Treatment of congenital heart disease associated pulmonary hypertension

先天性心脏病相关肺动脉高压的治疗

• 批准号: 8831801
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 150万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8831801
• 关键词: Acute; Adolescent; Anesthetics; Animal Model; Biological; Blood; Blood Pressure; Blood Vessels; Breathing; Canis familiaris; Cardiac Output; Cardiopulmonary Bypass; Caring; Child; Clinical; Congenital Abnormality; Congenital Heart Defects; Continuous Infusion; Data; Development; Dose; Drug Kinetics; Drug Targeting; Equilibrium; Exhibits; FDA approved; Foundations; Free Radicals; Functional disorder; Future; Heart Block; Heart Rate; Human Volunteers; Hydrogen Peroxide; Hydroxylamine; Incidence; Infant; Intensive Care; Investigation; Label; Left; Life; Live Birth; Lung; Marketing; Medical; Modeling; Morbidity - disease rate; Muscle Tonus; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitrogen; Operative Surgical Procedures; Oxidation-Reduction; Oxygen; Pathway interactions; Perioperative; Peripheral Resistance; Peroxonitrite; Pharmacodynamics; Pharmacology; Phase; Placebo Control; Plasma; Postoperative Period; Prevention; Prodrugs; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary Vascular Resistance; Randomized; Rattus; Reaction; Reactive Oxygen Species; Recovery; Research Institute; Rodent Model; Safety; Shunt Device; Source; Superoxides; Techniques; Technology; Testing; Therapeutic; Thromboxanes; Time; Toxicology; Vascular Smooth Muscle; Vascular remodeling; Vasoconstrictor Agents; Vasodilator Agents; Work; aerosolized; catalase; catalyst; clinically relevant; congenital heart disorder; in utero; in vivo; inhaled nitric oxide; innovation; mimetics; mortality; novel; pressure; prevent; public health relevance; restoration; single molecule

 DESCRIPTION (provided by applicant): Restoration of the balance of the free radicals nitric oxide (NO) and superoxide in the pulmonary vasculature may prevent life-threatening perioperative pulmonary hypertension (PH) in children with congenital heart defects (CHD) undergoing surgical correction of a left-to-right shunt. In rodent models of PH, intratracheal (IT) administration of R-190, a bifunctional NO donor and redox catalyst prodrug intended to correct free radical imbalance, selectively and profoundly reduces mean pulmonary arterial pressure (MPAP) without impacting systemic mean arterial pressure (MAP) or heart rate (HR). R-100, the metabolite of R-190, inhibits vascular remodeling. R-190 is dephosphorylated in vivo to form an intermediate, R-188, which is then hydrolyzed to form para-hydroxyphenylacetate (PHPA) and 3- nitratoproxyl-hydroxylamine. The freed PHPA detoxifies peroxynitrite, the reaction product of NO with superoxide anion, while the liberated 3-nitratoproxyl-hydroxylamine oxidizes to form R-100, a molecule serving as: a) a nitric oxide donor via its organic nitrate, and b) a broad-spectrum catalyst of reactive oxygen species degradation via its nitroxide moiety. The fusion of all the above functional domains into a single entity (R-190) assures that their multiple biologica activities are co-localized. The unique potency, selectivity, and sustained duration of effect justify development of R-190 for perioperative prevention of PH in CHD. Aim #1: Establish the pharmacodynamic (PD) profile of R-190 in a lamb model of PH induced by a thromboxane mimetic Juvenile lambs will undergo continuous infusion with the pulmonary-selective vasoconstrictor U-46619 to achieve a MPAP = 25-30 mmHg. R-190 (0, 1, 3, 10, 30 mg/kg nebulized per IT) will be compared to inhaled NO (iNO) for the amplitude and duration of its effect on SVR and PVR. Blood will be collected for correlation of PVR and SVR with the plasma concentrations of R-190 and its major metabolites. Aim #2: Determine the efficacy of R-190 in a lamb model of perioperative pulmonary hypertension induced by cardiopulmonary bypass (CPB) and surgical correction of a congenital left-t0- right shunt Juvenile lambs with PH (MPAP = ~25 mmHg) induced by in utero placement of a pulmonary - aortic window will undergo CPB and surgical closure of the arteriovenous connection. Directly following CPB, the effect of a single dose of nebulized IT R-190 or vehicle control will be compared to iNO (40 ppm) for the amplitude and duration of its effect on SVR and PVR. Aim #3: Establish the acute safety, stability, and tolerance of the aerosolized R-190 by IND-enabling toxicology and safety pharmacology studies. Lovelace Biomedical and Environmental Research Institute will carry out GLP-grade in vivo dose range- finding and 14 day repeat-dose toxicology investigations in juvenile rats and dogs, with a 14-day recovery period. RTX will then prepare and submit a full IND application to the FDA for a Phase 1a clinical dose- escalation study.

 描述（由申请人提供）：恢复肺血管系统中自由基一氧化氮（NO）和超氧化物的平衡可以预防患有先天性心脏缺陷（CHD）的儿童在接受手术矫正时出现危及生命的围手术期肺动脉高压（PH）。在 PH 啮齿动物模型中，气管内 (IT) 分流。 R-190 是一种双功能 NO 供体和氧化还原催化剂前药，旨在纠正自由基失衡，可选择性地显着降低平均肺动脉压 (MPAP)，而不影响全身平均动脉压 (MAP) 或心率 (HR)。 100 是 R-190 的代谢产物，可抑制血管重塑。R-190 在体内去磷酸化，形成中间体 R-188，然后水解形成。对羟苯乙酸酯 (PHPA) 和 3-硝基丙氧基羟胺 释放的 PHPA 对过氧亚硝酸盐（NO 与超氧阴离子的反应产物）进行解毒，同时释放的 3-硝基丙氧基羟胺氧化形成 R-100，一种服务分子：a) a)通过其有机硝酸盐提供一氧化氮供体，以及 b) 反应性广谱催化剂通过其硝基氧部分将所有上述功能域融合成一个实体（R-190），确保了它们的多种生物活性是共定位的，其独特的效力、选择性和持续时间证明了其开发的合理性。 R-190 用于围手术期预防 CHD 中的 PH 目标 1：在血栓素模拟物诱导的 PH 羔羊模型中建立 R-190 的药效学 (PD) 曲线。幼年羔羊将接受肺部选择性血管收缩剂 U-46619 的持续输注，以达到 MPAP = 25-30 mmHg R-190（每次 IT 雾化 0、1、3、10、30 mg/kg）与吸入进行比较。将收集 NO (iNO) 对 SVR 和 PVR 影响的幅度和持续时间，以将 PVR 和 SVR 与R-190 及其主要代谢物的血浆浓度 目标 2：确定 R-190 在体外循环 (CPB) 诱导的围手术期肺动脉高压羔羊模型中的功效以及先天性左-t0-右分流青少年的手术矫正。因宫内放置肺主动脉窗而引起 PH (MPAP = ~25 mmHg) 的羔羊将接受体外循环和动静脉手术闭合紧接 CPB 后，将单剂量雾化 IT R-190 或媒介物对照与 iNO (40 ppm) 的效果进行比较，了解其对 SVR 和 PVR 的影响幅度和持续时间：建立急性目标。 Lovelace 生物医学和环境研究所将通过 IND 毒理学和安全药理学研究对雾化 R-190 的安全性、稳定性和耐受性进行 GLP 级体内剂量范围寻找和研究。然后，RTX 将在幼年大鼠和狗中进行 14 天的重复剂量毒理学研究，并有 14 天的恢复期，然后向 FDA 准备并向 FDA 提交完整的 IND 申请，以进行 1a 期临床剂量递增研究。