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。吸入烟雾的治疗是支持性的--目前还没有具体的对策来保护肺部免受伤害。我们发现，在典型的绵羊烟雾吸入和烧伤模型中，由聚腺苷二磷酸核糖聚合酶(PARP)介导的核细胞死亡机制可以解释急性肺损伤和炎症。在第一阶段，我们测试了我们的新型超高效PARP抑制剂INO-1001，观察到肺损伤显著减少：INO-1001显著增加PaO2/FiO2(PF)比率，减少中性粒细胞渗透、湿/干比率和肺淋巴流量。在烟雾吸入和肺炎假单胞菌感染的绵羊模型上，INO-1001可显著提高肺泡灌洗液比例，降低气道峰压和肺分流分数。本第二阶段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。我们将利用一项前瞻性、随机、双盲研究，对200名急性烟雾吸入患者进行PARP抑制研究。入选的患者将包括具有以下所有特征的患者：1)烫伤和24小时前，2)皮肤烧伤和20%的BSA，3)有烟雾吸入的证据(根据以下大多数标准：创伤现场测得或反向推算的碳氧血红蛋白&gt；40%，碳质痰，早期PF比率下降，气管内分泌物带血，或支气管镜检查发现支气管变黑)，以及4)患者医生的临床判断，机械通气的持续时间很可能超过7天。这项临床研究将在14家美国机构进行，这些机构在烟雾吸入性损伤的危重护理方面表现出了临床和研究领先地位。INO-1001的给药将在严重呼吸衰竭发生之前开始，并持续5天，这是烟雾吸入引起肺部炎症和呼吸功能不全的关键时期。将评估三个主要临床终点：1)PF比率，2)机械通气持续时间，3)动态肺顺应性，以及另外一个次要终点，死亡率。拟议的临床试验有望为FDA批准用于治疗急性烟雾吸入性损伤的孤儿药物INO-1001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.