Oral V2 receptor antagonist (RWJ-351647) in patients with cirrhosis and ascites: A randomized, double-blind, placebo-controlled, single ascending dose study

P. J. Thuluvath, A. Maheshwari, F. Wong, H. W. Yoo, R. W. Schrier, Chirag Parikh, S. Steare, J. Korula

Research output: Contribution to journalArticle

Abstract

Background: RWJ-351647 is a selective V2 receptor antagonist that inhibits vasopressin-induced water reabsorption in the kidney. Aim: To investigate the safety and tolerability of RWJ-351647 compared with placebo after single oral dose administration to patients with cirrhosis and ascites, on a stable treatment with furosemide and spironolactone. Methods: Single oral doses of 1, 2 and 5 mg of RWJ-351647 were administered to 24 patients with ascites on stable concomitant diuretic treatment. Results: RWJ-351647 had a tmax of 1 to 1.1 h and mean half-life of 10.4-17.4 h. There was no affect on the pharmacokinetics of concomitant diuretics. Increases in cumulative urine volume and free water excretion, and a decrease in urine osmolality were noted in a dose-dependent manner reaching the statistical significance at the 5-mg dose. Four patients exhibited a decrease of >2 kg in weight in the 24 h after dosing. RWJ-351647 was well tolerated, with no evidence of a dose-related increase in adverse events when compared with placebo. No changes in either serum chemistry or plasma AVP (arginine vasopressin) and renin levels were observed despite the observed aquaresis. Conclusion: RWJ-351647 is an effective aquaretic causing dose-dependent increases in urine output and free water clearance, when co-administered with conventional diuretics in patients with cirrhosis and ascites.

Original languageEnglish (US)
Pages (from-to)973-982
Number of pages10
JournalAlimentary Pharmacology and Therapeutics
Volume24
Issue number6
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

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Vasopressin Receptors
Ascites
Fibrosis
Placebos
Diuretics
Urine
Water
Spironolactone
Arginine Vasopressin
Furosemide
Renin
Osmolar Concentration
Oral Administration
Half-Life
RWJ-351647
Pharmacokinetics
Kidney
Safety
Weights and Measures
Therapeutics

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Oral V2 receptor antagonist (RWJ-351647) in patients with cirrhosis and ascites : A randomized, double-blind, placebo-controlled, single ascending dose study. / Thuluvath, P. J.; Maheshwari, A.; Wong, F.; Yoo, H. W.; Schrier, R. W.; Parikh, Chirag; Steare, S.; Korula, J.

In: Alimentary Pharmacology and Therapeutics, Vol. 24, No. 6, 01.09.2006, p. 973-982.

Research output: Contribution to journalArticle

Thuluvath, P. J. ; Maheshwari, A. ; Wong, F. ; Yoo, H. W. ; Schrier, R. W. ; Parikh, Chirag ; Steare, S. ; Korula, J. / Oral V2 receptor antagonist (RWJ-351647) in patients with cirrhosis and ascites : A randomized, double-blind, placebo-controlled, single ascending dose study. In: Alimentary Pharmacology and Therapeutics. 2006 ; Vol. 24, No. 6. pp. 973-982.
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abstract = "Background: RWJ-351647 is a selective V2 receptor antagonist that inhibits vasopressin-induced water reabsorption in the kidney. Aim: To investigate the safety and tolerability of RWJ-351647 compared with placebo after single oral dose administration to patients with cirrhosis and ascites, on a stable treatment with furosemide and spironolactone. Methods: Single oral doses of 1, 2 and 5 mg of RWJ-351647 were administered to 24 patients with ascites on stable concomitant diuretic treatment. Results: RWJ-351647 had a tmax of 1 to 1.1 h and mean half-life of 10.4-17.4 h. There was no affect on the pharmacokinetics of concomitant diuretics. Increases in cumulative urine volume and free water excretion, and a decrease in urine osmolality were noted in a dose-dependent manner reaching the statistical significance at the 5-mg dose. Four patients exhibited a decrease of >2 kg in weight in the 24 h after dosing. RWJ-351647 was well tolerated, with no evidence of a dose-related increase in adverse events when compared with placebo. No changes in either serum chemistry or plasma AVP (arginine vasopressin) and renin levels were observed despite the observed aquaresis. Conclusion: RWJ-351647 is an effective aquaretic causing dose-dependent increases in urine output and free water clearance, when co-administered with conventional diuretics in patients with cirrhosis and ascites.",
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T2 - A randomized, double-blind, placebo-controlled, single ascending dose study

AU - Thuluvath, P. J.

AU - Maheshwari, A.

AU - Wong, F.

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AU - Schrier, R. W.

AU - Parikh, Chirag

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