Optimization of a Rabbit Retained Hemothorax Model for Evidence-Based Pharmacologic Interventions

摘要 残留性血胸是一种与胸部创伤相关的胸腔出血并发症， 恶性肿瘤、抗凝或止血疾病，每年影响数千名美国患者， 呼吸系统损害，是很难管理，现在主要是手术治疗。很多病人很穷 外科候选人和去皮质术是一个重大的胸部手术，需要显着的发病率。文献 提示胸膜内纤溶治疗（IPFT）可能是有益的，但没有药物被批准用于RH， 也没有确定的给药方案。药物干预RH是可取的，但临床前 由于缺乏合适的临床前模型来测试新的战略方法，测试受到阻碍。这 该项目通过开发和验证一个适合这种情况的兔RH模型来解决这一差距 试验.文献中报道的少数先前模型不适用于该测试，并且具有止血和 纤维蛋白溶解系统与人类有很大不同。我们有丰富的经验，在成功的创造 和使用类似RH的兔模型，其特征在于胸膜组织，如在四环素诱导的胸膜炎中， 损伤或脓胸。我们与NHLBI合作，使用这些模型来推进脓胸的新疗法。 SMARTT和带来了这样一种药物;单链尿激酶纤溶酶原激活剂（scuPA）的I期 临床试验测试。我们还成立了一家公司;肺治疗公司。(LTI)吸引了足够的 资金独立地使scuPA进入国际第二阶段测试，这是计划开始在第一 2020年的季度。我们的初步数据表明，我们可以生成模型，并使用验证 完成我们设想的工作的性能指标最终将用于指导scuPA的剂量 或使用其他有前途的药物进行近期临床试验测试。这个项目是LTI感兴趣的， NHLBI的使命。我们唯一的目标是生成将被表征的兔RH模型， 使用每个子目标的经过严格审查的性能指标进行验证。在子目标中，我们将建立 根据我们的经验和初步研究结果，确定了生成模型的最佳条件。我们将使用国家- 最先进的小动物胸部CT和超声成像、肺功能测试和形态测定分析 组织损伤作为性能指标，以验证模型的开发并测试年龄和 性别对生殖健康成果的影响。该模型也将推进胸膜机化的发病机制的理解 与RH相关，这可能不同于其他形式的胸膜损伤。我们的团队具有独特的优势， 完成我们的目标并生成兔子模型。通过再次与NHLBI合作，我们 未来将使用该模型生成临床前数据，以实现RH scuPA的临床试验测试， 支持LTI。该模型将可预见地推进该领域，使其他几个测试成为可能。 有前途的策略，可以转化为临床试验测试，最终可能受益于患者提供 新的，耐受性良好的和更有效的药物治疗的患者患有RH的后果。

Abstract Retained hemothorax is a complication of bleeding into the pleural space that is associated with chest trauma, malignancy, anticoagulation or hemostatic disorders, affects thousands of US patients annually, promotes respiratory compromise, is difficult to manage and is now mainly treated surgically. Many patients are poor surgical candidates and decortication is a major chest surgery that entails significant morbidities. The literature suggests that intrapleural fibrinolytic therapy (IPFT) can be salutary, but there are no agents approved for RH, nor are there established dosing schedules. Pharmacologic interventions for RH are desirable but preclinical testing has been hampered by the lack of suitable preclinical models to test new strategic approaches. This project addresses that gap through the development and validation of a rabbit RH model amenable to such testing. The few prior models reported in the literature are not suitable for this testing and have hemostatic and fibrinolytic systems that differ importantly from humans. We have extensive experience in the successful creation and use of rabbit models that like RH are characterized by pleural organization, as in tetracycline-induced pleural injury or empyema. We have used the models to advance new therapeutics for empyema, partnered with NHLBI SMARTT and have brought one such agent; single chain urokinase plasminogen activator (scuPA) to phase I clinical trial testing. We also founded a company; Lung Therapeutics, Inc. (LTI) that has attracted sufficient funding to independently bring scuPA to international phase II testing, which is scheduled to begin in the first quarter of 2020. Our preliminary data demonstrate that we can generate the model and use validated performance measures to accomplish the work that we envision will ultimately be used to guide dosing of scuPA or the use of other promising agents for near-term clinical trial testing. This project is of interest to LTI and fits the mission of the NHLBI. Our sole aim is to generate the rabbit RH model which will be characterized and validated using the well-vetted performance measures for each subaim. In the subaims, we will establish the optimal conditions to generate the model based on our experience and preliminary findings. We will use state- of-the-art small animal chest CT and ultrasound imaging, pulmonary function testing and morphometric analyses of tissue injury as performance measures to validate development of the model and test the effects of age and gender on RH outcomes. The model will also advance understanding of the pathogenesis of pleural organization associated with RH, which likely differs from other forms of pleural injury. Our team is uniquely positioned to accomplish our objective and generate the rabbit model. By again partnering with NHLBI through Catalyze, we will in future use the model to generate preclinical data to enable clinical trial testing of scuPA of RH, which may involve the support of LTI. The model will predictably advance the field, enabling the testing of several other promising strategies that can be translated to clinical trial testing that may ultimately benefit patients by providing new, well-tolerated and more effective pharmacotherapy for patients suffering from the consequences of RH.