Pre-Clinical Studies of the NO Scavenger Cobinamide

NO 清除剂 Cobinamide 的临床前研究

• 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
• 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

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）：感染性休克，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）是一种非常有效的血管扩张剂，其在休克时通过诱导NO合成酶（NOS）过量产生，显然有助于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动物败血症模型中显示出一定的成功，但不幸的是，在III期临床试验中，其中一种药物导致死亡率增加，可能是由于内皮细胞NOS抑制导致组织和器官灌注减少。NO清除剂在降低休克时高浓度NO方面比NOS抑制剂具有理论上的优势，因为前者的化合物应优先中和过量的循环NO。没有显著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）都在败血症的动物模型中显示出希望，并且NOX-100在败血症休克的早期人类临床试验中有益。我们发现，钴胺是钴胺素生物合成中的第二种前体，也是大多数维生素B12制剂的污染物，它与>结合的亲和力是钴胺素的100倍。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所需的浓度下没有表现出毒性。利用一种成熟的细菌性败血症果蝇模型，我们发现cobinamide显著提高了果蝇的存活率，其机制似乎是清除过量的NO。在这个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；这项工作的结果将成为研究者进行临床试验时新药申请的基础。