0
selected
-
1.
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
-
-
Free full text
-
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).
-
2.
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.
-
3.
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
-
-
Free full text
-
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.
-
4.
Effects of 17beta-oestradiol plus different doses of drospirenone on adipose tissue, adiponectin and atherogenic metabolites in postmenopausal women.
Tankó, LB, Christiansen, C
Journal of internal medicine. 2005;(6):544-53
-
-
Free full text
-
Abstract
OBJECTIVE To investigate how variation in the dose of the progestogen influence the impact of 17beta-oestradiol plus drospirenone (DRSP) treatment on adipose tissue and its secretor function with direct implications for atherogenic metabolites. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING Primary care, single study site. SUBJECTS A total of 240 healthy postmenopausal women 53-65 years old, 178 completer. INTERVENTION Daily treatment with 1 mg 17beta-oestradiol plus 1, 2, or 3 mg DRSP, or placebo for 2 years. MAIN OUTCOME MEASURES Absolute changes in central (CFM) and peripheral fat mass (PFM; dual-energy X-ray absorptiometry, DEXA), adipokines [interleukin (IL)-6 and adiponectin], atherogenic metabolites [triglycerides, high-density lipoprotein cholesterol (HDL-C), glucose] and blood pressure. RESULTS Oestradiol plus 1 mg DRSP evoked significant decreases in CFM and the CFM/PFM ratio from baseline. These benefits virtually decreased with increasing dose of DRSP confounded by dose-dependent increases in CFM and PFM in smokers (P-value for trends <0.001), in whom the increases in bioavailable oestradiol were half of that in nonsmokers (P < 0.001). Treatment with 3 mg DRSP induced decreases in serum adiponectin by month 6 (P < 0.05), which persisted in nonsmokers only and led to significant increases in glucose and triglycerides and decreases in HDL-C (P < 0.05). Adiponectin in smokers normalized by the end of the study parallel with the increases in body fat mass. CONCLUSIONS Interactions of the sex steroids with adipose tissue and its secretor function are important determinants of the overall impact of hormone therapy on cardiovascular risk. A DRSP dose up to 2 mg does not seem to exert adverse effects when combined with 1 mg 17beta-oestradiol.
-
5.
Effect of spironolactone on K(+) homeostasis and ENaC expression in lymphocytes from chronic hemodialysis patients.
Michea, L, Vukusich, A, González, M, Zehnder, C, Marusic, ET
Kidney international. 2004;(4):1647-53
-
-
Free full text
-
Abstract
BACKGROUND Cardiac disease is the major cause of death in hemodialysis patients (HD). It is now clear that aldosterone has deleterious effects in the cardiovascular system. In the present study, we evaluated the effects of an aldosterone-antagonist, spironolactone, on the extrarenal regulation of potassium in HD patients. Furthermore, to validate the effectiveness of the spironolactone dose-design, we measured the expression of Na(+)-channel (ENaC alpha subunit) in peripheral blood mononuclear cells (PBMC), before and after a two-week course of spironolactone. METHODS The study design included a two-week baseline period, followed by spironolactone treatment (50 mg three times weekly for 15 days), and by a two-week washout period and then a two-week placebo period. An oral K(+) load (0.3 mEq/K(+) kg body weight plus carbohydrates) was administered at the end of each period, and time-course of plasma potassium was evaluated. ENaC expression in PBMC was assessed before and after spironolactone. RESULTS The maximal increase in plasma potassium after the K(+) carbohydrate load was: control 5.33 +/- 0.88 mEq K(+)/L; spironolactone 5.23 +/- 0.68 mEq K(+)/L; placebo 5.38 +/- 0.61 mEq K(+)/L (N= 9). No patients developed hyperkalemia during the spironolactone treatment period. ENaC expression was significantly higher in all six HD patients studied, compared to control subjects (P < 0.05). Treatment with spironolactone in HD patients reduced alpha subunit mRNA expression to values similar to those of normal subjects. CONCLUSION Spironolactone may be considered for the treatment of selected chronic HD patients. The effect of the drug on a known target of aldosterone, the ENaC, demonstrates the effectiveness of the drug to block aldosterone effects in nonepithelial tissues.