Conivaptan Research Articles

Arginine vasopressin deficiency and conivaptan (a V1a-V2 receptor antagonist) treatment reverses liver damage and fibrosis in rats with chronic portocaval anastomosis.

Arginine vasopressin (AVP) is a naturally occurring hormone synthesized in the hypothalamus. AVP demonstrates pro-fibrotic effects as it stimulates hepatic stellate cells to secrete transforming growth factor-β (TGF-β) and collagen. Previous work in liver cirrhotic (CCL4 -induced) hamsters demonstrated that AVP deficiency induced by neurointermediate pituitary lobectomy (NIL) can restore liver function. Therefore, we hypothesized that liver fibrosis would decrease in portocaval anastomosis (PCA) rats, which model chronic liver diseases, when they are treated with the V1a-V2 AVP receptor antagonist conivaptan (CV). In this study, changes in liver histology and gene expression were analysed in five experimental groups: control, PCA, NIL, PCA + NIL and PCA + CV, with NIL surgery or CV treatment administered 8 weeks after PCA surgery. Body weight gain was assessed on a weekly basis, and serum liver function, liver weight and liver glycogen content were assessed following euthanasia. Most PCA-induced phenotypes were reverted to normal levels following AVP-modelled deficiency, though hypoglycemia and ammonium levels remained elevated in the PCA + CV group. Liver histopathological findings showed a significant reversal in collagen content, less fibrosis in the triad and liver septa and increased regenerative nodules. Molecular analyses showed that the expression of fibrogenic genes (TGF-β and collagen type I) decreased in the PCA + CV group. Our findings strongly suggest that chronic NIL or CV treatment can induce a favourable microenvironment to decrease liver fibrosis and support CV as an alternative treatment for liver fibrosis.

Effects of Vasopressin (AVP) Deficiency and Conivaptan (an AVP Receptors Antagonist) on Liver Physiology and Fibrosis in Rats with Protracted Portacaval Anastomosis

Liver fibrosis is due to the over deposition of collagens on the extracellular matrix, causing fibrotic septa and liver failure. Portocaval anastomosis (PCA) is a model of liver disease. Fibrogenesis is stimulated by AVP. We have described the healthy effect of the AVP deficiency, induced by neurointermediate pituitary lobectomy (NIL), on liver functions and cirrhosis. We hypothesize that blocking the AVP receptors with the V1a-V2 AVP receptor antagonist conivaptan (CV) will induce the same healthy effects of NIL on liver fibrosis. Male Wistar rats were divided in 6 groups (8-10 each): Sham surgery (SHAM), PCA, NIL, PCA+NIL, CV and PCA+CV. SHAM, NIL and the 4 groups with PCA were operated at week 0, whereas NIL surgery in the PCA+NIL group was done at week 8. CV treatments (30 mg/day/im/8 weeks) in the CV group started at week 0, whereas in the PCA+CV group started at week 8. NIL and CV groups were sacrificed at week 8, whereas SHAM, PCA, PCA+NIL and PCA+CV groups were sacrificed at week 16. At sacrifice, serum levels of ALT, AST, bilirubin, NH4, urea, albumin and glucose were assessed. Livers were weighed and samples were processed for glycogen content and the other processed for light microscopy analysis (slide tissues stained with H-E, Masson and Sirius red). Results are summarized in Table 1. Table 1. Comparative effects of sham surgery (SHAM), portocaval anastomosis (PCA), neurointermediate pituitary lobectomy (NIL), PCA+NIL, conivaptan (CV) and PCA+CV on body weight, liver weight, glycogen liver content and serum biochemical parameters of liver functions GROUPS SHAM PCA NIL PCA+NIL CV PCA+CV (Basal values) Body weight = ↓ (-29%) ↓ (-22%) (- ↓(-29%) = ↓ (23%) (g) NS vs SHAM NS vs SHAM NS vs SHAM NS vs SHAM Liver weight = ↓ (-54%) = = = ↓ (-22%) (g) p<0.05 vsSHAM NS vsSHAM ALT(U/L) = ↑↑↑ ↑↑↑ = = = AST(U/L) = ↑↑↑ ↑↑↑ ↑↑ = = Total bilirubin (mg/dL) = ↑↑↑ = = = = Unconjugated bilirubin (mg/dL) = ↑↑↑ = = = = Albumin(g/dL) = = = = = = Glucose (mg/dL) = = = = = ↓↓↓ NH4(µg/dL) = ↑↑↑ = = = ↑↑↑ Urea(mg/dL) = ↓↓↓ = = = = Liver glycogen(mg/gr of tissue) = ↓↓↓ = = = = Liver histopathology. In the PCA group, mainly in the periportal areas, small inflammatory infiltrates and big deposits of collagen were developed. Compared with the PCA, PCA+NIL and PCA+CV groups showed less inflammatory areas and much less collagen deposits. Conclusions, all results showed that: 1) AVP deficiency restores to normality the liver physiology and histology in the protracted liver disease, 2) Except the alterations in glycemia and NH4 metabolism, similar restored effects in liver histophysiology were induced by CV, suggesting that similar cellular mechanisms are involved, 3) Results strongly support that AVP is an important role in the pathophysiology of the liver fibrosis and possibly other fibrotic diseases.

Vasopressin antagonism in heart failure: a review of the hemodynamic studies and major clinical trials.

For decades, plasma arginine vasopressin (AVP) levels have been known to be elevated in patients with congestive heart failure (HF). Excessive AVP signaling at either or both the V1a and V2 receptors could contribute to the pathophysiology of HF by several mechanisms. V1a activation could cause vasoconstriction and/or direct myocardial hypertrophy as intracellular signaling pathways are closely related to those for angiotensin II. V2 activation could cause fluid retention and hyponatremia. A hemodynamic study with the pure V2 antagonist tolvaptan (TV) showed minimal hemodynamic effects. Compared with furosemide in another study, the renal and neurohormonal effects of TV were favorable. Several clinical trials with TV as adjunctive therapy in acute HF have shown beneficial effects on fluid balance and dyspnea, with no worsening of renal function or neurohormonal stimulation. Two smaller studies, one in acute and one in chronic HF, have shown comparable clinical and more favorable renal and neurohormonal effects of TV compared with loop diuretics. However, long-term treatment with TV did not alter outcomes in acute HF. No data are available other than single-dose studies of an intravenous pure V1a antagonist, which showed a vasodilating effect if plasma AVP levels were elevated. One hemodynamic study and one short-duration clinical trial with the balanced intravenous V1a/V2 antagonist conivaptan (CV) showed hemodynamic and clinical effects largely similar to those with TV in similar studies. A new orally effective balanced V1/V2 antagonist (pecavaptan) is currently undergoing phase II study as both adjunctive and alternative therapy during and after hospitalization for acute HF. The purpose of this review is to summarize what we have learned from the clinical experience with TV and CV, and to suggest implications of these findings for future work with newer agents.

Bioanalytical Method Development and Validation for the Determination of Vasopressin Receptor Antagonist Conivaptan in Mouse Plasma at NanoLevel and its Pharmacokinetic Application

Background: Conivaptan inhibits two of vasopressin receptor (vasopressin receptor V1a and V2). Conivaptan is used for the treatment of hyponatremia, and in some instances, for the treatment of the heart failure. Methods: The present study aimed to develop a simple, sensitive, and accurate HPLC with ultraviolet detection for the assay of conivaptan (CON) in mouse plasma using bisoprolol as internal standard (IS). A precipitation procedure was used to extract CON and the IS from the mouse plasma. CON was chromatographically separated using a C18 analytical column at 25°C. The separation was carried out using a mixture of phosphate buffer (50 mM): acetonitrile (60: 40, v/v, pH 4.5) with a flow rate of 1.0 mL/min and detection was performed at 240 nm. Results: The assay was validated according to the US Food and Drug (FDA) guidelines. The method demonstrated linearity over a concentration range of 150 - 2000 ng/mL (correlation coefficient: r 2 = 0.9985). The mean recovery of CON from the mouse plasma was 101.13%. All validation parameters for CON were within the acceptable range. Conclusion: The investigated method has been shown to be suitable for estimating the CON in plasma samples, and this method is sensitive and highly selective, allowing the estimation of its concentrations up to the nano-scale. The suggested method was successfully used in a pharmacokinetic study of CON in mouse plasma.

Development and validation of an HPLC\u2013MS/MS method for the determination of arginine-vasopressin receptor blocker conivaptan in human plasma and rat liver microsomes: application to a metabolic stability study

PurposeTo develop and validate a bio-analytical HPLC–MS/MS method for the determination of conivaptan (CVA) an arginine-vasopressin receptor blocker in human plasma and in rat liver microsomes (RLMs).MethodsAnalytes were separated on a reversed phase C18 column (50 mm × 2.1 mm, 1.8 μm). The mobile phase was a mixture of acetonitrile and 10 mM ammonium formate (40:60 v/v, pH 4.0) and was pumped isocratically for 4 min at a flow rate of 0.2 ml/min. Multiple reaction monitoring in positive ionization mode was used for the assay.ResultsThe method yielded a linear calibration plot (r2= 0.9977 and 0.9998) over 5–500 ng/ml with a limit of detection at 1.52 and 0.88 ng/ml for human plasma and RLMs, respectively. The reproducibility of detection of CVA in human plasma and RLMs was found to be in an acceptable range.ConclusionThe method developed in this study is applicable for accurately quantifying CVA in human plasma and rat liver microsomal samples. The optimized procedure was applied to study of metabolic stability of CVA. Conivaptan concentration rapidly decreased in the first 2 min of RLMs incubation and the conversion reached a plateau for the remainder of the incubation period. The in vitro half-life (t1/2) was estimated at 11.51 min and the intrinsic clearance (CLin) was 13.8 ± 0.48 ml/min/kg.

Hypernatremia: A known complication of conivaptan

Hypernatremia: A known complication of conivaptan

Pharmaceutical Development of a Parenteral Formulation of Conivaptan Hydrochloride

Conivaptan hydrochloride injection (Vaprisol®) was developed for the treatment of hyponatremia. Because the drug is very slightly soluble in water, pH control and cosolvency techniques were used to achieve the optimum concentration required for clinical trial material. Stability studies on retained samples of the clinical trial material for early-phase trials showed white visible particulates mainly in the headspace of the glass ampoule long after completion of the trials. The mechanism for generation of the particulate matter was formation of freebase of conivaptan hydrochloride because of increase in pH. The pH of the formulation for late-phase clinical trials, primary stability studies, and commercial production was fine-tuned to prevent particulate formation. The formulation contains propylene glycol and ethanol. Considering the nature of the cosolvent used in the formulation, the amount of di(2-ethylhexyl)phthalate (DEHP) delivered from an infusion system was evaluated, and we confirmed that the level of DEHP was lesser than that mentioned in the guideline. In the course of the scale-up studies for commercialization, the formulation failed the filter integrity test after the compounding solution was filtered. The dimethylsiloxane extracted from the silicon tubing used for solvent transfer coated the filter surface, which resulted in suppression of the bubble point value. The formulation and manufacturing process enabled conivaptan hydrochloride to be approved and launched in the market as a parenteral formulation. Formulation scientists have recognized a trend that promising new chemical entities in the drug discovery phase often do not have ideal physicochemical properties for formulation. In particular, poor solubility is one of the challenges for development of a parenteral dosage form. Here, we describe the case of such a new chemical entity, a very slightly soluble hydrochloric salt, which was handed over from a drug discovery research laboratory to a pharmaceutical laboratory. pH control and cosolvency techniques were used to achieve the optimum concentration required for the product. However, a couple of issues emerged; we performed confirmatory studies in the course of development, and the results of these studies were used to design the formulation and manufacturing process. Most prominent issues were particulate matter formation on the inner surface the headspace of the ampoule and failure of the filter integrity test. In addition, we discuss the root causes and the mechanisms of the above issues and the measures taken to prevent them. A part of them are crucial, and information obtained from this study is important for development of new chemical entities as injectables in the future.

Erratum to: Use of Conivaptan (Vaprisol) for Hyponatremic Neuro-ICU Patients

The online version of the original article can be found underdoi:10.1007/s12028-010-9379-5.A. M. Naidech (&) S. M. Liebling S. L. Bassin M. J. Alberts R. A. BernsteinDepartment of Neurology, Northwestern University,710 N Lake Shore Drive, 11th floor, Chicago, IL 60611, USAe-mail: a-naidech@northwestern.eduJ. PaparelloDepartment of Internal Medicine, Northwestern University,710 N Lake Shore Drive, 11th floor, Chicago, IL 60611, USAK. LevasseurNorthwestern Memorial Hospital, 251 E Huron, Chicago,IL 60611, USAK. MuroDepartment of Neurological Surgery, Northwestern University,710 N Lake Shore Drive, 11th floor, Chicago, IL 60611, USA

Efficacy and safety of 30-minute infusions of conivaptan in euvolemic and hypervolemic hyponatremia

The efficacy and safety of conivaptan administered via 30-minute i.v. infusion to patients with euvolemic or hypervolemic hyponatremia were evaluated. Hospitalized adults with a baseline serum sodium concentration (SSC) of 115-130 meq/L and euvolemia or hypervolemia on clinical evaluation were randomized to receive conivaptan hydrochloride 20 mg once or twice daily or placebo via 30-minute i.v. infusion. The primary efficacy measure was the change in SSC from baseline to 48 hours. A total of 49 patients received one of the three treatment regimens. Conivaptan once and twice daily produced significant least-squares mean changes from baseline in SSC at 48 hours of 3.46 meq/L (95% confidence interval [CI], 1.75-5.18 meq/L) and 6.22 meq/L (95% CI, 4.34-8.10 meq/L), respectively (p = 0.028 between conivaptan-treated groups). These changes were significantly greater compared with those in the placebo group at hour 4 (p = 0.049) and at all time points onward of hour 28 (p ≤ 0.019) for the once-daily regimen and at all time points for the twice-daily regimen (p = 0.045 at hour 4, then p ≤ 0.010). Both conivaptan regimens were more efficacious than placebo in all secondary efficacy outcomes. Conivaptan was generally well tolerated, with infusion-site reactions being the most common adverse effects (AEs). Conivaptan hydrochloride 20 mg, administered once or twice daily via 30-minute i.v. infusion, significantly increased SSCs over 48 hours in patients with euvolemic or hypervolemic hyponatremia when compared with placebo. Common AEs were similar to those seen with continuous conivaptan infusions.

ChemInform Abstract: Nonpeptide Arginine Vasopressin Antagonists for Both V1A and V2 Receptors: Synthesis and Pharmacological Properties of 4′-(1,4,5,6-Tetrahydroimidazo[4,5-d] [1]benzoazepine-6-carbonyl)benzanilide Derivatives and 4′-(5,6-Dihydro-4H-thia

Arginine vasopressin (AVP) has a dual action mainly in the periphery, i.e., vasoconstriction and water reabsorption via V1A and V2 receptors; it may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of orally active AVP antagonists for both V1A and V2 receptors based on the hypothesis that the blockade of both V1A and V2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6- carbonyl)benzanilide and 4'-(5,6-dihydro-4H- thiazolo[5,4-d][1]benzoazepine-6-carbonyl)benzanilide were synthesized and examined for AVP antagonist activity for both V1A and V2 receptors. As a result, it was found that the 4'-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbon yl)-2- phenylbenzanilide derivatives showed potent binding affinity for both V1A and V2 receptors. Especially, 4'-(2-methyl-1,4,5,6- tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phe nylbenzanilide monohydrochloride (18, YM087 = conivaptan hydrochloride) exhibited potent binding affinity and AVP antagonist activity, after intravenous administration, for both V1A and V2 receptors. Furthermore, YM087 exhibited the most potent oral activity for the V2 receptor. Details of the synthesis and pharmacological properties of this series are presented.

Pharmacokinetics of conivaptan hydrochloride, a vasopressin V 1A/V 2-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study

Background: Conivaptan is a nonpeptide vasopressin V 1A/V 2-receptor antagonist that produces a controlled increase in serum sodium concentration in hospitalized patients with euvolemic or hyper-volemic hyponatremia. Objective: This study evaluated the pharmacokinetics of conivaptan in patients with euvolemic or hypervolemic hyponatremia and with or without underlying congestive heart failure who were participating in an efficacy and tolerability clinical trial. Methods: Data from an open-label, multicenter study were used to evaluate the pharmacokinetics of conivaptan in hyponatremic patients. Patients received a 20-mg loading dose intravenously over 30 minutes, followed by a continuous 4-day infusion of 20 or 40 mg/d. In the entire cohort, plasma conivaptan concentrations were determined at baseline, at the end of the loading dose (0.5 hour), at 24 hours, on days 3 and 4, and at the follow-up visit on day 11. A subset of patients at 2 study sites (the “pharmacokineticrich” subset) provided additional samples for pharmacokinetic analysis on day 1 at 1, 4, and 24 hours; on day 2 at 24 hours; and on day 5 at 1, 2, 7, 12, and 24 hours. Results: Plasma conivaptan concentrations were evaluated in 31 patients who received conivaptan 20 mg/d (mean [SD] age, 73.1 [14.3] years; weight, 68.1 [17.2] kg; 71.0% female; 87.1% white, 9.7% black, 3.2% other) and 172 patients who received co-nivaptan 40 mg/d (mean [SD] age, 71.5 [14.4] years; weight, 65.6 [15.9] kg; 64.0% female; 90.1% white, 6.4% black, 3.5% other). The pharmacokinetic-rich subset included 8 patients who received conivap-tan 20 mg/d (mean [SD] age, 76.3 [12.4] years; weight, 71.5 [14.7] kg; 87.5% female; 100% white) and 8 who received conivaptan 40 mg/d (mean [SD] age, 78.3 [7.9] years; weight, 71.3 [15.6] kg; 37.5% female; 100% white). In the overall patient group, plasma conivaptan concentrations were the highest after the 30-minute (C 0.5h) loading dose (mean [SD] C 0.5h = 733 [323] and 701 [343] ng/mL with conivap-tan 20 and 40 mg/d, respectively) and then declined during day 1 to concentrations (C 24h) (mean [SD] C 24h = 84 [78] and 215 [129] ng/mL with conivaptan 20 and 40 mg/d, respectively) that were maintained by the continuous infusion of 20 or 40 mg/d. At the end of infusion (96 hours), the mean (SD) plasma conivaptan concentrations were 176 (196) and 308 (321) ng/mL for conivaptan 20 and 40 mg/d, respectively. A ratio of 1.75 indicated near dose proportionality; however, interpatient variability was evident. No apparent differences in plasma conivaptan concentrations measured at 0.5 or 96 hours were observed between patients with euvolemic or hypervolemic hypona-tremia or between patients with or without congestive heart failure. In the pharmacokinetic-rich subset, for conivaptan 20 and 40 mg/d, respectively, conivaptan clearance was 18.7 and 9.5 L/h, the elimination t1/2 was 5.3 and 10.2 hours, and exposure to conivaptan in terms of AUC ∞ was 6996 and 30,771 ng · h/mL. Conclusion: The results of this study suggest that the pharmacokinetics of conivaptan 20 and 40 mg/d do not differ by volume status or the presence or absence of congestive heart failure.

Conivaptan: Evidence supporting its therapeutic use in hyponatremia.

The available treatment options for euvolemic and hypervolemic hyponatremia are limited, and consist mainly of fluid restriction, diuresis, or hypertonic solutions. Most of these therapies are neither well tolerated nor totally effective, and many are associated with significant adverse effects. Vasopressin receptor antagonists, also known as vaptans, are a new class of agents that now offer an additional treatment option for hyponatremic patients. Conivaptan hydrochloride, a competitive antagonist of vasopressin V1a and V2 receptors, is the first agent in this class to be approved for treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. This review critically assesses the evidence that support the use of conivaptan for the treatment of patients with euvolemic and hypervolemic hyponatremia. Conivaptan is effective in raising serum sodium levels in a predictable and safe fashion in euvolemic and hypervolemic hyponatremic patients. Conivaptan provides the first molecularly targeted approach for correcting hyponatremia in hospitalized patients.

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.

New premixed conivaptan formulation approved in the US.

New premixed conivaptan formulation approved in the US.

Current issues for nurse practitioners: Hyponatremia

To review the assessment, diagnosis, and management of hyponatremia (serum sodium <135 mEq/L), the most common electrolyte disturbance as a result of dysregulation of water balance in hospitalized or institutionalized patients. Comprehensive search using keywords AVP receptor antagonists, hyponatremia, SIADH, conivaptan, tolvaptan, lixivaptan, nurse practitioner, and others was carried out using the National Library of Medicine (PubMed) Web site from which full-text articles were obtained. Meeting abstracts were obtained from scientific sessions including the American Society of Nephrology Renal Week 2004 and the Endocrine Society's 87th Annual Meeting (2005). The Vaprisol (conivaptan hydrochloride injection) package insert was referenced and obtained from FDA.gov. A diagnosis of hyponatremia requires thorough investigation for underlying causes and prompt treatment to prevent poor patient outcomes. In clinical trials, a new class of drugs called the arginine vasopressin (AVP) receptor antagonists or aquaretics has been shown to be safe and effective for the treatment of hyponatremia. Among this class of agents, intravenous conivaptan hydrochloride, indicated for the treatment of euvolemic hyponatremia in hospitalized patients, is the first drug in class approved for use. Elderly patients, and those with certain conditions such as heart failure, tuberculosis, cirrhosis, and head injury, may be at increased risk for hyponatremia. In hospitalized patients following surgery and the use of certain medications, hyponatremia is a common condition. A thorough understanding of the physiology of water balance and the risk factors associated with hyponatremia is essential for prompt and effective intervention. Awareness of the limitations of conventional therapies and the availability of new treatment options for hyponatremia allows clinicians to optimize patient care.

Conivaptan satisfactory for surges in sodium

Conivaptan satisfactory for surges in sodium

Conivaptan: New treatment for hyponatremia

The pharmacology, bioavailability and pharmacokinetics, clinical efficacy, adverse effects and toxicities, drug interactions, dosage and administration, and safety issues related to the use of conivaptan are discussed. Conivaptan hydrochloride is a nonpeptide, V1A and V2 vasopressin-receptor antagonist. It is available as an i.v. formulation in 4-mL ampules containing 20 mg of conivaptan hydrochloride. The drug is active both orally and i.v. Conivaptan injection is approved for the treatment of euvolemic hyponatremia in hospitalized patients. Three double-blind, placebo-controlled, randomized, multicenter studies have been conducted in the United States and internationally. The studies used various dosing regimens for conivaptan but maintained the same efficacy endpoints. Each study showed conivaptan to be effective in increasing serum sodium and in water clearance. Conivaptan is being evaluated in the treatment of acute decompensated heart failure and chronic heart failure, but the safety of this drug has not been fully established. The drug has been generally well tolerated in clinical trials with both oral and i.v. administration. The approved dosing regimen consists of a 20-mg i.v. loading dose administered over 30 minutes, followed by a continuous infusion of 20 mg administered over 24 hours. Clinical studies evaluating conivaptan have been short term; longer-term effects of hemodynamic parameters are unknown. Conivaptan, the first vasopressin antagonist approved for the treatment of euvolemic hyponatremia, has a unique mechanism of action that results in free-water excretion and offers a new option for the treatment of resistant hyponatremia in the acute setting when patients have not responded to standard management.

Recognition and treatment of hyponatremia in acutely ill hospitalized patients

Objective: The objective of this paper was to discussthe diagnosis, pathophysiology, and management of hyponatremia among critically ill, hospitalized patients (eg, after surgery or in the intensive care unit). Methods: English-language literature published between 1967 and 2006 was searched using several key words ( AVP receptor antagonists, hyponatremia, SIADH, conivaptan, tolvaptan, and lixivaptan) and by accessing MEDLINE and ScienceDirect. Meeting abstracts from scientific sessions (American Society of Nephrology Renal Week 2004 and the Endocrine Society's 87th Annual Meeting [2005]) were reviewed. The package insert for conivaptan hydrochloride injection was referenced from . Clinical trials included in this review were randomized and placebo controlled. Results: Based on the literature we researched, hyponatremia is the most common electrolyte disorder encountered in critical care and is associated with a variety of conditions, including congestive heart failure and the syndrome of inappropriate antidiuretic hormone secreion. Because hyponatremia can arise in hypervolemic, euvolernic, and hypovolemic states, clinicians may not recognize its presence and cause. Incorrect rnanagement can lead to significant morbidity and mortality. Physicians need to recognize risk factors and symptoms and use appropriate treatment guidelines for hyponatremia. Traditionally, therapy for hyponatremia has been limited by efficacy and safety concerns. Arginine vasopressin (AVP) receptor antagonists, therapeutic agents that promote aquaresis in patients with hyponatremia by targeting V 1a receptors in the vascular smooth muscle, V 2 receptors in the kidney, or both, are under development. A dual-receptor antagonist targeting both V 1a and V 2 receptors is now approved for the treatment of euvolernic hyponatremia in hospitalized patients. Conclusions: Hyponatremia, an electrolyte abnormalityfound in critically ill patients, can be associated with significant morbidity and mortality. AVP receptor antagonists show promise as effective and tolerable treatments for patients with hyponatremia.

A Novel Vasopressin Dual V1A/V2 Receptor Antagonist, Conivaptan Hydrochloride, Improves Hyponatremia in Rats with Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)

We investigated the effects of intravenous administration of conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on blood electrolytes and plasma osmolality in rats with an experimental syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The experimental SIADH rat model was developed by means of continuous administration of arginine vasopressin (AVP) via a subcutaneously implanted osmotic mini pump, and hyponatremia was induced by additional water loading. This model possesses similar characteristics to those observed in patients with SIADH, specifically decreases in blood sodium concentration and plasma osmolality. In this experimental model, intravenous administration of conivaptan (0.1, 1 mg/kg) significantly increased blood sodium concentration and plasma osmolality. On the other hand, intravenous administration of furosemide (10 mg/kg) did not increase either blood sodium concentration or plasma osmolality in the SIADH rats. Moreover, furosemide significantly lowered blood potassium concentration. These results show that conivaptan improves hyponatremia in rats with SIADH, supporting the therapeutic potential of conivaptan in treatment of patients with hyponatremia associated with SIADH.

A New Class of Drugs for Hyponatremia

Vasopressin-receptor antagonists are being developed to treat hyponatremia. The only one currently available in the U.S. is conivaptan (Vaprisol), an