Conivaptan: promise of treatment in heart failure

Conivaptan, the first vasopressin receptor antagonist approved by the FDA, is available for the treatment of hyponatremia in euvolemic and hypervolemic patients. The renin-angiotensin-aldosterone system is activated in heart failure (HF) causing clinical worsening. Arginine vasopressin levels are also elevated in HF. Conivaptan is an effective and FDA approved for the treatment of euvolemic and hypervolemic hyponatremia and may offer an extra treatment option in HF by targeting V_1a and V₂ receptors. In this article we review the physiology, preclinical studies as well as the human clinical studies on the use of conivaptan and its potential and promise in the treatment of HF.     

Intravenous Conivaptan

*Conivaptan is an arginine vasopressin V1A and V2 receptor antagonist. The intravenous formulation is approved in the US for use in the treatment of euvolemic and hypervolemic hyponatremia. Conivaptan produces a dose-dependent electrolyte-sparing aquaresis (solute-free water excretion), increasing serum sodium levels. *In a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial in adults with euvolemic or hypervolemic hyponatremia, the area under the serum sodium concentration-time curve over a 4-day treatment duration (primary endpoint) was significantly greater in intravenous conivaptan 40 mg/day recipients than in placebo recipients. *The total time during treatment that patients had serum sodium levels > or = 4 mEq/L above baseline was significantly longer in intravenous conivaptan than placebo recipients. In conivaptan recipients, an increase in serum sodium levels of > or = 4 mEq/L above baseline was achieved approximately 1 day after the first dose of the drug. *In addition, the mean change from baseline in free water clearance and effective water clearance over the first day of treatment was significantly greater with intravenous conivaptan than with placebo. *Given the nature of the treatment, the tolerability profile for intravenous conivaptan was generally acceptable in patients with hyponatremia. The most common adverse events were injection related (e.g. injection-site phlebitis), hypotension, and pyrexia.     

New Topics in Vasopressin Receptors and Approach to Novel Drugs: Research and Development of Conivaptan Hydrochloride (YM087), a Drug for the Treatment of Hyponatremia

Hyponatremia is the most common electrolyte disorder in hospitalized patients and is associated with the risk of intractable seizures and death. The effectiveness of conventional therapies for hyponatremia is inconsistent, and the rapid correction of plasma sodium levels is thought to result in the occurrence of neurological complications. Arginine vasopressin (AVP) is the primary regulator of renal electrolyte-free water reabsorption via AVP-receptor type 2 (V2-R), and inappropriate or excessive AVP secretion independent of serum osmolality frequently causes excessive water retention, which is the etiological basis of hyponatremia. Therefore, the use of V2-R antagonists as anti-hyponatremic drugs in the clinical setting is anticipated to be reliable and safe. Conivaptan hydrochloride (YM087) is a novel dual AVP–R antagonist for AVP-R types 1a (V1a) and V2-R. In vitro studies have shown that it possesses high affinity for V1a-R and V2-R without any species differences. It also potently inhibited AVP-induced intracellular signaling through human V2 and V1a receptors with no agonistic activity. Conivaptan hydrochloride improved the plasma sodium concentration and plasma osmolality in hyponatremic rats, and its effectiveness was demonstrated in hyponatremic patients. This drug has been approved for use in the United States, which will bring relief to patients with hyponatremia.     

Tolvaptan: a vasopressin antagonist for the management of euvolemic and hypervolemic hyponatremia

Tolvaptan is a new vasopressin antagonist developed for the treatment of hypervolemic or euvolemic hyponatremia. It has greater affinity for the V(2) receptor than native vasopressin or any other vasopressin antagonist. Blockade of the V(2) receptor induces solute-free water excretion without affecting normal electrolyte excretion. The pharmacokinetics and pharmacodynamics of tolvaptan are suitable for once-daily dosing. Throughout all phases of clinical studies, it was shown to be safe for short- and long-term use. Tolvaptan effectively increases serum sodium levels in patients with heart failure, cirrhosis and syndrome of inappropriate secretion of antidiuretic hormone. In patients hospitalized owing to heart failure, tolvaptan decreased bodyweight, increased urine output and improved dyspnea compared with placebo. However, tolvaptan has not proven to be beneficial for the long-term management of heart failure. Currently, tolvaptan is the only oral agent in its class available in the USA and Europe.     

The therapeutic use of vaptans for the treatment of dilutional hyponatremia

Hyponatremia is a very common electrolyte abnormality. Dilutional hyponatremia is very difficult to treat effectively due to the complications of conventional treatment. Arginine-vasopressin (AVP) plays an integral role in circulatory and water homeostasis. AVP is a hormone released in response to increases in plasma tonicity or decreases in plasma volume in an attempt to maintain the plasma osmolality between 284 and 295 mOsm/L. AVP receptor antagonists or "vaptans" are a new class of drugs that allow for the safe and efficacious treatment of dilutional hyponatremia. Conivaptan, a mixed V1a/V2 receptor antagonist, and tolvaptan, a selective V2 receptor antagonist, are the only 2 vaptans approved by the US Food and Drug Administration.     

Therapeutic potential of vasopressin receptor antagonists

Arginine vasopressin (AVP) is a neuropeptide hormone that plays an important role in circulatory and sodium homeostasis, and regulating serum osmolality. Several clinical conditions have been associated with inappropriately elevated levels of AVP including heart failure, cirrhosis of the liver and the syndrome of inappropriate secretion of antidiuretic hormone. Three receptor subtypes that mediate the actions of AVP have been identified (V(1A), V(2) and V(1B)). Activation of V(1A) receptors located in vascular smooth muscle cells and the myocardium results in vasoconstriction and increased afterload and hypertrophy. The V(2) receptors located primarily in the collecting tubules mediate free water absorption. The V(1B) receptors are located in the anterior pituitary and mediate adrenocorticotropin hormone release. The cardiovascular and renal effects of AVP are mediated primarily by V(1A) and V(2) receptors. Antagonism of V(1A) receptors results in vasodilatation and antagonism of V(2) receptors resulting in aquaresis, an electrolyte-sparing water excretion. Several non-peptide AVP antagonists (vasopressin receptor antagonists [VRAs]) also termed 'vaptans' have been developed and are vigorously being studied primarily for treating conditions characterised by hyponatraemia and fluid overload. Conivaptan is a combined V(1A)/V(2)-receptor antagonist that induces diuresis as well as haemodynamic improvement. It has been shown in clinical trials to correct euvolaemic and hypervolaemic hyponatraemia, and has been approved by the US FDA for the treatment of euvolaemic hyponatraemia as an intravenous infusion. Tolvaptan, a selective V(2)-receptor antagonist, has undergone extensive clinical studies in the treatment of hyponatraemia and heart failure. It has been shown to effectively decrease fluid in volume overloaded patients with heart failure and to correct hyponatraemia. A large outcome study (n = 4133 patients) will define its role in the management of heart failure. Lixivaptan and satavaptan (SR-121463) are other selective V(2)-receptor antagonists being evaluated for the treatment of hyponatraemia. In addition, a potential role for the vaptans in attenuating polyuria in nephrogenic diabetes insipidus and cyst development in polycystic kidney disease is being explored. Ongoing clinical trials should further define the scope of the potential therapeutic role of VRAs.     

Development and therapeutic indications of orally-active non-peptide vasopressin receptor antagonists

Vasopressin (AVP) is a cyclic nonapeptide hormone that exhibits many physiological effects including free water reabsorption, vasoconstriction, cellular proliferation and adrenocorticotrophic hormone (ACTH) secretion. In a healthy organism, AVP plays an important role in the homeostasis of fluid osmolality and volume status. However, in several diseases or conditions such as the syndrome of inappropriate secretion of AVP (SIADH), congestive heart failure, arterial hypertension, liver cirrhosis, nephrotic syndrome, dysmenorrhoea and ocular hypertension, AVP may play an important role in their pathophysiology. Recently, orally-active non-peptide AVP receptor antagonists were developed by random screening of chemical entities and optimisation of lead compounds. These include agents specific for the V(1)-vascular and V(2)-renal AVP receptor subtypes. Dual V(1)/V(2) AVP receptor antagonists are also being studied. Some of these non-peptide receptor antagonists have been studied extensively, while others are currently under investigation. Potential therapeutic indications for AVP receptor antagonists comprise: 1) The blockade of V(1)-vascular AVP receptors in arterial hypertension, congestive heart failure, Raynaud's syndrome, peripheral vascular disease and dysmenorrhea. 2) The blockade of V(2)-renal AVP receptors in the syndrome of inappropriate secretion of vasopressin, congestive hart failure, liver cirrhosis, nephrotic syndrome and any state of excessive retention of free water and subsequent dilutional hyponatraemia. 3) The blockade of V(3)-pituitary AVP receptors in ACTH-secreting tumours. This review examines the pharmacology of orally-active non-peptide AVP receptor antagonists and their clinical applications.     

Development and therapeutic indications of orally-active non-peptide vasopressin receptor antagonists

Vasopressin (AVP) is a cyclic nonapeptide hormone that exhibits many physiological effects including free water reabsorption, vasoconstriction, cellular proliferation and adrenocorticotrophic hormone (ACTH) secretion. In a healthy organism, AVP plays an important role in the homeostasis of fluid osmolality and volume status. However, in several diseases or conditions such as the syndrome of inappropriate secretion of AVP (SIADH), congestive heart failure, arterial hypertension, liver cirrhosis, nephrotic syndrome, dysmenorrhoea and ocular hypertension, AVP may play an important role in their pathophysiology. Recently, orally-active non-peptide AVP receptor antagonists were developed by random screening of chemical entities and optimisation of lead compounds. These include agents specific for the V₁-vascular and V₂-renal AVP receptor subtypes. Dual V₁/V₂ AVP receptor antagonists are also being studied. Some of these non-peptide receptor antagonists have been studied extensively, while others are currently under investigation. Potential therapeutic indications for AVP receptor antagonists comprise (1) The blockade of V1-vascular AVP receptors in arterial hypertension, congestive heart failure, Raynaud's syndrome, peripheral vascular disease and dysmenorrhoea. (2) The blockade of V2-renal AVP receptors in the syndrome of inappropriate secretion of vasopressin, congestive heart failure, liver cirrhosis, nephrotic syndrome and any state of excessive retention of free water and subsequent dilutional hyponatraemia. (3) The blockade of V3-pituitary AVP receptors in ACTH-secreting tumours. This review examines the pharmacology of orally-active non-peptide AVP receptor antagonists and their clinical applications.     

Vasopressin-receptor antagonists: a new class of agents for the treatment of hyponatremia

Hyponatremia is a very common electrolyte disorder often caused by the dysregulation of arginine vasopressin (AVP) secretion and the effects of the hormone at its receptors and is associated with significant morbidity and mortality. Recent developments in the understanding of water homeostasis and AVP actions at the kidney, both in normal circumstances and in pathologic conditions, has created the possibility of new therapies that directly target the inappropriate excess of AVP stimulation of vasopressin V(2) receptors (V2Rs) in the kidney. Preclinical and clinical trial results indicate that AVP V2R antagonism is a highly promising and rational approach for the treatment of dilutional hyponatremia caused by excessive retention of water. This review of hyponatremia and its therapy is intended to educate clinicians who manage patients who have hyponatremia and its complications. Background information on hyponatremia is presented and the pertinent published literature with regard to the diagnosis and therapy of this disorder is summarized with a specific focus on AVP-receptor antagonists. Agents that antagonize AVP V2Rs and promote aquaresis, the electrolyte-sparing excretion of free water, are likely to be effective and well tolerated therapies for the treatment of dilutional hyponatremia.     

Conivaptan: potential therapeutic implications in heart failure

Conivaptan, a dual vasopressin receptor antagonist, is a member of an emerging class of medications for the treatment of euvolemic hyponatremia. These agents induce a free-water diuresis as compared to the natriuretic effect of loop diuretics and make them an intriguing prospect for the treatment of congestive heart failure. Article also includes recent patents on this topic.     

Tolvaptan: a vasopressin antagonist for the management of euvolemic and hypervolemic hyponatremia

Tolvaptan is a new vasopressin antagonist developed for the treatment of hypervolemic or euvolemic hyponatremia. It has greater affinity for the V₂ receptor than native vasopressin or any other vasopressin antagonist. Blockade of the V₂ receptor induces solute-free water excretion without affecting normal electrolyte excretion. The pharmacokinetics and pharmacodynamics of tolvaptan are suitable for once-daily dosing. Throughout all phases of clinical studies, it was shown to be safe for short- and long-term use. Tolvaptan effectively increases serum sodium levels in patients with heart failure, cirrhosis and syndrome of inappropriate secretion of antidiuretic hormone. In patients hospitalized owing to heart failure, tolvaptan decreased bodyweight, increased urine output and improved dyspnea compared with placebo. However, tolvaptan has not proven to be beneficial for the long-term management of heart failure. Currently, tolvaptan is the only oral agent in its class available in the USA and Europe.     

Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure,liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Arginine vasopressin (AVP) is the major physiological regulator of renal water excretion and blood volume. The AVP pathways of V_1aR-mediated vasoconstriction and V₂R-induced water retention represent a potentially attractive target of therapy for edematous diseases. Experimental and clinical evidence suggests beneficial effects of AVP receptor antagonists by increasing free water excretion and serum sodium levels. This review provides an update on the therapeutic implication of newly developed AVP receptor antagonists in respective disorders, such as chronic heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion.     

The potential role for lixivaptan in heart failure and in hyponatremia

INTRODUCTION: Hypervolemia and hyponatremia are common features in heart failure and have been associated with increased morbidity and mortality. Stimulation of arginine vasopressin (AVP) plays an important role in the development of both hypervolemia and hyponatremia. Lixivaptan is a selective vasopressin type 2 (V(2)) receptor antagonist that has been demonstrated to have the ability to induce aquaresis, the electrolyte sparing excretion of water, resulting in fluid removal as well as correction of hyponatremia. AREAS COVERED: This article describes the prevalence, pathophysiology and current treatment limitations of hyponatremia, highlights the importance of arginine vasopressin and the potential role of arginine vasopressin antagonists and reviews all available literature on lixivaptan, a selective V(2) receptor antagonist. EXPERT OPINION: The available experience of lixivaptan in heart failure, although limited, is encouraging. Its aquaretic effect provides the basis for its use to correct hypervolemia and hyponatremia in patients with heart failure, and the absence of neurhormonal stimulation provides positive signal for the exploration of its potential in improving outcomes.     

Vasopressin receptor antagonists in heart failure

Vasopressin receptor antagonists are a new class of drugs that address the problems of fluid retention, hyponatremia, and renal dysfunction in heart failure. Elevated vasopressin levels in heart failure cause myocardial fibrosis, hypertrophy and vasoconstriction by activating the V1a receptors, as well as water retention and hyponatremia by activating V2 receptors. Antagonism of V1a receptors alone is of little benefit. In contrast, antagonism of V2 receptors results in increased free water excretion and increased sodium concentration. Vasopressin receptor antagonists may be viewed as the first new class of agents with predominantly aquaretic effects, in contrast to the natriuretic effects of loop diuretics. The predominant action of vasopressin receptor antagonists is water excretion, without depletion of other electrolytes, and less neurohormonal stimulation compared with loop diuretics. Classified as neurohormonal antagonists, vasopressin receptor antagonists acutely may improve congestion and hyponatremia, while chronically preventing progression of left ventricular dysfunction. Several compounds have been evaluated in late-stage clinical trial programs, and at least one may be used as an adjunct to standard medical therapy, combining aquaresis for congestion with neurohormonal antagonism for morbidity and mortality. We reviewed recent patents dealing with heart failure, hyponatremia, anti-diuretic hormone, and vasopressin antagonists.     

Development and therapeutic indications of orally-active non-peptide vasopressin receptor antagonists

Vasopressin (AVP) and oxytocin (OT) are cyclic nonapeptides whose actions are mediated by the stimulation of specific G-protein-coupled receptors (GPCRs) currently classified into V(1)-vascular (V(1)R), V(2)-renal (V(2)R) and V(3)-pituitary (V(3)R) AVP receptors and OT receptors (OTR). The signal transduction pathways coupled to the different subtypes of AVP/OT receptors are reviewed. The recent cloning of the different members of the AVP/OT family of receptors now allows the extensive characterisation of the molecular determinants involved in agonist and antagonist binding, as well as signal transduction coupling. Potential therapeutic uses of AVP receptor antagonists include: the blockade of V(1)-vascular AVP receptors in arterial hypertension, congestive heart failure (CHF) and peripheral vascular diseases; the blockade of V(2)-renal AVP receptors in the syndrome of inappropriate vasopressin secretion, CHF, liver cirrhosis, nephrotic syndrome and any state of excessive retention of free water and subsequent hyponatraemia; the blockade of V(3)-pituitary AVP receptors in adrenocorticotropin (ACTH)-secreting tumours. The pharmacological and clinical profile of orally-active non-peptide AVP receptor antagonists is reviewed.     

Effect of conivaptan, a combined vasopressin V(1a) and V(2) receptor antagonist, on vasopressin-induced cardiac and haemodynamic changes in anaesthetised dogs.

The neurohormonal factor arginine vasopressin (AVP) produces potent systemic vasoconstriction as well as water retention in the kidneys via the V(1a) and V(2) receptors, respectively. Therefore, AVP may be considered as an aggravating factor of cardiac failure. In the present study, the effects of intravenous (i.v.) infusion of AVP on cardiovascular parameters and the effect of conivaptan (YM087, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a vasopressin V(1a)/V(2) receptor antagonist, on AVP-induced cardiac and haemodynamic changes were investigated in pentobarbitone-anaesthetised dogs. The i.v. infusion of AVP (0.12-4mUkg(-1)min(-1)) dose-dependently produced decreases in the cardiac contractility indicator LV dP/dt(max) and cardiac output (CO) and increases in left ventricular end-diastolic pressure (LVEDP) and total peripheral resistance (TPR). These changes accurately mimic the cardiovascular symptoms of congestive heart failure. The i.v. bolus injection of conivaptan (0.1mgkg(-1)) rapidly attenuated the AVP (4mUkg(-1)min(-1))-induced decrease in CO and reversed the AVP-induced elevation in both LVEDP and TPR. In conclusion, i.v. infusion of AVP produced cardiac dysfunction and vasoconstriction in pentobarbitone-anaesthetised dogs. Conivaptan demonstrated the ability to dramatically improve the impaired cardiovascular parameters induced by AVP. The results suggest the potential usefulness of conivaptan in treating congestive heart failure.     

New agents for managing hyponatremia in hospitalized patients.

PURPOSE: An overview of hyponatremia is provided, including its pathophysiology, clinical manifestations, signs and symptoms, and treatment, particularly with arginine vasopressin (AVP)-receptor antagonists. SUMMARY: Hyponatremia (generally defined as a serum sodium concentration of <135 meq/L) is one of the most common electrolyte disorders in hospitalized and clinic patients. It may be caused by a number of conditions, including infections, heart disease, surgery, malignancy, and medication use. Clinical signs and symptoms such as hallucinations, lethargy, weakness, bradycardia, respiratory depression, seizures, coma, and death have been reported. Conventional treatment consists of fluid restriction and administration of hypertonic saline and pharmacologic agents, such as demeclocycline, lithium carbonate, and urea. These treatment options are often of limited effectiveness or difficult for patients to tolerate. AVP promotes the reabsorption of water in the renal collecting ducts by activation of V(2) receptors, resulting in water retention and dilution of serum solutes. The AVP-receptor antagonists, conivaptan, lixivaptan, and tolvaptan, are being studied for the treatment of hyponatremia. Conivaptan has been shown in clinical trials to increase free-water excretion and safely normalize serum sodium concentrations in patients with hyponatremia and is well tolerated. Also in clinical trials, lixivaptan and tolvaptan have safely improved serum sodium concentrations in patients with hyponatremia. CONCLUSION: Hyponatremia is a serious health condition for which treatment should be carefully performed. As new agents for treating hyponatremia, AVP-receptor antagonists have demonstrated efficacy and safety in clinical trials and may serve as significant improvements in the current treatment options for managing this disorder.     

Recent advances in the treatment of hyponatremia

Hyponatremia is a common and potentially serious electrolyte disorder, most often caused by excessive arginine vasopressin (AVP) secretion. Conventional management of hyponatremia is based on graded steps starting from water restriction in mild cases to administration of saline in symptomatic cases, which may not be effective. A major new approach in the treatment of hyponatremia is the development of AVP receptor antagonists that directly inhibit the effect of increased AVP which results in the excretion of electrolyte free water. This review summarizes pathophysiology, conventional treatment and future directions in the treatment of hyponatremia.     

Recent advances in the treatment of hyponatremia

Hyponatremia is a common and potentially serious electrolyte disorder, most often caused by excessive arginine vasopressin (AVP) secretion. Conventional management of hyponatremia is based on graded steps starting from water restriction in mild cases to administration of saline in symptomatic cases, which may not be effective. A major new approach in the treatment of hyponatremia is the development of AVP receptor antagonists that directly inhibit the effect of increased AVP which results in the excretion of electrolyte free water. This review summarizes pathophysiology, conventional treatment and future directions in the treatment of hyponatremia.     

Lixivaptan: a novel vasopressin receptor antagonist

Arginine vasopressin, also known as antidiuretic hormone, is a neuropeptide that functions in the maintenance of body water homeostasis. Inappropriate secretion of vasopressin has been implicated in the pathophysiology of multiple diseases, including polycystic kidney disease, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and the hyponatremia commonly associated with cirrhosis and congestive heart failure. Vasopressin receptor antagonists are novel agents that block the physiologic actions of vasopressin. Lixivaptan is a vasopressin receptor antagonist with high V2 receptor affinity and is now undergoing Phase III clinical trials. Studies so far have demonstrated that lixivaptan is efficacious in the correction of hyponatremia in SIADH, heart failure and liver cirrhosis with ascites, and few adverse effects have been noted. Thus, lixivaptan remains a promising therapeutic modality for the treatment of multiple diseases and prevention of the associated morbidity and mortality associated with hyponatremia.