Dexamethasone as an Effective Therapy for Ocular Injuries by Vesicating Agents.

地塞米松是治疗眼部损伤的有效疗法。

• 批准号: 10220981
• 负责人: Rajesh Agarwal
• 金额: $ 72.12万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220981
• 关键词: Address; Adverse effects; Arsenicals; Blindness; Chemical Weapons; Clinical; Colorado; Cornea; Corneal Injury; Data; Development; Dexamethasone; Dose; Drug Prescriptions; Evaluation; Exposure to; Eye; Eye Injuries; FDA approved; Female; Food, Drug and Cosmetic Act; Frequencies; Functional disorder; Gelatinase B; Human; Inflammation; Inflammation Mediators; Injury; Intellectual Property; Lead; Licensure; Mechlorethamine; Medical emergency; Modeling; Molecular; Mustard; Mustard Gas; Organ; Organ Culture Techniques; Oryctolagus cuniculus; PTGS2 gene; Pathway interactions; Pharmaceutical Preparations; Positioning Attribute; Process; Regulatory Pathway; Reporting; Research; Safety; Sampling Studies; Source; Suggestion; Technology Transfer; Therapeutic; Therapeutic Agents; Time; Tissues; Topical Preparation; Toxic effect; Treatment Protocols; Universities; Vascular Endothelial Growth Factors; Vesicants; analog; base; cost; drug development; effective therapy; efficacy study; gender difference; in vivo; in vivo Model; innovation; lead optimization; lewisite; limbal; male; mass casualty; neovascularization; stem cells; targeted treatment; therapeutic target

Project Summary Abstract Sulfur mustard (SM), nitrogen mustard (NM) and lewisite (LEW) are vesicating agents that are among the most potent chemical weapons, and are the current focus for the development of countermeasures. In the past, lack of NM-, SM- and LEW-induced ocular injury models to identify the mechanisms of toxicity and therapeutic targets has been a major impediment to developing effective therapies. However, in recent years, we have successfully developed and characterized all three vesicants (NM, SM, and LEW)-induced ocular (corneal) injury models in vivo in rabbits, relevant to humans. Also, we identified an increased expression of COX-2 and iNOS, VEGF, and MMP-9 as possible mediators of inflammation, neovascularization (NV) and microvesication, respectively, in ocular injuries by these three vesicants. This is an important finding as it suggests that an agent effective against the ocular injury induced by one of these vesicants would also be effective against the others. Indeed, in our proof of concept efficacy studies, we demonstrated that dexamethasone (DEX, an FDA approved drug) is an effective agent in ameliorating all three vesicants (NM, SM, LEW)-induced ocular injuries in vivo in rabbits. This is a significant finding because the regulatory pathway for this new use of DEX is much easier to pursue, since the new use application for DEX would be able to rely on the existing safety and efficacy data of the reference DEX application, leading to less data needed for the application and an easier approval pathway. An advantage of DEX, based on review by the CU technology transfer office, is that there are no competitive intellectual property (IP) barriers to bringing this new use to market. The further advantage of using DEX is that we do not need to generate additional IP in order to create a commercial product, as DEX is available at a low cost from multiple sources as a generic and branded prescription drug, and will have no shortages in times of a medical emergency. Together, based on our completed studies and clear regulatory pathway forward, our hypothesis is that DEX has strong potential to reverse both mustard- and arsenical-induced ocular injury, and that as a promising targeted `optimized lead' therapeutic, it can be easily available for human use in medical emergency. Our specific aims are to: 1) optimize dosing frequency of DEX to treat vesicating agents-induced in vivo ocular injury in rabbits; 2) evaluate the most effective DEX treatment regimen to counteract vesicating agents-induced corneal injury in human corneal organ culture; 3) define the molecular mechanism of DEX in rescuing vesicating agents-induced ocular injury; and 4) develop and follow regulatory strategies for approval of DEX indication as an effective countermeasure against vesicating agent-induced ocular injury. Completion of our aims is anticipated to make dexamethasone ready for next stage of advanced drug development process with a clear path for FDA approval as an effective rescue medication for vesicants-induced ocular injuries.

项目摘要摘要 硫芥末（SM），氮芥末（NM）和Lewisite（Lew）是囊泡剂，是最多的剂 有效的化学武器，是当前发展对策的重点。过去，缺乏 NM，SM-和LEW诱导的眼损伤模型，以识别毒性和治疗的机制 靶标一直是开发有效疗法的主要障碍。但是，近年来，我们有 成功开发并表征了所有三种囊泡（NM，SM和LEW）诱导的眼（角膜） 与人类有关的兔子的损伤模型。此外，我们确定了COX-2和 iNOS，VEGF和MMP-9可能是炎症，新血管形成（NV）和微神经的介体， 这三种小囊泡分别在眼部受伤中。这是一个重要的发现，因为它表明 对这些囊泡人之一诱导的眼损伤有效的代理也将有效 其他的。确实，在我们的概念效能研究证明中，我们证明了地塞米松（Dex，一个 FDA批准的药物）是改善所有三种囊泡（NM，SM，LEW）诱导的有效药物 兔子体内的眼部损伤。这是一个重要的发现，因为这种新用途的监管途径 DEX的攻击要容易得多，因为DEX的新使用应用程序将能够依靠现有 参考DEX应用程序的安全性和功效数据，导致应用程序所需的数据较少，并且 更容易的批准途径。根据CU技术转移办公室的评论，DEX的优势是 将这种新用途带入市场没有竞争性的知识产权（IP）障碍。进一步 使用DEX的优势是，我们不需要生成其他IP即可创建一个商业 产品，因为DEX以多种来源的低成本提供，作为一种通用和品牌处方药， 在医疗紧急情况下，不会短缺。共同基于我们完成的研究和 明确的监管途径向前 芥末和砷引起的眼部损伤，作为有希望的目标“优化铅” 治疗性，可以轻松地在医疗紧急情况下使用。我们的具体目的是：1） 优化DEX的剂量频率以治疗兔子在体内眼损伤中诱导的囊泡剂； 2）评估 最有效的DEX治疗方案，用于抵消囊泡剂引起的角膜损伤的人类 角膜器官培养； 3）定义DEX在拯救囊泡剂引起的眼部时的分子机制 受伤; 4）制定并遵循监管策略，以批准DEX指示为有效 与囊泡剂引起的眼部损伤的对策。预计我们目标的完成 使地塞米松为下一阶段的高级药物开发过程做好准备，并以清晰的途径 FDA批准是囊泡诱导的眼部损伤的有效救援药物。