Vasopressin Antagonists — Progress and Promise
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《新英格兰医药杂志》
Hyponatremia is the most common in-hospital electrolyte disorder that a physician encounters. Its management has been the subject of numerous studies and reviews. In patients with chronic heart failure or cirrhosis, water retention, mediated by the vasopressin V2 receptor in the renal collecting tubule, is an initially positive defense against a decrease in cardiac output or the dilated splanchnic circulation in cirrhosis.1 The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is, of course, another matter. Water retention in SIADH serves no physiologic purpose, and hyponatremia may be serious enough to require emergency measures.
Until now, the management of hyponatremia has centered on a series of graded steps, starting with water deprivation in the mildest cases and extending to the careful administration of saline in symptomatic patients.2 Management is not always easy, especially in the patient with chronic heart failure or marked hyponatremia, for whom pontine and extrapontine myelinolysis are potential hazards if correction occurs too rapidly.
For many years, there has been interest in developing vasopressin V2-receptor antagonists as therapeutic agents that would allow the physician to deal more directly and safely with the problem of hyponatremia. There has also been a growing understanding that the V2 receptor may not be the only important player in hyponatremia. Others include the V1A receptor, involved in the pressor actions of the hormone, and the V1B receptor, involved in vasopressin-stimulated secretion of adrenocorticotropin, and other less well characterized receptors.3,4 Activation of the V1A receptor is especially important in the treatment of patients with euvolemic and hypervolemic hyponatremia, who have high, sustained plasma levels of vasopressin. Indeed, vasopressin received its name from the early observation that it is a powerful pressor of the peripheral circulation and, as has been shown in studies in dogs, a constrictor of the coronary arterial bed.5 Evidence from studies in animals suggests that vasopressin has direct effects on the heart, increasing calcium levels in the cultured myocyte6 and producing myocyte hypertophy in the isolated perfused rat heart.7 Vasopressin may also potentiate the synthesis of endothelin and contribute to the effects of angiotensin II, as discussed by Udelson et al.8 The role of the V1A receptors in the treatment of patients with cardiovascular disease has recently been reviewed by Goldsmith.9
These V1A-mediated actions increase in importance in view of the fact that in patients with heart failure, systemic vasopressin levels may rise early in the course of the disease, before hyponatremia develops.10,11 All these considerations have encouraged the design and trial of vasopressin-receptor antagonists, which may permit the physician to intervene early to block the adverse effects of the hormone.
The design and evaluation of receptor antagonists have a long and painful history. Peptide antagonists of the V2 receptor were the first compounds tried; although effective in animal models, these compounds were ineffective or actually proved to be agonists in humans. More recently, with the help of high-throughput technology, nonpeptide-receptor antagonists have been generated and shown to be effective in humans. Several are under investigation in clinical trials. Tolvaptan, a V2-receptor antagonist, and conivaptan (Vaprisol, Astellas), a combined V1/V2-receptor antagonist, are, respectively, in phase 3 clinical trials and approved for parenteral use in the United States. Both tolvaptan and conivaptan are benzazepine derivatives (Figure 1).
Figure 1. Structure of the Oral Vasopressin-Receptor Antagonists Conivaptan and Tolvaptan.
In this issue of the Journal, Schrier et al. report the results of two multicenter, randomized, placebo-controlled, double-blind trials of oral tolvaptan involving subjects with hyponatremia.12 The subjects had chronic heart failure, cirrhosis, SIADH, or hyponatremia from other causes, with a severity ranging from mild to marked. This report, combining the results of two trials in the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2), is one of a recent series of reports on the efficacy of V2 antagonists in the treatment of hyponatremia discussed by Schrier et al.12 The current report presents results for a 30-day period in which many of the subjects (number not given) were treated in an outpatient, rather than an in-hospital, setting and includes a self-administered assessment of the subjects' physical and mental well-being. This report confirms earlier studies in showing that tolvaptan significantly and rapidly increased serum sodium concentrations and urine output above those in control subjects receiving placebo. Furthermore, the increase was sustained over the 30 days of each of the two trials and fell during the week after discontinuation of the drug. Tolvaptan was started at a dose of 15 mg per day and the dose was increased during the next 4 days to 30 mg per day, then to 60 mg per day, in accordance with the study protocol that an increased dose be administered to subjects whose serum sodium concentration remained less than 135 mmol per liter and had increased less than 5 mmol per liter during the prior 24 hours after receipt of the initial dose. In 4 of the 223 subjects assigned to tolvaptan, the predefined potentially clinically important serum sodium concentration of 146 mmol per liter was exceeded during the first 24 hours after the initial treatment; data are not provided on excessive serum sodium concentrations during the full study period. The dose was reduced or discontinued for a day or the fluid intake was increased if the serum sodium reached unacceptably high concentrations. Side effects included thirst and dry mouth; more serious adverse events occurring in eight subjects assigned to tolvaptan included hypotension, dizziness, and syncope. Adverse events occurred in the control group as well, often reflecting underlying disease; these included cardiac failure, hepatic encephalopathy, acute dyspnea, and edema. The number of deaths was similar in the combined tolvaptan and placebo groups. In scores on the self-administered questionnaire, subjects with marked hyponatremia who received tolvaptan showed improvement in some cognitive domains of the mental component, including overall well-being and ability to concentrate, but scores on the physical component showed no significant differences between the two groups.
The study is encouraging in terms of the efficacy of tolvaptan as a V2-receptor antagonist and its use, at least during a limited period, in the outpatient setting. At the same time, it is clear that careful oversight of the use of this agent is required, not only by means of frequent clinic visits and measurement of serum sodium, but also through daily measurement of body weight by patients. An important question is the extent to which added benefits might be realized if the V1A-mediated actions of vasopressin were brought under control with the use of combined V1A/V2-receptor antagonists.9 This question remains to be answered in future studies of this promising new generation of receptor antagonists.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
This article was published at www.nejm.org on November 14, 2006.
References
Schrier RW. Water and sodium retention in edematous disorders: role of vasopressin and aldosterone. Am J Med 2006;119:Suppl 1:S47-S53.
Janicic N, Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am 2003;32:459-481.
Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006;69:2124-2130.
Streefkerk JO, van Zwieten PA. Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents. Auton Autacoid Pharmacol 2006;26:141-148.
Maturi MF, Martin SE, Markle D, et al. Coronary vasoconstriction induced by vasopressin: production of myocardial ischemia in dogs by constriction of nondiseased small vessels. Circulation 1991;83:2111-2121.
Xu YJ, Gopalakrishnan V. Vasopressin increases cytosolic free in the neonatal rat cardiomyocyte: evidence for V1 subtype receptors. Circ Res 1991;69:239-245.
Fukuzawa J, Haneda T, Kikuchi K. Arginine vasopressin increases the rate of protein synthesis in isolated perfused adult rat heart via the V1 receptor. Mol Cell Biochem 1999;195:93-98.
Udelson JE, Smith WB, Hendrix GH, et al. Acute hemodynamic effects of conivaptan, a dual V(1a) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001;104:2417-2423.
Goldsmith SR. Is there a cardiovascular rationale for the use of combined vasopressin V1a/V2 receptor antagonists? Am J Med 2006;119:Suppl 1:S93-S96.
Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724-1729.
Nakamura T, Funayama H, Yoshimura A, et al. Possible vascular role of increased plasma arginine vasopressin in congestive heart failure. Int J Cardiol 2006;106:191-195.
Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099-2112.(Richard M. Hays, M.D.)
Until now, the management of hyponatremia has centered on a series of graded steps, starting with water deprivation in the mildest cases and extending to the careful administration of saline in symptomatic patients.2 Management is not always easy, especially in the patient with chronic heart failure or marked hyponatremia, for whom pontine and extrapontine myelinolysis are potential hazards if correction occurs too rapidly.
For many years, there has been interest in developing vasopressin V2-receptor antagonists as therapeutic agents that would allow the physician to deal more directly and safely with the problem of hyponatremia. There has also been a growing understanding that the V2 receptor may not be the only important player in hyponatremia. Others include the V1A receptor, involved in the pressor actions of the hormone, and the V1B receptor, involved in vasopressin-stimulated secretion of adrenocorticotropin, and other less well characterized receptors.3,4 Activation of the V1A receptor is especially important in the treatment of patients with euvolemic and hypervolemic hyponatremia, who have high, sustained plasma levels of vasopressin. Indeed, vasopressin received its name from the early observation that it is a powerful pressor of the peripheral circulation and, as has been shown in studies in dogs, a constrictor of the coronary arterial bed.5 Evidence from studies in animals suggests that vasopressin has direct effects on the heart, increasing calcium levels in the cultured myocyte6 and producing myocyte hypertophy in the isolated perfused rat heart.7 Vasopressin may also potentiate the synthesis of endothelin and contribute to the effects of angiotensin II, as discussed by Udelson et al.8 The role of the V1A receptors in the treatment of patients with cardiovascular disease has recently been reviewed by Goldsmith.9
These V1A-mediated actions increase in importance in view of the fact that in patients with heart failure, systemic vasopressin levels may rise early in the course of the disease, before hyponatremia develops.10,11 All these considerations have encouraged the design and trial of vasopressin-receptor antagonists, which may permit the physician to intervene early to block the adverse effects of the hormone.
The design and evaluation of receptor antagonists have a long and painful history. Peptide antagonists of the V2 receptor were the first compounds tried; although effective in animal models, these compounds were ineffective or actually proved to be agonists in humans. More recently, with the help of high-throughput technology, nonpeptide-receptor antagonists have been generated and shown to be effective in humans. Several are under investigation in clinical trials. Tolvaptan, a V2-receptor antagonist, and conivaptan (Vaprisol, Astellas), a combined V1/V2-receptor antagonist, are, respectively, in phase 3 clinical trials and approved for parenteral use in the United States. Both tolvaptan and conivaptan are benzazepine derivatives (Figure 1).
Figure 1. Structure of the Oral Vasopressin-Receptor Antagonists Conivaptan and Tolvaptan.
In this issue of the Journal, Schrier et al. report the results of two multicenter, randomized, placebo-controlled, double-blind trials of oral tolvaptan involving subjects with hyponatremia.12 The subjects had chronic heart failure, cirrhosis, SIADH, or hyponatremia from other causes, with a severity ranging from mild to marked. This report, combining the results of two trials in the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2), is one of a recent series of reports on the efficacy of V2 antagonists in the treatment of hyponatremia discussed by Schrier et al.12 The current report presents results for a 30-day period in which many of the subjects (number not given) were treated in an outpatient, rather than an in-hospital, setting and includes a self-administered assessment of the subjects' physical and mental well-being. This report confirms earlier studies in showing that tolvaptan significantly and rapidly increased serum sodium concentrations and urine output above those in control subjects receiving placebo. Furthermore, the increase was sustained over the 30 days of each of the two trials and fell during the week after discontinuation of the drug. Tolvaptan was started at a dose of 15 mg per day and the dose was increased during the next 4 days to 30 mg per day, then to 60 mg per day, in accordance with the study protocol that an increased dose be administered to subjects whose serum sodium concentration remained less than 135 mmol per liter and had increased less than 5 mmol per liter during the prior 24 hours after receipt of the initial dose. In 4 of the 223 subjects assigned to tolvaptan, the predefined potentially clinically important serum sodium concentration of 146 mmol per liter was exceeded during the first 24 hours after the initial treatment; data are not provided on excessive serum sodium concentrations during the full study period. The dose was reduced or discontinued for a day or the fluid intake was increased if the serum sodium reached unacceptably high concentrations. Side effects included thirst and dry mouth; more serious adverse events occurring in eight subjects assigned to tolvaptan included hypotension, dizziness, and syncope. Adverse events occurred in the control group as well, often reflecting underlying disease; these included cardiac failure, hepatic encephalopathy, acute dyspnea, and edema. The number of deaths was similar in the combined tolvaptan and placebo groups. In scores on the self-administered questionnaire, subjects with marked hyponatremia who received tolvaptan showed improvement in some cognitive domains of the mental component, including overall well-being and ability to concentrate, but scores on the physical component showed no significant differences between the two groups.
The study is encouraging in terms of the efficacy of tolvaptan as a V2-receptor antagonist and its use, at least during a limited period, in the outpatient setting. At the same time, it is clear that careful oversight of the use of this agent is required, not only by means of frequent clinic visits and measurement of serum sodium, but also through daily measurement of body weight by patients. An important question is the extent to which added benefits might be realized if the V1A-mediated actions of vasopressin were brought under control with the use of combined V1A/V2-receptor antagonists.9 This question remains to be answered in future studies of this promising new generation of receptor antagonists.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
This article was published at www.nejm.org on November 14, 2006.
References
Schrier RW. Water and sodium retention in edematous disorders: role of vasopressin and aldosterone. Am J Med 2006;119:Suppl 1:S47-S53.
Janicic N, Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am 2003;32:459-481.
Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006;69:2124-2130.
Streefkerk JO, van Zwieten PA. Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents. Auton Autacoid Pharmacol 2006;26:141-148.
Maturi MF, Martin SE, Markle D, et al. Coronary vasoconstriction induced by vasopressin: production of myocardial ischemia in dogs by constriction of nondiseased small vessels. Circulation 1991;83:2111-2121.
Xu YJ, Gopalakrishnan V. Vasopressin increases cytosolic free in the neonatal rat cardiomyocyte: evidence for V1 subtype receptors. Circ Res 1991;69:239-245.
Fukuzawa J, Haneda T, Kikuchi K. Arginine vasopressin increases the rate of protein synthesis in isolated perfused adult rat heart via the V1 receptor. Mol Cell Biochem 1999;195:93-98.
Udelson JE, Smith WB, Hendrix GH, et al. Acute hemodynamic effects of conivaptan, a dual V(1a) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001;104:2417-2423.
Goldsmith SR. Is there a cardiovascular rationale for the use of combined vasopressin V1a/V2 receptor antagonists? Am J Med 2006;119:Suppl 1:S93-S96.
Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724-1729.
Nakamura T, Funayama H, Yoshimura A, et al. Possible vascular role of increased plasma arginine vasopressin in congestive heart failure. Int J Cardiol 2006;106:191-195.
Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099-2112.(Richard M. Hays, M.D.)