Long Circulating Low Molecular Weight Heparins Pulmonary

描述（由申请人提供）：静脉血栓栓塞（VTE）是一种致命的血液凝固障碍，在美国每年每1000人中有2人患病，导致超过60万人住院治疗和6万人死亡。静脉血栓栓塞可表现为深静脉血栓形成或肺栓塞。肺栓塞的死亡可能在症状出现的几分钟内发生。传统上用于静脉血栓栓塞短期和长期治疗的药物包括未分离肝素和华法林。然而，使用这些传统药物治疗静脉血栓栓塞有许多局限性，包括在给药肝素时需要针头、不可预测的药理反应、频繁监测和剂量调整以及安全性差。由于传统的静脉血栓栓塞抗凝治疗的局限性，低分子量肝素（LMWH），一种较小的未分离肝素片段，最近被用作静脉血栓栓塞短期治疗的首选药物。尽管低分子肝素比未分离肝素有许多优点，但由于两个重要的缺点，这些药物的临床实用性受到限制：[1]与未分离肝素一样，低分子肝素仍然需要皮下注射，[1]低分子肝素的作用时间相对较短。这些限制可以通过通过肺部途径给药在长循环药物载体中配制的低分子whs来解决。本提案要验证的假设是：经肺途径给药的长循环低分子肝素是一种无创的、可行的短期和长期静脉血栓栓塞治疗的抗凝治疗方法。本提案的目标将通过配制依诺肝素来实现，依诺肝素是一种广泛使用的低分子肝素，在存在或不存在吸收促进剂的情况下，具有长循环脂质体和纳米颗粒。将在啮齿动物模型上测试制剂的循环时间、生物分布和功效。该药物的安全性将在一系列的实验中进行研究，包括人类支气管上皮细胞的细胞毒性研究、支气管肺泡灌洗液分析和蛙腭粘膜纤毛清除率的测量。该项目的长期目标是生成关于所建议的输送系统的安全性和有效性的临床前数据，并在健康志愿者和血栓栓塞性疾病患者中进行测试。

DESCRIPTION (provided by applicant): Venous thromboembolism (VTE) is a fatal blood clotting disorder that affects up to two people per 1000 each year in the United States resulting in more than 600,000 hospitalizations and 60,000 deaths. Venous thromboembolism may manifest as deep vein thrombosis or pulmonary embolism. Fatality from a pulmonary embolism may occur within a few minutes of the onset of symptoms. Drugs that have traditionally been used for the short and long term treatment of VTE include unfractionated heparin and warfarin. However, treatment of VTE using these traditional drugs has many limitations, including the requirement of needles in the administration of heparin, unpredictable pharmacological response, frequent monitoring and dosage adjustments, and poor safety profiles. Because of the limitations of traditional anti-coagulant therapy for VTE, low molecular weight heparin (LMWH), which are smaller fragments of unfractionated heparin, has recently been used as a drug of choice for the short term treatment of VTE. Although LMWHs offer several advantages over unfractionated heparin, the clinical usefulness of these drugs has been limited because of two important disadvantages: [1] like unfractionated heparins, LMWHs still need to be administered by subcutaneous injections and [2] LMWHs have a relatively short duration of action. These limitations can be addressed by administering LMWHs formulated in long circulating drug carriers via the pulmonary route. The hypothesis to be tested in this proposal is: Long circulating LMWHs administered via the pulmonary route is a noninvasive and viable anticoagulant therapy for the short and long term management of venous thromboembolism. The goal of this proposal will be accomplished by formulating enoxaparin, a widely used LMWH, with long circulating liposomes and nanoparticles in the presence or absence of absorption enhancers. The circulation time, bio-distribution and efficacy of the formulations will be tested in rodent models. The safety will be investigated in a series of experiments including cytotoxicity studies in human bronchial epithelial cells, analysis of bronchoalveloar lavage fluid and measurement of mucociliary clearance rate in frog palate models. The long term goal of this project is to generate preclinical data on the safety and efficacy of the proposed delivery system and to test it in healthy volunteers and in patients with thromboembolic disorders.