OPC 41061 IN PTS WITH HYPONATREMIA SECONDARY TO LIVER DISEASE

University Of Colorado Denver, Aurora CO

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Abstract

The investigators hypothesize that (1) arginine vasopressin, or antidiuretic hormone, via stimulation of its renal or V2 receptor contributes to the impairment in renal water excretion associated with liver disease, (2) selective antagonism of the VS receptor for AVP will result in a decrease in urinary osmolality, an increase in free water excretion, and a decrease in body weight, and (3) selective antagonism of the V2 receptor for AVP will correct the serum sodium concentration towards normal. A frequently encountered electrolyte disorder such as hyponatremia can produce severe neurological complications by causing brain edema. Individuals with mild cases of hyponatremia (sodium levels between 130 and 135 mEq/L) tend to do well, however severe hyponatremia is associated with substantial morbidity and mortality. Endstage liver disease (cirrhosis), congestive heart failure, nephrotic syndrome and the Syndrome of Inappropriate ADH secretion (SIADH) are conditions frequently associated with hyponatremia in which total body sodium is increased. Treatment of these conditions with traditional diuretics usually makes the hyponatremia worse. In these conditions, the excretion of free water is impaired causing hyponatremia resulting from an increased level of circulating AVP. Baroreceptors and osmoreceptors play a part in stimulating the release of AVP from the hypothalamo-neurophypophyseal axis. AVP stimulates water absorption in renal collecting ducts via CAMP-dependent V2 receptors. A logical treatment for hyponatremia resulting from increased levels of AVP is using an antagonist of the V2 receptor. At present , treatment of hyponatremia is limited to restriction of fluid intake. Several experts have underlined the potential importance that vasopressin V2 antagonists might have in the therapy of hyponatremia as these drugs would allow excretion by the kidney of free water (aquaresis). By creating a negative water balance, V2 antagonists would then increase plasma sodium concentration toward normal. The primary eficacacy variable will be plasma sodium concentration and the secondary efficacy variables will be urine osmolality, urine volume, and body weight.