Lixivaptan, a non-peptide vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia

Lixivaptan (VPA-985), being developed by Biogen Idec and Cardiokine, under license from Wyeth (now part of Pfizer), is a non-peptide, selective vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia associated with heart failure. Arginine vasopressin, the native V2 receptor ligand, stimulates water reabsorption via activation of V2 receptors that are expressed in the collecting ducts of the kidney. In preclinical studies, lixivaptan displayed competitive antagonist activity at V2 receptors in vitro, and increased urine volume and decreased urine osmolality in rats and dogs. The therapeutic benefits of lixivaptan are being evaluated in patients with conditions that are associated with water excess and hyponatremia. Phase II clinical trials in patients with congestive heart failure, liver cirrhosis with ascites or syndrome of inappropriate antidiuretic hormone have demonstrated that, unlike traditional diuretics, lixivaptan increases water clearance without affecting renal sodium excretion or activating the neurohormonal system. Administration of lixivaptan in combination with the diuretic furosemide has been tested in rats as well as in trials in healthy volunteers, in which the two agents were well tolerated. Ongoing phase III trials will determine the role of lixivaptan in the management of hyponatremia, especially when associated with heart failure.     

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.     

Hyponatremia: an update on current pharmacotherapy

Introduction: Hyponatremia is the most common electrolyte disorder in clinical practice, and it is associated with adverse outcomes. Severe hyponatremia can result in cerebral edema and hypoxia. Moreover, even mild hyponatremia can lead to gait instability and cognitive dysfunction, especially in the elderly. The main cause of hyponatremia is nonosmotic secretion of arginine vasopressin with resultant electrolyte-free water retention. Thus, the available management for chronic hyponatremia must increase solute-free water excretion, such as occurs with blocking vasopressin receptors with selective V2 antagonists.

Areas covered: Several recent trials have assessed the efficacy and safety of hyponatremia treatment using vasopressin receptor antagonists (vaptans). These trials documented the efficacy of vaptans to reverse hyponatremia. Moreover, treatment of hypervolemic hyponatremia, such as in heart failure or liver cirrhosis, with vasopressin receptor antagonist results in increased solute-free excretion without activation of the neurohumoral systems. The current review covers results on management of hyponatremia with different vasopressin receptor antagonists.

Expert opinion: Approaches, such as vasopressin receptor antagonists or urea, have been shown to reverse moderate hyponatremia. However, these agents have not been used to treat severe hyponatremia in clinical trials. Future studies in severe hyponatremic states are required to assess the impact of vaptans on clinically significant end points, such as morbidity and mortality.     

Tolvaptan: a selective vasopressin type 2 receptor antagonist in congestive heart failure

The neurohormone arginine vasopressin plays a significant role in the regulation of volume homeostasis, which is mediated via vasopressin type 2 (V2) receptors in the collecting tubules of the kidney. Diseases that are accompanied by abnormal volume homeostasis, including congestive heart failure and cirrhosis, are a frequent cause of hospital admissions and increasing healthcare costs. Recently, several nonpeptide V2 receptor antagonists have emerged as promising agents in the management of these conditions with the advantage of having no electrolyte abnormalities, neurohormonal activation or worsening renal insufficiency. Tolvaptan, a highly selective nonpeptide V2 receptor antagonist, has demonstrated an improvement in the volume status, osmotic balance and haemodynamic profile in preclinical and Phase II trials in patients with congestive heart failure and is currently undergoing testing in Phase III trials. This review discusses the evidence for the potential uses of tolvaptan, and its pharmacology and pharmacokinetics, particularly in congestive heart failure.     

伴有低钠血症的心力衰竭的治疗进展

心力衰竭时的低钠血症是一种高容量性稀释性低钠血症,其发生机制与心输出量减少,使血管升压素分泌增加,使肾小管对水的重吸收增加所致。常规治疗方法疗效不佳。血管升压素受体拮抗药是伴有低钠血症的心力衰竭治疗的最有效方法。     

Treatment of hyponatremia: the role of lixivaptan

Hyponatremia is the most common electrolyte disorder and is associated with serious neurologic sequelae and increased mortality. Conventional treatment options for hyponatremia, such as fluid restriction, hypertonic saline, loop diuretics, demeclocycline or urea, are ineffective in the long-term. The present review considers the role of vasopressin receptor inhibitors (vaptans), focusing on lixivaptan, in the treatment of patients with euvolemic or hypervolemic hyponatremia. Lixivaptan is an oral selective V2 receptor inhibitor, which produces a significantly greater increase of serum sodium levels compared with placebo. These effects seem promising, but more trials are needed to examine whether the beneficial effect of lixivaptan on serum sodium concentration translates into clinical benefit in these patient populations.     

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.     

Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected

Several fluid retentive states such as heart failure, cirrhosis of the liver, and syndrome of inappropriate antidiuretic hormone secretion are associated with inappropriate elevation in plasma levels of arginine vasopressin (AVP), a neuropeptide that is secreted by the hypothalamus and plays a critical role in the regulation of serum osmolality and in circulatory homeostasis. The actions of AVP are mediated by three receptor subtypes V1a, V2, and V1b. The V1a receptor regulates vasodilation and cellular hypertrophy while the V2 receptor regulates free water excretion. The V1b receptor regulates adrenocorticotropin hormone release. Conivaptan is a nonpeptide dual V1a/V2 AVP receptor antagonist. It binds with high affinity, competitively, and reversibly to the V1a/V2 receptor subtypes; its antagonistic effect is concentration dependent. It inhibits CYP3A4 liver enzyme and elevates plasma levels of other drugs metabolized by this enzyme. It is approved only for short-term intravenous use. Infusion site reaction is the most common reason for discontinuation of the drug. In animals conivaptan increased urine volume and free water clearance. In heart failure models it improved hemodynamic parameters and free water excretion. Conivaptan has been shown to correct hyponatremia in euvolemic or hypervolemic patients. Its efficacy and safety for short-term use have led to the Food and Drug Administration (FDA) approval of its intravenous form for the correction of hyponatremia in euvolemic and hypervolemic states. Despite its ability to block the action of AVP on V1a receptors, no demonstrable benefit from this action was noted in patients with chronic compensated heart failure and it is not approved for this indication. Consideration should be given to further evaluation of its potential benefits in patients with acute decompensated heart failure.     

Tolvaptan for the treatment of heart failure: a review of the literature

INTRODUCTION: It has been > 25 years since it was first discovered that arginine vasopressin levels are elevated in heart failure and this elevation is proportional to the severity of heart failure. Tolvaptan is an oral nonpeptide V?-selective antagonist and has been shown to induce free water excretion without increasing urine sodium, an effect termed 'aquaresis'. AREAS COVERED: This paper aims to review the physiology, chemistry, pharmacokinetics, clinical efficacy and safety of tolvaptan in HF. A PubMed literature search was performed using 'tolvaptan' and the MeSH term 'heart failure', yielding 89 references. EXPERT OPINION: Clinical trials conducted in ambulatory and hospitalized patients with HF have found treatment with tolvaptan causes rapid and sustained body weight reductions concurrent with increases in urine output, improves and/or normalizes serum sodium in hyponatremic patients, reduces signs and symptoms of congestion and increases thirst. However, tolvaptan has not been shown to decrease HF re-hospitalization or mortality. As an adjunct to standard therapy, tolvaptan is unique in that it is virtually the only novel agent tested in patients hospitalized for acute heart failure syndrome (AHFS) to reach its primary end point for short-term efficacy without causing deleterious side effects. There is theoretical concern that chronic V? receptor blockade may cause harmful long-term side effects via enhanced V(1a) receptor activation, potentially offsetting any favorable effects on congestion and hyponatremia. The 'vaptan' class of drugs is an active and promising area for clinical investigation and future research is necessary to clarify the therapeutic role of selective and nonselective vasopressin inhibition in chronic HF and AHFS.     

加压素V2受体拮抗剂

充血性心力衰竭(CHF)是发病率和死亡率均很高的疾病。CHF病人体内高水平的精氨酸加压素是导致CHF病人低纳血症和死亡率居高的原因之一，而加压素V2受体拮抗剂可缓解水、纳潴留。本文综述加压素V2受体拮抗剂的作用机制及新近开发的若干加压素V2受体拮抗剂用于CHF的治疗研究。     

In vitro and in vivo pharmacological characterisation of the potent and selective vasopressin V(1A) receptor antagonist 4-[4-(4-Chloro-phenyl)-5-[1,2,3]triazol-2-ylmethyl-4H-[1,2,4]triazol-3-yl]-piperidin-1-yl-(3,5-difluoro-phenyl) methanone (PF-00738245)

The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin receptors plays an important role in disease conditions including polycystic kidney disease, congestive heart failure and dysmenorrhoea. The development of potent and selective vasopressin receptor ligands is needed to help dissect the function of the specific subtypes in disease pathogenesis. Here we report the pharmacological characterisation of PF-00738245 in in vitro binding and functional assays using cells expressing vasopressin V(?A), V(?B) or V? receptors. PF-00738245 inhibited AVP binding to the recombinant human vasopressin V(?A) receptor (K(i)=2.85 nM) and blocked AVP-induced rat aortic ring and human myometrial contraction (pK(B)=7.35 and 8.62 respectively). PF-00738245 was selective for the vasopressin V(1A) receptor by demonstrating minimal binding to vasopressin V(?B) (3.6% inhibition at 10 μM) or functional activity at vasopressin V? receptors (8.1% agonist and -8.4% antagonist activity at 10 μM) as well as the oxytocin receptor (46.3% antagonist activity at 10 μM). The in vivo pharmacological properties were tested orally in the rat and PF-00738245 dose dependently blocked the effect of AVP on a capsaicin-induced cutaneous flare response. Taken together the data support the use of PF-00738245 as a potent and selective vasopressin V(?A) receptor antagonist which may have utility in the treatment of disease conditions which are propagated by elevation in vasopressin V(?A) receptor signalling.     

Lixivaptan (American Home Products)

Lixivaptan is a non-peptide, orally-active vasopressin antagonist under development by American Home Products for the potential treatment of hyponatremia associated with diseases such as heart failure, liver cirrhosis and nephrotic syndrome. By 1997, it was in phase II trials in the US and elsewhere for hyponatremia [2424051. It selectively prevents vasopressin-dependent water resorption, increasing water excretion with low electrolyte loss [266993] and is selective towards the human V2 versus V1 receptors [295987].     

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.     

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.     

伴有低钠血症的心力衰竭治疗新药——托伐普坦

心力衰竭时常伴随低钠血症。心力衰竭的一般治疗方法对低钠血症疗效不佳。托伐普坦是精氨酸加压素V_2受体的拮抗药。托伐普坦通过抑制肾脏集合管水的重吸收,使肾脏对水的排泄增加,起到纠正低钠血症、增加尿量、改善心力衰竭症状等作用。临床研究表明托伐普坦在伴有低钠血症的心力衰竭治疗中发挥重要作用。     

Tolvaptan: a selective vasopressin type 2 receptor antagonist in congestive heart failure

The neurohormone arginine vasopressin plays a significant role in the regulation of volume homeostasis, which is mediated via vasopressin type 2 (V₂) receptors in the collecting tubules of the kidney. Diseases that are accompanied by abnormal volume homeostasis, including congestive heart failure and cirrhosis, are a frequent cause of hospital admissions and increasing healthcare costs. Recently, several nonpeptide V₂ receptor antagonists have emerged as promising agents in the management of these conditions with the advantage of having no electrolyte abnormalities, neurohormonal activation or worsening renal insufficiency. Tolvaptan, a highly selective nonpeptide V₂ receptor antagonist, has demonstrated an improvement in the volume status, osmotic balance and haemodynamic profile in preclinical and Phase II trials in patients with congestive heart failure and is currently undergoing testing in Phase III trials. This review discusses the evidence for the potential uses of tolvaptan, and its pharmacology and pharmacokinetics, particularly in congestive heart failure.     

Conivaptan Yamanouchi

Yamanouchi is developing conivaptan, a diuretic and active vasopressin V1a and V2 antagonist, which has an aquaretic effect, for the potential treatment of hyponatremia and heart failure. In January 2004, Yamanouchi submitted an NDA in the US for injectable conivaptan for the treatment of hyponatremia and, in December 2004, the FDA issued approval, although additional safety data were requested.     

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.     

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.     

Pharmacology of conivaptan hydrochloride (YM087), a novel vasopressin V1A/V2 receptor antagonist

Pharmacology of conivaptan hydrochloride (YM087) was investigated in in vitro and in vivo studies. In radioligand binding study, YM087 showed high affinity for both V1A and V2 receptors in animal and human species. Affinity of YM087 for V1A and V2 receptors was comparable to that of vasopressin (AVP). In functional antagonistic activity study, YM087 concentration-dependently inhibited AVP-induced intracellular Ca2+ elevation via human V1A receptors and AVP-stimulated cAMP accumulation via human V2 receptors. Intravenous administration of YM087 dose-dependently inhibited AVP-induced pressor responses and produced a dose-dependent aquaresis in rats and dogs. Oral administration of YM087 showed a potent and long-lasting antagonistic activity on V1A and V2 receptors. YM087 was effective in dogs with heart failure and in heart failure rats with hyponatremia and edema. These results reveal that YM087 is the first orally active V1A/V2 receptor antagonist and suggest that YM087 may be useful in the treatment of congestive heart failure and hyponatremia.