Pre-Clinical Studies of the NO Scavenger Cobinamide

NO 清除剂 Cobinamide 的临床前研究

基本信息

批准号：
7267962
负责人：
GERRY R BOSS
金额：
$ 19.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7267962
关键词：
Affect Affinity Anabolism Animal Model Animals Bacterial Model Benzimidazoles Binding Buffers Canis familiaris Cardiovascular system Clinical Clinical Pathology Clinical Trials Cobalamin Conduct Clinical Trials Cultured Cells Cytokine Signaling Data Detection Development Dose Drosophila genus Drug Kinetics Enzymes Exhibits Feasibility Studies Goals Hemoglobin High Pressure Liquid Chromatography Histopathology Human Hypotension Kidney Label Lethal Dose 50 Ligation Malpighian Tubules Mammalian Cell Maximum Tolerated Dose Measures Methods Modeling Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Nucleotides Organ Perfusion Pharmaceutical Preparations Phase III Clinical Trials Physiological Plasma Play Preparation Production Puncture procedure Range Rate Rattus Refractory Research Personnel Role Secondary to Sepsis Septic Shock Serum Shock Signal Transduction Signaling Molecule Standards of Weights and Measures System Tail Time Tissues Toxic effect Vasoconstrictor Agents Vasodilator Agents Vitamin B 12 Work base benzimidazole cobinamide fly human NOS2A protein inhibitor/antagonist liver function mortality novel pre-clinical preclinical study septic success

项目摘要

DESCRIPTION (provided by applicant): Septic shock, as well as other forms of shock, have extremely high mortality rates, and this, in part, is secondary to the severe hypotension that characterize these clinical states. Nitric oxide (NO) is an extremely potent vasodilator, and its overproduction in shock by inducible NO synthase (NOS) clearly contributes to the vasopressor-refractory hypotension of shock. Non- selective inhibitors of the three mammalian NOS enzymes showed some success in animal models of sepsis, but unfortunately one of these agents led to increased mortality in a Phase III Clinical Trial, possibly secondary to decreased tissue and organ perfusion from inhibition of endothelial NOS. NO scavengers have a theoretical advantage over NOS inhibitors in reducing high NO concentrations in shock, since the former compounds should preferentially neutralize excess circulating NO, without significantly affecting intra- and inter-cellular NO signaling. Indeed, three different NO scavengers, hemoglobin, NOX-100, and cobalamin (vitamin B12) have all shown promise in animal models of sepsis, and NOX-100 has been beneficial in early human clinical trials of septic shock. We have found that cobinamide, the penultimate precursor in the biosynthesis of cobalamin and a contaminant of most vitamin B12 preparations, binds NO with >100 times more affinity than cobalamin. In cultured mammalian cells and in Drosophila Malpighian tubules, cobinamide was an effective NO scavenger, and did not exhibit toxicity at concentrations that would be required to treat states of excess NO. Using a well-established Drosophila model of bacterial sepsis, we have found that cobinamide strikingly increased fly survival, and the mechanism appeared to be from scavenging excess NO. In this R21 application, we propose to perform pre-clinical animal studies to determine if cobinamide is a potentially useful drug candidate; the results of this work will form the basis for an Investigator's New Drug application in anticipation of conducting clinical trials.

描述（由申请人提供）：脓毒性休克以及其他形式的休克具有极高的死亡率，这在一定程度上是继发于这些临床状态特征的严重低血压。一氧化氮 (NO) 是一种极其有效的血管扩张剂，休克时诱导型一氧化氮合酶 (NOS) 产生过量一氧化氮，显然会导致休克时血管加压难治性低血压。三种哺乳动物 NOS 酶的非选择性抑制剂在脓毒症动物模型中显示出一些成功，但不幸的是，其中一种药物在 III 期临床试验中导致死亡率增加，可能继发于抑制内皮 NOS 导致的组织和器官灌注减少。 NO清除剂在降低休克中高NO浓度方面比NOS抑制剂具有理论上的优势，因为前者化合物应优先中和过量的循环NO，而不会显着影响细胞内和细胞间NO信号传导。事实上，三种不同的 NO 清除剂：血红蛋白、NOX-100 和钴胺素（维生素 B12）都在脓毒症动物模型中显示出良好的前景，并且 NOX-100 在脓毒症休克的早期人体临床试验中也有效果。我们发现钴酰胺是钴胺素生物合成中的倒数第二个前体，也是大多数维生素 B12 制剂的污染物，它与 NO 的结合亲和力比钴胺素高 100 倍以上。在培养的哺乳动物细胞和果蝇马氏小管中，cobinamide 是一种有效的 NO 清除剂，并且在治疗过量 NO 状态所需的浓度下不会表现出毒性。使用成熟的细菌性败血症果蝇模型，我们发现可宾酰胺显着提高了果蝇的存活率，其机制似乎是通过清除过量的一氧化氮。在此 R21 申请中，我们建议进行临床前动物研究，以确定 Cobinamide 是否是一种潜在有用的候选药物；这项工作的结果将构成研究者新药申请的基础，以期进行临床试验。