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Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study.
Wada, T, Inagaki, M, Yoshinari, T, Terata, R, Totsuka, N, Gotou, M, Hashimoto, G
Clinical and experimental nephrology. 2021;(2):120-130
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Abstract
BACKGROUND We investigated the efficacy and safety of apararenone (MT-3995), a non-steroidal compound with mineralocorticoid receptor agonist activity, in patients with stage 2 diabetic nephropathy (DN). METHODS The study had two parts: a dose-response, parallel-group, randomized, double-blind, placebo-controlled, multicenter, phase 2, 24-week study and an open-label, uncontrolled, 28-week extension study. Primary and secondary endpoints were the 24-week percent change from baseline in urine albumin to creatine ratio (UACR) and 24- and 52-week UACR remission rates. Safety parameters were changes from baseline in estimated glomerular filtration rate (eGFR) and serum potassium at 24 and 52 weeks, and incidences of adverse events (AEs) and adverse drug reactions (ADRs). RESULTS In the dose-response period, 73 patients received placebo and 73, 74, and 73 received apararenone 2.5 mg, 5 mg, and 10 mg, respectively. As a percentage of baseline, mean UACR decreased to 62.9%, 50.8%, and 46.5% in the 2.5 mg, 5 mg, and 10 mg apararenone groups, respectively, at week 24 (placebo: 113.7% at week 24; all P < 0.001 vs placebo). UACR remission rates at week 24 were 0.0%, 7.8%, 29.0%, and 28.1% in the placebo and apararenone 2.5 mg, 5 mg, and 10 mg groups, respectively. eGFR tended to decrease and serum potassium tended to increase, but these events were not clinically significant. AE incidence increased with dose while ADR incidence did not. CONCLUSION The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable. CLINICAL TRIAL REGISTRATION NCT02517320 (dose-response study) and NCT02676401 (extension study).
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Topical Mineralocorticoid Receptor Blockade Limits Glucocorticoid-Induced Epidermal Atrophy in Human Skin.
Maubec, E, Laouénan, C, Deschamps, L, Nguyen, VT, Scheer-Senyarich, I, Wackenheim-Jacobs, AC, Steff, M, Duhamel, S, Tubiana, S, Brahimi, N, et al
The Journal of investigative dermatology. 2015;(7):1781-1789
Abstract
A major deleterious side effect of glucocorticoids is skin atrophy. Glucocorticoids activate the glucocorticoid and the mineralocorticoid (MR) receptor, both present in the epidermis. We hypothesized that glucocorticoid-induced epidermal atrophy may be related to inappropriate occupancy of MR by glucocorticoids. We evaluated whether epidermal atrophy induced by the topical glucocorticoid clobetasol could be limited by coadministration of MR antagonist. In cultured human skin explants, the epidermal atrophy induced by clobetasol was significantly limited by MR antagonism (canrenoate and eplerenone). Blockade of the epithelial sodium channel ENaC by phenamil was also efficient, identifying a role of MR-ENaC cascade in keratinocytes, acting through restoration of clobetasol-induced impairment of keratinocyte proliferation. In the SPIREPI randomized double-blind controlled trial, gels containing clobetasol, the MR antagonist spironolactone, both agents, or placebo were applied on four zones of the forearms of 23 healthy volunteers for 28 days. Primary outcome was histological thickness of the epidermis with clobetasol alone or clobetasol+spironolactone. Spironolactone alone did not affect the epidermal thickness but coapplication of clobetasol and spironolactone significantly limited clobetasol-induced atrophy and was well tolerated. Altogether, these findings identify MR as a factor regulating epidermal homeostasis and suggest that topical MR blockade could limit glucocorticoid-induced epidermal atrophy.
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Mineralocorticoid receptor antagonism in acutely decompensated chronic heart failure.
Ferreira, JP, Santos, M, Almeida, S, Marques, I, Bettencourt, P, Carvalho, H
European journal of internal medicine. 2014;(1):67-72
Abstract
BACKGROUND/OBJECTIVES Mineralocorticoid receptor antagonist (MRA) use in acutely decompensated chronic heart failure (ADCHF) may improve congestion through diuretic effect and prevent neurohormonal activation. We aimed to evaluate the clinical effect and safety of spironolactone in ADCHF. METHODS Prospective, experimental, single-center, and single-blinded trial. Patients were treated with: standard ADCHF therapy or oral spironolactone 50-100mg/d plus standard ADCHF therapy. RESULTS During a 1year period, 100 patients were enrolled, 50 included in the treatment group. Mean (SD) spironolactone dose (mg) at day 1 was 94.5±23.3 and at day 3 was 62.7±24.3. Worsening renal function (increase in pCr≥0.3mg/dL from day 1 to day 3) was more likely to occur in control group (20% vs. 4%; p=0.038), serum potassium did not differ between groups, and plasma NTproBNP had a significant decrease in spironolactone group at day 3 (median [IQR], 2488 [4579] vs. 1555 [1832]; p=0.05). Furthermore, a greater proportion of patients in the treatment group were free of congestion at day 3: less edema, rales, jugular venous pressure (JVP) and orthopnea (all, p<0.05). In addition, a significantly higher proportion of patients were on oral furosemide at day 3 (44% vs. 82%; p<0.001). CONCLUSIONS Our study supports the safety of high dose spironolactone in ADCHF and suggests a positive impact in the resolution of congestion. The important findings of our pilot study need to be confirmed in larger trials.
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Displacement of cortisol from human heart by acute administration of a mineralocorticoid receptor antagonist.
Iqbal, J, Andrew, R, Cruden, NL, Kenyon, CJ, Hughes, KA, Newby, DE, Hadoke, PW, Walker, BR
The Journal of clinical endocrinology and metabolism. 2014;(3):915-22
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Abstract
CONTEXT Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with heart failure and myocardial infarction, often attributed to blocking aldosterone action in the myocardium. However, binding of aldosterone to MR requires local activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol to cortisone and thereby prevents receptor occupancy by cortisol. In vivo activity of 11β-HSD2 and potential occupancy of MR by cortisol in human heart have not been quantified. OBJECTIVE This study aimed to measure in vivo activity of 11β-HSD2 and to establish whether cortisol binds MR in human heart. PARTICIPANTS AND INTERVENTIONS Nine patients without heart failure undergoing diagnostic coronary angiography were infused to steady state with the stable isotope tracers 9,11,12,12-[(2)H]4-cortisol and 1,2-[(2)H]2-cortisone to quantify cortisol and cortisone production. Samples were obtained from the femoral artery and coronary sinus before and for 40 minutes after bolus iv administration of an MR antagonist, potassium canrenoate. Coronary sinus blood flow was measured by venography and Doppler flow wire. RESULTS There was no detectable production of cortisol or cortisone across the myocardium. After potassium canrenoate administration, plasma aldosterone concentrations increased substantially but aldosterone was not detectably released from the myocardium. In contrast, plasma cortisol concentrations did not change in the systemic circulation but tissue-bound cortisol was released transiently from the myocardium after potassium canrenoate administration. CONCLUSIONS Human cardiac 11β-HSD2 activity appears too low to inactivate cortisol to cortisone. Cortisol is displaced acutely from the myocardium by MR antagonists and may contribute to adverse MR activation in human heart.
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Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial.
Esteghamati, A, Noshad, S, Jarrah, S, Mousavizadeh, M, Khoee, SH, Nakhjavani, M
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2013;(11):2823-33
Abstract
BACKGROUND Addition of spironolactone (SPR) to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) might provide antiproteinuric effects beyond what is gained by either medication alone. This study was designed to assess the long-term efficacy of SPR/ARB combination in comparison with the standard ACE/ARB regimen in diabetic nephropathy. METHODS In an open-label, parallel-group, single-center, randomized clinical trial (NCT01667614), 136 patients with diabetes and proteinuria, already treated with enalapril and losartan, were included. In 74 patients, ACE inhibitors were discontinued. After a wash-out period of 2 weeks, 25 mg SPR daily was initiated. The remainder of the patients (n = 62) received ACE inhibitors and ARBs as before. Patients were followed every 3 months for 18 months. During each visit, systolic and diastolic blood pressure (BP), urinary albumin excretion (UAE), serum creatinine, estimated glomerular filtration rate (eGFR) and serum potassium concentrations were determined. RESULTS After 18 months, three patients in the SPR/ARB group developed asymptomatic hyperkalemia. SPR/ARB significantly reduced both systolic and diastolic BP (P < 0.001 and 0.001, respectively). SPR/ARB decreased UAE by 46, 72 and 59% after 3, 12 and 18 months, respectively. Compared with the continuation regimen, SPR/ARB was superior in UAE reduction (P = 0.017 after 18 months), independent of BP change. In both groups, eGFR declined significantly over the trial course and the decline rate did not differ significantly between the two groups. CONCLUSIONS Addition of SPR to ARB provides added benefits with respect to BP control and proteinuria diminution. These antiproteinuric effects are not accompanied by prevention of eGFR loss compared with conventional therapy with ACE/ARB.
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Potassium sparing diuretics as adjunct to mannitol therapy in neurocritical care patients with cerebral edema: effects on potassium homeostasis and cardiac arrhythmias.
Bilotta, F, Giovannini, F, Aghilone, F, Stazi, E, Titi, L, Zeppa, IO, Rosa, G
Neurocritical care. 2012;(2):280-5
Abstract
BACKGROUND Mannitol therapy to treat cerebral edema induces osmotic diuresis and electrolyte loss. In neurocritical care patients, potassium is the electrolyte that most often needs replacement. Objective of this study was to evaluate the effects of adding potassium sparing diuretic (canrenone) to mannitol therapy on potassium urinary excretion, potassium plasma levels, and incidence of new cardiac arrhythmias in patients receiving neurocritical care for cerebral edema. METHODS Fifty-six patients were prospectively assigned to mannitol or mannitol plus i.v. canrenone. Potassium urinary excretion, potassium plasma levels, urinary volume, and the incidence of new cardiac arrhythmias were recorded during the first 8 days of therapy. RESULTS In patients treated with mannitol the potassium urinary excretion was stable over the first 3 days and significantly increased, compared to baseline, on day 4th to 8th (baseline 20.3 ± 10.6 mEq/l/die, day 8th 24.6 ± 10.6 mEq/l/die, P < 0.05); while potassium plasma levels significantly decreased. In patients receiving mannitol plus canrenone potassium urinary excretion decreased from day 3rd to 8th (baseline 21.9 ± 11.6 mEq/l/die, day 8th 15.9 ± 10.9 mEq/l/die, P < 0.015) and potassium plasma levels increased but remained within normal values range. The incidence of new cardiac arrhythmias was higher in the mannitol group than the mannitol plus canrenone group (35.7 vs. 10.7%; P < 0.01). Urinary volumes, potassium balance, and sodium plasma concentration were similar in the 2 study groups. CONCLUSION In patients receiving neurocritical care for cerebral edema, the adjunct of a potassium sparing diuretic (canrenone) to mannitol therapy reduces potassium urinary loss, prevents hypokalemia, and reduces the incidence of new cardiac arrhythmias.
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Combined oral contraceptive pills containing desogestrel or drospirenone enhance large vessel and microvasculature vasodilation in healthy premenopausal women.
Thompson, AK, Przemska, A, Vasilopoulou, D, Newens, KJ, Williams, CM
Microcirculation (New York, N.Y. : 1994). 2011;(5):339-46
Abstract
OBJECTIVE To determine the effects of different COCs on endothelial function. BACKGROUND COCs all contain ethinylestradiol, but different progestins; three of the more common progestins are DSG, LN, and DR. Ethinylestradiol enhances some measures of vascular reactivity, but certain progestins may increase risk of vascular diseases and impair endothelial vasodilation. METHODS Twenty-nine healthy women taking COCs containing 30 μg ethinylestradiol and 150 μg DSG (Marvelon, n = 10), 150 μg LN (Microgynon, n = 10), or 3 mg DR (Yasmin, n = 9) had their vascular reactivity measured using various techniques during their pill-free week (days 5-7) and the third week of active pills (days 26-28). A reference group (n = 10) underwent the same measurements on two consecutive cycles. RESULTS FMD and LDI were significantly higher during active-pill visits than pill-free visits in women taking DSG and DR (p < 0.02), but not in women taking LN. There were no differences between the duplicate measures in the reference group. CONCLUSIONS COCs containing 150 μg DSG or 3 mg DR significantly increase endothelium-dependent vasodilation in both large vessels and peripheral microvasculature. These effects may be due to the progestins exhibiting differential effects on eNOS expression.
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Effect of spironolactone on urinary protein excretion in patients with chronic kidney disease.
Sengul, E, Sahin, T, Sevin, E, Yilmaz, A
Renal failure. 2009;(10):928-32
Abstract
AIM: To investigate antiproteinuric effect of spironolactone in patients with chronic kidney disease (CKD) treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1 receptor blockers (ARBs). METHODS This study was performed in 33 CKD patients with proteinuria. 24 h urinary protein excretion and biochemical parameters were obtained before the therapy. Then, spironolactone (25 mg/d) was added to the therapy. The antiproteinuric effect of spironolactone was examined for eight weeks. RESULTS At eight weeks, there was a significant decrease in proteinuria (p < 0.001, 47.9% decrease). Systolic and diastolic blood pressures were significantly decreased (p < 0.004, p < 0.001, respectively). However, no correlation was detected between the reductions in systolic and diastolic BP and the reduction in proteinuria (p = 0.464, p = 0.239, respectively). Serum potassium level increased significantly (p < 0.001). CONCLUSIONS Our study suggests that spironolactone significantly reduces urinary protein excretion. This strategy may be useful to slow the progression of CKD. However, hyperkalemia is the most important side effect of treatment, and it is necessary to monitor potassium level. Further studies are needed to determine the efficacy of spironolactone on proteinuria.
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The effects of spironolactone on nephron function in patients with diabetic nephropathy.
Ustundag, A, Tugrul, A, Ustundag, S, Sut, N, Demirkan, B
Renal failure. 2008;(10):982-91
Abstract
Increasing evidence suggests that circulating aldosterone per se contributes directly to renal and cardiovascular diseases. We sought to evaluate the effects of a three-month treatment with 25 mg spironolactone, an aldosterone receptor antagonist, on nephron function in 20 type II diabetic patients with persistent microalbuminuria, despite at least six months' use of an ACEi or ARB (combination group), and in eleven type II diabetic patients with persistent microalbuminuria who have never used an ACEi or an ARB (spironolactone group). In the combination group, urinary protein excretion (UPE, p = 0.015), urinary albumin excretion (UAE, p = 0.010), and the urinary albumin to creatinine ratio (ACR, p = 0.007) decreased, and serum potassium (sK(+), p = 0.004) was significantly elevated. ACR (p = 0.016) decreased significantly in the spironolactone group. In 31 patients given spironolactone (all patients group), UPE (p = 0.019), UAE (p = 0.002), and ACR (p = 0.011) decreased, and serum creatinine (sCr, p = 0.025) and sK(+) (p = 0.002) were significantly elevated. Changes in albuminuria showed a positive correlation with changes in GFR (p = 0.002) and a negative correlation with changes in sCr (p = 0.007), and changes in ACR showed a negative correlation with changes in sCr (p = 0.004) in all patient groups. In our study, we observed that spironolactone, both alone and in combination with ACEi/ARB treatment, was well tolerated, and that it slowed down the progression of diabetic nephropathy with a marked antialbuminuric effect. Our results showed that the antialbuminuric effect developed by the decrease of intraglomerular pressure, particularly in patients with persistent microalbuminuria despite long-term ACEi/ARB treatment; adding aldosterone blockers to treatment was beneficial.
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[Effect of long term therapy with spironolactone on parameters of 24-hour heart rhythm variability and ventricular arrhythmias in patients with heart failure receiving optimal therapy].
Skvortsov, AA, Mareev, VIu, Orlova, IaA, Chelmakina, SM, Baklanova, NA, Belenkov, IuN
Kardiologiia. 2008;(2):52-64
Abstract
UNLABELLED Aim of the investigation was the study of influence of spironolactone (25-75 mg/day) on clinico-functional and neurohormonal, 24-hour variability of cardiac rhythm, and ventricular disturbances of heart rhythm in patients with chronic heart failure (CHF) receiving optimal therapy. Forty nine patients were included in the study--44 men (89,8%) and 5 women (10.2%) in the age from 28 to 75 years with II-IV NYHA functional class (FC) CHF, LV ejection fraction (EF) 35%, plasma levels of creatinine 150 micromol/L and potassium 5 mmol/L. Main causes of development of CHF were dilated cardiomyopathy, ischemic heart disease (large focal postinfarction cardiosclerosis) and decompensated hypertensive heart [25/20/4 (51%/40.8%/8.2%), respectively]. As a result of randomization 2 groups of observation were formed: group 1-19 patients receiving spironolactone in a 24 hour dose 25-75 mg, group 2-control group-30 patients without therapy with spironolactone. Inhibitors of angiotensin converting enzyme (ACE) took 100%, beta-adrenoblockers--63.2% of patients. Control examination was conducted before randomization, in 6 and 12 months of follow up. During period of observation no changes of FC were noted in control group. In the spironolactone group after 6 months f treatment in 6 patients FC improved (p=0.028). By the end of follow up the given effect lost its significance, but in 5 (38.5%) patients by termination of the study FC II of CHF was noted, what was accompanied with moderate increase of distance walked during 6-minute walk test from 354 to 378 m. Addition of spironolactone to conducted therapy was followed by increase of concentration of aldosterone by 153 (84; 426) microg/ml, p=0.009, what discriminated (p=0.007) the given patients from control group and provoked increase of plasma rennin activity. Median concentration of angiotensin II changed not substantially [0.78 (-1.84; 2.66) mg/ml] after 12 months of treatment. Changes of noradrenalin, vasopressin, and endothelin were insignificant in both groups of observation. After 12 months of treatment median of changes of concentration of atrial natriuretic peptide was -51.9 ( -87; -43.9) microg/ml. At the same time in control group was observed gradual growth of concentrations of the given peptide from initial 107.3 to 168.5 microg/ml by the moment of termination of the study. Basic influence on spectral and temporal indexes of HRV spironolactone exerted in day time of 24 hours with increase of by 24.5 (10; 34) ms (p=0.042) after 6 months of treatment. Maximal lowering of number of ventricular extrasystoles from initial 75 (39; 477) to 12 (0; 15) (p=0.043) were achieved with administration of spironolactone in combination with ACE inhibitor and beta-adrenoblocker after 12 months of treatment what was followed with decrease of number of patients with episodes of of ventricular tachycardia from 50 to 18% (p=0.035). Addition of spironolactone in a dose of 75 mg/day to optimal therapy including ACE inhibitor and b-adrenoblocker is accompanied with betterment of clinical state and FC of patients with CHF. CONCLUSION Neurohormonal markers of application of spironolactone in combination with ACE inhibitor appear elevation of activity of plasma renin and concentration of aldosterone in combination with lowering of concentration of atrial natriuretic peptide in plasma of patients with CHF. Long term block of aldosterone at receptor level is accompanied with betterment of parameters of HRV in patients with CHF during day time. Addition of spironolactone to therapy with ACE inhibitor and beta-adrenoblocker bisoprolol decreases quantity and severity of ventricular rhythm disturbances in patients with moderate and severe CHF.