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Sponsors and Collaborators: |
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Office of Dietary Supplements (ODS) |
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Information provided by: | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) |
ClinicalTrials.gov Identifier: | NCT00000395 |
This study looks at how the arthritis drug methotrexate works in low doses to treat rheumatoid arthritis. (High doses of methotrexate are used to treat some types of cancer.) Methotrexate blocks the action of the B-vitamin known as folic acid. We are studying the biochemical reactions affected by this vitamin because we think that blocking many of these reactions may be necessary for methotrexate to work in treating rheumatoid arthritis. Through these studies, we hope to gain a better understanding of how this drug and related drugs work as treatments for arthritis.
Condition | Intervention | Phase |
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Rheumatoid Arthritis Adjuvant Arthritis |
Drug: Methotrexate |
Phase II |
Study Type: | Interventional |
Study Design: | Diagnostic, Randomized, Double-Blind, Placebo Control, Crossover Assignment, Pharmacodynamics Study |
Official Title: | Mechanisms of Antifolate Efficacy in Arthritis |
Estimated Enrollment: | 40 |
Study Start Date: | September 1996 |
Estimated Study Completion Date: | December 2001 |
Low-dose methotrexate therapy suppresses autoimmune arthritis in human and animal models. We hypothesize 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 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 methotrexate therapy of rheumatoid arthritis.
Several studies indicate that supplemental folinic acid (5-formyltetrahydrofolate) used in large doses during low-dose methotrexate 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.
We will test our hypotheses both in people with rheumatoid arthritis and in Lewis rat adjuvant arthritis. Our objectives include: (1) determining if the dose level of methotrexate that is clinically optimal in the treatment of Lewis rat adjuvant arthritis interferes with normal adenosine metabolism; (2) determining the effectiveness of drugs that interfere with adenosine metabolism (deoxycoformycin, aminoimidazole carboxamide, and aminoimidazole carboxamide with a suboptimal dose of methotrexate) in Lewis rat adjuvant arthritis; and (3) determining whether supplemental folic acid and folinic acid during methotrexate therapy normalize adenosine metabolism in patients with rheumatoid arthritis. The information we obtain will enhance the understanding of the biochemical action of antifolates/antimetabolites that are effective in the treatment of human and animal arthritis.
Ages Eligible for Study: | 18 Years to 85 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
United States, Alabama | |
The University of Alabama at Birmingham | |
Birmingham, Alabama, United States, 35294 |
Principal Investigator: | Sarah L. Morgan, M.D., R.D. | University of Alabama Department of Nutrition Sciences |
Study ID Numbers: | R29 AR42674, NIAMS-035 |
Study First Received: | November 3, 1999 |
Last Updated: | December 28, 2006 |
ClinicalTrials.gov Identifier: | NCT00000395 |
Health Authority: | United States: Federal Government |
Rheumatoid arthritis Lewis rat adjuvant arthritis Antifolate efficacy Autoimmunity Adenosine metabolism |
Methotrexate therapy Skeletal disorder Dietary supplement Antiarthritic agent Folic acid |
Folic Acid Autoimmune Diseases Arthritis, Experimental Musculoskeletal Diseases Joint Diseases Arthritis |
Connective Tissue Diseases Arthritis, Rheumatoid Methotrexate Rheumatic Diseases Adenosine |
Antimetabolites Antimetabolites, Antineoplastic Immunologic Factors Immune System Diseases Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Physiological Effects of Drugs Enzyme Inhibitors Reproductive Control Agents |
Folic Acid Antagonists Abortifacient Agents, Nonsteroidal Immunosuppressive Agents Pharmacologic Actions Therapeutic Uses Abortifacient Agents Antirheumatic Agents Dermatologic Agents Nucleic Acid Synthesis Inhibitors |