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NALOXONE EFFECT ON RENAL FUNCTIONS IN LIVER CIRRHOSIS

纳洛酮对肝硬化肾功能的影响

基本信息

批准号：
2045352
负责人：
DAVID LEEHEY
金额：
$ 7.14万
依托单位：
EDWARD HINES JR VA HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-02-01 至 1995-01-31
项目状态：
已结题

项目摘要

Renal functional abnormalities (impaired renal hemodynamics and water and electrolyte excretion) are commonly seen in patients with liver cirrhosis. Circulating levels of endogenous opioids with antidiuretic properties may be increased in liver cirrhosis, and the opioid antagonist naloxone increases creatinine clearance and water and electrolyte excretion in water-loaded patients with cirrhosis and ascites. Question 1: Are the diuretic effects of the opioid antagonist naloxone in patients with cirrhosis and ascites associated with an increase in renal hemodynamics (renal plasma flow and glomerular filtration rate) or circulating levels of hormones known to affect renal hemodynamics or tubular functions? Can a chronic infusion of naloxone result in sustained renal effects? Question 2: Can the effects of diuretics currently utilized in cirrhotic patients be enhanced by simultaneous administration of naloxone? Question 3: Are endogenous opioid systems activated in cirrhotic patients? Patients with alcoholic cirrhosis and ascites with essentially normal (creatinine clearance greater than or equal to 70 mL/min) or depressed (less than 70 mL/min) glomerular filtration rate will undergo both acute (5h) and chronic (48h) naloxone infusion studies in order to determine its effects on renal hemodynamics, water and electrolyte excretion, and hormones known to affect renal functions. Measurements will include effective renal plasma flow and glomerular filtration rate (inulin, PAH, and radioisotopic methods), water and solute excretion parameters, plasma renin, angiotensin II, aldosterone, catecholamines, vasopressin, atrial natriuretic peptide, glucagon, and insulin-like growth factor (IGF-1), urinary vasodilator prostaglandin and thromboxane metabolites. Plasma endogenous opioids (beta-endorphin, enkephalins, and dynorphin) will be determined by HPLC/RIA in order to determine which opioids are increased in cirrhotic patients and whether the circulating level correlates with basal renal functional parameters or the magnitude of the renal hemodynamic/diuretic response to naloxone. We expect that naloxone will increase glomerular filtration rate, thus resulting in diuresis; more importantly, naloxone should markedly potentiate the effect of currently-used diuretics for this condition (furosemide and spironolactone). As there are currently no therapeutic agents which predictably improve renal hemodynamics in patients with liver cirrhosis and ascites, our study findings should not only provide basic information on the role of endogenous opioids in liver disease but might prove to be clinically very useful.

肾功能异常（肾血流动力学和水和水受损）电解质排泄）常见于肝硬化患者。具有抗利尿作用的内源性阿片类药物的循环水平可能肝硬化时会增加，阿片类拮抗剂纳洛酮增加肌酐清除率以及水和电解质的排泄患有肝硬化和腹水的多水患者。问题1：是阿片类拮抗剂纳洛酮对患者的利尿作用与肾血流动力学增加相关的肝硬化和腹水（肾血浆流量和肾小球滤过率）或循环水平已知影响肾血流动力学或肾小管功能的激素？可以一个长期输注纳洛酮会导致持续的肾脏影响吗？问题 2：目前在肝硬化患者中使用的利尿剂的效果可以吗？同时服用纳洛酮可增强效果吗？问题3：是肝硬化患者内源性阿片类药物系统被激活？酒精性肝硬化且腹水基本正常的患者（肌酐清除率大于或等于 70 mL/min）或抑郁（低于70毫升/分钟）肾小球滤过率将经历急性（5小时）和长期（48小时）纳洛酮输注研究以确定其对肾脏血流动力学、水和电解质排泄的影响已知影响肾功能的激素。测量将包括有效肾血浆流量和肾小球滤过率（菊粉、PAH、和放射性同位素方法）、水和溶质排泄参数、血浆肾素、血管紧张素 II、醛固酮、儿茶酚胺、加压素、心房利钠肽、胰高血糖素和胰岛素样生长因子 (IGF-1)，尿血管扩张剂前列腺素和血栓素代谢物。等离子体内源性阿片类药物（β-内啡肽、脑啡肽和强啡肽）通过 HPLC/RIA 测定，以确定哪些阿片类药物在肝硬化患者的循环水平是否与基础水平相关肾功能参数或肾功能的大小对纳洛酮的血流动力学/利尿反应。我们预计纳洛酮将增加肾小球滤过率，从而导致利尿；更多的重要的是，纳洛酮应该显着增强目前用于治疗这种情况的利尿剂（呋塞米和螺内酯）。由于目前尚无治疗药物可预测地改善肝硬化患者的肾血流动力学腹水，我们的研究结果不应仅提供基本信息内源性阿片类药物在肝脏疾病中的作用，但可能被证明是临床上非常有用。