Bifunctional Redox Agent for the Treatment of PPHN

用于治疗 PPHN 的双功能氧化还原剂

• 批准号: 8195649
• 负责人: Garry John Southan
• 金额: $ 23.79万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195649
• 关键词: Acute; Address; Adolescent; Adverse event; Aftercare; Animal Model; Animals; Biological; Biological Assay; Birth; Blood Circulation; Blood Pressure; Blood Vessels; Blood flow; Blood gas; Breathing; Canis familiaris; Cardiac foramen ovale; Cardiovascular system; Chromosome abnormality; Clinical; Complex; Data; Dependency; Dose; Drug Delivery Systems; Drug Kinetics; Ductus Arteriosus; Exhibits; Extracorporeal Membrane Oxygenation; Free Radicals; Funding; Future; Gases; Gold; Hemorrhage; Human; Hydrogen Peroxide; Hypotension; In Situ; In Vitro; Infant; Infection; Infusion procedures; Injury; Intravenous infusion procedures; Investigation; Lead; Left; Life; Ligation; Lung; Mechanical ventilation; Medical; Micronucleus Tests; Modeling; Monitor; Monocrotaline; Muscle; Neonatal; Newborn Infant; Nitrates; Nitric Oxide; Nitrogen; Oxidants; Oxidation-Reduction; Oxygen; Patients; Peripheral; Peroxonitrite; Persistent Fetal Circulation Syndrome; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Pilot Projects; Placebo Control; Plasma; Production; Pulmonary Vascular Resistance; Pyrrolidines; Randomized; Rattus; Reaction; Refractory; Regimen; Relative (related person); Safety; Shunt Device; Small Business Innovation Research Grant; Stroke; Superoxide Dismutase; Superoxides; Technology; Therapeutic; Tissues; Toxicogenetics; Toxicology; United States National Institutes of Health; Up-Regulation; Vasodilator Agents; Withdrawal; Withholding Treatment; arteriole; base; catalase; catalyst; clinically relevant; hemodynamics; in utero; in vivo; inhaled nitric oxide; innovation; instrumentation; mimetics; neonate; neurobehavioral; novel; pressure; professor; prospective; pulmonary arterial hypertension; pup; pyrrolidine; respiratory; response; small molecule

DESCRIPTION (provided by applicant): Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening neonatal condition wherein an elevation in pulmonary vascular resistance after birth diverts pulmonary blood flow via a right-to-left shunt, at the levels of the ductus arteriosus and foramen ovale, into the systemic circulation. Current therapy includes mechanical ventilation, oxygen, and inhalational nitric oxide (iNO), a gas that selectively dilates the pulmonary vasculature but is only effective in 30-50% of patients. Non-responders to iNO therapy are supported via extracorporeal membrane oxygenation (ECMO). Although PPHN has multiple biological triggers, our current understanding is consistent with a convergence to a final common effector mechanism of injury produced by an excess of superoxide and a deficiency of NO in the newborn pulmonary vasculature. The imbalance of these two free radicals directly impairs the ability of the pulmonary arteriole to dilate appropriately after birth. To address this unmet need, and overcome the limitations in response to iNO therapy, Radikal Therapeutics is developing R-100, a small molecule agent formed from the covalent linkage of: 1) an organic nitrovasodilator domain that releases NO, and 2) a pyrrolidine nitroxide domain that acts as a superoxide dismutase mimetic, catalase mimetic, and peroxynitrite decomposition catalyst. R-100 has been shown to be dramatically effective in selectively relieving pulmonary arterial hypertension in monocrotaline-challenged rats and in pilot studies of newborn lamb models of severe PPHN refractory to iNO. Phase I Specific Aim: Contrast the efficacy and selectivity of iNO and R-100 in a newborn lamb model of severe PPHN refractory to iNO. We will carry out a dose-escalation study in anesthetized and mechanically-ventilated newborn lambs in which PPHN has been induced by in utero ligation of the ductus arteriosus. R-100 is expected to be superior to iNO in selectively reducing mean pulmonary arterial blood pressure. Criteria for progression to the Phase 2 NIH SBIR: Treatment with R-100 must satisfy, relative to baseline hemodynamics, all of the following hemodynamic endpoints: 1) > 50% reduction in the elevation relative to baseline in mean pulmonary arterial blood pressure (MPAP), 2) > 50% increase relative to baseline in pulmonary blood flow, 3) < 10% reduction in peripheral mean arterial blood pressure, 4) < 10% increase in baseline MPAP after cessation of treatment, and 5) equivalence or superiority to iNO on all of the above parameters. Phase II Specific Aim: Establish the subacute safety and tolerance of IV R-100 in GLP toxicology and safety pharmacology studies. Genetic toxicology studies will include the Ames, chromosomal aberration assay, and rat micronucleus assay. Safety pharmacology studies will include juvenile rat neurobehavioral and respiratory studies and juvenile canine cardiovascular studies. Toxicology investigations will be carried out over 4 weeks in newborn rats and dog pups. These studies will identify the No Observed Adverse Event Level (NOAEL) in each species, and provide the regulatory basis for a dose range to be explored for safety, tolerance, and pharmacokinetics in human neonates. PUBLIC HEALTH RELEVANCE: Persistent pulmonary hypertension of the newborn (PPHN) is a rare but life-threatening condition of the term infant in which the blood pressure in the lungs fails to decrease to a normal level after birth. Existing therapy for this condition involves the inhalation of nitric oxide gas, but this proves ineffective in more than a third of infants. We are developing a novel drug that targets the basic mechanisms of PPHN and has been shown to be effective in pilot studies in a large animal PPHN model wherein inhaled nitric oxide exhibits only a weak response. We now propose to define the value of our technology in a definitive clinically-relevant animal model of PPHN.

描述（由申请人提供）：新生儿持续性肺动脉高压（PPHN）是一种危及生命的新生儿疾病，其中出生后肺血管阻力升高，通过右向左分流使肺血流发生分流，其水平为动脉导管和卵圆孔进入体循环。目前的治疗包括机械通气、氧气和吸入一氧化氮 (iNO)，这是一种选择性扩张肺血管系统的气体，但仅对 30-50% 的患者有效。对 iNO 治疗无反应的患者可通过体外膜肺氧合 (ECMO) 获得支持。尽管 PPHN 有多种生物触发因素，但我们目前的理解与新生儿肺血管系统中超氧化物过量和 NO 缺乏所产生的最终共同损伤效应机制一致。这两种自由基的不平衡直接损害出生后肺小动脉适当扩张的能力。为了解决这一未满足的需求，并克服 iNO 疗法的局限性，Radikal Therapeutics 正在开发 R-100，这是一种由以下物质共价连接而成的小分子药物：1) 释放 NO 的有机硝基血管舒张剂结构域，2) 吡咯烷硝基氧结构域，充当超氧化物歧化酶模拟物、过氧化氢酶模拟物和过氧亚硝酸盐分解催化剂。 R-100 已被证明能够显着有效地选择性缓解野百合碱攻击大鼠的肺动脉高压，以及对 iNO 难治性严重 PPHN 的新生羔羊模型的初步研究。 I 期具体目标：对比 iNO 和 R-100 在 iNO 难治性严重 PPHN 新生羔羊模型中的功效和选择性。我们将在麻醉和机械通气的新生羔羊中进行剂量递增研究，其中通过子宫内动脉导管结扎诱导 PPHN。预计 R-100 在选择性降低平均肺动脉血压方面优于 iNO。进展到第 2 期 NIH SBIR 的标准：相对于基线血流动力学，R-100 治疗必须满足以下所有血流动力学终点：1) 平均肺动脉血压 (MPAP) 相对于基线的升高降低 > 50% ), 2) 肺血流量相对于基线增加 > 50%，3) 外周平均动脉血压降低 < 10%，4) 增加 < 10%停止治疗后的基线 MPAP，以及 5) 在所有上述参数上与 iNO 等效或优于 iNO。 II 期具体目标：在 GLP 毒理学和安全药理学研究中建立 IV R-100 的亚急性安全性和耐受性。遗传毒理学研究将包括艾姆斯试验、染色体畸变试验和大鼠微核试验。安全药理学研究将包括幼年大鼠神经行为和呼吸研究以及幼年犬心血管研究。毒理学研究将在新生大鼠和幼犬身上进行 4 周多的时间。这些研究将确定每个物种的未观察到不良事件水平（NOAEL），并为探索人类新生儿的安全性、耐受性和药代动力学的剂量范围提供监管基础。 公共卫生相关性：新生儿持续性肺动脉高压 (PPHN) 是足月婴儿的一种罕见但危及生命的疾病，这种疾病在出生后肺部血压未能降至正常水平。现有的治疗方法包括吸入一氧化氮，但这对超过三分之一的婴儿无效。我们正在开发一种针对 PPHN 基本机制的新药物，并已在大型动物 PPHN 模型的初步研究中被证明是有效的，其中吸入一氧化氮仅表现出微弱的反应。我们现在建议在明确的临床相关 PPHN 动物模型中定义我们的技术的价值。