pituitrin and lixivaptan

Current treatment of acute decompensated heart failure (ADHF) has not reduced the significant morbidity or mortality associated with this disease, and has promoted drug development aimed at neurohormonal targets. Hypervolemic hyponatremia, which is linked to the nonosmotic release of arginine vasopressin, is associated with a poor prognosis in patients with heart failure (HF). Vasopressin acts on V(2) and V(1a) receptors to cause water retention and vasoconstriction, respectively. Clinical trials have demonstrated that vasopressin receptor antagonists (VRAs) are effective in treating hypervolemic hyponatremia in ADHF without a negative impact on renal function. The small hemodynamic benefit seen with VRA use appeared to result from V(2)-receptor antagonist-induced increase in urine output rather than from a vasodilatory drug effect. VRA use in ADHF trials was associated with minimal symptomatic improvement and no impact on morbidity or mortality. At present, clinical trial evidence does not support the routine use of VRAs in ADHF. Given the favorable renal profile of VRAs, studies on the possible benefit of VRAs in ADHF patients with renal insufficiency and diuretic resistance appear warranted.

Topics: Acute Disease; Animals; Antidiuretic Hormone Receptor Antagonists; Benzamides; Benzazepines; Clinical Trials as Topic; Heart Failure; Hemodynamics; Humans; Hyponatremia; Prognosis; Pyrroles; Tolvaptan; Vasoconstriction; Vasopressins

To evaluate acute hemodynamic, short-term, and long-term effects of vasopressin antagonists in patients with heart failure (HF).. Searches of the PubMed database (1966-February 2010) were conducted. Search terms included AVP receptor antagonist, CHF, tolvaptan, conivaptan, lixivaptan, HF, and hyponatremia. Manufacturers' prescribing information, manufacturer Web site searches, and searches made on www.clinicaltrials.gov were also included.. All clinical trials identified from the reference search and data sources were reviewed. Articles were included if they were relevant to short-term and long-term outcomes of patients with HF who were treated with vasopressin antagonists.. Trials of conivaptan, tolvaptan, and lixivaptan were evaluated. The evidence indicates that all agents increase urine output >10 mL/h, and conivaptan and tolvaptan decrease pulmonary capillary wedge pressure (-2.6 +/- 0.7, -5.4 +/- 0.7, and -4.6 +/- 0.7 mm Hg for placebo, conivaptan 20 mg, and conivaptan 40 mg, respectively; -5.67 +/- 4.58 to -6.38 +/- 4.12 mmHg for tolvaptan, and -4.16 +/- 4.57 mm Hg for placebo) in patients with HF. Both of these changes occur without inducing electrolyte abnormalities or renal dysfunction. Trials with conivaptan in acute HF have not demonstrated a benefit in cardiac index, mean arterial pressure, or vascular resistance. Data from clinical trials indicate that tolvaptan may decrease dyspnea (p < 0.05) and pedal edema (p < 0.001). To date, no large-scale trials of any agent have demonstrated an improvement in left ventricular systolic function, rehospitalization, worsening HF, or death.. Vasopressin antagonists cannot be considered routine pharmacotherapy for HF. Further, conivaptan should not be used for the treatment of acute HF. There is not enough literature to advocate for or against the use of lixivaptan in patients with HF. Tolvaptan may be considered for the treatment of hyponatremia.

Topics: Azepines; Benzamides; Benzazepines; Heart Failure; Humans; Hyponatremia; Neurotransmitter Agents; Pyrroles; Tolvaptan; Vasopressins

The non-peptide vasopressin antagonists (VPA), called vaptans, were developed in the 1990s to antagonize both the pressor and antidiuretic effects of vasopressin. There are three subtypes of VPA receptors: V1a, V1b and V2. V1a receptors are widely distributed in the body, mainly the blood vessels and myocardium. The V1b receptors are located mainly in the anterior pituitary gland and play a role in ACTH release. V2 receptors are located in the collecting tubular renal cells. Both V1a and V1b receptors act through the intracellular phosphoinositol signalling pathway, Ca(++) being the second messenger. V2 receptors work through AMPc generation, which promotes aquaporin 2 (AQP2) trafficking and allows water to enter the cell. The vaptans act competitively at the AVP receptor. The most important are mozavaptan, lixivaptan, satavaptan and tolvaptan, all of which are selective V2 antagonists and are administered through the oral route. In contrast, conivaptan is a dual V1 and V2 antagonist administered through the endovenous route. The main characteristics of vaptans are their effect on free water elimination without affecting electrolyte excretion. There are several studies on the effects of these drugs in hypervolemic hyponatremia (heart failure, hepatic cirrhosis) as well as in normovolemic hyponatremia (inappropriate secretion of ADH [SIADH]). Current studies show that the vaptans are effective and well tolerated, although knowledge of these drugs remains limited. There are no studies of the use of vaptans in severe hyponatremia. Osmotic demyelination syndrome due to excessively rapid correction of hyponatremia has not been described.

Topics: Adult; Antidiuretic Hormone Receptor Antagonists; Aquaporin 2; Benzamides; Benzazepines; Calcium Signaling; Clinical Trials as Topic; Cyclic AMP; Double-Blind Method; Drug Therapy, Combination; Heart Failure; Humans; Hyponatremia; Inappropriate ADH Syndrome; Kidney Tubules, Collecting; Liver Cirrhosis; Morpholines; Multicenter Studies as Topic; Neoplasms; Pituitary Gland, Anterior; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vasopressin; Second Messenger Systems; Spiro Compounds; Tolvaptan; Vasopressins

Etiopathogenesis, diagnostics and therapy of hyponatremias are summarized for clinicians. Hyponatremia is the most common electrolyte abnormality. Mild to moderate hyponatremia and severe hyponatremia are found in 15-30% and 1-4% of hospitalized patients, respectively. Pathophysiologically, hyponatremias are classified into two groups: hyponatremia due to non-osmotic hypersecretion of vasopressin (hypovolemic, hypervolemic, euvolemic) and hyponatremia of non-hypervasopressinemic origin (pseudohyponatremia, water intoxication, cerebral salt wasting syndrome). Patients with mild hyponatremia are almost always asymptomatic. Severe hyponatremia is usually associated with central nervous system symptoms and can be life-threatening. Diagnostic evaluation of patients with hyponatremia is directed toward identifying the extracellular fluid volume status, the neurological symptoms and signs, the severity and duration of hyponatremia, the rate at which hyponatremia developed. The first step to determine the probable cause of hyponatremia is the differentiation of the hypervasopressinemic and non-hypervasopressinemic hyponatremias with measurement of plasma osmolality, glucose, lipids and proteins. For further differential diagnosis of hyponatremia, the determination of urine osmolality, the clinical assessment of extracellular fluid volume status and the measurement of urine sodium concentration provide important information. The most important representative of euvolemic hyponatremias is SIADH. The diagnosis of SIADH is based on the exclusion of other hyponatremic conditions; low plasma osmolality (<275 mosmol/kg) and inappropriate urine concentration (urine osmolality >100 mosmol/kg) are of pathognomic value. Acute (<48 hrs) severe hyponatremia (<120 mmol/l) necessitates emergency care with rapid restoration of normal osmotic milieu (1 mmol/l/hr increase rate of serum sodium). Patients with chronic symptomatic hyponatremia have a high risk of osmotic demyelination syndrome in brain if rapid correction of the plasma sodium occurs (maximal rate of correction of serum sodium should be 0.5 mmol/l/hr or less). The conventional treatments for chronic asymptomatic hyponatremia (except hypovolemic patients) include water restriction and/or the use of demeclocycline or lithium or furosemide and salt supplementation. Vasopressin receptor antagonists have opened a new forthcoming therapeutic era. V2 receptor antagonists, such as lixivaptan, tolvaptan, satavaptan and the V2+

Topics: Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Blood Volume; Brain Diseases; Central Nervous System; Chronic Disease; Demeclocycline; Demyelinating Diseases; Diagnosis, Differential; Diuretics; Extracellular Fluid; Furosemide; Humans; Hyponatremia; Inappropriate ADH Syndrome; Lithium Compounds; Morpholines; Osmolar Concentration; Osmosis; Pyrroles; Severity of Illness Index; Sodium; Spiro Compounds; Time Factors; Tolvaptan; Vasopressins

In a national heart failure registry, hyponatremia (serum sodium < 130 mEq/L) was initially reported in 5% of patients and considered a risk factor for increased morbidity and mortality. In a chronic heart failure study, serum sodium level on admission predicted an increased length of stay for cardiovascular causes and increased mortality within 60 days of discharge. Hyponatremia in patients with congestive heart failure (CHF) is associated with a higher mortality rate. Also, by monitoring and increasing serum sodium levels during hospitalization for CHF, patient outcomes may improve. This review describes the pathophysiology of hyponatremia in relation to CHF, including the mechanism of action of vasopressin receptors in the kidney, and assesses the preclinical and clinical trials of vasopressin receptor antagonists--agents recently developed to treat hyponatremia. In hospitalized patients with CHF, hyponatremia plays a major role in poor outcomes. Vasopressin receptor antagonists have been shown to be safe and effective in clinical trials in patients with hyponatremia.

Topics: Arginine Vasopressin; Azepines; Benzamides; Benzazepines; Chronic Disease; Clinical Trials as Topic; Diuretics; Heart Failure; Humans; Hyponatremia; Models, Biological; Pyrroles; Registries; Renin-Angiotensin System; Sodium; Tolvaptan; Treatment Outcome; Vasopressins

The first non-peptide vasopressin receptor antagonist (VRA) was recently approved by the United States Food and Drug Administration, and several others are now in late stages of clinical development. Phase 3 trials indicate that these agents predictably reduce urine osmolality, increase electrolyte-free water excretion, and raise serum sodium concentration. They are likely to become a mainstay of treatment of euvolemic and hypervolemic hyponatremia. Although tachyphylaxis to the hydro-osmotic effect of these agents does not appear to occur, their use is accompanied by an increase in thirst, and they do not always eliminate altogether the need for water restriction during treatment of hyponatremia. Experience with use of these agents for treatment of acute, severe, life-threatening hyponatremia as well as chronic hyponatremia is limited. Further studies are needed to determine how they are best used in these situations, but the risk of overly rapid correction of hyponatremia seems low. Results of long-term trials to determine the ability of VRAs to reduce morbidity or mortality in congestive heart failure or to slow the progression of polycystic kidney disease are awaited with great interest.

Topics: Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Clinical Trials as Topic; Diabetes Insipidus, Nephrogenic; Fibrosis; Heart Failure; Humans; Hyponatremia; Osmolar Concentration; Polycystic Kidney Diseases; Pyrroles; Receptors, Vasopressin; Sodium; Tolvaptan; United States; United States Food and Drug Administration; Vasopressins

Effects of vasopressin via V1a- and V2-receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatraemia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis and ocular hypertension. As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of disorders such as cerebral ischaemia and stroke, Raynaud's disease, dysmenorrhoea and tocolytic treatment. V1b selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1a (relcovaptan) or V2 (tolvaptan, lixivaptan) selectivity or non-selective activity (conivaptan) which may be advantageous in some disorders. The V1a/V2 non-selective vasopressin antagonist conivaptan is the first vaptan which is approved by the FDA for the treatment of euvolaemic hyponatraemia.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Binding Sites; Cardiovascular Diseases; Clinical Trials as Topic; Hormone Antagonists; Humans; Indoles; Pyrroles; Pyrrolidines; Tolvaptan; Vasopressins; Water-Electrolyte Imbalance

Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, vasopressin receptor antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (conivaptan), OPC-41061 (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia.

Topics: Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Humans; Hyponatremia; Inappropriate ADH Syndrome; Morpholines; Pyrroles; Randomized Controlled Trials as Topic; Spiro Compounds; Tolvaptan; Vasopressins

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.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Heart Failure; Humans; Pyrroles; Receptors, Vasopressin; Tolvaptan; Vasopressins

Vasopressin antagonists are a class of neurohormonal antagonists with applications in both the short-term and long-term management of patients with acute decompensated heart failure (ADHF). The pharmacologic effects of vasopressin antagonists include changes in fluid balance and hemodynamics that may improve symptoms and outcomes in patients hospitalized with ADHF. With chronic therapy, vasopressin antagonists offer the potential to improve outcomes through a variety of mechanisms, including more effective treatment of congestion, preservation or improvement of renal function, or a reduction in the use of concomitant loop diuretic therapy. Several vasopressin antagonists are currently in advanced clinical trials for the treatment of ADHF, chronic stable heart failure, and hyponatremia.

Topics: Acute Disease; Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Heart Failure; Humans; Pyrroles; Stroke Volume; Tolvaptan; Treatment Outcome; Vasoconstriction; Vasopressins

Vasopressin, or antidiuretic hormone, is a peptide hormone that is released from the posterior pituitary gland in response to changes in blood pressure and plasma osmolality. The main pathophysiological states associated with high plasma vasopressin concentrations are cirrhosis, cardiac failure and syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Pharmacological treatments for disorders of excess vasopressin secretion have been limited. However, oral bio-available selective and non-selective V(1) and V(2) receptor antagonists have recently become available for clinical use. Water retention in cirrhosis is a common problem, leading to ascites, peripheral oedema and hyponatraemia. Raised plasma vasopressin concentrations and decreased delivery of glomerular filtrate are believed to be the most important factors in the development of water retention. V(2) receptor antagonists are aquaretic agents that promote water excretion and improve hyponatraemia. Their potential role in cirrhosis has been examined in a number of recent studies that have shown increased free water clearance and serum sodium concentrations with few adverse effects. V(2) receptor antagonists represent a novel and promising new class of agent that may have major clinical utility in the treatment of patients with liver cirrhosis.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Controlled Clinical Trials as Topic; Diuretics; Heart Failure; Homeostasis; Humans; Inappropriate ADH Syndrome; Liver Cirrhosis; Models, Animal; Morpholines; Piperidines; Pyrroles; Quinolones; Rats; Spiro Compounds; Vasopressins

Topics: Azepines; Benzamides; Brain Diseases, Metabolic; Humans; Hyponatremia; Inappropriate ADH Syndrome; Liver Cirrhosis; Pyrroles; Vasopressins

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].

Topics: Animals; Azepines; Benzamides; Clinical Trials as Topic; Humans; Hyponatremia; Pyrroles; Structure-Activity Relationship; Vasopressins

Hyponatraemia is a frequent electrolyte disorder. It is primarily attributable to vasopressin excess plus sustained fluid intake. Hyponatraemia causes CNS symptoms, especially during the first 2-4 days; these symptoms are related to brain swelling. Hyponatraemia occurs in the setting of liver cirrhosis and congestive cardiac failure, in which it is related to stimulation by low arterial blood pressure acting through baroreceptors. Hyponatraemia also occurs in the syndrome of inappropriate antidiuretic hormone secretion, usually from neoplasms releasing vasopressin. The conventional treatment of hyponatraemia used to be fluid restriction and treatment of the underlying disorder. This kind of treatment has been unreliable, cumbersome and difficult to comply with for the patient. In the future, effective vasopressin V2 antagonists will become available for clinical use in the treatment of hyponatraemia, and are expected to improve the management of hyponatraemia. Pharmacological characteristics and observations of biological effects of three antagonists are reported in the present article.

Topics: Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Humans; Hyponatremia; Morpholines; Pyrroles; Receptors, Vasopressin; Spiro Compounds; Vasopressins

Water retention and dilutional hyponatremia, mainly attributable to an impairment of free water excretion and increased vasopressin activity, are well-documented complications in cirrhotic patients with ascites. VPA-985 is a selective, nonpeptide, orally active, vasopressin-2-receptor antagonist. The aim of this study was to determine the pharmacodynamics, safety, and pharmacokinetics of ascending single doses (25, 50, 100, 200, and 300 mg) in cirrhotic patients with ascites in a randomized, double-blind, placebo-controlled trial. Each dose level was studied in 5 patients (4 active and 1 placebo). After an overnight fast and fluid restriction (continued for 4 hours after dose administration), all patients were given placebo on baseline day and an oral suspension of VPA or placebo on the following day. VPA produced a significant dose-related increase in daily urine output (1,454 +/- 858 mL to 4,568 +/- 4,385 mL with VPA 300 mg) and a dose-related decrease in urine osmolality. The free water clearance reached greater than 3 mL/min for doses 100 mg or greater. Simultaneously, significant increases in serum osmolality, sodium, and vasopressin levels were found. There was a significant increase in sodium urine excretion. VPA was rapidly absorbed and maximum serum concentrations were achieved within 1 hour after administration. Elimination half-life ranged from 9.0 hours after 100 mg to 22.6 hours after 200 mg. In conclusion, VPA induced a dose-related aquaretic response, suggesting a therapeutic potential in managing water retention in patients with liver cirrhosis with ascites.

Topics: Adult; Aged; Antidiuretic Hormone Receptor Antagonists; Ascites; Azepines; Benzamides; Double-Blind Method; Drinking; Electrolytes; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Osmolar Concentration; Pyrroles; Renin; Sodium; Urine; Urodynamics; Vasopressins; Water; Water-Electrolyte Balance