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（通过应用提供）：肺脉管系统中自由基一氧化氮（NO）和超氧化物的平衡的恢复可能会防止在经过左右右转的手术校正的先天性心脏缺陷（CHD）儿童中威胁生命的周期性肺动脉高压（PH）。在pH的啮齿动物模型中，气管内（IT） R-190的给药是双功能的无供体和氧化还原催化剂前药，旨在纠正自由基失衡，有选择地和深刻地降低平均肺动脉压（MPAP），而不会影响全身平均动脉压（MAP）或心脏速率（HR）。 R-100（R-190的代谢产物）抑制血管重塑。 R-190在体内被脱磷酸化，形成中间体R-188，然后将其水解形成二羟基苯基乙酸酯（PHPA）和3-硝基丙型羟基羟胺。游离PHPA排毒的过氧亚硝酸盐，NO与超氧化阴离子的反应产物，而解放的3-硝酸羟基羟胺氧化物形成了R-100，一种分子，一种分子，用于：a）通过其有机硝酸盐和宽阔的氧化物量的Nitrric氧化物供体通过其宽阔的氧化型牛肉化的细胞化含量，将其用于宽广的氧化型果皮，并通过其宽度型氧化量。上述所有功能域融合到单个实体中（R-190）确保其多个生物学活性是共定位的。独特的效力，选择性和持续的效果持续时间证明了R-190的开发是合理的，以定期预防CHD中的pH。 AIM＃1：在由血栓烷模拟的幼年羔羊诱导的pH模型中建立R-190的药物大型动力学（PD），将对肺部选择性血管收缩剂U-46619进行连续输注，以达到MPAP = 25-30 mmHg。将R-190（每IT的0、1、3、10、10、30 mg/kg静脉）与遗传的NO（INO）进行比较，其对SVR和PVR的影响的持续时间和持续时间。将收集血液以将PVR和SVR与R-190及其主要代谢产物的血浆浓度相关。目标＃2：确定R-190在心肺旁路（CPB）引起的周期性肺动脉高压模型中的有效性（CPB）（CPB）以及对pH（MPAP = 〜25 mmHg）的先天性左T0-左T0-右分流幼型羔羊（MPAP = 〜25 mmHg）的孔子，在子宫内的射击和孔子的射击不足将被验证-Arortor-aIrt-aIrt-Altero suber-aIrtial-aIrtir suber-aIrtir-ailtir suber-aIrtir will-aIrtic will ther-ailort-aIrtir will cop a polmon and seriric will动脉连接。直接在CPB之后，将将单剂量的雾化IT R-190或媒介物控制的效果与INO（40 ppm）的放大器和其对SVR和PVR的影响的持续时间进行比较。 AIM＃3：建立通过毒理学和安全药理学研究来确定气泡R-190的急性安全性，稳定性和耐受性。 Lovelace生物医学和环境研究所将在少年大鼠和狗进行14天的恢复期间进行体内剂量范围调查和14天的重复剂量毒理学研究。然后，RTX将准备并向FDA提交完整的IND应用程序进行1A期临床剂量升级研究。