MECHANISMS OF ANTIFOLATE EFFICACY IN ARTHRITIS

抗叶酸治疗关节炎的功效机制

• 批准号: 2769605
• 负责人: SARAH LUISE MORGAN
• 金额: $ 10.66万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2769605
• 关键词: adenosine; antiarthritic agent; clinical research; diet therapy; dietary supplements; drug adverse effect; folate; human subject; human therapy evaluation; laboratory rat; metabolism; methotrexate; rheumatoid arthritis; skeletal disorder chemotherapy

DESCRIPTION: Low-dose methotrexate therapy suppresses autoimmune arthritis in humans and animal models. The hypothesis of the proposed research is that the effect of MTX in the treatment of rheumatoid arthritis (RA) is due to the inhibition of aminoimidazole-carboxamide ribotide transformylase, a folate-dependent enzyme that 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 MTX therapy of RA. Several studies indicate that supplemental folinic acid (5-formyl-tetrahydrofolate) used in large doses during low-dose MTX therapy for RA causes a flare in joint inflammation. However, supplemental folic acid (pteroylglutamic acid) does not lessen the efficacy of the therapy. It is further hypothesized that if MTX 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 accumulation of these compounds. These hypotheses will be tested both in patients with RA and in Lewis rat adjuvant arthritis. Objectives include: A) to determine if the dose of MTX which is clinically optimal in the treatment of Lewis rats interferes with normal adenosine metabolism; B) to determine the effectiveness of drugs which interfere with adenosine metabolism in Lewis rat adjuvant arthritis; and C) to determine whether supplemental folic acid and folinic acid during MTX therapy normalize adenosine metabolism in patients with RA. 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.

描述：低剂量甲氨蝶呤治疗抑制自身免疫性关节炎 在人类和动物模型中。 拟议研究的假设是 MTX治疗类风湿性关节炎（RA）的效果是由于 抑制氨基咪唑-甲酰胺核苷酸转化酶， 叶酸依赖性酶，催化从头开始的最后一步， 肌苷一磷酸的生物合成。 由此产生的积累 氨基咪唑甲酰胺核苷抑制腺苷脱氨酶，因此 干扰正常的腺苷代谢。 众所周知的是 腺苷脱氨酶缺乏的儿童 严重联合免疫缺陷综合症 这表明腺苷 脱氨酶活性是免疫能力的关键， MTX治疗RA的疗效机制。 多项研究表明， 大剂量补充亚叶酸（5-甲酰-四氢叶酸） 在低剂量MTX治疗RA期间，引起关节炎症的发作。 然而，补充叶酸（蝶酰谷氨酸）并不减少 治疗的有效性。 进一步假设，如果MTX疗效是 由氨基咪唑-甲酰胺核苷酸转化酶抑制驱动， 叶酸补充剂不应改变尿中氨基咪唑水平 甲酰胺、腺苷和脱氧腺苷，而亚叶酸 补充应该防止这些化合物的积累。 这些 将在RA患者和刘易斯大鼠佐剂中检验假设 关节炎 目的包括：A）确定MTX的剂量， 刘易斯大鼠治疗中的临床最佳药物干扰正常 腺苷代谢; B）确定药物的有效性， 干扰刘易斯大鼠佐剂性关节炎中腺苷代谢;和C） 确定MTX治疗期间补充叶酸和亚叶酸 治疗使RA患者腺苷代谢正常化。 的信息 从拟议的研究中获得的信息将提高对 抗叶酸剂/抗代谢物的生物化学作用， 治疗人类和动物关节炎。