Mechanisms of fenofibrate alone or combined with propranolol in burned patients

描述(申请人提供)：严重烧伤的反应特征是持续的高代谢和分解代谢状态，导致肌肉组织的大量损失，即使在喂食状态下也是如此。在烧伤总面积的30%的患者中，蛋白质分解在95%的烧伤创面愈合后持续约一年。内源性儿茶酚胺被认为是创伤或烧伤后高代谢反应的主要介质。血浆儿茶酚胺水平的慢性升高导致高动力循环、基础能量消耗增加、外周胰岛素抵抗伴高血糖、外周脂肪分解增加、免疫功能低下、骨骼肌蛋白质分解代谢和肥厚性瘢痕形成。对烧伤的高代谢反应也以严重的心动过速和心脏做功增加为特征，这对心脏有害。持续的心动过速和肌肉分解代谢严重影响康复，并导致在恢复正常的身体和功能活动之前过度延迟。我们研究所最近的研究表明，高血糖和胰岛素抵抗对生存、伤口愈合和骨骼肌分解代谢有负面影响。严重烧伤患者的胰岛素抵抗可持续至少3年，进一步推迟患者恢复正常，并降低他们的生活质量。在之前的资助期间，我们证明了单独使用强化胰岛素或与心得安联合使用可以改善严重烧伤患者的预后。然而，胰岛素的使用与高水平的低血糖相关。因此，我们现在将使用一种不存在低血糖风险的抗高血糖疗法。我们已经证明，急性应用非诺贝特，一种贝特类药物，可以降低严重烧伤患者的血糖水平。我们现在将单独或与心得安联合应用非诺贝特，以确定其在胰岛素抵抗、伤口愈合、败血症和心功能方面的临床疗效和潜在作用机制。我们假设血糖水平的降低和儿茶酚胺的阻断将导致烧伤后长期的分解代谢和高代谢反应的减弱，这些反应将通过单用非诺贝特或与心得安联合应用于烧伤后一年而得到改善。总共300名患者将被随机分为两组，每天单独服用非诺贝特或与心得安联合服用。将这些患者的数据与同等数量的安慰剂或心得安治疗的患者进行比较，将使用我们已经资助的P50烧伤中心试验的数据，该试验将于2015年1月完成。

DESCRIPTION (provided by applicant): The response to a severe burn is characterized by persistent hypermetabolic and catabolic state that result in the massive loss of muscle tissue, even in the fed state. In patients with > 30% of total body surface area burned, protein breakdown persists for approximately one year after the burn wound is 95% healed. Endogenous catecholamines have been implicated as primary mediators of the hypermetabolic response to trauma or burn. Chronic elevation of plasma catecholamine levels results in the development of hyperdynamic circulation, increased basal energy expenditure, peripheral insulin resistance with hyperglycemia, increased peripheral lipolysis, depressed immune function, skeletal muscle protein catabolism and hypertrophic scarring. The hypermetabolic response to burns is also characterized by a profound tachycardia and increased cardiac work that are detrimental to the heart. The persistence of tachycardia and muscle catabolism significantly compromises rehabilitation and results in an excessive delay before resuming normal physical and functional activities. Recent studies from our institution have shown the negative impact of hyperglycemia and insulin resistance on survival, wound healing, and skeletal muscle catabolism. Insulin resistance can last for at least 3 years in severely burned patients, further delaying a patient's return to normal and reducing their quality of life. In the previous funding period, we demonstrated that administration of intensive insulin alone or in combination with propranolol improves outcomes for severely burned patients. However, the use of insulin was associated with high levels of hypoglycemia. Therefore, we now will utilize an anti-hyperglycemic therapy that does not have the risk of hypoglycemia. We have shown that acute administration of fenofibrate, a fibrate, reduces blood glucose levels in severely burned patients. We will now administer fenofibrate alone or in combination with propranolol to determine the clinical efficacy and underlying mechanisms of action on insulin resistance, wound healing, sepsis, and cardiac function. We hypothesize that reduction of blood glucose levels, along with blockade of catecholamines, will result in attenuation of the long-term post-burn catabolic and hypermetabolic responses, and that these responses will be ameliorated by the therapeutic use of fenofibrate alone or in combination with propranolol, administered for one year post burn. A total of 300 patients will be randomized to receive daily administration of Fenofibrate alone or in combination with propranolol. Comparison of the data from these patients to an equal number of placebo- or propranolol-treated patients will be accomplished using data from our already funded P50 burn center trial which will be completed by January 2015.