PARS inhibitor therapy of smoke inhalation injury

PARS抑制剂治疗烟雾吸入性损伤

• 批准号: 6401315
• 负责人: PRAKASH G JAGTAP
• 金额: $ 27.06万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6401315
• 关键词: burn therapy; burns; cardiac output; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; hemodynamics; histology; lung injury; nonhuman therapy evaluation; pentosyltransferase; pharmacokinetics; sheep; smoke inhalation; vascular resistance

Smoke inhalation and burn injury induce an inflammatory pneumonitis that may progress to severe respiratory failure. Current treatment options are limited to supportive measures. We propose to test the feasibility of a revolutionary anti-inflammatory approach in the management of smoke inhalation induced acute lung injury (ALI). A recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) Pathway", has been implicated in the pathogenesis of inflammatory injury. Triggered by oxidant-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP- ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates. PARS activation also strongly upregulates expression of pro-inflammatory cytokines, chemokines, and adhesion molecules. The administration of PARS inhibitors has been shown to have a protective effect in experimental models of inflammation and altered blood flow, including arthritis, stroke, and endotoxic shock. The central objective of this grant proposal is to establish that Inotek's lead PARS inhibitor, PJ-34, improves hemodynamics, end-organ injury, and oxygenation in an ovine model of thermal injury induced ALI. After smoke inhalation and burn injury, sheep will be treated with PJ-34 (3-30 mg/kg i.v.). The percent change from baseline pulmonary vascular resistance, systemic vascular resistance, cardiac output, and PaO2/FiO2 ratio will be compared to untreated controls. At 48 h, we will measure the effect of PJ-34 on a comprehensive series of inflammatory indices of lung injury to assess lipid peroxidation, neutrophil infiltration, histology, and peroxynitrite formation. We will correlate the efficacy of PJ-34 with its serum concentration, in order to create a pharmacodynamic profile. We expect that PJ-34 will dose-dependently reduce lung inflammation and injury in this clinically relevant model of combined smoke inhalation and burn injury. PROPOSED COMMERCIAL APPLICATIONS: The annual domestic impact of burn injury and smoke inhalation induced ALI on the health care market is estimated at > $50 million. The worldwide market (developed countries only) is four times larger. Given the absence of a specific, safe, and convenient existing therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high sustained price point ($1000 per patient). Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) equal $250 million (annual).

吸入和烧伤损伤会诱导炎症性肺炎，可能会导致严重的呼吸衰竭。当前的治疗选择仅限于支持措施。我们建议测试革命性抗炎方法在烟雾吸入诱发急性肺损伤（ALI）中的可行性。最近发现的炎症性损伤机制，即“聚（ADP-核糖）合成酶（PARS）途径”，与炎症性损伤的发病机理有关。由氧化剂诱导的DNA单链断裂触发，PARS催化adp-核糖的能量耗尽聚合，导致NAD耗竭，抑制糖溶解和线粒体呼吸，以及最终的细胞内高能磷酸盐。 PAR激活还强烈上调促炎细胞因子，趋化因子和粘附分子的表达。在炎症和血液流动改变的实验模型（包括关节炎，中风和内毒性休克）的实验模型中，PARS抑制剂的给药具有保护作用。该赠款提案的核心目的是确定Inotek的铅PAR抑制剂PJ-34，改善了热损伤诱导的ALI的卵巢模型中的血液动力学，最终器官损伤和氧合。吸入烟雾和烧伤后，将用PJ-34（3-30 mg/kg I.V.）治疗绵羊。将基线肺血管耐药性，全身血管抗性，心输出量和PAO2/FIO2比的变化百分比变化，将与未处理的对照相提并论。在48小时内，我们将衡量PJ-34对肺损伤的全面炎症指标的影响，以评估脂质过氧化，嗜中性粒细胞浸润，组织学和过氧亚硝酸盐形成。我们将将PJ-34的功效与其血清浓度相关联，以创建药效学谱。我们预计，在这种临床相关的烟雾吸入和烧伤损伤的模型中，PJ-34会依赖于剂量降低肺部炎症和损伤。拟议的商业应用：烧伤伤害和吸入烟雾引起的ALI对卫生保健市场的年度影响估计为5000万美元。全球市场（仅发达国家）大四倍。鉴于缺乏特定，安全和方便的现有疗法，Inotek预计将在高水平的渗透率和持续价格高（每位患者$ 1000）的情况下迅速获得市场接受。估计在市场进入和成熟后全球总销售收入（FDA批准后4年）等于2.5亿美元（年度）。