PARS inhibitor therapy for smoke inhalation

描述（由申请人提供）： 烟雾吸入是热损伤的主要共病因素。烟雾吸入治疗是支持性的-没有特定的对策来保护肺免受损伤。我们报告的发现，核细胞死亡机制，介导的聚（ADP-核糖）聚合酶（PARP），占急性肺损伤和炎症在一个经典的绵羊烟雾吸入和烧伤模型。在I期研究中，我们测试了我们的新型超强效PARP抑制剂INO-1001，并观察到肺损伤显著减少：INO-1001显著增加PaO 2/FiO 2（PF）比值，减少中性粒细胞浸润、湿干比和肺淋巴流量。在吸入烟雾和假单胞菌肺炎的绵羊中，INO-1001显著增加PF比率，降低气道峰压和肺分流分数。该2期SBIR的中心目标是确定PARP激活在临床烟雾吸入性损伤中的致病作用。我们将在200例因急性烟雾吸入而入院的患者中进行一项前瞻性、随机、双盲的PARP抑制研究。入组患者将包括具有以下所有特征的患者：1）热损伤< 24小时，2）皮肤烧伤> 20% BSA，3）烟雾吸入证据（以下标准中的大多数证明了这一点：在创伤现场测量或后推的碳氧血红蛋白> 40%，碳质痰，PF比率早期降低，带血的气管内分泌物，或通过支气管镜检查变黑的支气管），和4）患者的医生的临床判断，即机械通气的持续时间将超过7天的可能性很高。该临床研究将在14个美国机构进行，这些机构在烟雾吸入性损伤的重症监护方面具有临床和研究领导地位。INO-1001的给药将在严重呼吸衰竭发作之前开始，并持续5天，这是吸入烟雾引起肺部炎症和呼吸功能不全的关键时期。将评价三个主要临床终点：1）PF比，2）机械通气持续时间，3）动态肺顺应性，并将随访另一个次要终点（死亡率）。拟议的临床试验预计将为FDA批准INO-1001用于治疗急性烟雾吸入性损伤的孤儿药提供基础。

DESCRIPTION (provided by applicant): Smoke inhalation is a major co-morbid factor in thermal injury. Therapy of smoke inhalation is supportive -there are no specific countermeasures to protect the lung from injury. We report the discovery that a nuclear cell death mechanism, mediated by poly (ADP-ribose) polymerase (PARP), accounts for the acute lung injury and inflammation in a classic ovine smoke inhalation and burn injury model. In Phase I, we tested our novel ultrapotent PARP inhibitor, INO-1001, and observed a dramatic reduction in lung injury: INO-1001 markedly increased the PaO2/FiO2 (PF) ratio and decreased neutrophil infiltration, wet-to-dry ratio, and lung lymph flow. In sheep challenged with smoke inhalation and Pseudomonal pneumonia, INO-1001 significantly increased the PF ratio and decreased peak airway pressure and pulmonary shunt fraction. The central objective of this Phase 2 SBIR is to establish the pathogenetic role of PARP activation in clinical smoke inhalation injury. We will utilize a prospective, randomized, double-blinded study of PARP inhibition in 200 patients admitted with acute smoke inhalation. Enrollment will include patients with all of the following characteristics: 1) thermal injury < 24 h old, 2) cutaneous burn injury > 20% BSA, 3) evidence of smoke inhalation (as evidenced by a majority of the following criteria: carboxyhemoglobin measured or back extrapolated > 40 % at the scene of trauma, carbonaceous sputum, an early decrease in PF ratio, blood tinged endotracheal secretions, or blackened bronchi by bronchoscopic exam), and 4) clinical judgment by the patient's physician that there is a high probability that the duration of mechanical ventilation will exceed 7 days. The clinical study will be conducted in 14 U.S. institutions with demonstrated clinical and research leadership in critical care of smoke inhalation injury. Administration of INO-1001 will be initiated prior to the onset of severe respiratory failure and continued for 5 days, the critical period of smoke inhalation induced pulmonary inflammation and respiratory insufficiency. Three primary clinical endpoints will be evaluated: 1) PF ratio, 2) duration of mechanical ventilation, and 3) dynamic pulmonary compliance, and an additional secondary endpoint, mortality, will be followed. The proposed clinical trial is expected to provide the foundation for FDA orphan drug approval of INO-1001 for treatment of acute smoke inhalation injury.