Bifunctional potassium-ATP channel opener and redox catalyst for therapy of spina
用于脊柱治疗的双功能钾-ATP 通道开放剂和氧化还原催化剂
基本信息
- 批准号:8769880
- 负责人:
- 金额:$ 23.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-15 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:A MouseAcetylcysteineAction PotentialsAcuteAdultAdverse effectsAnimal ModelAnimalsAntioxidantsArrhythmiaAscorbic AcidBlindedCardiacChemicalsChemistryClinicClinicalCollaborationsControl GroupsContusionsDevelopmentDiazoxideDiseaseDoseDrug ExposureDrug TargetingExhibitsFemaleFoundationsHeartHemorrhagic ShockHistologicHydrogen PeroxideHydroxyl RadicalHyperglycemiaHypotensionInjuryInvestigationIschemic PreconditioningKidneyKineticsLabelLaminectomyLimb structureLungMarketingMeasuresMedicalMitochondriaModelingMotorMusNeurological outcomeOhioOperative Surgical ProceduresOrphan DrugsOutcomeOxidation-ReductionPathogenesisPathologicPathway interactionsPenetrationPeroxonitritePharmaceutical PreparationsPhasePilot ProjectsPinacidilPlacebo ControlPlasmaPoly(ADP-ribose) PolymerasesPotassiumPre-Clinical ModelPreventionProduct RPyrrolidinesRandomizedReactionRecoveryRecovery of FunctionReperfusion InjuryReperfusion TherapyResuscitationRodentRodent ModelSecondary toSeriesSmall Business Innovation Research GrantSolutionsSpin TrappingSpinalSpinal CordSpinal cord injuryStressSuperoxidesTestingTherapeuticTherapeutic AgentsTissuesTocopherolsToxic effectTraumaUniversitiesVentricular Fibrillationantioxidant therapyattenuationbasecatalasecatalystclinical practiceclinically relevantdrinking waterfunctional outcomesimprovedindexinginnovationmimeticsnovelpre-clinicalprofessorprospectivepublic health relevancepyrrolidineresponsesmall molecule
项目摘要
DESCRIPTION (provided by applicant): Radikal Therapeutics (RTX) is developing a first-in-class cytoprotective small molecule (R-801) for the prevention of spinal cord injury (SCI) based upon the chemical fusion of 2 discrete chemical domains that: 1) target redox stress via a nitroxide spin-trap moiety, and 2) trigger the endogenous ischemic-preconditioning response via mitochondrial-selective K+-ATP channel activation. We have confirmed a powerful effect of R- 801 in rodent models of trauma, including hemorrhagic shock and ischemia reperfusion injury of the heart, lung, limb, and kidney. In a pilot study of spinal cord trauma (SCT), resuscitation of mice with R-801 produced an accelerating and non-plateauing improvement in motor function (20% total recovery over the first 10 days). R-801 has shown no evidence of toxicity in rodents and large animals. At present, R-801 is the first and only safe, effective, and selective mito-K+-ATP channel opener in development, as no other firm or academic center has succeeded to date in inventing a safe, effective, and selective mito-K+-ATP channel opener. We now propose to verify the pre-clinical feasibility of R-801 in a classic model of SCT and to deepen the understanding of its mechanism of action. Phase 1 SBIR Specific Aim: Establish the PD profile of R-801 in an experimental murine model of SCI. In order to test the hypothesis that R-801 effectively resuscitates SCT, RTX will carry out a pathologic and functional analysis in a prospective, randomized, single-blinded, placebo-controlled investigation in mice. In collaboration with Professor Philip Popovich (Ohio University), adult female CD1 mice will be subjected to SCT using a standardized model of contusion injury. Sham injury (laminectomy without SCT) and vehicle control groups will be compared to a group receiving R-801. The initial 2 doses of R-801 (80 mg/kg/dose), given 1 and 3 h after SCT, will be administered intraperitoneally (IP) in order to obtain a rapid tissue penetration of high levels of the drug int spinal cord tissue. Thereafter, R-801 will be provided in the drinking water (as a 0.2% solution) in order to optimize steady-state drug exposure. In Series A, mice (n=10 per group) will be sacrificed 48 h after SCT for histologic and immunohistochemical analysis of the spinal cord for evidence of of poly(ADP-ribose) polymerase activation and ONOO- formation. In Series B, open field locomotor function will be analyzed in adult female SCI mice (n=10 per group) for a period of 2 months post SCT. Mice will be acclimated to the open field ~1 week prior to SCT. Indices of functional recovery will be measured using the Open field-testing (Basso Mouse Scale; BMS) locomotor rating scale. BMS scores will then be obtained pre-injury and again at weekly intervals. Terminal plasma concentrations of R-801 will be obtained, in order to construct a PD profile relating the efficacy in each dose group to functional, morphologic, and immunohistochemical endpoints. Verification that R-801 resuscitation ameliorates morphologic and functional outcomes will provide a logical foundation for commercial development of parenteral R-801 as an emergent therapy for acute SCI.
描述(由申请人提供):Radikal Therapeutics(RTX)正在开发一种用于预防脊髓损伤(SCI)的一流细胞保护性小分子(R-801),该小分子基于2个离散化学结构域的化学融合:1)通过氮氧自由基自旋捕获部分靶向氧化还原应激,2)通过脑组织选择性K+-ATP通道激活触发内源性缺血预处理反应。我们已经证实了R- 801在啮齿动物创伤模型中的强大作用,包括心脏、肺、肢体和肾脏的出血性休克和缺血再灌注损伤。在一项脊髓创伤(SCT)的初步研究中,用R-801复苏小鼠可加速和非平稳改善运动功能(前10天总恢复率为20%)。R-801在啮齿类动物和大型动物中没有毒性证据。目前,R-801是第一个也是唯一一个正在开发的安全、有效和选择性的mito-K+-ATP通道开放剂,因为迄今为止还没有其他公司或学术中心成功地发明了一种安全、有效和选择性的mito-K +-ATP通道开放剂。我们现在建议验证R-801在经典SCT模型中的临床前可行性,并加深对其作用机制的理解。1期SBIR特定目的:在SCI实验鼠模型中建立R-801的PD特征。为了检验R-801有效复苏SCT的假设,RTX将在小鼠中进行前瞻性、随机、单盲、安慰剂对照研究中进行病理学和功能分析。与Philip Popovich教授(俄亥俄州大学)合作,将使用标准化挫伤模型对成年雌性CD 1小鼠进行SCT。将假损伤(无SCT的椎板切除术)和溶剂对照组与接受R-801的组进行比较。在SCT后1和3 h给予的最初2次R-801剂量(80 mg/kg/剂)将通过腹膜内(IP)给药,以使脊髓组织中的高水平药物快速渗透。此后,将在饮用水中提供R-801(作为0.2%溶液),以优化稳态药物暴露。在系列A中,SCT后48小时处死小鼠(每组n=10),对脊髓进行组织学和免疫组织化学分析,以确定聚(ADP-核糖)聚合酶活化和ONOO形成的证据。在系列B中,将在SCT后2个月的时间内在成年雌性SCI小鼠(每组n=10)中分析旷场运动功能。在SCT前约1周,使小鼠适应开放场地。将使用旷场试验(Basso小鼠量表; BMS)运动评定量表测量功能恢复指数。然后将在受伤前获得BMS评分,并以每周为间隔再次获得。将获得R-801的终末血浆浓度,以构建每个剂量组中疗效与功能、形态学和免疫组织化学终点相关的PD曲线。验证R-801复苏改善形态和功能的结果将提供一个逻辑基础的商业开发的肠外R-801作为急性SCI的紧急治疗。
项目成果
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PRAKASH G JAGTAP其他文献
PRAKASH G JAGTAP的其他文献
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