Treatment of Wound Infection with Novel Uncharged Silver Carbene Complexes

描述（由申请人提供）：三种新型不带电荷的银卡宾杀菌剂已被证明对多种病原体有效，将被配制成两种不同的软膏配方，并在糖尿病大鼠感染愈合模型中进行测试。将银卡贝尼配制成一种透明（凝胶）伤口软膏，允许在治疗时观察伤口，或一种闭塞的凡士林软膏，预计具有不同的保湿和给药特性，因此将采用水基凝胶。拟议研究的主要具体目标包括将卡宾银抗菌剂制备和配制/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，并在两个对数范围内评估配制成药膏的每种化合物的毒性，从药膏中MIC90的浓度开始。建议治疗的主要目标是：1)解决感染，2)最小化炎症，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的研究的基础上的，这些研究揭示了这些银碳络合物有希望的生物应用特性。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，同时对这些化合物的作用机制有更深入的了解。

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.