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.