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The bioavailabilities of three spironolactone tablet formulations specially selected for major differences in in vitro dissolution tests were compared in normal male volunteers by measuring plasma and urinary levels of the pharmacologically active spironolactone metabolite canrenone. It was possible to demonstrate small but statistically significant differences in plasma canrenone concentration-time curves derived from the three formulations together with significant differences in the time course of urinary canrenone excretion. The bioavailabilities of the three formulations did not differ significantly although the tablet with the poorest in vitro dissolution produced a significant delayed peak canrenone concentration. The dissolution rate methodology and results are described and an approach to the development of improved in vitro dissolution tests for spironolactone is suggested. The use of a new method for canrenone estimation resulted in the incidental detection of two other quantitatively significant spironolactone metabolites and preliminary information is given on these.
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Peritoneal fibrosis (PF) is an important complication of long-term peritoneal dialysis. Although mineralocorticoid and mineralocorticoid receptor (MR) have attracted increasing attention in the field of vascular injury, including the heart, kidney, and vessels, little is known about the role of mineralocorticoid in PF. This work was designed to explore the effects of MR blockade on PF. We developed a new model of PF in rats based on mechanical scraping of the peritoneum. This model is characterized by acute-phase inflammation (neutrophil and macrophage infiltration on days 0-3) and late-phase PF (alpha-smooth muscle actin-positive fibroblast infiltration, type III collagen accumulation, and neoangiogenesis on days 7-14). Peritoneal thickening peaked on day 14. MR was expressed in rat peritoneum and a rat fibroblast cell line. Expression of its effector kinase [serum- and glucocorticoid-induced kinase-1 (Sgk1)], transforming growth factor-beta (TGF-beta), plasminogen activator inhibitor-1 (PAI-1), and CD31-positive vessels increased during the course of PF. Rats were treated with spironolactone, angiotensin receptor blockade (ARB), or angiotensin-converting enzyme inhibitor (ACEI)-ARB-spironolactone starting at 6 h after peritoneal scraping. All parameters, including peritoneal thickening, number of macrophages and CD31-positive vessels, and expression of monocyte chemoattractant protein-1, TGF-beta, PAI-1, and Sgk1, were significantly suppressed by spironolactone (10 mg x kg(-1) x day(-1)). The effects of spironolactone (10 and 20 mg x kg(-1) x day(-1)) were very similar to those of triple blockade. ARB, but not ACEI, significantly reduced peritoneal thickening. Furthermore, peritoneal function assessed by peritoneal equilibration test was significantly improved by spironolactone. Our results suggest that MR is a potential target to prevent inflammation-induced PF in patients on peritoneal dialysis.
Increased bone mineral density (BMD) has been reported in young women with androgen excess. To determine whether antiandrogen treatment in young women with androgen excess reduces BMD in these patients, the authors measured BMD before and a year after the beginning of antiandrogen therapy with spironolactone and linestrenol in 17 consecutive androgenized patients (median age 22 years). After a year's treatment BMD declined in 15 out of 17 patients, the mean decrease--0.032 g/cm2 (95% CI of the difference 0.016-0.048)--being highly significant (p < 0.001). Androstenedione decrease was the only hormonal variable significantly correlating with BMD decrease (r = 0.5; p = 0.037) according to simple linear regression. A decrease of BMD might become a key factor in deciding about the duration of antiandrogen treatment with spironolactone in functional hyperandrogenemia.
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CRIP was intravenously administered for gamma imaging after 4 weeks of MI in 63 Swiss-Webster mice and in 6 unmanipulated mice. Of 63 animals, 50 were treated with captopril (C), losartan (L), spironolactone (S) alone, or in combination (CL, SC, SL, and SCL), 8 mice received no treatment. Echocardiography was performed for assessment of cardiac remodeling. Hearts were characterized histopathologically for the presence of myofibroblasts and thick and thin collagen fiber deposition.
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Adult Sprague Dawley rats were randomized into four groups; controls, spironolactone-treated rats (Spir), diabetic rats (DM), and diabetic rats treated with spironolactone (DM+Spir) for 4 weeks. Blood pressure and cardiac levels of aldosterone and oxidants/antioxidants were measured.
ELISA method showed that the level of FN in the supernatant of cultured rat mesangial cells stimulated with ALD increased significantly in a dose- and time-dependent manner. Also the expressions of FN mRNA and TGF-beta1 mRNA were increased significantly by ALD in a dose- and time-dependent manner by semi-quantitative RT-PCR. SPI inhibited the stimulating effect of ALD on synthesis of FN and expressions of FN mRNA and TGF-beta1 mRNA in cultured rat mesangial cells.
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An extremely ill patient, with Cushing's syndrome caused by an ACTH-secreting pituitary macroadenoma, experienced complications of end-stage cardiomyopathy, profound psychosis, and multiple metabolic disturbances. Initially treated unsuccessfully by a combination of conventional surgical, medical, and radiotherapeutic approaches, he responded dramatically to high-dose long-term mifepristone therapy (up to 25 mg/kg x d). Treatment efficacy was confirmed by the normalization of all biochemical glucocorticoid-sensitive measurements, as well as by the significant reversal of the patient's heart failure, the resolution of his psychotic depression, and the eventual unusual return of his adrenal axis to normal. His 18-month-long mifepristone treatment course was notable for development of severe hypokalemia that was attributed to excessive cortisol activation of the mineralocorticoid receptor, which responded to spironolactone administration. This case illustrates the efficacy of high-dose long-term treatment with mifepristone in refractory Cushing's syndrome. The case also demonstrates the potential need for concomitant mineralocorticoid receptor blockade in mifepristone-treated Cushing's disease, because cortisol levels may rise markedly, reflecting corticotroph disinhibition, to cause manifestations of mineralocorticoid excess.
Our data revealed that aldosterone reduced the expression of adiponectin and inhibited the transport of glucose in cardiomyocytes and that MR blockade reversed these affects. In vivo, MR blockade improved insulin-sensitive parameters and increased adiponectin expression in the myocardia of high-fat diet rats. Furthermore, aldosterone promoted p38MAPK expression but negatively affected PPARα expression, and the downregulation of adiponectin by aldosterone was reversed by MR blockade, a PPARα agonist, and a p38 MAPK inhibitor.
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The aim of the present study was to evaluate the effect of low-dose spironolactone initiated during the early stages of hypertension development and to assess the effects of chronic pressure overload on ventricular remodeling in rats. Male spontaneously hypertensive rats (SHRs) (4 weeks) were randomized to receive daily spironolactone (20 mg/kg) or vehicle (mineral oil) from 4 weeks to 8 months of age. Systolic blood pressure was measured non-invasively by tail-cuff pletysmography at baseline, 4 and 8 months. Hemodynamic assessment was performed at the end of treatment by arterial and ventricular catheterization. An in situ left ventricular pressure-volume curve was created to evaluate dilatation and wall stiffness. Systolic blood pressure at 1 month of age was higher in SHRs than in the Wistar group; it increased throughout the follow-up period and remained elevated with treatment (Wistar: 136 ± 2, SHR: 197 ± 6.8, SHR-Spiro: 207 ± 7.1 mmHg; p < 0.05). Spironolactone reduced cardiac hypertrophy (Wistar: 1.25 ± 0.03 SHR: 1.00 ± 0.03, SHR-Spiro: 0.86 ± 0.02 g; p < 0.05) and left ventricular mass normalized to body weight (Wistar: 2.51 ± 0.06, SHR: 2.70 ± 0.08, 2.53 ± 0.07 mg/g; p < 0.05). Moreover, the left ventricular wall stiffness that was higher in SHRs was partially reduced by spironolactone treatment (Wistar: 0.370 ± 0.032; SHR: 0.825 ± 0.058; SHR-Spiro: 0.650 ± 0.023 mmHg/ml; p < 0.05). Our results show that long-term spironolactone treatment initiated at the early stage of hypertension development reduces left ventricular hypertrophy and wall stiffness in SHRs.
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Pregnant rats were treated with 40 mg spironolactone (sp) po from the 13th to the 21st day p.c. The foetuses were prepared and histologically examined on day 22. The male foetuses showed distinct signs of feminization especially of the external genitalia. The anogenital distance was nearly 48% shorter than that of the controls. The prostatic utricle persisted more distinctly, and the number and size of the prostatic buds were significantly reduced. The degree of feminization of the male foetuses which is achieved under the influence of sp (40 mg/day) is the same as that which can be induced by 1--3 mg cyproterone acetate.
The erection frequency in Vilsartan group was higher, compared with other two groups(P < 0.05), in which no significant difference was observed (P > 0.05). There was no significant difference in erection rates among these three groups. The number of nNOS-containing nerve fibers in two intervention groups was higher than the control group(P < 0.01), but no significant difference existed between these two groups(P > 0.05).
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We used the patch-clamp technique to analyse the open/close kinetics of single, outwardly rectifying, intermediate-conductance (ORIC) Cl- channels from cultured epithelial cells under control conditions and in presence of different inhibitors. As observed previously in excised inside/out patches under control conditions, the switching kinetics were characterized by one open-state time constant (tau0 is approximately 30 ms) and three closed-state time constants (tau(cl)is approximately = to 0.2 ms, tau(c2) is approximately = 2 ms and tau(c3) is approximately = 60 ms). Aldosterone, six further steroids and two aldosterone antagonists inhibited channel open probability (NPo) concentration dependently with the potency at 10 micromol/l increasing in the sequence: hydrocortisone, corticosterone, P-oestradiol, cortisone, aldosterone, testosterone, progesterone, canrenone, spironolactone. Although all substances decreased tau(o), neither the steroids nor the aldosterone antagonists affected tau(cl), tau(c2) or tau(c3) or induced additional transitions with additional time constants. Instead, the steroids increased the prevalence of tau(c2) in the dwell-time histograms and the aldosterone antagonists increased the prevalence of tau(c3), both in a concentration-dependent manner. These observations may be explained by a model in which one open state leads to one of three closed states with rate constants alpha, beta and gamma, and in which beta or gamma increase under the influence of steroids or aldosterone antagonists, respectively. Cytosol, which contains a Cl- channel inhibitor of unknown molecular structure, (Krick et al., Pflügers Arch 418:491, 1991) was also tested, but the results did not conform to the blocker mechanisms described above. This shows that there are even further modes of channel inhibition and argues against the cytosolic Cl- channel inhibitor being a steroid.
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The effect of spirolactones on the urinary excretion of individual 17-oxosteroids and of pregnanediol in man was investigated under various conditions. After purification by thin-layer chromatography, the 17-oxosteroids and pregnanediol were determined by gas chromatography. Eleven male subjects (age 21-34 years) received a daily dose of 200 mg spironolactone (Aldactone) orally on seven consecutive days. Five female subjects (age 20-35 years) and ten pregnant women (age 20-35 years; 28th.-39th. week of gestation) were given a daily intravenous injection of 600 mg potassium canrenoate (Aldactone pro injectione) on three consecutive days. In the male subjects, the excretion of individual 17-oxosteroids and of pregnanediol was significantly reduced during administration of spironolactone. In the nonpregnant female subjects, the excretion of etiocholanolone and dehydroepiandrosterone was diminished, whereas in the pregnant women, the excretion of pregnanediol and dehydroepiandrosterone was decreased during treatment with potassium canrenoate. These results suggest that the reduced urinary excretion of steroids may be due to an inhibition of steroid metabolising enzymes by spirolactones. It seems likely that spirolactones affect the enzymatic conversion fo cholesterol to pregnenolone.