for The North American VPA-985 Study Group Hyponatremia in advanced cirrhosis and ascites or congestive heart failure (CHF) is the result of an inappropriate increase in vasopressin secretion, which acts through activation of specific V 2 receptors in the distal renal nephron to increase water reabsorption. This study investigates the efficacy and safety of 3 different doses of the V 2 receptor antagonist, VPA-985, in correcting hyponatremia over a 7-day inpatient study period. Forty-four hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with syndrome of inappropriate antidiuretic hormone (SIADH) were studied on a constant sodium intake, with VPA doses of 25, 125, and 250 mg twice daily or placebo. Serum sodium measurements were repeated after every daily dose, and the next dose withheld for excessive serum sodium rises. Fluid intake was adjusted according to previous 24-hour urinary outputs. Adverse events were based on clinical signs of dehydration or encephalopathy. VPA-985 produced a significant overall aquaretic response compared with placebo, with significant dose related increases in free water clearance (P < .05) and serum sodium (P < .05), without significant changes in orthostatic blood pressure or serum creatinine levels. Five patients (50%) on 250 mg twice daily had to have medication withheld on multiple occasions. End-of-study plasma vasopressin levels increased significantly in the 2 larger dose groups. In conclusion, VPA-985 appears effective and safe in appropriate doses in correcting abnormal renal water handling and hyponatremia in conditions associated with water retention. Higher doses of VPA-985 may produce significant dehydration and will require close monitoring with their use.
(HEPATOLOGY 2003;37:182-191.)See Editorial on Page 13 P atients with advanced cirrhosis and ascites or with congestive heart failure (CHF) have a disturbance in water metabolism, resulting in decreased renal free water excretion and dilutional hyponatremia. 1 The presence of hyponatremia in hospitalized patients with alcoholic cirrhosis or CHF is associated with a significantly increased mortality. 2,3 The inability of these patients to excrete an appropriate amount of free water is related to many factors, the most important of which is the nonosmotic stimulation of vasopressin release. [4][5][6] Plasma vasopressin levels are increased despite low plasma osmolality, 7 reflecting the resetting of the osmostat to a lower osmolar threshold for vasopressin suppression. 8 Vasopressin exerts its effects on water metabolism through the activation of specific V 2 receptors, which are expressed on the cells of the ascending limb of the loop of Henle and on the cells of the collecting duct of the nephron. 9 In the collecting duct, the activation of the V 2 receptor increases water reabsorption directly through the insertion of water channels into the otherwise water-impermeable collecting duct cells. 10 V 2 receptor antagonists, by competitive binding to the V 2 receptor, can displace vasopressin and, the...