Effect of diflunisal (IND68092) on familial amyloidosis

二氟尼柳 (IND68092) 对家族性淀粉样变性的影响

• 批准号: 7276604
• 负责人: JOHN L BERK
• 金额: $ 129.73万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7276604
• 关键词: Anti-Inflammatory Agents; Award; Budgets; Cardiomyopathies; Carrier Proteins; Daily; Data; Development; Diflunisal; Disease; Disease Progression; Dose; Double-Blind Method; Familial Amyloidosis; Genes; Grant; Immunoblotting; Inherited Polyneuropathy; International; Kidney; Liver; Measures; Mediating; Mutate; Neurologic; Organ; Orphan; Orphan Disease; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Polyneuropathy; Prealbumin; Qualifying; Randomized; Research Personnel; Score; Serum; Stabilizing Agents; Toxic effect; United States; United States Food and Drug Administration; amyloid fibril formation; compliance behavior; cost; design; human study; indexing; liver transplantation; monomer; prevent; programs; trial comparing

DESCRIPTION (provided by applicant): Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant disease mediated by misfolding of transthyretin, a transport protein produced by the liver. Less than 200,000 patients with FAP exist in the United States, qualifying FAP for Orphan Disease status. Replacing amyloidogenic transthyretin gene by liver transplantation is the only effective therapy at present. A tetramer in its native state, transthyretin is only amyloidogenic when dissociated to its monomeric form. Our data indicates that diflunisal, a commercially available non-steroidal anti-inflammatory agent, stabilizes transthyretin tetramers, preventing amyloid fibril formation by misfolded transthyretin monomers. Our phase I human study demonstrated that moderate doses of diflunisal stabilized transthyretin tetramers with no evident toxicities. To examine the effect of diflunisal on mutated transthyretin tetramer stability and FAP disease progression, we propose conducting an international, multi-center, randomized, placebo-controlled, double blind trial comparing diflunisal 250 mg taken orally twice daily to no drug treatment. In the proposed study we will: Aim 1. Define the effect of diflunisal on FAP disease progression over 2 years. A. We will employ validated composite neurologic scales and echocardiographic measures of infiltrative cardiomyopathy to serially assess end-organ disease state in patients with FAP receiving diflunisal or placebo over 2 years, using a randomized, double blind, multi-center design. B. The tolerability of daily diflunisal in FAP patients will be determined by monthly renal, liver, and hematologic indices. Aim 2. Examine transthyretin tetramer stability in FAP patients randomly assigned to the diflunisal and placebo groups. The stability of tetrameric transthyretin (TTR) in the sera of FAP patients randomized to diflunisal or placebo treatment will be evaluated by PAGE analysis followed by immunoblotting. poiuytrewq c Diflunisal drug levels will be determined to assess treatment compliance. We will correlate FAP disease progression with TTR stabilization.

描述（由申请人提供）：家族性淀粉样变性多发性神经病（FAP）是一种致死性常染色体显性遗传疾病，由转甲状腺素蛋白（一种由肝脏产生的转运蛋白）错误折叠介导。美国仅有不到 200,000 名 FAP 患者，符合孤儿病资格。通过肝移植替代淀粉样变甲状腺素蛋白基因是目前唯一有效的治疗方法。转甲状腺素蛋白在其天然状态下是四聚体，只有在解离成单体形式时才会产生淀粉样蛋白。我们的数据表明，二氟尼柳是一种市售非甾体抗炎药，可稳定运甲状腺素蛋白四聚体，防止错误折叠的运甲状腺素蛋白单体形成淀粉样原纤维。 我们的第一阶段人体研究表明，中等剂量的二氟尼柳可稳定转甲状腺素蛋白四聚体，没有明显的毒性。为了检查二氟尼柳对突变转甲状腺素蛋白四聚体稳定性和 FAP 疾病进展的影响，我们建议进行一项国际、多中心、随机、安慰剂对照、双盲试验，比较每日两次口服二氟尼柳 250 mg 与不接受药物治疗。在拟议的研究中，我们将： 目标 1. 确定二氟尼柳对 2 年内 FAP 疾病进展的影响。答：我们将采用随机、双盲、多中心设计，采用经过验证的复合神经系统量表和浸润性心肌病超声心动图测量来连续评估接受二氟尼柳或安慰剂超过 2 年的 FAP 患者的终末器官疾病状态。 B. FAP 患者每日二氟尼柳的耐受性将根据每月的肾、肝和血液学指标来确定。目标 2. 检查随机分配到二氟尼柳组和安慰剂组的 FAP 患者中转甲状腺素蛋白四聚体的稳定性。将通过 PAGE 分析和免疫印迹评估随机接受二氟尼柳或安慰剂治疗的 FAP 患者血清中四聚运甲状腺素蛋白 (TTR) 的稳定性。 poiuytrewq c 将测定二氟尼药物水平以评估治疗依从性。我们将 FAP 疾病进展与 TTR 稳定相关联。