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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。腹水是肝硬化的主要并发症之一，其通常的治疗包括钠限制饮食和利尿剂。通常的利尿方案包括螺内酯和速尿的组合。这对大多数患者都有效；然而，有些人对这种治疗产生抗药性，并对治疗构成挑战。在各种液体潴留状态下（如肝硬化患者静脉注射白蛋白，肾病综合征患者静脉注射磺胺恶唑），已经有了一些方法来减轻对利尿剂的耐药性。既往研究表明，肾小球滤过率（GFR）降低是肝硬化腹水患者对利尿剂产生利尿剂抵抗的机制之一。最近有研究表明，米多宁和α -1激动剂可以改善非氮化肝硬化伴腹水患者的GFR。基于这一背景，我们假设midodrine联合给药可以通过影响呋塞米的药代动力学和药效学和/或肾脏血流动力学来增强呋塞米对肝硬化腹水患者的疗效。我们建议对肝硬化腹水患者进行一项随机、两期交叉研究，以评估middodrine联合用药是否能增强对呋塞米的反应。两个阶段是(a)静脉滴注呋塞米40mg +口服米多宁15mg (b)呋塞米40mg +口服安慰剂。我们将测量midodrine联合给药对呋塞米反应（尿量和钠排泄）、药代动力学（消除半衰期、vd、血清清除率）和药效学（通过将呋塞米排泄率与碘甲酸酯清除率相关联）的影响。本研究将探讨midodrine联合给药对肝硬化腹水患者速尿药代动力学和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.