Topical Treatment of Diabetic Wounds to Increase Dermal Microvascular Blood Flow

项目概述/摘要糖尿病足溃疡（DFU）及其相关的高发病率和死亡率是糖尿病患者足部问题的结果，是一项重大的公共卫生挑战。据估计，2001年美国治疗DFU和截肢的费用约为110亿美元。不正常的伤口愈合是导致截肢的主要原因，是I型和II型糖尿病的并发症。一氧化氮（NO）气体已被证明在促进和调节各种伤口愈合过程中发挥重要作用。NO也被证明有希望作为一种抗菌治疗药物，对人类病原体具有广泛的有效性。目前大多数一氧化氮疗法（除吸入疗法外）涉及全身或局部治疗，使用旨在刺激细胞内诱导型一氧化氮合酶（NOS）的药物。除了内源性NO通过NOS在伤口愈合中的作用外，外源性NO后伤口愈合的改善也有报道，包括直接使用NO气体或使用局部合成NO和其他细胞毒性氮氧化物（亚硝酸，NO2）的凝胶或面霜。然而，在十几个或更多当前和未决的基于NO的药物临床试验中，没有一个局部方法使用外源性NO生成凝胶，因此依赖于NOS途径在局部产生微量NO。直接输送更多治疗相关剂量的NO气体用于局部/皮肤应用已经完成，尽管该方法由于NO在空气中的不稳定性和在临床环境中难以产生而变得复杂。一种更合理的基于一氧化氮的伤口愈合治疗方法在临床环境中应用方便、安全、剂量可预测，并且不会有化学杂质从而影响伤口愈合过程。Lynntech的团队正在开发一种简单的化学合成方法，用于产生足够持续和高纯度的非原位NO，用于皮肤应用，从而允许局部“凝胶”应用于伤口治疗，特别是糖尿病足溃疡。初步结果表明，这种化学物质能够以浓度依赖的方式有效地产生持续数量的一氧化氮，并且将一氧化氮凝胶应用于啮齿动物模型的全层烧伤，也显示出在愈合（伤口关闭）和再上皮化方面的显著改善。在该项目的第一阶段，Lynntech的团队将进行分析性、体外和体内研究，为第二阶段的临床前试验做准备。第一阶段将专注于化学和凝胶基质的表征和优化，这将允许对给定的糖尿病溃疡进行可预测的剂量。此外，该项目将描述对临床相关病原体的抗菌效果，并将在体内评估使用两种不同剂量定时方案的高剂量和低剂量治疗糖尿病溃疡。I期和II期项目的目的是完成临床前试验，以支持向FDA提交IND申请，并同时将该技术推向制药行业。根据美国糖尿病协会的数据，6.3%的美国人患有糖尿病。与糖尿病相关的常见并发症之一是下肢溃疡。事实上，糖尿病是导致非创伤性下肢截肢的最常见原因。糖尿病足溃疡（DFU）是严重影响患者生活质量的主要问题，导致住院时间延长，并可能需要大面积截肢。通过使用单一、廉价和安全的局部凝胶减少DFU愈合时间和防止感染，患者可以预期更好的愈合结果，缩短住院时间和医疗护理时间，并降低护理成本。

DESCRIPTION (provided by applicant): Project Summary/Abstract Diabetic foot ulcers (DFU) and the related excess morbidity and mortality as a consequence of foot problems in people with diabetes represent a major public health challenge. The cost for the treatment of DFU and amputation in US in 2001 was estimated to be around 11 billion dollars. Abnormal wound healing which is the major cause of these amputations is a complication of both, type I and type II diabetes. Nitric oxide (NO) gas has been shown to play a significant role in the promotion and regulation of diverse wound healing processes. NO has also been shown to have promise as an antimicrobial therapeutic and has broad range of effectiveness against human pathogens. Most current nitric oxide therapies (other than inhalation therapies) involve systemic or topical treatments with drugs designed to stimulate inducible nitric oxide synthase (NOS) intracellularly. In addition to a role of endogenous NO in wound healing through NOS, improvement of wound healing following exogenous NO has also been reported, including direct application of NO gas or application of topical gels or creams that synthesize NO and other cytotoxic nitrogen oxide species (nitrous acid, NO2). However, of the dozen or more current and pending NO-based pharmaceutical clinical trials, none of the topical approaches utilize an exogenous NO producing gel and thus rely on NOS pathways to generate minute amounts of NO locally. The direct delivery of more therapeutically relevant doses of NO gas for topical/dermal applications has been accomplished, although the method is complicated by NO's instability in air and difficulty to produce in a clinical setting. A more rational NO-based wound healing treatment would be convenient and safe to apply in a clinical setting, have a predictable dose, and would not have chemical impurities thus impacting the wound healing process. Lynntech's team is developing a simple, chemical synthesis methodology for generating sufficiently sustained and high purities of NO ex-situ for dermal applications, and thus allows for application of a topical `gel' to wound treatments specifically diabetic foot ulcers. Preliminary results have shown the ability of this chemistry to efficiently produce sustained amounts of NO in a concentration dependant manner, and application of the NO gel to full thickness burns in a rodent model has also shown significant improvements in rate of healing (wound closure) and re-epithelization. In Phase I of this project, Lynntech's team will pursue analytical, in vitro and in vivo studies in preparation of preclinical trials to be conducted in Phase II. Phase I will focus on characterization and optimization of the chemistry and gel matrix which will allow for a predictable dose on a given diabetic ulcer. Also, the project will characterize the antimicrobial effectiveness against clinically relevant pathogens and will conclude with in vivo evaluation of a high and low dose treatment of diabetic ulceration using two different dose timing protocols. The purpose of the Phase I and II projects is to complete preclinical trials to support filing of an IND with the FDA and concurrent marketing of the technology to the pharmaceutical sector. PUBLIC HEALTH RELEVANCE According to the American Diabetes Association, 6.3% of Americans have diabetes. One of the common complications associated with diabetes is lower extremity ulceration. In fact, diabetes is the most frequent cause of non-traumatic lower limb amputations. Diabetic foot ulceration (DFU) is a major problem that significantly impairs the quality of life of the patient, leads to prolonged hospitalization, and may require a major amputation. By reducing the time to heal DFU and protect against infection by using a single, inexpensive and safe topical gel, patients can expect better healing outcomes, shortened hospital stays and medical care duration, and reduced cost for that care.