Novel Formulation of Topical Losartan for Treatment of Wounds in Aging

描述(申请人提供)：压疮的发展是影响老年人的最痛苦、最虚弱和最昂贵的条件之一。在老年人中，皮肤破裂和愈合不良的风险增加既有外在的(大小便失禁、活动不动)，也有内在的(弹性、灌流和氧合降低)。尽管在过去的几年里，伤口护理已经有所改善，但针对影响伤口愈合的生物途径的药理药物还很少开发出来。肾素-血管紧张素系统(RAS)的失调越来越多地与伤口的异常愈合有关。这项建议的目的是进一步发展局部形式的血管紧张素受体阻滞剂氯沙坦在衰老小鼠模型伤口愈合的增殖/重塑阶段的使用。这项研究旨在优化这种动物模型中的剂量和安全信息，以加速转化为人类受试者。这笔赠款的第一个目的是 为了比较5%、10%和15%氯沙坦软膏在24月龄C57BL/6小鼠创面愈合的增殖/重塑阶段应用的有效性和安全性，通过比较创面愈合时间的差异，通过比较愈合组织的抗张强度，并通过比较治疗组和安慰剂组的血压、肾功能和死亡率来比较治疗组和安慰剂组之间的疗效和安全性。第二个目的是通过多普勒和组织学研究，通过对创面组织血管紧张素受体1、2和转化生长因子β的蛋白和基因表达的定量和比较，研究3种剂量的氯沙坦与安慰剂软膏相比对创面愈合的不同机制影响。一支经验丰富的多学科团队已经成立，他们在动物模型、伤口护理、伤口研究、RAS生物学、生物统计学和关注老龄化的临床翻译方面具有专业知识，以完成这项研究。伤口闭合将用醋酸盐痕迹来测量，抗拉强度和弹性将通过愈合皮肤的张力计来测量。多普勒测量将使用多普勒激光扫描仪进行，组织学将针对附件和血管组织。标准的定量聚合酶链式反应和蛋白质印迹分析将被用来评估伤口愈合中的RAS和转化生长因子相关成分。预期的结果包括确定最佳、安全和有效剂量的氯沙坦软膏，以加速伤口愈合并最大限度地提高愈合组织的质量，以及确定与影响伤口愈合的氯沙坦反应的RAS和转化生长因子相关的变化。这样的结果将有助于将这些发现快速转化为人类受试者，并具有迅速改变目前老年人伤口愈合护理范例的巨大潜力。

DESCRIPTION (provided by applicant): The development of pressure ulcers is one of the most painful, debilitating, and costly conditions that impact older adults. The increased risk for skin breakdown and poor healing in older adults is both extrinsic (incontinence, immobility) and intrinsic (decreased elasticity, perfusion, and oxygenation). Although improvements in wound care have been made over the past several years, few pharmacological agents targeting the biological pathways that impact wound healing have been developed. Dysregulation in the renin-angiotensin system (RAS) has been increasingly implicated in abnormal wound healing. The purpose of this proposal is to further develop the use of a topical form of the angiotensin receptor blocker, losartan, during the proliferative/remodeling phases of wound healing in an aging mouse model. The study is designed to optimize dosing and safety information in this animal model in order to accelerate translation into human subjects. The first aim of this grant is to compare efficacy and safety of 5%, 10%, and 15% losartan ointment applied during proliferation/remodeling phase of wound healing in 24 month old C57Bl/6 mice through determining the difference in time to wound closure, through the comparison of healed tissue tensile strength, and through comparison of blood pressure, renal function, and mortality between treatment and placebo groups. The second aim is to study the differential mechanistic impact of the 3 losartan doses compared to placebo ointment on wound healing through Doppler and histological studies and through quantification and comparison of angiotensin receptors type 1 and 2 and TGF-¿ protein and gene expression in wound tissue. An experienced, multidisciplinary team with expertise in animal models, wound care, wound study, RAS biology, biostatistics and aging focused clinical translation has been formed to complete this study. Wound closure will be measured with acetate tracings, and tensile strength and elasticity will be measured by tensiometry from healed skin. Doppler measurements will be made with Doppler laser scanner, and histology will target adnexal and vascular tissues. Standard quantitative PCR and western blot analyses will be used to assess RAS and TGF-¿ related components in wound healing. Expected findings include the identification of an optimal, safe and effective dose of losartan ointment that accelerates wound healing and maximizes the quality of the healed tissue, and the identification of RAS and TGF-¿ related changes in response to losartan that influence wound healing. Such results will facilitate the rapid translation of these findings into human subjects, and have great potential to rapidly shift the present wound healing care paradigm in older adults.