Alkylglycoside Mediated Pulmonary Delivery of Heparins

烷基糖苷介导的肝素肺部输送

• 批准号: 6804856
• 负责人: Fakhrul Ahsan
• 金额: $ 22.28万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-07-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804856
• 关键词: cardiovascular disorder chemotherapy; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; glycosides; heparin; inhalation drug administration; laboratory rat; lung lavage; molecular weight; nonhuman therapy evaluation; pharmacokinetics; venous thrombosis

DESCRIPTION (provided by applicant): Historically, heparin has been used as an anticoagulant for the treatment of deep vein thrombosis (DVT), a devastating disease that affects two million Americans annually and an estimated 600,000 of which develop pulmonary embolism, a fatal complication resulting in 200,000 deaths a year. Recently, low molecular weight heparins (LMWHs) have been used as an alternative to unfractionated heparins in the treatment of DVT and pulmonary embolism. However, the main limitation to the broader utilization of LMWHs in an ambulatory setting is the requirement of administering the drug by painful subcutaneous injections. This proposal is designed to test the hypothesis that pulmonary route can provide a viable, noninvasive, and efficacious means of administering LMWHs. In this regard, enoxaparin will be formulated with a series of alkylglycosides, a newer family of nonionic surfactants, and the safety and efficacy of the formulations will be investigated in anesthetized rat model. The first series of experiments will be conducted to determine the optimal absorption enhancer that can effectively enhance pulmonary absorption of LMWHs. Absorption of LMWHs, administered via pulmonary route after laryngoscopic visualization of the trachea, will be evaluated by measuring plasma anti-factor Xa activity in vivo rat model. Once an optimal absorption enhancer is identified, enoxaparin formulations will be compared with other LMWHs to determine if one of the LMWHs is better suited than the others for pulmonary delivery. The efficacy of the proposed formulation in the treatment of DVT will be investigated in rat jugular vein thrombosis model. The safety of the formulations will be determined by studying the effect of the formulation on mucociliary clearance function of the respiratory tract. Bronchoalveolar lavage will be conducted to determine cellular and biochemical changes that may occur in the lung due to exposure to the optimized formulation. The long-term goals of this project are i) to develop a formulation for pulmonary delivery of LMWHs that can be used to provide safe and effective control of deep vein thrombosis and pulmonary embolism and ii) to evaluate the mechanism by which alkylglycosides enhance pulmonary absorption of LMWHs.

描述（由申请人提供）：历史上，肝素一直被用作治疗深静脉血栓 (DVT) 的抗凝剂，这是一种毁灭性的疾病，每年影响 200 万美国人，估计其中有 600,000 人出现肺栓塞，这是一种致命的并发症每年有 20 万人死亡。最近，低分子量肝素（LMWH）已被用作普通肝素的替代品，用于治疗 DVT 和肺栓塞。然而，在门诊环境中更广泛使用 LMWH 的主要限制是需要通过痛苦的皮下注射来给药。该提案旨在检验以下假设：肺途径可以提供一种可行、无创且有效的 LMWH 给药方式。在这方面，依诺肝素将与一系列烷基糖苷（一种较新的非离子表面活性剂家族）一起配制，并将在麻醉大鼠模型中研究该制剂的安全性和有效性。第一系列实验将确定能够有效增强低分子肝素肺部吸收的最佳吸收促进剂。通过喉镜观察气管后经肺部途径给药的 LMWH 的吸收，将通过测量大鼠模型体内血浆抗 Xa 因子活性来评估。一旦确定了最佳吸收促进剂，依诺肝素制剂将与其他 LMWH 进行比较，以确定其中一种 LMWH 是否比其他 LMWH 更适合肺部输送。将在大鼠颈静脉血栓形成模型中研究所提出的制剂治疗 DVT 的功效。制剂的安全性将通过研究制剂对呼吸道粘液纤毛清除功能的影响来确定。将进行支气管肺泡灌洗以确定由于接触优化制剂而可能在肺部发生的细胞和生化变化。该项目的长期目标是 i) 开发一种 LMWH 肺部输送制剂，可用于安全有效地控制深静脉血栓形成和肺栓塞，以及 ii) 评估烷基糖苷增强肺部吸收的机制LMWH。