Radiocontrast Nephropathy: Redox Degradation Catalyst and Nitric Oxide Donor

放射性对比肾病：氧化还原降解催化剂和一氧化氮供体

• 批准号: 8449038
• 负责人: Zsuzsanna Kinga Zsengeller
• 金额: $ 24.51万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449038
• 关键词: 3-nitrotyrosine; Acetylcysteine; Acute; Acute Kidney Failure; Address; Adenosine; Animal Model; Antioxidants; Biological Models; Blood; Bolus Infusion; Brain; Breathing; Cell Survival; Cells; Chemicals; Clinical; Colon; Complex; Complication; Consensus; Control Groups; Coupled; Creatinine; Creatinine clearance measurement; Cytoprotective Agent; DNA Damage; DNA Repair; Dehydration; Development; Diabetes Mellitus; Diagnostic; Dialysis procedure; Dose; Drug Exposure; Drug Kinetics; Elderly; Electron Microscopy; Endotoxic Shock; Exposure to; Foundations; Free Radicals; GTP-Binding Proteins; Gases; Gelatinase A; Gelatinases; Generations; Glucose; Half-Life; Heart; Hematoxylin and Eosin Staining Method; Histologic; Hydration status; Hydrogen Peroxide; Hydroxyl Radical; Hypoxia; Image; Immunologics; Impairment; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Intravenous; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Liver; Lung; Mediating; Medical; Mitochondrial Swelling; Modality; Modeling; Mus; Muscle; Necrosis; Nitric Oxide; Nitric Oxide Donors; Normal saline; Nuclear; Organ; Oxidants; Oxidation-Reduction; Patients; Peroxidases; Peroxonitrite; Pharmacodynamics; Pharmacologic Substance; Plasma; Poly Adenosine Diphosphate Ribose; Population; Prevention; Prophylactic treatment; Prostaglandin-Endoperoxide Synthase; Proteins; Pyrrolidines; Rattus; Reactive Oxygen Species; Renal Blood Flow; Renal Tissue; Renal function; Reperfusion Injury; Reperfusion Therapy; Resuscitation; Risk; Rodent; Rodent Model; Serum; Single-Blind Study; Spleen; Sprague-Dawley Rats; Stomach; Streptozocin; Stress; Structure of parenchyma of lung; Superoxides; System; Testing; Tissues; Tubular formation; arteriole; base; catalase; catalyst; cell injury; clinically relevant; comparative; cytotoxicity; design; diabetic; diabetic rat; high risk; immunoreactivity; innovation; intravenous administration; kidney cell; kidney medulla; mimetics; nephrogenesis; neutrophil; nitrosative stress; novel; p65; patient population; prevent; professor; prophylactic; public health relevance; pyrrolidine; receptor; renal ischemia; response; small molecule; transcription factor; uptake; vasoconstriction

DESCRIPTION (provided by applicant): We are developing a novel small molecule cytoprotective drug (R-100) for the prevention of contrast- induced nephropathy (CIN) following IV radiocontrast media (CM) injection. R-100 is a novel cell- permeable redox-active agent formed from the covalent fusion of 2 chemical moieties: 1) an organic nitrovasodilator that donates nitric oxide, and 2) a pyrrolidine nitroxide that acts as a trifunctional degradation catalyst of reactive oxygen species. In rats subjected to renal ischemia/reperfusion injury (RIRI), IV administration of R-100 prior to reperfusion reduced the 6 h elevations in serum creatinine, serum NGAL, tissue myeloperoxidase, and histologic score by 75-90% (p<10-14) and restored the reduction of creatinine clearance from 90% to 50% (p<0.01). In a murine RIRI model, 24 h creatinine elevations were entirely eliminated by a single dose of R-100 prior to reperfusion (p<0.01). Aim #1: Establish the pharmacodynamic (PD) profile of R-100 in models of CIN in healthy and diabetic rodents under conditions of normal hydration and aggressive volume loading Rats will be subjected to dehydration, prostaglandin synthetase inhibition, and an IV challenge of CM. A sham injury group will be compared to treatment of CM-challenged healthy rats with 3 dose levels of IV R-100, N-acetyl-cysteine (NAC), or vehicle control initiated 10 min before CM administration and continued for 48 h. Rats will then be evaluated at 48 h for renal function (and parameters reflecting renal injury, including protein release into the blood (NGAL, KIM-1), pro-inflammatory transcription factor expression (cytoplasmic I¿B¿ degradation, nuclear p65 translocation), histologic damage, and nuclear damage and DNA repair (PARP activation and nitrosative stress as noted by poly(ADP-ribose) and 3-nitrotyrosine (3-NT) tissue immunoreactivity). In order to better model the patient population at greatest risk of CIN, the optimal dose of R-100 will then be further evaluated, using the same experimental approach and design as before, but in rats previously rendered diabetic 2 weeks earlier by injection of streptozotocin (STZ). Finally, we will investigate whether further benefit may be obtained in the diabetic setting by combining the administration of R-100 with aggressive volume resuscitation. Aim #2: Establish the pharmacokinetics (PK) of R-100 in a rodent model of CIN We will carry out PK studies in rodents exposed to the same conditions utilized to generate CIN as in Aim #1. A full PK profile will be generated, to define plasma half-life, clearance, and volume of distribution. The exposure to cumulative plasma concentrations of R-100 and the renal tissue concentration of R-100 will be correlated with the morphologic, immunologic, and functional endpoints detailed in Aim #1, in order to construct a PD profile relating drug exposure to effect. The proposed studies will provide a rational foundation for advanced commercial development of R-100, with the intent that this product will serve as first-line prophylaxis in high-risk diabeic patients undergoing CM injection.

描述（由申请人提供）：我们正在开发一种新型小分子细胞保护药物（R-100），用于预防静脉注射放射性造影剂（CM）后的造影剂肾病（CIN）。R-100是一种新型的细胞渗透性氧化还原活性剂，由2个化学部分的共价融合形成：1）提供一氧化氮的有机硝基血管扩张剂，和2）作为活性氧物质的三官能降解催化剂的吡咯烷氮氧化物。在遭受肾缺血/再灌注损伤（RIRI）的大鼠中， 在再灌注前IV给予R-100使6小时血清肌酐、血清NGAL、组织髓过氧化物酶和组织学评分的升高降低了75-90%（p<10-14），并使肌酐清除率的降低从90%恢复到50%（p<0.01）。在鼠RIRI模型中，在再灌注前通过单剂量的R-100完全消除了24小时肌酐升高（p<0.01）。目标一：在正常水合和积极体积负荷条件下，在健康和糖尿病啮齿动物的CIN模型中建立R-100的药效学（PD）特征大鼠将接受脱水、前列腺素合成酶抑制和CM的IV激发。将假损伤组与CM激发的健康大鼠进行比较，CM激发的健康大鼠在CM给药前10分钟开始接受3种剂量水平的IV R-100、N-乙酰半胱氨酸（NAC）或溶剂对照，并持续48小时。然后在48 h评价大鼠的肾功能（以及反映肾损伤的参数，包括蛋白质释放到血液中（NGAL，KIM-1），促炎性转录因子表达，（细胞质I B）降解，核p65易位），组织学损伤，以及核损伤和DNA修复（PARP活化和亚硝化应激，如聚（ADP-核糖）和3-硝基酪氨酸（3-NT）组织免疫反应性所示）。为了更好地模拟CIN风险最大的患者群体，然后将使用与之前相同的实验方法和设计进一步评估R-100的最佳剂量，但是在先前通过注射链脲佐菌素（STZ）提前2周患糖尿病的大鼠中。最后，我们将研究在糖尿病患者中，将R-100与积极的容量复苏相结合是否会获得进一步的益处。目标二：在CIN啮齿动物模型中建立R-100的药代动力学（PK）我们将在暴露于与目标1中用于产生CIN的相同条件的啮齿动物中进行PK研究。将生成完整的PK曲线，以定义血浆半衰期、清除率和分布容积。R-100累积血浆浓度和R-100肾组织浓度的暴露量将与目标1中详述的形态学、免疫学和功能终点相关，以构建药物暴露量与效应相关的PD曲线。拟定的研究将为R-100的高级商业开发提供合理的基础，目的是使该产品作为接受CM注射的高危糖尿病患者的一线预防药物。