Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis

Inoue, Tomoo; Ohnishi, Akihiro; Matsuo, Atsushi; Kawai, Bunpei; Kunihiro, Naoko; Tada, Yasuhiro; Koizumi, Fumiaki; Chau, Tommy; Okada, Keiko; Yamamura, Yoshitaka; Tanaka, Teruji

doi:10.1016/s0009-9236(98)90107-2

Cited by 60 publications

(27 citation statements)

References 22 publications

(4 reference statements)

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“…The first studies on vaptans in cirrhosis were performed in patients with ascites but without hyponatremia. 37,41 In this population, the oral administration of vaptans is associated with a marked increase in urine volume, reduction in urine osmolality, and increase in solute-free water excretion, which is responsible for a negative fluid balance. Urine sodium excretion does not change significantly.…”

Section: Effects Of Vaptans In Patients With Cirrhosismentioning

confidence: 99%

Hyponatremia in cirrhosis: Pathogenesis, clinical significance, and management

Ginès¹,

Guevara²

2008

Hepatology

273

269

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Hyponatremia is a frequent complication of advanced cirrhosis related to an impairment in the renal capacity to eliminate solute-free water that causes a retention of water that is disproportionate to the retention of sodium, thus causing a reduction in serum sodium concentration and hypo-osmolality. The main pathogenic factor responsible for hyponatremia is a nonosmotic hypersecretion of arginine vasopressin (or antidiuretic hormone) from the neurohypophysis related to circulatory dysfunction. Hyponatremia in cirrhosis is associated with increased morbidity and mortality. There is evidence suggesting that hyponatremia may affect brain function and predispose to hepatic encephalopathy. Hyponatremia also represents a risk factor for liver transplantation as it is associated with increased frequency of complications and impaired short-term survival after transplantation. The current standard of care based on fluid restriction is unsatisfactory. Currently, a new family of drugs, known as vaptans, which act by antagonizing specifically the effects of arginine vasopressin on the V2 receptors located in the kidney tubules, is being evaluated for their role in the management of hyponatremia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatremia. Long-term administration of vaptans seems to be effective in maintaining the improvement of serum sodium concentration, but the available information is still limited. Treatment with vaptans represents a novel approach to improving serum sodium concentration in cirrhosis.

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Section: Effects Of Vaptans In Patients With Cirrhosismentioning

confidence: 99%

Hyponatremia in cirrhosis: Pathogenesis, clinical significance, and management

Ginès¹,

Guevara²

2008

Hepatology

273

269

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“…2 A benzazepine derivative named OPC-31260 was the first nonpeptide V2-receptor antagonist, and was introduced in 1992. [10][11][12] Two other compounds, SR-121463A 13 and VPA-985, 14,15 are now available. Compared with OPC-31260, these compounds exhibit a higher affinity and selectivity for V2-receptors, suggesting better efficacy.…”

mentioning

confidence: 99%

Pharmacodynamic effects of a nonpeptide antidiuretic hormone V2 antagonist in cirrhotic patients with ascites

Guyader

Patat²,

Ellis-Grosse³

et al. 2002

Hepatology

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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. I n normal individuals, the administration of a water load (20 mL/kg body weight of 5% glucose intravenously or water orally over 45 min) is followed by an increase in the excretion of a hypotonic (Ͻ100 mOsm/ kg) urine flow responsible for an increase in free water clearance (FWC) reaching 6 to 12 mL/min. Cirrhotic patients without ascites have normal water handling. 1 Up to 75% of cirrhotic patients with ascites, however, have moderate reduction (1-6 mL/min) of FWC after a water load. In approximately 30% of cases, the impairment is severe (Ͻ1 mL/min after water load) leading to spontaneous hyponatremia because those patients are unable to excrete regular water intake. 2 Hyponatremia can also be triggered or aggravated by the use of diuretics in about 25% of cases. Pathophysiologic mechanisms leading to water overload are not fully understood, but several factors may be involved, among them: (1) reduced delivery of filtrate to the ascending limb of the loop of Henle, secondary to enhancement of proximal sodium reabsorption and decrease of glomerular filtration rate; (2) reduced renal synthesis of prostaglandins; and (3) increased secretion of antidiuretic hormone. 3 There is some evidence to indicate that increased plasma arginine vasopressin (AVP) concentration plays a major role: a correlation between plasma AVP levels and the magnitude of FWC impairment 4 ; the temporal relationship between impairment of water excretion and vasopressin hypersecretion in rats with experimental cirrhosis; 5 the aquaretic effect of -opioid agonists, which act through inhibition of AVP release

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“…This has also been seen in patients with cirrhosis 11,12 and in patients with hyponatremia secondary to SIADH. 13,14 In a study by Wong et al, 44 hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with SIADH) were studied on a constant sodium intake, with lixivaptan doses of 25, 125, and 250 mg twice daily or placebo.…”

Section: Lixivaptan (Vpa 985)mentioning

confidence: 67%

Vasopressin receptor antagonists

Parashar

Martinucci

Panesar

2007

Dialysis & Transplantation

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A rginine vasopressin (AVP) is a human peptide hormone released during states of hypovolemia that stimulates the kidneys to conserve water by concentrating urine and reducing urine volume. It is synthesized in the hypothalamus as a pre-prohormone precursor and stored in the posterior pituitary gland.It is now believed that the role of AVP is central to the pathogenesis of various diseases such as congestive heart failure (CHF), cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). These clinical syndromes are characterized by elevated plasma levels of vasopressin and clinically manifest as a fluid retentive state. Therefore, patients become hyponatremic. There is a growing interest and effort to develop selective and long-lasting pharmaceutical agents that antagonize this effect.Over the past two decades, various vasopressin receptor antagonists (VRAs) have been developed and studied. The first nonpeptide vasopressin receptor antagonist was recently approved by the United States Food and Drug Administration (FDA), and other similar agents are presently in different stages of development. Clinically, these agents have the ability to reduce urine osmolality and increase free water excretion while preserving sodium and raising serum sodium concentration. This aquaretic effect is in contradistinction to that seen with traditional diuretics, which increase sodium excretion together with water excretion. Vasopressin PhysiologyArginine vasopressin, also known as antidiuretic hormone, is a 9-amino-acid peptide synthesized in the supraoptic and paraventricular nuclei of the hypothalamus. AVP is transported to the posterior lobe of the pituitary and stored in secretory granules. The two most important stimuli of AVP release are low blood volume and hypernatremia. Low blood volume is sensed by baroreceptors in the carotid artery, aortic arch, and left atrium and in response stimulate the release of vasopressin from the supraoptic and paraventricular nuclei. The body's protective mechanism to prevent the development of cardiovascular collapse when hypovolemia and hypotension are occurring is mediated by the vasoconstrictive properties of AVP.Vasopressin release is also regulated by osmoreceptors in the hypothalamus. The osmolality threshold for secretion is approximately 280 mOsm/kg, after which a small increase in plasma osmolality leads to enhanced vasopressin secretion. It is also known that vasopressin secretion also may be stimulated by non-osmotic and nonhemodynamic factors including nausea, pain, hypoglycemia, exercise, and drugs. Once secreted into serum, vasopressin has a half-life of approximately 10 minutes and is degraded by a cysteine amino-terminal peptidase called vasopressinase. Vasopressin ReceptorsADH receptors are G-protein-coupled receptors. There are 3 subtypes that differ in their localization and signal transduction mechanisms ( Table I). The vasopressin V1a receptor (V1aR) is a Gq-coupled receptor that activates phospholipase C and increases the concentration of intrace...

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Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis

Cited by 60 publications

References 22 publications

Hyponatremia in cirrhosis: Pathogenesis, clinical significance, and management

Hyponatremia in cirrhosis: Pathogenesis, clinical significance, and management

Pharmacodynamic effects of a nonpeptide antidiuretic hormone V2 antagonist in cirrhotic patients with ascites

Vasopressin receptor antagonists

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