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. ? ? ?
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