PENTOXIFYLLINE AS A RESCUE TREATMENT IN DUCHENNE MUSCULAR DYSTROPHY

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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.