marked protective effect against the hepatotoxic effect of D-galactosamine (275 mg/kg) in rats. Further progress in defining the mechanism of protection from D-galactosamine hepatic necrosis by spironolactone will require assessment of effects of spironolactone on uridine nucleotide metabolism.

A clinical trial of a spironolactone/thiazide combination in the treatment of hypertension in Zambian Africans.

Abstract: SummaryA clinical trial was carried out to compare the eflects of placebo and of a spironolactone-althiazide combination in the treatment of 24 Zambian Africans with hypertension. After an initial 2 weeks on placebo, patients received 100 mg spironolactone plus 60 mg althiazide daily for 12 weeks. They were then treated with placebo again for 3 to 5 weeks, followed by a second active treatment period of 6 to 8 weeks in dosages ranging from 50 mg spironolactone plus 30 mg althiazide to 150 mg spironolactone plus 90 mg althiazide according to the previous response. A statistically significant (p <0.001) reduction was noted in both systolic and diastolic blood pressures whilst on active treatment. Mean reductions were 30/16 mmHgfor supine and 35/21 mmHg for standing blood pressures. Treatment with the combination product did not influence serum potassium or creatinine levels. Mean blood urea, however, increased from 23.6 to 35.1 mg/100 ml and the mean serum uric acid from 6.7 to 8.9 mg/100 ml. No serious sid...