A multicenter, open-label, dose-ranging study to exploratively evaluate the efficacy, safety, and dose–response of tolvaptan in patients with decompensated liver cirrhosis
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We examined the efficacy of tolvaptan, an orally effective nonpeptide vasopressin V2 receptor antagonist, in a Japanese clinical study in patients with intractable ascites and/or lower limb edema associated with decompensated liver cirrhosis.
Tolvaptan was orally administrated at titrated doses of 15, 30, and 60 mg once daily after breakfast for 3 days at each dose to 18 liver cirrhosis patients with persistent ascites and/or lower limb edema despite receiving oral furosemide at 40 mg/day or higher.
Decreased body weight and abdominal circumference and improvement of ascites and edema were observed following tolvaptan administration beginning from 15 mg. Composite ascites/edema improvement rate was 88.2% at individual maximum doses and 64.7, 80.0, and 90.9%, respectively, after 3-day administration at 15, 30, and 60 mg. Changes in body weight after 3-day administration at 15, 30, and 60 mg were −1.6 ± 0.9, −2.6 ± 1.2, and −3.4 ± 2.1 kg (mean ± SD), respectively, and decreases of 1 kg or more were seen from day 2 (24 h after first dosing). Changes in abdominal circumference ranged from −2.8 to −6.0 cm. Cumulative 24-h urine volumes after 3-day administration at 15, 30, and 60 mg were, respectively, 3240.3 ± 1014.5, 3943.3 ± 1060.6, and 4537.4 ± 1621.3 mL/day (mean ± SD). Urine osmolarity was markedly decreased and remained decreased until the end of treatment.
Tolvaptan dose-dependently decreased body weight and abdominal circumference and improved ascites and edema beginning from 15 mg, demonstrating a potent aquaretic effect.
KeywordsTolvaptan (OPC-41061) Vasopressin V2 receptor antagonist Decompensated liver cirrhosis Intractable ascites Leg edema
The authors are most grateful to their fellow researchers and hospitals for their contribution to data collection.
- 1.Guyton AC, Hall JE. Textbook of medical physiology. 10th ed. Philadelphia, PA: WB Saunders Company; 2000. p. 855–6.Google Scholar
- 4.Costello-Boerrigter LC, Smith WB, Boerrigter G, Ouyang J, Zimmer CA, Orlandi C, et al. Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am J Physiol Renal Physiol. 2006;290:273–8.CrossRefGoogle Scholar
- 5.Lieberman FL, Ito S, Reynolds TB. Effective plasma volume in cirrhosis with ascites. Evidence that a decreased value does not account for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR), a fall in GFR during drug-induced diuresis. J Clin Invest. 1969;48(6):975–81.CrossRefPubMedGoogle Scholar
- 7.Levy M. Pathophysiology of ascites formation. In: Epstein M, editor. The kidney in liver disease. 2nd ed. New York: Elsevier, 1982. p. 245–80.Google Scholar
- 10.Inuyama Symposium Kirokukannkoukai, editors. Proceedings of the 12th Inuyama Symposium: hepatitis A and fulminant hepatitis (in Japanese). Tokyo: Chugai Igakusha; 1982. p. 124.Google Scholar
- 15.Lin SH, Hsu YJ, Chiu JS, Chu SJ, Davids MR, Halperin ML, et al. Osmotic demyelination syndrome: a potentially avoidable disaster. Q J Med. 2003;96:935–47.Google Scholar