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（由申请方提供）：肺血管中自由基一氧化氮（NO）和超氧化物的平衡的恢复可以预防接受左向右分流手术矫正的先天性心脏病（CHD）儿童发生危及生命的围手术期肺动脉高压（PH）。在PH的啮齿动物模型中，肠内（IT） 施用R-190（旨在纠正自由基失衡的双功能NO供体和氧化还原催化剂前药）选择性地和深刻地降低平均肺动脉压（MPAP）而不影响全身平均动脉压（MAP）或心率（HR）。R-100是R-190的代谢产物，可抑制血管重塑。R-190在体内脱磷酸化形成中间体R-188，然后水解形成对羟基苯乙酸酯（PHPA）和3-硝基丙氧基-羟胺。释放的PHPA使过氧亚硝酸盐解毒，过氧亚硝酸盐是NO与超氧阴离子的反应产物，而释放的3-硝基丙氧基-羟胺氧化形成R-100，R-100是一种分子，用作：a）通过其有机硝酸盐的一氧化氮供体，和B）通过其氮氧部分的活性氧物质降解的广谱催化剂。所有上述功能结构域融合成一个单一的实体（R-190），确保其多种生物活性是共定位的。独特的效力、选择性和持续的作用时间证明了R-190用于CHD围手术期PH预防的合理性。目标一：在血栓烷模拟物诱导的PH的羔羊模型中建立R-190的药效学（PD）特征幼龄羔羊将接受肺选择性血管收缩剂U-46619的连续输注，以达到MPAP = 25-30 mmHg。将比较R-190（每次IT雾化0、1、3、10、30 mg/kg）与吸入NO（iNO）对SVR和PVR影响的幅度和持续时间。将采集血液，以确定PVR和SVR与R-190及其主要代谢产物血浆浓度的相关性。目标二：确定R-190在心肺转流（CPB）诱导的围手术期肺动脉高压羔羊模型和先天性左-右分流的手术矫正中的有效性子宫内放置肺-主动脉窗诱导的PH（MPAP = ~25 mmHg）幼龄羔羊将接受CPB和动静脉连接的手术闭合。CPB后立即将单次雾化IT R-190或溶剂对照与iNO（40 ppm）对SVR和PVR影响的幅度和持续时间进行比较。目的#3：通过IND启用毒理学和安全药理学研究确定雾化R-190的急性安全性、稳定性和耐受性。Lovelace Biomedical and Environmental Research Institute将在幼龄大鼠和犬中进行GLP级体内剂量范围探索和14天重复给药毒理学研究，恢复期为14天。RTX随后将准备并向FDA提交一份完整的IND申请，进行1a期临床剂量递增研究。