MECHANISMS OF ANTIFOLATE EFFICACY

抗叶酸功效的机制

• 批准号: 6274097
• 负责人: SARAH LUISE MORGAN
• 金额: $ 2.59万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-26 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6274097
• 关键词: adenosine; clinical research; clinical trials; combination chemotherapy; folate; folate antagonist; human subject; human therapy evaluation; methotrexate; neurotransmitter metabolism; rheumatoid arthritis; tetrahydrofolates

Low-dose methortrexate therapy suppresses autoimmune arthritis in human and animal models. It is our hypothesis that the effect of methotrexate in the treatment of rheumatoid arthritis is due to the inhibition of aminoimidazole-carboxamide ribotide transformylase, a folate-dependent enzyme which catalyzes the last step in the de novo biosynthesis of inosine monophosphate. The resulting accumulation of aminoimidazole carboxamide riboside inhibits adenosine deaminase, therefore, interfering with normal adenosine metabolism. It is well known that children with adenosine deaminase deficiency have severe-combined-immunodeficiency syndrome. This suggests that adenosine deaminase activity is key to immune competence and is associated with the mechanism of efficacy in methotrexate therapy of rheumatoid arthritis. Several studies indicate that supplemental folinic acid (5- formytetrahydrofolate) used in large doses during low-dose methortrexate therapy for rheumatoid arthritis causes a flare in joint inflammation. However, supplemental folic acid (pteroylglutamic acid) does not lessen the efficacy of the therapy. We further hypothesize that if methotrexate efficacy is driven by aminoimidazole carboxamide ribotide transformylase inhibition, folic acid supplementation should not alter urinary levels of aminoimidazole carboxamide, adenosine, and deoxyadenosine, while folinic acid supplementation should prevent the accumulation of these compounds. Our hypotheses will be tested both in patients with rheumatoid arthritis and in Lewis rat adjuvant arthritis. Objectives include A) to determine whether supplemental folic acid and folinic acid during methotrexate therapy normalize adenosine metabolism in patients with rheumatoid arthritis. The information obtained from the proposed research will enhance the understanding of the biochemical action of antifolates/ antimetabolites that are effective in the treatment of human and animal arthritis. To date, six patients have been enrolled in the trial. Because the trial is blinded, no data is yet available. It is planned inthe upcoming year to enroll patients, up to a total of 50 patients.

小剂量甲氨蝶呤治疗自身免疫性关节炎 动物模型。 我们的假设是氨甲蝶呤的作用 类风湿性关节炎的治疗是由于抑制 叶酸依赖性氨基咪唑-甲酰胺核糖核酸转移酶 一种酶，催化生物合成的最后一步 肌苷一磷酸 氨基咪唑的累积 羧酰胺核苷抑制腺苷脱氨酶，因此，干扰 腺苷代谢正常众所周知， 腺苷脱氨酶缺乏症 综合征 这表明腺苷脱氨酶活性是 免疫能力，并与疗效的机制， 甲氨蝶呤治疗类风湿关节炎 一些研究表明，补充亚叶酸（5- 甲酰四氢叶酸）在低剂量甲氨蝶呤期间大剂量使用 类风湿性关节炎的治疗会引起关节炎的发作。 然而，补充叶酸（蝶酰谷氨酸）不会减少 治疗的有效性 我们进一步假设如果甲氨蝶呤 效力由氨基咪唑甲酰胺核苷酸转化酶驱动 抑制作用，补充叶酸不应改变尿液中的 氨基咪唑甲酰胺、腺苷和脱氧腺苷，而亚叶酸 补充酸可以防止这些化合物的积累。 我们的假设将在类风湿性关节炎患者中进行测试， 和刘易斯大鼠佐剂性关节炎。 目标包括：A）确定 甲氨蝶呤治疗期间是否补充叶酸和亚叶酸 治疗使类风湿患者腺苷代谢正常化 关节炎 从拟议研究中获得的信息将 提高对抗叶酸剂的生化作用的认识/ 有效治疗人类和动物疾病的抗代谢物 关节炎 迄今为止，已有6名患者入组试验。 因为审判 设盲，尚未获得数据。 它计划在明年 入组患者，最多共50例患者。