GOLD-BASED ANTI-ARTHRITIS DRUGS: METABOLISM & TOXICITY

金基抗关节炎药物：新陈代谢

• 批准号: 3157162
• 负责人: RICHARD C ELDER
• 金额: $ 12.52万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1988-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3157162
• 关键词: X ray crystallography; antirheumatic agents; asthma; chromatography; drug adverse effect; drug metabolism; gold; infrared spectrometry; nuclear magnetic resonance spectroscopy; tissue /cell culture

These drugs have been shown to be effective in induding remission of rheumatoid arthritis (RA). However, very little is known about their metabolism, mode of action or cause of toxicity. In order to better manage the therapy of RA patients and avoid toxic side effects, it is necessary to understand the metabolism and toxicity of these drugs at the molecular level. Metabolism of auranofin, triethylphosphine-S-tetraacetylthioglucosegold(I), an orally administered, experimental drug and myochrisine, sodium gold(I)thiomalate, an injected drug in widespread use will be monitored by the development of new analytical techniques with the necessary sensitivity, generality and rapidity to make drug metabolism studies feasible on groups of patients. The principal technique will utilize an inductively coupled plasma (ICP) emission spectrometer as a detector for high performance liquid chromatography (HPLC). The detector will have sensitivities of 0.01 ppm for gold and 0.05 ppm for sulfur and phosphorus, all of which will be monitored in an element specific mode. Various HPLC column packings will be utilized to separate the drugs and their metabolites from other components of blood, urine and synovial fluids of asthmatic and arthritic patients. The asthmatic cohort will serve as a control group for the arthritic cohort. Comparisons will be made within each group and between groups to determine if there are correlations of qualitative and/or quantitative metabolite distribution in patients with therapeutic efficacy or toxicity. A second analytical technique will use synchrotron radiation X-rays at the Stanford Synchrotron Radiation Laboratory for EXAFS, XANES and DAS studies of metabolites to establish local structure around the gold atoms in metabolites. More classical characterization by NMR and IR spectroscopies and single crystal X-ray diffraction will be used as well. Where necessary for the development of analytical techniques or useful to suggest possible human metabolites, model studies using tissue culture of Chinese hamster ovary cells or animal studies will be undertaken.

这些药物已被证明是有效的，包括缓解 类风湿性关节炎（RA）。 然而，人们对其知之甚少。 代谢、作用方式或毒性原因。 为了更好地管理 治疗类风湿关节炎，避免毒副作用，有必要 了解这些药物在分子水平上的代谢和毒性 水平 金诺芬的代谢， 三乙基膦-S-四乙酰硫代葡萄糖金（I），一种口服给药的， 实验药物和myochrisine，硫代苹果酸钠金（I），注射 广泛使用的药物将通过开发新的 分析技术，具有必要的灵敏度，通用性和 快速使药物代谢研究在患者群体中可行。 主要技术将利用电感耦合等离子体（ICP） 发射光谱仪作为高性能液体检测器 色谱法（HPLC）。 探测器的灵敏度为0.01 ppm 0.05 ppm的硫和磷，所有这些都将是 以特定元素模式进行监控。 各种HPLC色谱柱填料将 用于将药物及其代谢物与其他药物分离， 哮喘和关节炎患者的血液、尿液和滑液成分 患者 哮喘队列将作为对照组， 关节炎队列。 将在每组内和各组之间进行比较。 组，以确定是否存在定性和/或 治疗有效患者的定量代谢物分布 或毒性。 第二种分析技术将使用同步辐射 斯坦福大学同步辐射实验室的X射线EXAFS，XANES 和DAS研究代谢物，以建立金周围的局部结构 代谢物中的原子。 NMR和IR更经典的表征 也将使用光谱和单晶X射线衍射。 必要时，开发分析技术或有助于 提示可能的人类代谢物，使用组织培养的模型研究 将进行中国仓鼠卵巢细胞或动物研究。