OPC 41061 IN PTS WITH HYPONATREMIA SECONDARY TO LIVER DISEASE

研究人员假设：（1）精氨酸加压素或抗利尿激素，通过刺激其肾脏或V2受体，导致与肝脏疾病相关的肾脏水排泄受损，（2）选择性拮抗AVP的VS受体将导致尿渗透压降低，游离水排泄增加和体重减轻，（3）选择性地拮抗AVP的V2受体，可使血清钠浓度向正常方向调整。常见的电解质紊乱如低钠血症可引起脑水肿，从而产生严重的神经系统并发症。 轻度低钠血症（钠水平在130至135 mEq/L之间）的个体往往表现良好，但重度低钠血症与大量发病率和死亡率相关。 终末期肝病（肝硬化）、充血性心力衰竭、肾病综合征和ADH分泌不当综合征（SIADH）是常与低钠血症相关的疾病，其中全身钠增加。 用传统利尿剂治疗这些疾病通常会使低钠血症恶化。 在这些条件下，游离水的排泄受损，导致低钠血症，这是由循环AVP水平增加引起的。 压力感受器和加压素受体参与刺激下丘脑-神经垂体轴释放AVP。 AVP通过cAMP依赖性V2受体刺激肾集合管中的水吸收。 AVP水平升高导致的低钠血症的合理治疗是使用V2受体拮抗剂。 目前，低钠血症的治疗仅限于限制液体摄入。 几位专家强调了加压素V2拮抗剂在低钠血症治疗中的潜在重要性，因为这些药物将允许肾脏排泄游离水（水分泌）。 通过建立负水平衡，V2拮抗剂将使血浆钠浓度升高至正常水平。 主要疗效变量为血浆钠浓度，次要疗效变量为尿渗透压、尿量和体重。

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.