Anti-Selectin Blocker for Liver Ischemic Injury

抗选择素阻滞剂治疗肝脏缺血性损伤

• 批准号: 6899381
• 负责人: LUIS H TOLEDO-PEREYRA
• 金额: $ 35.95万
• 依托单位: BIOMEDICA MANAGEMENT CORPORATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899381
• 关键词: biological signal transduction; cardiovascular disorder chemotherapy; combination chemotherapy; disease /therapy duration; dosage; drug design /synthesis /production; drug interactions; drug screening /evaluation; genetically modified animals; inhibitor /antagonist; integrins; ischemia; laboratory mouse; liver disorder chemotherapy; liver ischemia /hypoxia; mitogen activated protein kinase; neutrophil; pentoxifylline; reperfusion; selectins; small molecule; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Our objective is to develop a new treatment that will prevent or decrease the tissue damage caused by neutrophil infiltration after ischemia/reperfusion (I/R), which occurs as the result of stroke, coronary ischemia, trauma and other related conditions. Compounds called selectins play an important role in this neutrophil-mediated injury. Drugs currently available for treatment have not resulted in optimal protective effects during clinical application. Preliminary studies in our laboratories already indicated that a recently discovered synthetic drug, TBC-1269, which acts as a selectin blocker, provides protection against tissue damage in rats subjected to severe liver ischemia/reperfusion. Our results from the completed Phase I feasibility studies (see Final Report in section C) indicated that TBC-1269 was significantly protective when given at the time of reperfusion and at a dose of 40 mg/kg, for animals undergoing severe (90 min) liver ischemia. Functional and histological parameters remained near-normal in animals receiving TBC-1269. During this proposed Phase II grant, we will expand our study of TBC-1269 to more precisely determine 1) the correct time and dosing for maximum drug effectiveness; 2) to compare the therapeutic value of TBC-1269 to other selectin blockers and selectin knockouts; 3) to evaluate the benefits of adding other drugs, such as anti-integrin beta 2-/alpha 4- and anti-TNF-alpha, to the treatment plan; and, 4) to examine potential cell signalling mechanisms (MAPK cascade). Results of this innovative study could significantly improve the clinical outcome for patients at risk for suffering from ischemial/reperfusion injuries. Treatment with TCB-1269 will enhance the quality of life of millions of patients suffering from the large number of maladies associated with ischemia/reperfusion ischemic maladies.

描述（由申请人提供）： 我们的目标是开发一种新的治疗方法，预防或减少缺血/再灌注（I/R）后中性粒细胞浸润造成的组织损伤，这种情况是由于中风、冠状动脉缺血、创伤和其他相关病症而发生的。称为选择素的化合物在这种中性粒细胞介导的损伤中发挥着重要作用。目前可用于治疗的药物在临床应用中尚未产生最佳的保护作用。我们实验室的初步研究已经表明，最近发现的一种合成药物 TBC-1269 可作为选择素阻滞剂，为遭受严重肝缺血/再灌注的大鼠提供针对组织损伤的保护。我们已完成的 I 期可行性研究结果（参见 C 部分的最终报告）表明，在再灌注时给予 TBC-1269，剂量为 40 mg/kg，对于经历严重（90 分钟）的动物具有显着的保护作用。肝脏缺血。接受 TBC-1269 的动物的功能和组织学参数仍然接近正常。在拟议的二期资助期间，我们将扩大对 TBC-1269 的研究，以更精确地确定 1) 实现最大药物效力的正确时间和剂量； 2) 比较TBC-1269与其他选择素阻断剂和选择素敲除药物的治疗价值； 3) 评估在治疗计划中添加其他药物（例如抗整合素β2-/α4-和抗TNF-α）的益处； 4) 检查潜在的细胞信号传导机制（MAPK 级联）。这项创新研究的结果可以显着改善有缺血/再灌注损伤风险的患者的临床结果。 TCB-1269 治疗将提高数百万患有大量与缺血/再灌注缺血性疾病相关疾病的患者的生活质量。