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)：恢复肺血管内自由基一氧化氮(NO)和超氧化物歧化酶(O2)的平衡，可以预防先天性心脏病(CHD)患儿在接受左向右分流手术矫正时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，气管内(IT) R-190是一种用于纠正自由基失衡的双功能一氧化氮供体和氧化还原催化剂前体药物，使用R-190可以选择性而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在体内被脱磷，形成中间体R-188，然后被水解形成对羟基苯乙酸酯(PHPA)和3-硝基-羟胺。释放的PHPA解毒过氧亚硝酸盐，过氧亚硝酸盐是NO与超氧阴离子反应的产物，而释放的3-硝酸羟胺氧化形成R-100，R-100分子是：a)通过其有机硝酸盐作为一氧化氮供体，b)通过其氮氧化物部分降解活性氧物种的广谱催化剂。所有上述功能结构域的融合成一个单一实体(R-190)确保了它们的多种生物学活性是共定位的。R-190的独特效力、选择性和持续时间为开发R-190预防冠心病围手术期PH提供了依据。目的#1：在拟血栓素诱导的羔羊PH模型中建立R-190的药效学(PD)模型。幼年羔羊将接受肺选择性血管收缩药U-46619的持续输注，以达到25-30毫米汞柱的最大呼气压力。将R-190(每IT雾化0、1、3、10、30 mg/kg)与吸入NO(INO)进行比较，以观察其对SVR和PVR作用的幅度和持续时间。将采集血液进行PVR和SVR与血浆R-190及其主要代谢物浓度的相关性研究。目的#2：探讨R-190对体外循环(CPB)围术期肺动脉高压和先天性左、右分流性肺动脉高压(MPAP=~25 mm Hg)的疗效。CPB结束后，单次雾化吸入IT R-190或车辆控制剂的效果将与iNO(40ppm)在SVR和PVR上的作用幅度和持续时间进行比较。目的#3：通过IND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生物医学和环境研究所将在幼年大鼠和狗身上进行GLP级体内剂量范围发现和14天重复剂量毒理学研究，恢复期为14天。然后，RTX将准备一份完整的IND申请，并提交给FDA进行1a期临床剂量递增研究。