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Trial NCT00000395

Resource URI: http://static.linkedct.org/resource/trials/NCT00000395
PropertyValue
linkedct:brief_title Antifolate Effectiveness in Arthritis
linkedct:collaborator_agency <http://static.linkedct.org/resource/collabagency/5950>
linkedct:condition <http://static.linkedct.org/resource/condition/11608>
linkedct:condition <http://static.linkedct.org/resource/condition/457>
linkedct:criteria Inclusion Criteria: - Individuals starting methotrexate for rheumatoid arthritis. - Study subjects should not currently be taking folic acid-containing vitamins. Exclusion Criteria: - Cancer, renal, or liver disease. - Previous use of methotrexate within the past 6 months or current use of folic acid-containing supplements.
linkedct:description 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.
linkedct:download_date Information obtained from ClinicalTrials.gov on December 30, 2009
linkedct:eligibility_gender Both
linkedct:eligibility_healthy_volunteers No
linkedct:eligibility_maximum_age 85 Years
linkedct:eligibility_minimum_age 18 Years
linkedct:end_date December 2001
linkedct:enrollment 40 (xsd:int)
linkedct:firstreceived_date November 3, 1999
linkedct:id NCT00000395
rdfs:label Trial NCT00000395
linkedct:lastchanged_date December 28, 2006
linkedct:lead_sponsor_agency National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
linkedct:location <http://static.linkedct.org/resource/location/177810>
linkedct:nct_id NCT00000395
linkedct:number_of_arms 0 (xsd:int)
linkedct:number_of_groups 0 (xsd:int)
linkedct:official_title Mechanisms of Antifolate Efficacy in Arthritis
linkedct:org_study_id R29 AR42674
linkedct:overall_official <http://static.linkedct.org/resource/overall_official/53127>
linkedct:overall_status Completed
linkedct:oversight <http://static.linkedct.org/resource/oversight/2918>
foaf:page <http://clinicaltrials.gov/show/NCT00000395>
linkedct:phase Phase 2
linkedct:reference <http://static.linkedct.org/resource/reference/2488>
linkedct:reference <http://static.linkedct.org/resource/reference/37405>
linkedct:reference <http://static.linkedct.org/resource/reference/39046>
linkedct:reference <http://static.linkedct.org/resource/reference/46115>
linkedct:reference <http://static.linkedct.org/resource/reference/46972>
linkedct:reference <http://static.linkedct.org/resource/reference/48471>
linkedct:reference <http://static.linkedct.org/resource/reference/48881>
linkedct:reference <http://static.linkedct.org/resource/reference/51687>
linkedct:reference <http://static.linkedct.org/resource/reference/53030>
linkedct:reference <http://static.linkedct.org/resource/reference/54034>
linkedct:reference <http://static.linkedct.org/resource/reference/54890>
linkedct:reference <http://static.linkedct.org/resource/reference/8600>
linkedct:results_reference <http://static.linkedct.org/resource/results_reference/4164>
linkedct:secondary_id NIAMS-035
linkedct:source National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
linkedct:start_date September 1996
linkedct:study_design Diagnostic, Randomized, Double-Blind, Placebo Control, Crossover Assignment, Pharmacodynamics Study
linkedct:study_type Interventional
linkedct:summary 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.
rdf:type linkedct:trials
linkedct:verification_date February 2003