Long Circulating Low Molecular Weight Heparins Pulmonary

描述（由申请人提供）：静脉血栓栓塞（VTE）是一种致命的凝血障碍，在美国，每年每1000人中有2人受到影响，导致超过600，000例住院和60，000例死亡。静脉血栓栓塞可表现为深静脉血栓形成或肺栓塞。肺栓塞的死亡可能发生在症状出现后的几分钟内。传统上用于VTE短期和长期治疗的药物包括普通肝素和华法林。然而，使用这些传统药物治疗VTE有许多局限性，包括肝素给药时需要针头、不可预测的药理学反应、频繁的监测和剂量调整以及不良的安全性。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），这是一个小片段的普通肝素，最近已被用作药物的选择，用于静脉血栓栓塞的短期治疗。虽然LMWH提供了几个优于普通肝素的优点，但这些药物的临床用途受到了限制，因为有两个重要的缺点：[1]像普通肝素一样，LMWH仍然需要通过皮下注射给药，[2] LMWH的作用持续时间相对较短。这些局限性可以通过经肺途径施用配制在长循环药物载体中的LMWH来解决。本提案中待检验的假设是：通过肺途径给予长循环低分子量肝素是一种用于静脉血栓栓塞短期和长期管理的无创和可行的抗凝治疗。该提案的目标将通过在存在或不存在吸收促进剂的情况下将依诺肝素（一种广泛使用的LMWH）与长循环脂质体和纳米颗粒一起配制来实现。将在啮齿动物模型中检测制剂的循环时间、生物分布和有效性。将在一系列实验中研究其安全性，包括人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模型中粘膜纤毛清除率的测量。本项目的长期目标是生成关于申报输送系统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.