Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis.
OBJECTIVE
Progressive cirrhosis is associated with increasing difficulty to handle free water. We examined the therapeutic potential of an orally active nonpeptide vasopressin-2 receptor antagonist (OPC-31260) in the management of edema and ascites in patients with cirrhosis. By means of its chemical blockade of the vasopressin-2 receptor in the kidney, we also assessed the ability of renal water handling in the early stage of cirrhosis.


METHODS
A single 30 mg dose of OPC-31260 was administered orally to eight biopsy-proven patients with cirrhosis who had ascites or peripheral edema. The aquaretic responses were compared with those in six healthy subjects.


RESULTS
In the patients with cirrhosis, OPC-31260 significantly (p < 0.01) increased the urinary excretion rate at 0 to 2 hours, and significantly (p < 0.01) lowered urine osmolality at 2 to 4 hours after administration. Free water clearance increased from -0.48 +/- 0.14 to +0.19 +/- 0.21 ml/min (p < 0.05) at 0 to 4 hours after administration. However, these aquaretic responses in the patients with cirrhosis were only approximately half the responses observed in the healthy subjects. A significant (p < 0.05) inverse relationship was observed between indocyanine green retention at 15 minutes after administration and the maximal free water clearance after administration to the patients with cirrhosis. Urinary sodium excretion did not change significantly in the patients, whereas it increased twofold in the healthy subjects. Urinary vasopressin excretion tended to increase in the patients, whereas it increased twofold to threefold (p < 0.01 to 0.05) from the baseline in the healthy subjects. Urinary prostaglandin E2 excretion was not increased, and serum sodium and plasma vasopressin levels were elevated only slightly in both groups.


CONCLUSIONS
Even though a hyporesponsiveness was observed in the group of patients with cirrhosis compared with the healthy group, the novel vasopressin-2 antagonist induced hypotonic diuresis in patients with cirrhosis, suggesting a therapeutic potential in managing water excess. This drug response may be a new index to assess impairment of water handling in patients with cirrhosis.
Inoue
T
T
Department of Internal Medicine (I), Daisan Hospital, Jikei University School of Medicine, Tokyo, Japan.
Ohnishi
A
A
Matsuo
A
A
Kawai
B
B
Kunihiro
N
N
Tada
Y
Y
Koizumi
F
F
Chau
T
T
Okada
K
K
Yamamura
Y
Y
Tanaka
T
T
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000652:urine; D001552:Benzazepines / Q000627:therapeutic use*; D015232:Dinoprostone / Q000652:urine; D004231:Diuresis / Q000187:drug effects*; D004573:Electrolytes / Q000652:urine; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004573:Electrolytes; D001127:Arginine Vasopressin; C076251:mozavaptan; D015232:Dinoprostone