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.

摘要 硫芥子气（SM）已被用作化学武器，并且SM的生产和使用不稳定。 这些地区的情况加剧了这种制剂可能被用于针对平民的蓄意恐怖袭击的风险， 大规模伤亡或针对军事人员。眼表对SM特别敏感，导致 角膜损伤、水肿、溃疡、新血管形成和视力丧失。推荐的眼部治疗方法 SM损伤是使用洗眼液去除剩余的药剂，然后用抗生素进行局部治疗， 皮质类固醇（抗炎剂）、镇痛剂和人工泪液。然而，仍然需要产品 可以延长愈合时间，减少视力丧失，预防潜伏性角膜炎。此外，目前没有美国 食品和药物管理局批准的药物用于SM诱导的眼损伤，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，具有抑制 炎症，减少感染，并改善粘膜表面愈合。在看到显著的愈合和 特定胍改性的糖基共聚物在兔眼碱烧伤中的抗炎作用 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 鉴定和测试SM眼损伤的治疗：1）合成新分子，2）在体外向下选择 炎症、愈合和粘连模型; 3）在SM眼损伤的兔模型中优化剂量。的 前两个完成的目标产生了两个强有力的候选分子，用于目标3中提出的SM研究。 鉴于成功鉴定了先导分子，启动了研究的最终目标， 与承包商进行拟定SM家兔研究。因为这项研究是三年前引用的， 成本假设不再成立。尽管研究的某些方面被减少或取消， 一项具有潜在统计意义结果的研究需要额外资金。本补充提案 描述了支持请求的研究设计。