OPC 41061 IN PTS WITH HYPONATREMIA SECONDARY TO LIVER DISEASE

OPC 41061 在继发于肝病的低钠血症患者中的应用

• 批准号: 6304303
• 负责人: BAHRI M BILIR
• 金额: $ 3.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6304303
• 关键词: clinical research; dosage; electrolyte balance; hormone inhibitor; hormone receptor; human subject; human therapy evaluation; hyponatremia; liver disorder; liver disorder chemotherapy; vasopressins

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.

研究人员推测：(1)精氨酸加压素，或抗利尿激素，通过刺激其肾脏或V2受体，有助于肝病相关的肾脏水排泄的损害；(2)选择性拮抗VS受体AVP将导致尿渗透压降低，游离水排泄增加，体重减轻；(3)选择性拮抗AVP V2受体将纠正血钠浓度接近正常。一种常见的电解质紊乱，如低钠血症，可通过引起脑水肿而产生严重的神经并发症。轻度低钠血症(钠水平在130mEq/L和135mEq/L之间)的患者往往表现良好，但严重低钠血症与相当高的发病率和死亡率相关。终末期肝病(肝硬变)、充血性心力衰竭、肾病综合征和ADH分泌异常综合征(SIADH)是常见的与全身钠升高的低钠血症相关的疾病。用传统利尿剂治疗这些情况通常会使低钠血症变得更严重。在这些情况下，游离水的排泄受到损害，导致循环中AVP水平升高而导致的低钠血症。压力感受器和渗透压感受器在刺激下丘脑-神经垂体轴的AVP释放中起作用。AVP通过cAMP依赖的V2受体刺激肾脏集合管的水吸收。对于由于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。一些专家强调了血管加压素V2拮抗剂在治疗低钠血症中可能具有的潜在重要性，因为这些药物将允许肾脏排出游离水(水缺乏)。通过创造负的水平衡，V2拮抗剂随后会将血浆钠浓度提高到正常水平。主要疗效变量将是血钠浓度，次要疗效变量将是尿渗透压、尿量和体重。