MIDODRINE ADMINISTRATION IN RESPONSE TO FUROSEMIDE IN PTS W/CIRRHOTIC ASCITES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。腹水是肝硬变的主要并发症之一，通常的治疗包括限钠饮食和利尿剂。通常的利尿方案包括螺内酯和速尿的组合。这在大多数患者中是有效的；然而，一些人对这种治疗产生抵抗力，并对治疗构成挑战。在不同的液体保留状态(例如，在肝硬变时静脉注射白蛋白或在肾病综合征中使用磺胺恶唑)，已经有几种方法来减轻对环状利尿剂的耐药性。先前的研究表明，肾小球滤过率降低是肝硬变腹水患者利尿剂抵抗环状利尿剂的机制之一。最近的研究表明米多君和α-1激动剂可以改善非氮质型肝硬变腹水患者的肾小球滤过率。基于这一背景，我们假设米多君联合应用可通过影响速尿的药代动力学和药效学和/或肾血流动力学来增强速尿对肝硬变腹水患者的疗效。我们建议对合并腹水的肝硬变患者进行随机、分两阶段的交叉研究，以评估米多君联合用药是否增强了对速尿的反应。两个阶段是(A)速尿40 mg静脉注射+米多君15 mg口服(B)速尿40 mg+口服安慰剂。我们将测量米多君对速尿的反应(尿量和钠排泄)、药代动力学(消除半衰期、Vd、血清清除量)和药效学(通过将速尿的排泄率与异硫氰酸酯清除量的排泄率联系起来)的影响。本研究将探讨米多君合用对速尿药代动力学的影响，以及对肝硬变腹水患者肾脏血流动力学的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AScites is one of the major complications of cirrhosis and its usual treatment consists of sodium restricted diet and diuretics. The usual diuretic regimen consists of a combination of spironolactone and furosemide. This is effective in majority of the patients; however, some become resistant to such therapy and pose a therapeutic challenge. There have been several efforts to develop methods to alleviate resistance to loop diuretics in various fluid retentive states (e.g. intravenous albumin administration in cirrhosis or sulfisoxazole in nephrotic syndrome). Previous studies have demonstrated that diminished glomerular filtration rate (GFR) is one of the mechanisms for diuretic resistance to loop diuretics in patients with cirrhotic ascites. It recently has been demonstrated that midodrine, and alpha-1 agonist, can improve the GFR in non-azotemic cirrhotics with ascites. Based on this background, we hypothesize that midodrine co-administration enhances the efficacy of furosemide in patients with cirrhotic ascites through its effects on pharmacokinetics and pharmacodynamics of the furosemide and/or the renal hemodynamics. We propose a randomized, two phased, crossover study of cirrhotics with ascites to assess whether midodrine co-administration enhances the response to furosemide. Two phases are (a) furosemide 40 mg intravenously + midodrine 15 mg orally (b) furosemide 40 mg + oral placebo. We will measure the effect of midodrine co-administration on the response to furosemide (urinary volume and sodium excretion), the pharmacokinetics (elimination of half-life, V d, serum clearance) and pharmacodynamics (by relating the excretion rate of furosemide to the excretion rate by iothalamate clearance). This study will examine the effects of midodrine co-administration on the pharmacokinetics of furosemide, and the renal hemodynamics in patients with cirrhotic ascites.