GOLD-BASED ANTI-ARTHRITIS DRUGS: METABOLISM & TOXICITY

这些药物已被证明能有效地缓解 类风湿关节炎(RA)。然而，人们对它们的了解很少 新陈代谢、作用方式或中毒原因。为了更好地管理 治疗类风湿关节炎患者，避免毒副作用，有必要 从分子水平了解这些药物的代谢和毒性 水平。金诺芬的新陈代谢， Triethylphosphine-S-tetraacetylthioglucosegold(I)，an口服， 实验药物和肌苷，硫代马来酸金(I)钠，注射用 将通过开发新的药物来监测广泛使用的药物 分析技术具有必要的灵敏度、一般性和 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)。 作为高性能液体探测器的发射光谱仪 高效液相色谱(HPLC)。该探测器的灵敏度为0.01ppm。 黄金和0.05ppm的硫和磷，所有这些都将是 以特定于元素的模式监视。各种高效液相色谱柱填料将 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、尿和滑液成分分析 病人。哮喘队列将作为对照组 关节炎队列。将在每个组内以及组内和组之间进行比较 小组，以确定是否存在定性和/或 影响疗效的患者代谢产物的定量分布 或者毒性。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EXAFS、XANES X射线 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。核磁共振和红外光谱更经典的表征 还将使用光谱分析和单晶X射线衍射仪。 对于发展分析技术是必要的，或对 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。

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.