OBJECTIVES: The purpose of this study was to examine the renal effects of a V2 receptor arginine vasopressin (AVP) antagonist in heart failure. BACKGROUND:Arginine vasopressin has been implicated in the renal water retention and dilutional hyponatremia associated with chronic heart failure. METHODS: We examined the effects of the oral, non-peptide, selective V2 receptor antagonist lixivaptan in 42 diuretic-requiring patients with mild-to-moderate heart failure in a randomized, double-blind, placebo-controlled, ascending single-dose study. After overnight fluid deprivation, patients received single-blind placebo on day -1 (baseline) and double-blind study medication (placebo [n = 12] or lixivaptan 10, 30, 75, 150, 250, or 400 mg [n = 5 per dose group]) on day 1, followed by 4 h of continued fluid restriction and additional 20 h with ad libitum fluid intake. RESULTS: At all but the 10-mg dose, lixivaptan produced a significant and dose-related increase in urine volume over 4 h, compared with placebo. During 24 h, increases in urine volume ranged from 1.8 l with placebo to 3.9 l after the 400-mg lixivaptan dose (p < 0.01). These increases in urine volumes were accompanied by significant increases in solute-free water excretion. At higher doses, serum sodium was significantly increased; AVP antagonism was well tolerated in these patients. CONCLUSIONS: These observations confirm a role for AVP in the renal water retention associated with heart failure and suggest that the V2 receptor antagonist lixivaptan may be a promising therapeutic agent for the treatment of heart failure.
RCT Entities:
OBJECTIVES: The purpose of this study was to examine the renal effects of a V2 receptor arginine vasopressin (AVP) antagonist in heart failure. BACKGROUND: Arginine vasopressin has been implicated in the renal water retention and dilutional hyponatremia associated with chronic heart failure. METHODS: We examined the effects of the oral, non-peptide, selective V2 receptor antagonist lixivaptan in 42 diuretic-requiring patients with mild-to-moderate heart failure in a randomized, double-blind, placebo-controlled, ascending single-dose study. After overnight fluid deprivation, patients received single-blind placebo on day -1 (baseline) and double-blind study medication (placebo [n = 12] or lixivaptan 10, 30, 75, 150, 250, or 400 mg [n = 5 per dose group]) on day 1, followed by 4 h of continued fluid restriction and additional 20 h with ad libitum fluid intake. RESULTS: At all but the 10-mg dose, lixivaptan produced a significant and dose-related increase in urine volume over 4 h, compared with placebo. During 24 h, increases in urine volume ranged from 1.8 l with placebo to 3.9 l after the 400-mg lixivaptan dose (p < 0.01). These increases in urine volumes were accompanied by significant increases in solute-free water excretion. At higher doses, serum sodium was significantly increased; AVP antagonism was well tolerated in these patients. CONCLUSIONS: These observations confirm a role for AVP in the renal water retention associated with heart failure and suggest that the V2 receptor antagonist lixivaptan may be a promising therapeutic agent for the treatment of heart failure.
Authors: William T Abraham; Juan M Aranda; John P Boehmer; Uri Elkayam; Edward M Gilbert; Stephen S Gottlieb; Gerd Hasenfuss; Marrick Kukin; Brian D Lowes; John B O'Connell; Luigi Tavazzi; Arthur M Feldman; Barry Ticho; Cesare Orlandi Journal: Clin Transl Sci Date: 2010-10 Impact factor: 4.689
Authors: Xiaofang Wang; Megan M Constans; Fouad T Chebib; Vicente E Torres; Lorenzo Pellegrini Journal: Am J Nephrol Date: 2019-05-22 Impact factor: 3.754
Authors: James A Iwaz; Elizabeth Lee; Hermineh Aramin; Danilo Romero; Navaid Iqbal; Matt Kawahara; Fatima Khusro; Brian Knight; Minal V Patel; Sumita Sharma; Alan S Maisel Journal: Drugs Date: 2016-02 Impact factor: 9.546