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，导致与肝病相关的肾水排泄受损，(2) VS 受体对 AVP 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减轻，(3) AVP 的 V2 受体选择性拮抗将纠正血清钠浓度趋于正常。经常遇到的电解质紊乱（例如低钠血症）会导致脑水肿，从而产生严重的神经并发症。 患有轻度低钠血症（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较高的发病率和死亡率相关。 终末期肝病（肝硬化）、充血性心力衰竭、肾病综合征和抗利尿激素分泌不当综合征（SIADH）通常与低钠血症相关，导致体内钠总量增加。 用传统利尿剂治疗这些病症通常会使低钠血症恶化。 在这些情况下，游离水的排泄受到损害，导致循环 AVP 水平升高导致低钠血症。 压力感受器和渗透压感受器在刺激下丘脑-神经垂体轴释放 AVP 中发挥作用。 AVP 通过 CAMP 依赖性 V2 受体刺激肾集合管中的水吸收。 对于因 AVP 水平升高而导致的低钠血症，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。 几位专家强调了加压素 V2 拮抗剂在低钠血症治疗中可能具有的潜在重要性，因为这些药物可以通过肾脏排泄游离水（缺水）。 通过创造负水平衡，V2 拮抗剂会将血浆钠浓度提高到正常水平。 主要功效变量是血浆钠浓度，次要功效变量是尿液渗透压、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.