Treatment of Wound Infection with Novel Uncharged Silver Carbene Complexes

描述（由申请人提供）：将三种新型不带电荷的银卡宾杀微生物剂配制成两种不同的软膏制剂，并在糖尿病大鼠的感染愈合模型中进行测试，这些杀微生物剂已被证明对多种病原体有效。将银卡宾配制成透明（凝胶）伤口软膏或封闭性凡士林基软膏中的一种，所述透明（凝胶）伤口软膏将允许在治疗时观察伤口，所述封闭性凡士林基软膏预期具有与水基凝胶不同的保湿性和药物递送特性。拟议研究的主要具体目的包括将银卡宾抗菌剂制备和配制/加工成软膏形式、化学和生物学表征、最大耐受剂量的测定以及在大鼠感染伤口模型中的评价。生物学表征包括测定每种化合物的MIC 90，并从MIC 90的浓度（软膏中）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。所提出的治疗的主要目的是：1）感染消退，2）炎症最小化，和3）促进伤口消退。这种创新和合理的局部抗微生物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络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微生物化合物的下一阶段开发成为可能，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工作机制。 公共卫生相关性：糖尿病足溃疡是一种常见类型的慢性伤口，影响多达25%的所有糖尿病患者，并且在许多情况下，糖尿病患者由于炎症反应受损而发生感染。感染可使糖尿病足溃疡的治疗和结局大大复杂化，所有患者中有65%发生骨髓炎，骨髓炎组中有14-24%截肢（American Diabetes Association，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治疗的20-25%，并且尽管在过去五十年中在糖尿病足部溃疡的治疗中已经取得了重要的医学进步，但是仍然存在对糖尿病足部溃疡的显著需求。 更有效的治疗来对抗感染和该患者群体中受损的伤口愈合。

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.