OPC 41061 IN PTS WITH HYPONATREMIA SECONDARY TO LIVER DISEASE

研究者推测：(1)精氨酸抗利尿激素，或称抗利尿激素，通过刺激其肾受体或V2受体，导致与肝脏疾病相关的肾水排泄障碍；(2)AVP对VS受体的选择性拮抗将导致尿渗透压降低、游离水排泄增加和体重下降。(3)选择性拮抗AVP的V2受体可使血清钠浓度趋于正常。低钠血症是一种常见的电解质紊乱，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，但严重的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）通常与低钠血症相关，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。在这些情况下，游离水的排泄受损，导致低钠血症，导致循环AVP水平升高。压力感受器和渗透感受器在刺激AVP从下丘脑-神经垂体轴释放中起作用。AVP通过camp依赖性V2受体刺激肾集管的水分吸收。对于AVP升高引起的低钠血症，合理的治疗方法是使用V2受体拮抗剂。目前，低钠血症的治疗仅限于限制液体摄入。一些专家强调了抗利尿激素V2拮抗剂在治疗低钠血症中的潜在重要性，因为这些药物可以使肾脏排出游离水（缺水）。通过产生负水平衡，V2拮抗剂会使血浆钠浓度趋于正常。主要的疗效变量是血浆钠浓度，次要的疗效变量是尿渗透压、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.