Treatment of Wound Infection with Novel Uncharged Silver Carbene Complexes

描述(由申请人提供)：三种已被证明对多种病原体有效的新型不带电荷的卡宾银微杀菌剂将被配制成两种不同的软膏配方，并在糖尿病大鼠的感染愈合模型中进行测试。将银卡宾配制成透明(凝胶)伤口软膏或封闭性凡士林软膏中的一种，前者可在治疗时观察伤口，后者预期具有与水性凝胶不同的保湿性和药物输送特性。这项研究的主要目标包括：银卡宾抗菌剂的制备和配方/加工成软膏，化学和生物学特性，最大耐受剂量的确定，以及在大鼠感染伤口模型中的评估。生物学特性包括测定每种化合物的MIC90，并从MIC90的浓度开始，在两个对数范围内评价配制成软膏的每种化合物的毒性。建议治疗的主要目标是：1)消除感染，2)最大限度地减少炎症，3)促进伤口愈合。这种创新和合理的局部抗菌治疗方法是建立在几项不同研究的基础上的，这些研究揭示了这些银卡宾化合物有希望的生物适用属性。该项目的最终目标是使一种或多种新型杀菌化合物能够进入下一阶段的开发，这些化合物将用于治疗感染的慢性伤口和烧伤，同时更好地了解这些化合物的作用机制。 公共卫生相关性：糖尿病足溃疡是一种常见的慢性伤口类型，影响多达25%的糖尿病患者，在许多情况下，糖尿病患者由于炎症反应受损而发生感染。感染会使糖尿病足部溃疡的治疗和结果变得非常复杂，在骨髓炎组中，65%的患者发生骨髓炎或截肢，比例为14-24%(美国糖尿病协会，1999)。与足部溃疡相关的并发症占每年花费数十亿美元的所有住院费用的20%-25%，尽管过去50年来糖尿病足部溃疡的治疗在医学上取得了重要进展，但仍有重大需求 在这些患者群体中，更有效的治疗方法来对抗感染和损害伤口愈合。

DESCRIPTION (provided by applicant): Three novel uncharged silver carbene microbicides that have been shown to be effective against a wide variety of pathogens will be formulated into two different ointment formulations and tested in an infected healing model in the diabetic rat. Formulation of the silver carbenes into one of either a transparent (gel) wound ointment that will allow viewing of the wound while being treated or an occlusive petrolatum-based ointment that is anticipated to have different moisture retention and drug delivery characteristics that a water-based gel will be carried out. The major specific aims of the proposed research involve the preparation & formulation/processing of the silver carbene antimicrobial agents into an ointment form, chemical and biological characterization, determination of maximum tolerated doses, and evaluation in an infected wound model in the rat. The biological characterization involves the determination of the MIC90 for each compound and evaluation of the toxicity of each compound formulated into an ointment over a two log range starting at a concentration (in the ointment) at the MIC90. The primary objectives of the proposed therapy are: 1) resolution of infection, 2) minimization of inflammation, and 3) encouragement of wound resolution. This innovative and rational approach to a topical antimicrobial therapy is founded on the basis of several different studies that have revealed promising bio-applicable attributes of these silver carbene complexes. The end-goal of this project is to enable the next phase of development of one or more of these novel microbicidal compounds that will be targeted for the treatment of infected chronic wounds and burns while developing a greater understanding of the mechanisms by which these compounds work. PUBLIC HEALTH RELEVANCE: Diabetic foot ulcers are a common type of chronic wound affecting as many as 25% of all diabetics and in many cases diabetics develop infection as a consequence of an impaired inflammatory response. Infection can greatly complicate treatment and outcomes for diabetic foot ulcers with 65% of all patients developing osteomyelitis and amputation in 14-24% of the osteomyelitis group (American Diabetes Association, 1999). Complications associated with foot ulcers account for 20-25% of all hospitalizations costing billions of dollars annually and despite the important medical advances that have been made in the treatment of diabetic foot ulcers in the past fifty years, there remains a significant need for more effective therapies to combat infection and impaired wound healing in this patient population.