PENTOXIFYLLINE AS A RESCUE TREATMENT IN DUCHENNE MUSCULAR DYSTROPHY

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。DMD是最常见和最具破坏性的肌肉萎缩症类型（全世界每3500名活产男性中就有1例发病率）。DMD的特点是肌营养不良蛋白完全丧失，导致进行性肌肉无力和消瘦。肌营养不良蛋白是一种肌膜蛋白，其主要功能是稳定肌膜。这种疾病的主要缺陷是位于X染色体短臂上的肌营养不良蛋白基因的突变。[2,3]由于该基因非常大，有很高的自发突变率，这使得通过遗传咨询和筛查来根除该疾病是不可能的。目前对肌营养不良蛋白缺乏引发的病理生理级联反应了解甚多（图1）。由此产生的不稳定和渗漏的肌膜引起一系列事件，导致肌肉坏死、纤维化和再生失败。肌肉坏死和纤维化的机制之一是由肥大细胞、抗原呈递树突状细胞、CD4和CD8淋巴细胞和多形核细胞介导的免疫反应。这项多机构研究将是一项为期12个月的双盲随机研究。64名DMD患者将被随机分为PTX组或安慰剂组。它们将通过QMT， MMT，定时功能测试进行评估。肺功能检查，挛缩测量和生活质量。待研究人群为：男性，7岁至100岁，流动，回顾性稳定12个月类固醇剂量。本研究的主要终点是比较PTX治疗组和安慰剂治疗组的肌肉力量。肌肉力量，定量肌肉力量将使用CQMS测量。记录连续两次最大努力的最大值。主要强度终点为QMT总分。次要终点：次要终点将包括手臂、腿部和握力QMT评分（包括成对的屈肌和伸肌以及握力）、MMT评分（使用改进的医学研究委员会肌肉力量评分方法测量）、功能评估、时间功能测试、PFT、PQOL、角形测量、TNF α和TGF β。

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. DMD is the most common and devastating type of muscular dystrophy (incidence 1 in 3500 live born males worldwide). DMD is characterized by a complete loss of dystrophin, leading to progressive muscle weakness and wasting. Dystrophin is a sarcolemma protein with the main function of stabilizing the muscle membrane. The primary defect in this disease is a mutation in the dystrophin gene located on the short arm of the X chromosome. [2,3] Because of the very large size of the gene there is a high spontaneous mutation rate which makes eradication of the disease by genetic counseling and screening impossible. Much is known at present about the pathophysiological cascade that is triggered by the lack of dystrophin (Figure 1). The resulting unstable and leaky muscle membrane gives rise to a cascade of events that result in muscle necrosis, fibrosis and failure of regeneration. One of the mechanisms involved in muscle necrosis and fibrosis is an immune response mediated by mast cells, antigen-presenting dendritic cells, CD4 and CD8 lymphocytes and polymorphonuclear cells. This multi-institutional study will be a 12-month double-blinded, randomized study. Sixty-four DMD patients will be randomized into either a PTX arm or a placebo arm. They will be evaluated by QMT, MMT, timed function testing. pulmonary function testing, contracture measurement and quality of life. The population to be studied is: Male, 7 years to 100 years, Ambulant, Retrospective stable 12 month dose of steroids. The primary endpoint of this study is the comparison of muscle strength of PTX treated subjects and placebo treated subjects. Muscle strength, Quantitative muscle strength will be measured using the CQMS. The highest value of two consecutive maximal efforts is recorded. The primary strength endpoint will be total QMT score. Secondary Endpoints: Secondary endpoints will include arm, leg and grip QMT scores consisting of paired flexors and extensors as well as hand grip, MMT score (measured using a modified Medical Research Council's muscle strength scoring method), functional evaluations, time function tests, PFT's, PQOL, goniometry, TNF alpha and TGF beta.