Safety of Lung Delivered Tissue Plasminogen Activator

描述(由申请人提供)：急性呼吸窘迫综合征(ARDS)是一种严重的健康危害，与高发病率和死亡率有关。不幸的是，在推进ARDS的治疗方面进展甚微。第一阶段STTR资金支持成功确定了用于肺部给药的组织纤溶酶原激活剂(TPA)的可行配方。第一阶段的成功结果为在动物身上进行研究以确定肺部分娩的安全性奠定了基础；这是我们第二阶段应用的主要目标。因此，这项应用代表了治疗ARDS的药理学创新工作的进步，并将I期研究扩展到体内动物模型，以验证tPA肺部给药将是安全和耐受性良好的假设。为此，这项建议的具体目的是：1)研制用于肺递送的肺tPA。将配制小鼠和人tPA用于临床前毒理学和药代动力学(PK)/药效学(PD)研究；2)通过评估急性(剂量递增)和慢性(重复剂量)毒性，评估肺型tPA的耐受性，方法是利用小鼠模型进行肺部滴注和静脉注射(IV)为肺部给药而配制的tPA。这些实验旨在测量毒性指标，如肺损伤、凝血平衡紊乱和出血；以及3)确定肺递送tPA的PK和Pd处置。这一目标将通过在大鼠模型中肺部和静脉注射肺制剂后测量肺和全身治疗蛋白浓度来实现。这些实验旨在评估在高剂量tPA(毒代动力学)后达到的全身tPA浓度的背景下，凝血稳态(PD终点)的破坏。与本申请中建议的工作的成功完成相关的预期结果是：1)建立肺部制剂的安全性概况；2)针对临床情况开发风险概率模型；以及3)准备符合FDA孤儿产品资助申请资格的IND申请。拟议的第二阶段项目将补充和扩展我们的第一阶段工作，并将促进开发一种有前景的、急需的治疗ARDS的新疗法。

DESCRIPTION (provided by applicant): The acute respiratory distress syndrome (ARDS) represents a significant health hazard that is associated with high morbidity and mortality rates. Unfortunately, little progress has been made in advancing the treatment of ARDS. Phase I STTR funding supported the successful determination of a feasible formulation of tissue plasminogen activator (tPA) for pulmonary delivery. The successful outcome of phase I established the rationale for studies in animals to determine the safety of lung delivered; this is the primary objective of our phase II application. Thus, this application represents the advancement of work for pharmacological innovation in the treatment of ARDS and extends phase I studies to in vivo animal models to test the hypothesis that pulmonary delivery of tPA will be safe and well tolerated. To this end, the specific aims of this proposal are to: 1) Formulate pulmonary tPA for lung delivery. Mouse and human tPA will be formulated for pre-clinical toxicology and pharmacokinetic (PK)/pharmacodynamic (PD) studies; 2) Assess the tolerability of the pulmonary formulated tPA by assessing both acute (dose escalating) and chronic (repeated dose) toxicity as determined by utilization of a mouse model which will be subjected to pulmonary instillation and intravenous (IV) administration of tPA formulated for lung delivery. These experiments are designed to measure indicators of toxicity such as pulmonary injury, disruption in coagulation homeostasis and hemorrhage; and 3) Determine the PK and PD disposition of pulmonary delivered tPA. This aim will be accomplished by measuring lung and systemic therapeutic protein concentrations following pulmonary and IV administration of the pulmonary formulation in a rat model. These experiments are designed to assess disruption in coagulation homeostasis (PD end point) in the context of systemic tPA concentrations that are achieved following high doses of tPA (toxicokinetics). The anticipated outcomes associated with the successful completion of the work proposed in this application are: 1) establishment of the safety profile of a pulmonary formulation; 2) the development of a risk probability model for the clinical situation; and 3) preparation of an IND application that is required for eligibility for an FDA Orphan Products Grant Application. The proposed Phase II project will complement and extend our Phase I work and will facilitate the development of a promising new, greatly needed therapeutic for the treatment of ARDS.