IND 117464 Use of Low Dose Pioglitazone to Treat Autosomal Dominant Polycystic Kidney Disease

迫切需要安全、廉价的治疗方法来延缓囊性肿大的进展。 以及伴随而来的肾实质破坏，导致大多数患者的肾功能衰竭 常染色体多囊肾病(ADPKD)患者。在ADPKD中，治疗开始得越早， 对患者的潜在益处更大，因此，治疗这种疾病的药物应该被认为是终身的。 心理治疗。我们的总体目标是开发从诊断时起就可以安全使用的有效药物。 在ADPKD患者中。拟议研究的目标是对药物进行初步评价 使用小剂量胰岛素增敏剂，PPARγ激动剂，吡格列酮治疗 ADPKD.我们先前的细胞培养研究表明，低剂量的PPARγ激动剂，包括吡格列酮， 抑制囊性纤维化跨膜电导调节剂(CFTR)氯通道的合成 排列在肾囊内的细胞类型。Cftr是推测参与跨上皮细胞活动的主要离子通道。 CL-和，其次，水流入囊腔导致囊腔扩张。我们的活体动物研究 已经表明，fda批准的两种pparγ激动剂，吡格列酮或罗格列酮，抑制了囊泡的生长。 在PKD的PCK大鼠模型中。除了抑制囊肿生长外，PPARγ激动剂治疗有望 对PKD的其他参数，如血脂异常、高血压和血管内皮细胞有有益的影响 功能。基于这些数据，我们假设小剂量吡格列酮的治疗将减慢。 人类ADPKD患者的囊性扩张和延缓疾病的进展。建议进行的研究 是一项双盲、安慰剂对照的交叉试验，吡格列酮(每天15毫克)与安慰剂治疗 ADPKD的治疗。这项研究是测试吡格列酮延缓的安全性和有效性的先导性研究。 与一年前相比，用MRI肾体积变化百分比评估PKD的进展 安慰剂。28个科目将被录取。一年的交叉设计提供了获得 通过允许每个患者作为自己的患者，在短期方案中提供有意义的安全性和有效性数据 控制力。这将有助于未来多中心随机试验的设计。基于来自大型 在正常志愿者和糖尿病患者中进行的量表研究表明，小剂量吡格列酮长期相对安全 定期治疗。因此，该药物为ADPKD患者的治疗提供了一种安全的选择，并增加了 在时间长短和生活质量方面。

There is a critical need for safe, inexpensive treatments that can delay the progression of cyst enlargement and the accompanying destruction of the renal parenchyma that leads to renal failure in the majority of autosomal polycystic kidney disease (ADPKD) patients. In ADPKD, the earlier the onset of treatment, the greater the potential benefit to the patient, therefore, drugs for this disease should be considered life-long therapy. Our overall goal is to develop efficacious drugs that can be safely used from the time of diagnosis in ADPKD patients. The objective in the proposed studies is to conduct a preliminary evaluation of drug therapy using a low dose of an insulin sensitizing agent, the PPARγ agonist, pioglitazone, in the treatment of ADPKD. Our previous cell culture studies showed that low doses of PPARγ agonists, including pioglitazone, inhibit the synthesis of the CFTR (cystic fibrosis transmembrane conductance regulator) Cl- channel in the cell type that lines the renal cysts. CFTR is the major ion channel postulated to be involved in transepithelial Cl- and, secondarily, water flux into the cyst lumen resulting in cyst expansion. Our in vivo animal studies have shown that the two FDA approved PPARγ agonists, pioglitazone or rosiglitazone, inhibited cyst growth in the PCK rat model of PKD. In addition to inhibiting cyst growth, PPARγ agonist therapy is expected to have beneficial effects on other parameters of PKD such as dyslipidemia, hypertension and endothelial function. Based on these data, we hypothesize that treatment with low dose pioglitazone will slow cyst expansion in human ADPKD patients and delay the progression of disease. The proposed study is a double-blind, placebo controlled, cross-over trial of pioglitazone (15 mg/day) versus placebo therapy for the treatment of ADPKD. The study is a pilot study to test the safety and efficacy of pioglitazone to slow progression of PKD assessed by percent change in kidney volume by MRI compared to one year of placebo. 28 subjects will be enrolled. A one year cross-over design provides the best opportunity to obtain meaningful safety and efficacy data in a short term protocol by allowing each patient to serve as his/her own control. This will facilitate the design of a future multi center randomized trial. Based on data from large scale studies in normal volunteers and diabetic patients, low dose pioglitazone is relatively safe for long term treatment. Thus, this drug may provide a safe option for treatment of ADPKD patients and an increase in length and quality of life.