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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 腹水是肝硬化的主要并发症之一，其通常的治疗包括限钠饮食和利尿剂。 通常的利尿剂方案包括螺内酯和呋塞米的组合。 这在大多数患者中是有效的;然而，一些患者对这种疗法产生耐药性并构成治疗挑战。 已经进行了几项努力来开发减轻各种液体潴留状态下对袢利尿剂的耐药性的方法（例如，肝硬化中静脉内白蛋白给药或肾病综合征中的磺胺异恶唑）。 既往研究表明，肾小球滤过率（GFR）降低是腹水患者对袢利尿剂产生利尿剂抵抗的机制之一。 最近已经证明米多君和α-1激动剂可以改善非氮质血症腹水患者的GFR。 基于这一背景，我们假设米多君联合给药通过其对呋塞米的药代动力学和药效学和/或肾脏血流动力学的影响，增强呋塞米在腹水患者中的疗效。 我们提出了一个随机的，两个阶段，交叉研究的腹水，以评估是否米多君联合管理提高对呋塞米的反应。 两个阶段是（a）呋塞米40 mg静脉注射+米多君15 mg口服（B）呋塞米40 mg +口服安慰剂。 我们将测量米多君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生物酞酸盐清除率的排泄率相关联）的影响。 本研究将探讨米多君联合用药对速尿药代动力学的影响，以及对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 biothalamate 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.