Identification of lead compounds to topically treat sulfur mustard injury to reduce ocular damage and improve vision.

鉴定用于局部治疗硫芥损伤的先导化合物，以减少眼部损伤并改善视力。

• 批准号: 10508049
• 负责人: Shenda Baker
• 金额: $ 3.37万
• 依托单位: SYNEDGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-17 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10508049
• 关键词: Adhesions; Adrenal Cortex Hormones; Alkalies; Analgesics; Anti-Inflammatory Agents; Antibiotics; Antiinflammatory Effect; Artificial Tears; Blindness; Characteristics; Chemical Weapons; Chemicals; Contractor; Cornea; Dose; Edema; Excision; Exposure to; Eye; Eye Injuries; Fibrosis; Funding; Infection; Inflammation; Injury; Keratitis; Lead; Lesion; Military Personnel; Modeling; Mucous Membrane; Mustard Gas; Occupational Exposure; Oryctolagus cuniculus; Pharmaceutical Preparations; Production; Research Design; Risk; Surface; Terrorism; Testing; Time; Topical application; Ulcer; United States Food and Drug Administration; Vesicants; Vision; Visual impairment; cost; healing; improved; in vitro Model; mass casualty; neovascularization; ocular surface; prevent

Abstract Sulfur Mustard (SM) has been employed as a chemical weapon, and production and use of SM in unstable regions heightens the risk that this agent could be used in a deliberate terrorist attack against civilians causing mass casualties or against military personnel. The ocular surface is uniquely susceptible to SM resulting in corneal lesions, edema, ulcerations, neovascularization and vision loss. The recommended treatment for ocular SM injury is removal of remaining agent using an eye wash, followed with topical treatments with antibiotics, corticosteroids (anti-inflammatory agents), analgesics and artificial tears. However, a need remains for products that improve healing times, reduce vision loss, and prevent the latent keratitis. Further, there are currently no US Food and Drug Administration approved drugs for SM induced ocular injuries to improve healing and reduce vision loss. Synedgen has developed a class of non-toxic polyglucosamine derivatives with the ability to suppress inflammation, reduce infection, and improve healing at mucosal surfaces. Having seen significant healing and anti-inflammatory effects with a particular guanidium modified glycopolymer in a rabbit ocular alkali burn, other derivatives were hypothesized to have potentially better ocular characteristics. This effort proposed three aims to identify and test a treatment for SM ocular injury: 1) synthesize new molecules, 2) down select in in vitro models of inflammation, healing and adhesion and 3) optimize dose in a rabbit model of SM ocular injury. The first two completed aims generated two strong candidate molecules for the SM study proposed in Aim 3. Given successful identification of lead molecules to initiate the final aim of the study, discussions were initiated with the contractor for the proposed SM rabbit study. Because that study was quoted over three years ago, the cost assumptions no longer hold. Although aspects of the study were reduced or eliminated, completion of the study with potentially statistically significant results requires additional funds. This supplemental proposal describes the study design to support the request.

抽象的 芥子气（SM）已被用作化学武器，其生产和使用不稳定 地区增加了该剂可能被用于对平民进行蓄意恐怖袭击的风险，造成 大规模伤亡或针对军事人员。眼表特别容易受到 SM 的影响，从而导致 角膜病变、水肿、溃疡、新生血管和视力丧失。推荐的眼部治疗方法 SM 损伤是使用洗眼液去除残留的药剂，然后使用抗生素进行局部治疗， 皮质类固醇（抗炎药）、镇痛药和人工泪液。然而，仍然需要产品 可以缩短愈合时间，减少视力丧失，并预防潜在的角膜炎。此外，目前美国还没有 美国食品和药物管理局批准了治疗 SM 引起的眼损伤的药物，以改善愈合并减少 视力丧失。 Synedgen 开发了一类无毒的聚葡萄糖胺衍生物，能够抑制 炎症、减少感染并改善粘膜表面的愈合。看到显着的治愈和 特定胍改性糖聚合物对兔眼碱烧伤的抗炎作用，其他 假设衍生物具有潜在的更好的眼部特征。这项工作提出了三个目标 确定并测试 SM 眼损伤的治疗方法：1) 合成新分子，2) 体外筛选 炎症、愈合和粘连模型，3) 优化 SM 眼损伤兔模型的剂量。这 前两个完成的目标为目标 3 中提出的 SM 研究产生了两个强有力的候选分子。 鉴于成功鉴定了先导分子以启动研究的最终目标，开始了讨论 与拟议的 SM 兔子研究承包商。因为该研究是在三年多前被引用的， 成本假设不再成立。尽管研究的某些方面被减少或消除，但完成 具有潜在统计显着性结果的研究需要额外的资金。本补充提案 描述支持该请求的研究设计。