Oxandrolone and Exercise: A potent therapy in the rehabilitation from burns

 描述(由申请人提供)：严重烧伤的儿童在烧伤后两年内表现出分解代谢状态。这种分解代谢状态导致显著的肌肉萎缩、虚弱、免疫抑制、慢性骨丢失、生长减慢，以及代谢、血流动力学、炎症和瘢痕反应的同时增加。在烧伤儿童中，运动训练可以改善瘦体重(LBM)、肌肉力量和心血管耐力，尽管它不能将这些参数恢复到健康儿童的水平。据报道，在接受口服合成睾酮类似物奥曲酮的烧伤儿童中，情况也有类似的改善。在PI的一项初步研究中，运动和氧雄酮的组合比单独运动或单用氧雄酮在更大程度上缓解了烧伤诱导的分解代谢。因此，本项目的目标是比较运动-羟雄酮联合疗法与目前烧伤护理标准(SOC)中单纯运动疗法的治疗和功能疗效。有待检验的中心假设是，运动-羟雄酮联合疗法在减轻烧伤引起的分解代谢、增加LBM、运动耐力和心血管功能方面优于单独运动。为此，100名严重烧伤的儿童(7岁至21岁；烧伤面积占总体表面积的30%)将被前瞻性地随机分成两组，分别接受奥曲酮液体(0.2 mg/kg/天，N=50)或安慰剂(N=50)。药物或安慰剂将从入院到12周的锻炼计划(有氧和抵抗力运动)结束，该计划将在出院时开始。两个具体目标将同时实现。目的1确定运动训练/康复加奥昔洛酮与单纯运动的生理治疗效果。 工作假设是，在改善LBM、肌肉功能和整体心血管功能--所有这些都与临床相关和重要的功能终点--方面，综合疗法将优于单独锻炼。目标2将确定运动训练/康复加奥昔洛酮相对于单纯运动的生化后果。工作假设是，在改善蛋白质平衡、改善胰岛素敏感性和降低肝脏/组织肥胖症方面，综合疗法将优于单独锻炼。该项目有望建立一种新的治疗方法，在烧伤诱导的分解代谢的临床和功能结果方面提供更实质性的改善。这也有望为其他肌肉萎缩或肌肉损失疾病的类似治疗提供基础。该项目的长期目标是确定临床有效的治疗干预措施，以促进严重烧伤儿童的康复和康复，以及NICHD改善受伤儿童康复的使命，使他们能够发挥其潜力，过上健康的生活。

 DESCRIPTION (provided by applicant): Children with severe burns manifest a catabolic state up to two years after burn. This catabolic state results in significant muscle wasting, weakness, immunosuppression, chronic bone loss, decreased growth, and concurs- rent increases in metabolic, hemodynamic, inflammatory, and scarring responses. In burned children, exercise training improves lean body mass (LBM), muscle strength, and cardiovascular endurance, though it does not restore these parameters to levels seen in healthy children. Similar improvements have been reported in burned children receiving oxandrolone, an oral synthetic testosterone analogue. In a preliminary study by the PI, the combination of exercise and oxandrolone eased burn-induced catabolism to a greater degree than ei- ther exercise or oxandrolone alone. Thus, the objective of this project is to compare the therapeutic and func- tional efficacy of the combined exercise-oxandrolone therapy with that of exercise alone, our current standard of burn care (SOC). The central hypothesis to be tested is that the combined exercise-oxandrolone therapy will be superior to exercise alone in attenuating burn-induced catabolism and increasing LBM, exercise endurance, and cardiovascular function. To this end, 100 severely burned children (7 to <21 years; burns e30% of the total body surface area) will be prospectively randomized to receive liquid oxandrolone (0.2 mg/kg/day, N=50) or placebo (N=50). Drug or placebo will be administered from hospital admission to the end of a 12-week exer- cise program (aerobic and resistive exercise), which will begin at hospital discharge. Two Specific Aims will be simultaneously pursued. Aim 1 will determine the physiological therapeutic efficacy of exercise train- ing/rehabilitation plus oxandrolone relative to that of exercise alone. The working hypothesis is that the combined therapy will be superior to exercise alone in improving LBM, muscle function, and overall cardiovas- cular function-all clinically relevant and vital functional endpoints. Aim 2 will determine the biochemical consequences of exercise training/rehabilitation plus oxandrolone relative to those of exercise alone. The working hypothesis is that the combined therapy will be superior to exercise alone in increasing protein balance, improving insulin sensitivity, and decreasing liver/tissue adiposity. This project is expected to estab- lish a new therapeutic approach that delivers more substantial improvements in the clinical and functional out- comes of burn-induced catabolism. It is also expected to provide a foundation for similar treatments in other muscle-wasting or muscle loss disorders. The long-term goal in this project is to identify clinically-effective, therapeutic interventions i the rehabilitation and recovery of severely burned children and NICHD's mission of improving rehabilitation of injured children so that they can fulfill their potential to live healthy productve lives.