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.