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      Vasopressin Antagonists: Role in the Management of Hyponatremia

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          Hyponatremia is a common electrolyte disorder associated with potentially serious or life-threatening consequences. Serum osmolality and sodium concentration [Na<sup>+</sup>] are regulated by thirst, the hormone arginine vasopressin (AVP), and renal water and sodium handling. Hyponatremia is frequently caused by dysregulation of AVP, which accompanies disorders of water retention, such as congestive heart failure (CHF) and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Clinical trials with AVP receptor antagonists have confirmed the important role of AVP in the pathophysiology of hyponatremia and suggest these agents are efficacious in treating hyponatremia associated with SIADH, cirrhosis, and CHF. Acting directly at AVP receptors in the renal tubules, these agents promote aquaresis – the electrolyte-sparing excretion of free water – in patients with hyponatremia. In clinical trials, AVP receptor antagonists have been shown to increase the serum [Na<sup>+</sup>] and urine output while decreasing urine osmolality.

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          Most cited references 40

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          Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial.

          Nearly 1 million hospitalizations for chronic heart failure occur yearly in the United States, with most related to worsening systemic congestion. Diuretic use, the mainstay therapy for congestion, is associated with electrolyte abnormalities and worsening renal function. In contrast to diuretics, the vasopressin antagonist tolvaptan may increase net volume loss in heart failure without adversely affecting electrolytes and renal function. To evaluate the short- and intermediate-term effects of tolvaptan in patients hospitalized with heart failure. Randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 trial conducted at 45 centers in the United States and Argentina and enrolling 319 patients with left ventricular ejection fraction of less than 40% and hospitalized for heart failure with persistent signs and symptoms of systemic congestion despite standard therapy. After admission, patients were randomized to receive 30, 60, or 90 mg/d of oral tolvaptan or placebo in addition to standard therapy, including diuretics. The study drug was continued for up to 60 days. In-hospital outcome was change in body weight at 24 hours after randomization; outpatient outcome was worsening heart failure (defined as death, hospitalization, or unscheduled visits for heart failure) at 60 days after randomization. Median (interquartile range) body weight at 24 hours after randomization decreased by -1.80 (-3.85 to -0.50), -2.10 (-3.10 to -0.85), -2.05 (-2.80 to -0.60), and -0.60 (-1.60 to 0.00) kg in the groups receiving tolvaptan 30, 60, and 90 mg/d, and placebo, respectively (P< or =.008 for all tolvaptan groups vs placebo). 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. There were no differences in worsening heart failure at 60 days between the tolvaptan and placebo groups (P =.88 for trend). In post hoc analysis, 60-day mortality was lower in tolvaptan-treated patients with renal dysfunction or severe systemic congestion. Tolvaptan administered in addition to standard therapy may hold promise for management of systemic congestion in patients hospitalized for heart failure.
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            The syndrome of inappropriate secretion of antidiuretic hormone.

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              Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial.

              In this study, we evaluated the effects of tolvaptan (OPC-41061), a novel, oral, nonpeptide vasopressin V2-receptor antagonist in patients with chronic heart failure (CHF). This was a double-blind study investigating the effects of three doses of tolvaptan and placebo in patients with CHF. After a run-in period, 254 patients were randomly assigned to placebo (n=63) or tolvaptan [30 mg (n=64), 45 mg (n=64), or 60 mg (n=63)] once daily for 25 days. Patients were not fluid-restricted and were maintained on stable doses of furosemide. At day 1, when compared with baseline, a decrease in body weight of -0.79+/-0.99, -0.96+/-0.93, and -0.84+/-0.02 kg was observed in the 30-, 45-, and 60-mg tolvaptan groups, respectively, and a body weight increase of +0.32+/-0.46 kg in the placebo group (P<0.001 for all treatment groups versus placebo). Although the initial decrease in body weight was maintained during the study, no further reduction was observed beyond the first day. An increase in urine volume was observed with tolvaptan when compared with placebo (3.9+/-0.6, 4.2+/-0.9, 4.6+/-0.4, and 2.3+/-0.2 L/24 hours at day 1 for 30-, 45-, and 60-mg tolvaptan groups, and placebo, respectively; P<0.001). A decrease in edema and a normalization of serum sodium in patients with hyponatremia were observed in the tolvaptan group but not in the placebo group. No significant changes in heart rate, blood pressure, serum potassium, or renal function were observed. In patients with CHF, tolvaptan was well tolerated; it reduced body weight and edema and normalized serum sodium in the hyponatremic patients.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                September 2006
                15 September 2006
                : 26
                : 4
                : 348-355
                Department of Medicine, Queen’s University, Kingston, Canada
                94539 Am J Nephrol 2006;26:348–355
                © 2006 S. Karger AG, Basel

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                Figures: 2, Tables: 1, References: 56, Pages: 8
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