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

AbstractBACKGROUND:
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.
AuthorsP J Thuluvath, A Maheshwari, F Wong, H W Yoo, R W Schrier, C Parikh, S Steare, J Korula
JournalAlimentary pharmacology & therapeutics (Aliment Pharmacol Ther) Vol. 24 Issue 6 Pg. 973-82 (Sep 15 2006) ISSN: 0269-2813 [Print] England
PMID16948809 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Antidiuretic Hormone Receptor Antagonists
  • Diuretics
  • RWJ-351647
  • Arginine Vasopressin
  • Benzodiazepines
  • Spironolactone
  • Furosemide
  • Sodium
  • Renin
Topics
  • Administration, Oral
  • Adult
  • Antidiuretic Hormone Receptor Antagonists
  • Arginine Vasopressin (blood)
  • Ascites (drug therapy)
  • Benzodiazepines (administration & dosage, adverse effects, pharmacokinetics)
  • Diuretics (pharmacokinetics, therapeutic use)
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Furosemide (pharmacokinetics, therapeutic use)
  • Humans
  • Liver Cirrhosis (drug therapy)
  • Male
  • Middle Aged
  • Osmolar Concentration
  • Renin (blood)
  • Sodium (blood)
  • Spironolactone (pharmacokinetics, therapeutic use)
  • Treatment Outcome
  • Urination (drug effects)

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