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Long Circulating Low Molecular Weight Heparins Pulmonary

长循环低分子肝素肺

基本信息

批准号：
7127816
负责人：
Fakhrul Ahsan
金额：
$ 21.49万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2010-07-17
项目状态：
已结题

项目摘要

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.

描述(申请人提供)：静脉血栓栓塞症(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60,000多人住院和60,000人死亡。静脉血栓栓塞症可表现为深静脉血栓形成或肺栓塞。肺栓塞的致死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，包括在给药时需要针头，不可预测的药理反应，频繁的监测和剂量调整，以及较差的安全性。由于传统抗凝治疗VTE的局限性，低分子肝素(LMWH)是普通肝素的较小片段，近年来已被用作VTE短期治疗的首选药物。虽然与普通肝素相比，低分子肝素有几个优点，但由于两个重要的缺点，这些药物的临床应用受到了限制：[1]与普通肝素一样，低分子肝素仍然需要皮下注射，[2]低分子肝素的作用时间相对较短。这些限制可以通过经肺途径给药在长循环药物载体中形成的低分子肝素来解决。这项建议中要检验的假设是：经肺途径给予长循环低分子肝素是一种非侵入性且可行的抗凝治疗方法，可用于静脉血栓栓塞症的短期和长期治疗。这项建议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。这些制剂的循环时间、生物分布和疗效将在啮齿动物模型中进行测试。安全性将通过一系列实验进行研究，包括对人支气管上皮细胞的细胞毒性研究，对支气管肺泡灌洗液的分析，以及在青蛙上颌模型上测量粘液纤毛清除率。该项目的长期目标是生成有关拟议给药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症患者身上进行测试。