Showing papers on "Spironolactone published in 1993"

Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension.

Abstract: Activation of the renin-angiotensin-aldosterone system in arterial hypertension can lead to remodeling of the myocardial collagen network, with progressive collagen accumulation in the cardiac interstitium. This reactive myocardial fibrosis, which is not secondary to myocyte necrosis, appears to be an important determinant of diastolic dysfunction and thus of pathologic hypertrophy. To examine the effects of the aldosterone antagonist spironolactone on myocardial fibrosis, we analyzed interstitial fibrosis in 7 different models of arterial hypertension in rats: 2 kidney, 1 clip model of renovascular hypertension (RHT); continuous subcutaneous aldosterone (0.75 micrograms/hr) infusion; RHT and aldosterone models treated with 20 mg/kg per day of subcutaneous spironolactone; uninephrectomized rats on a high sodium diet; and age- and sex-matched controls with or without spironolactone treatment. Systolic arterial pressure was comparably elevated in RHT and aldosterone models; it was modestly lowered but not normalized by 8 weeks of spironolactone treatment at the low doses used. Such treatment also failed to prevent left ventricular hypertrophy (LVH) in all experimental groups with hypertension. Spironolactone, however, was able to prevent myocardial fibrosis in RHT and aldosterone models of acquired arterial hypertension irrespective of the development of LVH and the presence of hypertension. These findings provide further evidence that elevated aldosterone levels play an important role in the adverse remodeling of the myocardium in arterial hypertension. The antifibrotic effects of spironolactone, if confirmed in human studies, may be a valuable strategy in treating hypertensive heart disease.

Spironolactone in congestive heart failure refractory to high-dose loop diuretic and low-dose angiotensin-converting enzyme inhibitor

Abstract: Patients with severe congestive heart failure (New York Heart Association [NYHA] functional classes III-IV) often can tolerate only low doses of angiotensin-converting enzyme (ACE) inhibitors because pronounced hypotension caused by additional ACE inhibitor increments may decrease renal perfusion. The use of high-dose loop diuretics is currently advised to overcome diuretic resistance in refractory congestive heart failure (CHF). In a baseline controlled study, we evaluated 21 patients with diuretic resistance and evident fluid retention for the responses to 5 days of double drug therapy consisting of high-dose loop diuretic (10 mg oral bumetanide) in combination with the maximum tolerable dose of an ACE inhibitor (individualized to blood pressure and kidney function). Five patients (24%) showed a gross natriuresis and reduction in excess weight > 25% in response to this therapy. The remaining 16 patients (76%) with insufficient responses (i.e., < 25% reduction in excess weight) subsequently received 100 mg spironolactone once a day for 7 days in addition to the double therapy. Spironolactone coadministration was highly effective in 13 of 16 patients (81%). Marked natriuresis and diuresis were achieved within the next week of treatment, and CHF symptoms regressed or disappeared. The clinical course was similar in the bumetanide-ACE inhibitor and the bumetanide-ACE inhibitor-spironolactone treatment (triple therapy) groups. Plasma aldosterone was significantly higher (p < 0.05) in the patients who needed spironolactone. The 3 patients who were considered refractory to triple therapy exhibited the highest baseline plasma aldosterone concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of familial male precocious puberty with spironolactone, testolactone, and deslorelin

Abstract: Combined antiandrogen (spironolactone) and aromatase inhibitor (testolactone) are effective for the short term treatment of familial male precocious puberty. During this therapy, plasma testosterone levels remain in the adult range, since spironolactone blocks the testosterone receptor without significantly affecting plasma testosterone levels. After our initial 18-month pilot study, we continued to treat eight boys with the combined therapy for 2.0-4.2 yr. During this time all boys exhibited a pubertal rise in gonadotropin secretion and a diminishing response to treatment, which was manifested by the recurrence of clinical features of puberty and an increase in the bone maturation rate (P < 0.05). Addition of the LHRH agonist deslorelin (4 micrograms/kg.day, sc) to the combined therapy decreased peak LH, plasma testosterone, bone maturation rate, and growth velocity (P < 0.05) over the next year. We conclude that the rise in gonadotropin levels during central activation of hypothalamic LHRH secretion in boys with familial male precocious puberty causes a partial escape from the combined effect of spironolactone and testolactone. The addition of deslorelin to the combined therapy appears to restore the control of puberty in this setting.

Serum lipoproteins during treatment with antihypertensive drugs.

Abstract: Several drugs used for antihypertensive therapy may modify the lipoprotein metabolism. Thiazides in high dosage and loop diuretics can increase serum low-density lipoprotein (LDL) cholesterol and/or very-LDL cholesterol and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio, while HDL cholesterol is largely unchanged; triglycerides (Tg) are also often elevated. Premenopausal women may be protected from this side effect. Whether diuretic-induced dyslipidemia is dose-dependent and low thiazide doses (i.e., hydrochlorothiazide < or = 12.5 mg daily) are interacting less, awaits clarification. beta-Blockers without intrinsic sympathomimetic activity increase serum triglycerides and tend to lower the potentially antiatherogenic HDL cholesterol. The diuretic-antihypertensive agent indapamide, given at a dose of 2.5 mg/day, is neutral with regard to serum lipoprotein and glucose metabolism. The potassium-sparing diuretic spironolactone, conventional sympatholytic agents, calcium-channel blockers, and probably the serotonin2-receptor antagonist ketanserin, exert no relevant effects on the lipoprotein profile. Angiotensin-converting enzyme inhibitors may slightly decrease serum triglycerides. alpha 1-Receptor blockers slightly decrease LDL cholesterol and Tg and increase HDL cholesterol. Drug-induced development or aggravation of dyslipidemia represents a potentially adverse influence. In the hypertensive population, effective blood pressure control with traditional drug therapy based on thiazide-type diuretics in high dosage led to a distinct decrease in cerebrovascular morbidity and mortality, but failed to satisfactorily reduce coronary complications. The prognostic relevance of drug-induced changes in serum lipoproteins, carbohydrate metabolism and other risk factors or correlates awaits further clarification.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-converting enzyme inhibitor and spironolactone combination therapy: New objectives in congestive heart failure treatment

Abstract: Secondary aldosteronism has deleterious effects in patients with congestive heart failure (CHF) and can contribute to congestion, ventricular arrhythmias, and sudden death. Mortality is higher in patients with elevated levels of plasma aldosterone. Aldosterone increases as CHF progresses as a result of activation of the renin-angiotensin-aldosterone system (RAAS). This is further amplified by the routine use of diuretics. Angiotensin-converting enzyme (ACE) inhibitors produce a profound and consistent inhibition of angiotensin II production, but they exert only a mild and transient antialdosterone effect. In a number of studies involving ACE inhibitors, plasma aldosterone levels at the end of the trial do not differ significantly from baseline. Spironolactone, a specific aldosterone receptor antagonist, may exert an independent and additive effect to that of ACE inhibitors. Apart from its renal effects, recent evidence suggests that spironolactone may exert direct cardiac and vascular effects inhibiting cardiac collagen hypertrophy and limiting vascular constriction. Combining an ACE inhibitor and spironolactone may achieve a more complete inhibition of the whole RAAS and may produce further clinical benefits. The efficacy and safety of such a combination has not been properly addressed. In the CONSENSUS trial, plasma potassium and creatinine levels were not necessarily adversely affected when enalapril was added to the regimens of patients receiving spironolactone, a condition existing in > 40% of the patients enrolled in this study. One prospective open study and other anecdotal reports suggest that combining spironolactone and ACE inhibitors resulted in clinical improvement without serious side effects in patients who could not tolerate further increases in the ACE inhibitor dose.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the potassium and magnesium-sparing properties of amiloride and spironolactone in diuretic-treated normal subjects.

Abstract: 1. The relative potencies of amiloride (5 and 20 mg) and spironolactone (25 and 100 mg) for plasma and erythrocyte electrolytes were investigated in a double-blind, randomised, balanced, crossover study in 12 normal men treated concomitantly with hydrochlorothiazide 100 mg daily for 1 week. 2. Participants satisfied an a priori requirement for a fall in plasma potassium concentration of at least 0.5 mmol l-1 after 7 days of treatment with hydrochlorothiazide alone. 3. After hydrochlorothiazide alone, plasma potassium and sodium concentrations fell (P < 0.001). There were associated reductions in erythrocyte sodium (P < 0.01). Plasma magnesium concentration did not change, although erythrocyte magnesium decreased (P < 0.001). 4. Both amiloride and spironolactone attenuated the thiazide-induced fall in plasma potassium (relative potency, amiloride:spironolactone 10:1, 95% confidence interval 6.3-16.2:1). Amiloride but not spironolactone was associated with a dose-related increase in plasma magnesium; a relative potency estimation was precluded. There was little evidence of influences of amiloride or spironolactone on erythrocyte electrolytes. 5. On a weight basis, amiloride is ten times more potent than spironolactone as a potassium-sparing agent in diuretic-treated subjects but neither agent had major effects on erythrocyte potassium. The drugs may have divergent actions on magnesium handling; hydrochlorothiazide alone had no influence on plasma magnesium.

Captopril and spironolactone therapy for refractory congestive heart failure

Abstract: Short- and long-term clinical effects of the angiotensin-converting enzyme (ACE) inhibitor captopril in severe congestive heart failure (CHF) were evaluated during a 3-year open study of 124 inpatients with New York Heart Association (NYHA) functional class III or IV CHF refractory to treatment with cardiac glycosides and high doses of loop diuretics. Captopril was added to each patient's regimen, which comprised combinations of furosemide (124 patients), digitalis (117 patients), and spironolactone (90 patients). By the end of the first month of captopril administration, improvement in NYHA functional class was seen in 89 patients (72%). During the first year of captopril treatment, the number of hospital admissions and hospital days declined significantly (p < 0.001) and functional class improved significantly (p < 0.001). Although most patients tolerated captopril well, 44% experienced hypotension, which in 10% of patients necessitated termination of captopril therapy. Although mean serum potassium levels tended to increase, serious hyperkalemia did not occur. After 1 year, a subset of 30 patients who had not initially received spironolactone deteriorated clinically and manifested increasing urinary aldosterone levels. Hypotension precluded increasing the captopril dose, but introduction of spironolactone improved clinical status in this cohort. The results suggest that rational therapy for severe CHF includes addition of the aldosterone antagonist spironolactone to low doses of captopril (or another ACE inhibitor) and high doses of loop diuretics, provided renal function is adequate.

Dose-Related Cardiovascular Effects of Spironolactone

Abstract: The aim of this study was to assess the shortterm hemodynamic effects of increasing doses of spironolactone (25, 50, and 75 mg/day) on oligurie patients (5 men, mean age 47 ± 12 years) undergoing hemodialysis for chronic renal impairment. Parameters of interest included heart rate (HR), cardiac output, systemic vascular resistance (SVR), arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure (PCWP). The study also evaluated how spironolactone modified the effects on arterial and right atrial pressures and PCWP of infusion of increasing doses of norepinephrine (20, 40, and 100 ng/ kg/min) and angiotensin II (2, 4, and 10 ng/kg/ min). Compared with placebo, the lowest dose of spironolactone (25 mg/day) produced statistically significant (p

The role of low-dose diuretics in essential hypertension.

Abstract: Diuretics have been used to treat hypertension since 1958. The doses used were relatively high. Dose-dependent side effects and the increasing availability of other drugs such as beta- and alpha-blockers, calcium-entry blockers, and angiotensin-converting enzyme (ACE) inhibitors, with equal antihypertensive efficacy but additional effects in cardiovascular diseases, led to a decrease in diuretic use. In controlled trials, little or no protection against coronary artery disease (CAD) was discussed as being due to the diuretics' side effects. The main side effects are hypokalemia, hyperglycemia, and hyperlipidemia. Hypokalemia occurs most often (up to 30%) in thiazide-treated hypertensive patients, and may cause arrhythmias in patients with CAD. This side effect is clearly dose-dependent and may be avoided by comedication with antikaliuretics. Glucose intolerance may develop in about 3% of diuretic-treated men and is reversible after discontinuation of the diuretic. This side effect is functionally correlated with hypokalemia and therefore is not seen when patients are given a comedication (for example, spironolactone prevents hypokalemia). Hypercholesterolemia was first reported in 1964 during long-term diuretic treatment. During the first 12 weeks of treatment, low-density lipoprotein (LDL) cholesterol increased 5-15% in men and postmenopausal women. After 1 year of therapy, the levels decreased to pretreatment values. However, in placebo-controlled trials, the placebo groups exhibited cholesterol levels falling below the diuretic group. Although the mechanisms and the clinical implications of these side effects are not completely understood, the perception grew that diuretics per se may have been at least partially responsible for the lack of protection against CAD.(ABSTRACT TRUNCATED AT 250 WORDS)

Edematous disorders: pathophysiology of renal sodium and water retention and treatment with diuretics.

Abstract: The pathogenesis of renal sodium and water retention in cardiac failure, cirrhosis, and the nephrotic syndrome may be explained by the unifying hypothesis of body fluid volume regulation. According to this hypothesis, underfilling of the arterial vascular compartment initiates a sequence of events, including activation of various neurohormonal vasoconstrictor systems, which results in enhanced renal sodium and water reabsorption, the failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. In patients with low-output cardiac failure, a decrease in cardiac output results in arterial underfilling. Peripheral arterial vasodilation diminishes the fullness of the arterial vascular compartment in patients with high-output cardiac failure and cirrhosis. In the nephrotic syndrome, the decrease in plasma oncotic pressure due to hypoalbuminemia initiates arterial underfilling. The factors that are responsible for the peripheral arterial vasodilation in patients with cirrhosis remain obscure. Diuretics are initially effective in reducing the excess of total-body sodium and water in edematous patients. Loop diuretics, with or without metolazone or a thiazide diuretic, are quite useful in patients with heart failure. In cirrhosis and the nephrotic syndrome, the specific aldosterone antagonist spironolactone, alone or in combination with other diuretics, has proven to be highly efficacious. However, in all instances, the emergence of diuretic resistance represents a major limitation of diuretic therapy for the edematous patient. This diuretic resistance may be mediated by further activation of vasoconstrictor, antinatriuretic neurohormones.

Method for inhibiting myocardial fibrosis by administering an aldosterone antagonist which suppresses aldoster one receptors

Abstract: This invention discloses a method of using an aldosterone antagonist such as spironolactone, at a dosage which does not disrupt a patient's normal electrolyte and water-retention balance, to inhibit myocardial fibrosis, including left ventricular hypertrophy (LVH).

Attenuation by spironolactone of the magnesiuric effect of acute frusemide administration in patients with liver cirrhosis and ascites.

Abstract: The effect of spironolactone on renal magnesium excretion under both basal conditions and conditions of frusemide-induced diuresis was studied in 11 control subjects with normal hepatic and renal function and in 12 patients with liver cirrhosis and ascites. In the control group, oral administration of spironolactone (200 mg daily for 5 days) resulted in a significant decrease in the mean renal excretion of both magnesium and potassium. In the cirrhotic patients, spironolactone did not significantly change the mean renal excretion of magnesium or potassium, but it produced a significant reduction in the frusemide-induced increase in the renal excretion of both potassium and magnesium. The study suggests that spironolactone decreases magnesium excretion in normal subjects and antagonizes the magnesiuric effect of frusemide in patients with liver cirrhosis and secondary aldosteronism.

Low dose spironolactone in the treatment of female hyperandrogenemia and hirsutism.

Abstract: Thirty one women with hyperandrogenism, clinically divided into polycystic ovary syndrome (PCOS)--28 women and idiopathic hirsutism (I.H.)--3 women, were treated with low dose spironolactone (50 mg or 75 mg daily) for average five months. There was an excellent clinical response in 19 (61%), incomplete response in 8 (26%), no response in 5 women. Six of 18 patients with sterility became pregnant during the one year after treatment and delivered a healthy infant at term. Two patients dropped out of the trial because of intolerance of the therapy. Remarkable change of the menstrual pattern characterised as polymenorrhea was major side effect of the therapy. Other side effects were not problem. Spironolactone caused statistically significant reduction in testosterone, luteinizing hormone and prolactin values at the end of the treatment. Our results demonstrate that low-dose spironolactone is effective in the treatment of hyperandrogenism in women.

Renal sodium handling and neurohumoral systems in patients with cirrhosis in sitting posture: effects of spironolactone and water immersion.

Abstract: Renal sodium handling, neurohumoral systems, and systemic hemodynamics were investigated under baseline conditions in sitting posture in 10 healthy subjects, 11 patients with cirrhosis without, and 10 patients with cirrhosis with ascites. Furthermore, the effects of head-out water immersion, 1-week spironolactone administration, or their combination was assessed in the two groups of patients. Patients without ascites exhibited a significant increase in plasma norepinephrine concentration and a tendency toward an increase in plasma aldosterone concentration. Patients with ascites had a significantly lower mean arterial blood pressure despite significant reduction of urinary sodium excretion and fractional sodium excretion as well as an increase of plasma renin activity, plasma aldosterone, and norepinephrine concentration. In patients with ascites, the increase in renal sodium excretion and fractional sodium excretion following water immersion or spironolactone was clearly augmented by the combination of the two maneuvers. The same pattern was observed in patients without ascites. Our findings (a) underscore the importance of studying hemodynamics, renal function, and neurohumoral systems also in upright posture, (b) suggest a role of sympatico-adrenergic activation and proximal sodium retention in preascitic patients, and (c) are compatible with the vasodilation hypothesis of ascites formation.

Refractory ascites: definition, pathogenesis and treatment

Abstract: Refractory ascites, that is ascites which cannot be mobilized by low sodium diet and maximal doses of diuretics (up to 400 mg spironolactone or potassium canrenoate and 160 mg furosemide per day), occurs in 5% of cirrhotic patients with ascites. The development of refractory ascites is mainly related to the progression of arterial vasodilation-mediated vascular underfilling and to the imbalance between reduced synthesis of renal vasodilating factors (especially renal prostaglandins) and extreme activation of vasoconstricting systems. Further features include increased sodium reabsorption in the proximal tubule and altered pharmacokinetics and pharmacodynamics of diuretics. In patients with impaired renal function (as is the case for most patients with refractory ascites), the marked reduction of renal perfusion and glomerular filtration rate, with the consequent decrease of filtered sodium load, becomes the main pathogenetic factor. The principal therapeutic options for refractory ascites include repeated paracentesis and implantation of the LeVeen shunt. Paracentesis is a rapid and safe procedure to remove ascites, but it does not correct sodium retention. Ascites recurrence, therefore, may occur after a brief interval. The LeVeen shunt allows for better long-term control of ascites, but severe complications may supervene, and shunt occlusion is common. Neither therapeutic procedure improves survival. Different experimental therapeutic procedures have been proposed. Administration of ornipressin corrects hyperdynamic circulation and improves renal function. Thromboxane synthase inhibitors, by reducing renal synthesis of thromboxane A2, potentiate the diuretic and natriuretic response to furosemide. More invasive procedures, including portosystemic shunt and transjugular intrahepatic stent, are rarely used in the treatment of refractory ascites.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperkalemia due to hyporeninemic hypoaldosteronism with liver cirrhosis and hypertension.

Abstract: A 49-year-old man with liver cirrhosis and hypertension was found to have hyperkalemia out of a degree of renal insufficiency and metabolic acidosis with low to normal anion gap, aggravated by volume contraction with diarrhea and medications (captopril, spironolactone and atenolol) interfering with potassium homeostasis. Plasma renin activity and serum aldosterone levels of this patient on a regular diet after discontinuation of medications were very low compared to those of five other cirrhotic patients with normokalemia as controls. Also, the renin-aldosterone stimulation testing on this patient performed by sodium restricted diet and furosemide, upright position and by angiotensin converting enzyme inhibition (captopril, 50 mg) showed the blunted renin and aldosterone responses to each of these stimuli, almost no changes from baseline renin and aldosterone levels, it was concluded that the underlying defect responsible for hyperkalemia in this case was hyporeninemic hypoaldosteronism and this was aggravated by other factors or drugs affecting potassium homeostasis.

Treatment of hyperandrogenic manifestations in polycystic ovary syndrome

Abstract: Etiopathogenesis of the polycystic ovarian disease is not clarified. Therefore, optimum therapy of hyperandrogenic syndromes, menstrual and fertility disorders pose a difficult problem. Sequential therapy with estrogens and progestagens is of value in young women, who are not planning to conceive in order to reduce hirsutism and regulate menses. A reduction of hirsutism, acne and seborrhea is produced within 3 months. However, cessation of the treatment produces the symptoms of excessive androgen production. Another method is therapy with antiandrogens, especially cyproterone acetate. This drug inhibits androgens biosynthesis and has also peripheral activity. Spironolactone is another antiandrogen frequently used, but it is known as a primarily diuretic agent. It acts primarily at the androgen receptor sites. Other antiandrogens such as ketoconazole and flutamide are used less frequently. It has been shown, that cimetidine--known H2 receptor inhibitor--also decreases the symptoms of hyperandrogenism. However, cimetidine has not been used for the treatment of polycystic ovarian disease. In cases of enzymatic defects in adrenocortical steroido-synthesis glucocorticoids are used, mainly low doses of triamcinolone and dexamethasone. Other therapies are preferred in case of polycystic ovarian disease in women, who want to conceive. Clomiphene citrate and gonadotropins, mainly FSH, are used to induce ovulation. If pharmacotherapy does not produce ovulation, wedge resection of the ovaries must be performed.

Congestive heart failure. Drug therapy: central or peripheral approach?

Abstract: Although prevention of heart failure recently has become a realistic issue, management of heart failure once the syndrome has developed, is mainly supportive, based on the various cardiac and peripheral changes which occur in the course of heart failure. Of these, abnormal neurohormonal activation is of major pathophysiologic and prognostic significance. Consequently, modulation of neuroendocrine activation is now recognized a prime target in the treatment of heart failure, besides diuretic therapy. In this respect, the value of converting enzyme inhibition is well established. Future developments in this area include dopaminergic agents, vasopressin antagonists, angiotensin II receptor antagonists, renin inhibitors, spironolactone and, possibly, ANF peptidase inhibitors. Besides diuretics, necessary when signs of fluid retention are present, the approach to heart failure management involves other pharmacologic issues. In view of abnormal vascular control with vasoconstriction prevailing during progressive heart failure, it clearly makes sense to vasodilate. However, of available vasodilators, only the combination of relatively high dose nitrates and hydralazine has proven to be of clinical significance, in terms of hemodynamics, exercise capacity and survival. It is possible, though, that novel generation dihydropyridine derivatives may prove beneficial as well. Thus far, there has been much debate concerning the usefulness and particularly the safety of positive inotrope therapy and inodilator treatment. Taken together, this concern relates to presence and predominance of cAMP-dependent mechanisms to induce these effects. Thus, sympathomimetic agents and phosphodiesterase inhibitors, such as milrinone or enoximone, are without beneficial effects, but instead shorten survival during long-term therapy. This may be different where compounds which act through cAMP-independent mechanisms, i.e., calcium sensitization or sodium channel stimulation, are concerned, but needs to be confirmed yet.(ABSTRACT TRUNCATED AT 250 WORDS)