Novel Formulation of Topical Losartan for Treatment of Wounds in Aging

描述（由申请人提供）：压疮的发展是影响老年人的最痛苦、最虚弱和最昂贵的疾病之一。老年人皮肤破裂和愈合不良的风险增加既有外在的（失禁，不动），也有内在的（弹性，灌注和氧合减少）。 尽管在过去几年中已经在伤口护理方面做出了改进，但是已经开发了很少的靶向影响伤口愈合的生物途径的药理学试剂。肾素-血管紧张素系统（RAS）的失调越来越多地涉及异常伤口愈合。该提案的目的是进一步开发局部形式的血管紧张素受体阻断剂氯沙坦在衰老小鼠模型中伤口愈合的增殖/重塑阶段的用途。该研究旨在优化该动物模型中的剂量和安全性信息，以加速转化为人类受试者。该补助金的第一个目的是 通过测定伤口闭合时间的差异，通过比较愈合组织的抗张强度，以及通过比较治疗组和安慰剂组之间的血压、肾功能和死亡率，比较在24个月大的C57 B1/6小鼠的伤口愈合的增殖/重塑阶段期间施用的5%、10%和15%氯沙坦软膏的功效和安全性。第二个目的是通过多普勒和组织学研究，并通过定量和比较伤口组织中1型和2型血管紧张素受体和TGF-β蛋白和基因表达，研究3种氯沙坦剂量与安慰剂软膏相比对伤口愈合的不同机制影响。为了完成本研究，组建了一个经验丰富的多学科团队，该团队在动物模型、伤口护理、伤口研究、RAS生物学、生物统计学和以老化为重点的临床翻译方面具有专业知识。将使用醋酸盐示踪测量伤口闭合，并通过张力测定法测量愈合皮肤的拉伸强度和弹性。将使用多普勒激光扫描仪进行多普勒测量，组织学将靶向附件和血管组织。标准定量PCR和蛋白质印迹分析将用于评估伤口愈合中的RAS和TGF-β相关组分。预期结果包括确定最佳、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，以及确定影响伤口愈合的氯沙坦反应中的RAS和TGF-β相关变化。这样的结果将促进这些发现快速转化为人类受试者，并有很大的潜力迅速改变目前的伤口愈合护理模式在老年人。

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.