Oral V<sub>2</sub> receptor antagonist (RWJ‐351647) in patients with cirrhosis and ascites: a randomized, double‐blind, placebo‐controlled, single ascending dose study

Thuluvath, Paul J.; Maheshwari, Anshul; Wong, Florence; Yoo, Han Wook; Schrier, Robert W.; Parikh, Chirag R.; Steare, S.E.; Korula, Jacob

doi:10.1111/j.1365-2036.2006.03088.x

Cited by 22 publications

(20 citation statements)

References 12 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, tolvaptan clearly acts as an aquaretic. Further, in this single-dose study no increase in blood pressure was observed, which could have theoretically occurred due to increased binding of AVP displaced from the V 2 R to the V 1A R. In a larger clinical trial (ACTIV in CHF; n = 254) chronic administration of tolvaptan for 25 days (30,45, and 60 mg once daily) resulted in a sustained decrease in body weight and urine osmolality and a slight increase in serum sodium (particularly in patients with hyponatremia at baseline) as compared to placebo [11]. No changes in heart rate, blood pressure, renal function, or serum potassium were observed.…”

Section: Tolvaptan (Opc-41061)mentioning

confidence: 66%

“…RWJ-351647 induces the expected diuresis and free water excretion in rats and cynomolgus monkeys after a single dose; 10-day administration in monkeys demonstrated no tolerance development [29]. In 24 patients with cirrhosis and ascites on stable doses of furosemide and spironolactone, single oral doses of RWJ-351647 (1, 2, and 5 mg) dose-dependently increased urine flow and free water excretion, and decreased urine osmolality, which was significant compared to placebo for the 5 mg dose [30].…”

Section: Rwj-351647mentioning

confidence: 87%

“…Thus, lixivaptan is a selective V 2 R antagonist. In 21 patients with chronic NYHA class II-III CHF, a single dose of lixivaptan (30,75,150, and 250 mg) increased urine output and solute free water excretion compared to placebo. Concurrently, the urinary excretion of AQP-2 decreased, in keeping with a decreased translocation into and increased retrieval of AQP-2 from the luminal membrane of tubular cells in the collecting duct [26].…”

Section: Lixivaptanmentioning

confidence: 93%

See 2 more Smart Citations

Pharmacology of vasopressin antagonists

2008

View full text Add to dashboard Cite

Congestive heart failure (CHF) is characterized by fluid and water retention, which frequently is a therapeutic challenge. Most conventional diuretics act primarily as saluretics, i.e. they inhibit renal tubular electrolyte reabsorption, which due to osmotic pressure promotes excretion of isotonic fluid. Arginine vasopressin (AVP) via the V(1A) receptor vasoconstricts and via the V(2) receptor promotes water reabsorption in the renal collecting duct by inserting aquaporin-2 water channels into the luminal membrane. Novel V(2) receptor antagonists act as powerful aquaretics, i.e. they excrete free water. We review the pharmacology of non-selective V(1A)/V(2) receptor antagonists and selective V(2) receptor antagonists currently in clinical development.

show abstract

Section: Tolvaptan (Opc-41061)mentioning

confidence: 66%

Section: Rwj-351647mentioning

confidence: 87%

Section: Lixivaptanmentioning

confidence: 93%

See 1 more Smart Citation

Pharmacology of vasopressin antagonists

2008

View full text Add to dashboard Cite

show abstract

“…Several V 2 -receptor antagonists have also been evaluated for the treatment of other edematous disorders, including heart failure (lixivaptan and tolvaptan) [17, 18] and cirrhosis (lixivaptan, OPC-31260, and RWJ-351647) [19,20,21]. The V 2 -receptor antagonists may also hold promise in the treatment of polycystic kidney disease; a phase 3 clinical trial is underway to determine the efficacy and safety of tolvaptan in patients with autosomal dominant polycystic kidney disease [22].…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

et al. 2007

View full text Add to dashboard Cite

Background: Most cases of hyponatremia – serum sodium concentration ([Na⁺]) <135 mEq/l (<135 mM) – are associated with an elevated plasma arginine vasopressin level. This study investigated the efficacy and tolerability of intravenous conivaptan (YM087), a vasopressin V_1A/V₂-receptor antagonist, in treating euvolemic and hypervolemic hyponatremia. Methods: Eighty-four hospitalized patients with euvolemic or hypervolemic hyponatremia (serum [Na⁺] 115 to <130 mEq/l) were randomly assigned to receive intravenous placebo or conivaptan administered as a 30-min, 20-mg loading dose followed by a 96-hour infusion of either 40 or 80 mg/day. The primary efficacy measure was change in serum [Na⁺], measured by the baseline-adjusted area under the [Na⁺]-time curve. The secondary measures included time from first dose to a confirmed ≧4 mEq/l serum [Na⁺] increase, total time patients had serum [Na⁺] ≧4 mEq/l higher than baseline, change in serum [Na⁺] from baseline to the end of treatment, and number of patients with a confirmed ≧6 mEq/l increase in serum [Na⁺] or normal [Na⁺] (≧135 mEq/l). Results: Both conivaptan doses increased area under the [Na⁺]-time curve during the 4-day treatment (p < 0.0001 vs. placebo). From baseline to the end of treatment, the least-squares mean ± standard error serum [Na⁺] increase associated with placebo was 0.8 ± 0.8 mEq/l; with conivaptan 40 mg/day, 6.3 ± 0.7 mEq/l; and with conivaptan 80 mg/day, 9.4 ± 0.8 mEq/l. Conivaptan significantly improved all secondary efficacy measures (p < 0.001 vs. placebo, both doses). Conivaptan was generally well tolerated, although infusion-site reactions led to the withdrawal of 1 (3%) and 4 (15%) of patients given conivaptan 40 and 80 mg/day, respectively. Conclusion: Among patients with euvolemic or hypervolemic hyponatremia, 4-day intravenous infusion of conivaptan 40 mg/day significantly increased serum [Na⁺] and was well tolerated.

show abstract

“…73,74 In addition, other studies such as Okita and associates have suggested a dose-dependent improvement in ascites, lower extremity edema and tolerance to diuretics with tolvaptan, but further research is needed to confirm these findings. 60,61,76,79,80 Conivaptan, approved for only 4 days of intravenous use in the hospital, for euvolemic and hypervolemic hyponatremia, 81 has limited data on its safety and efficacy. [82][83][84] In general, conivaptan was well tolerated with the most common adverse reaction being infusion-site reactions.…”

Section: Clinical Associationsmentioning

confidence: 99%

Hyponatremia: Clinical Associations, Prognosis, and Treatment in Cirrhosis

Sharma²,

Saab³

2012

Exp Clin Transplant

View full text Add to dashboard Cite

Hyponatremia has long been associated with worsened clinical outcomes in patients with cirrhosis and those awaiting liver transplant. However, in the last several years, new modalities of therapy, particularly aquaretics known as "vaptans," and comprehensive prognostic models have been increasingly studied in the hopes of bolstering serum sodium levels and altering liver transplant candidate status. To examine the most recent, comprehensive, and pertinent data, a systematic review of both prospective and retrospective studies available on MEDLINE was completed, which provided information detailing clinical associations, treatment, and prognoses seen in those with hyponatremia in cirrhosis. Clinical associations with hyponatremia in cirrhosis including hepatorenal syndrome and hepatic encephalopathy were identified. For hyponatremia in those awaiting liver transplant, tolvaptan is an effective agent in temporarily normalizing serum sodium levels with minimal risk of osmotic demyelination. Prognostic models incorporating serum sodium levels were better able to predict urgency and need for transplant; yet the benefits and posttransplant effects of redefining a liver allocation score have yet to be established. Key words: Hyponatremia, Cirrhosis, Outcomes IntroductionHyponatremia is a common electrolyte disturbance in patients with advanced liver disease. [1][2][3][4] In the setting of cirrhosis, hyponatremia can be classified as either hypovolemic hyponatremia, which occurs in the setting of overtreatment with diuretics or excessive losses from the gastrointestinal tract, or hypervolemic hyponatremia, which results in decreased effective circulating volume from increased arterial from splanchnic vasodilatation leading to excessive secretion of arginine vasopressin. 1,5,6 Hyponatremia can occur both before and after liver transplant. Pretransplant, it is associated with several clinical manifestations of decompensation, 4,7,8 and the degree of hyponatremia may increase the accuracy of the model for end-stage liver disease (MELD) score to predict survival. [8][9][10][11] Treatment of hyponatremia has not been demonstrated to improve survival in patients with advanced liver disease, and rapid correction can lead to life-threatening neurologic complications. 12,13 This systematic review focuses on the prevalence, clinical associations, treatment, and prognosis of hypervolemic hyponatremia in patients with liver disease. An algorithm will be developed to guide management based on best available data. Methods Search strategy and identification of studiesWe searched database MEDLINE for all studies on hyponatremia in the setting of cirrhosis as related to clinical implications, prognosis, and treatment. We used combinations of the key words: "hyponatremia," "sodium," "liver cirrhosis," "prevalence," "incidence," "intensive care units," "hepatorenal syndrome," "ascites," "central pontine myelinolysis," "therapeutics," "prognosis," and "liver Experimental and Clinical Transplantation (2013) 1: 3-11Christine Yu et a...

show abstract

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

Abstract: SUMMARYBackground RWJ-351647 is a selective V 2 receptor antagonist that inhibits vasopressin-induced water reabsorption in the kidney.

Cited by 22 publications

References 12 publications

Pharmacology of vasopressin antagonists

Pharmacology of vasopressin antagonists

Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

Hyponatremia: Clinical Associations, Prognosis, and Treatment in Cirrhosis

Contact Info

Product

Resources

About

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

Abstract: SUMMARYBackground RWJ-351647 is a selective V 2 receptor antagonist that inhibits vasopressin-induced water reabsorption in the kidney.

Cited by 22 publications

References 12 publications

Pharmacology of vasopressin antagonists

Pharmacology of vasopressin antagonists

Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

Hyponatremia: Clinical Associations, Prognosis, and Treatment in Cirrhosis

Contact Info

Product

Resources

About

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