Disease relevance of Tolvaptan

• These results support the importance of cAMP in the pathogenesis of polycystic kidney disease, confirm the effectiveness of a VPV2 antagonist to be used in clinical trials for this disease, and suggest that OPC-31260 and OPC-41061 inhibit Ras/mitogen-activated protein kinase signaling in polycystic kidneys [1].
• Thus, in animal models, analogous to the hyponatremia forms seen in humans, tolvaptan presents exciting therapeutic implications in the management of patients with severe hyponatremia [2].
• CONCLUSION: Tolvaptan has been shown to reduce body weight in patients with worsening heart failure without inducing renal dysfunction or causing hypokalemia [3].
• Data from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial, which randomized 319 patients hospitalized for HF to receive placebo or tolvaptan, were retrospectively analyzed [4].
• Edema at day 7 or discharge improved significantly with tolvaptan in trial B (P = .02) but did not reach significance in trial A (P = .07) [5].
• Hyponatremia recurred in tolvaptan-treated patients after discontinuation [6].

Psychiatry related information on Tolvaptan

• Experiments were designed to demonstrate the efficacy of tolvaptan reducing mortality in an acute model, and controlling the extent of serum sodium elevation without causing abnormal animal behavior suggesting neurological symptoms in a chronic model [2].

High impact information on Tolvaptan

• Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat [1].
• PCK kidneys have increased Ras-GTP and phosphorylated ERK levels and 95-kD/68-kD B-Raf ratios, changes that are corrected by the administration of OPC-31260 or OPC-41061 [1].
• Renal and neurohumoral effects of tolvaptan and furosemide were assessed in an open-label, randomized, placebo-controlled crossover study in 14 patients with NYHA II-III CHF [7].
• OPC-41061 inhibited cAMP production induced by AVP with no intrinsic agonist activity [8].
• In rats, OPC-41061 inhibited [3H]-AVP binding to V1a-receptors (Ki = 325 +/- 41 nM) and V2-receptors (Ki = 1.33 +/- 0. 30 nM), showing higher receptor selectivity (V1a/V2 = 244) than with human receptors [8].

Chemical compound and disease context of Tolvaptan

• Vasopressin v(2) receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia [9].

Biological context of Tolvaptan

• This review discusses the evidence for the potential uses of tolvaptan, and its pharmacology and pharmacokinetics, particularly in congestive heart failure [10].
• The decrease in body weight with tolvaptan was not associated with changes in heart rate or blood pressure, nor did it result in hypokalemia or worsening renal function [11].

Associations of Tolvaptan with other chemical compounds

• Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) [3].
• Although tolvaptan and lixivaptan are selective for the vasopressin-2 (V(2)) receptor responsible for the antidiuretic actions of AVP, conivaptan demonstrates activity at both the V(2) receptor and the V(1a) receptor responsible for the vasoconstricting properties of AVP [12].

Gene context of Tolvaptan

• OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats [8].
• The AVP-receptor antagonists, conivaptan, lixivaptan, and tolvaptan, are being studied for the treatment of hyponatremia [13].
• Tolvaptan is primarily metabolized via CYP3A4 [14].

Analytical, diagnostic and therapeutic context of Tolvaptan

• However, rats treated with repeated oral administrations of tolvaptan (1, 3, and 10 mg/kg) produced dose-dependent aquaresis (i.e. urine volume increased and urine osmolality decreased) that resulted in a gradual increase in plasma sodium concentration [2].
• Rats receiving dose titrations of tolvaptan (0.25, 0.5, 1, 2, 4, and 8 mg/kg) increased plasma sodium to healthy levels without causing abnormal animal behavior suggesting neurological symptoms or death, improved hyponatremia-driven increases in wet weight and water content in the organs [2].
• By November 2003, tolvaptan was undergoing phase III clinical trials [15].
• The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55) [16].
• METHODS AND RESULTS: This was a double-blind study investigating the effects of three doses of tolvaptan and placebo in patients with CHF [17].

References