Ignite Creation Date:
2024-05-05 @ 11:20 AM
Last Modification Date:
2024-10-26 @ 9:01 AM
Study NCT ID:
NCT00000395
Status:
COMPLETED
Last Update Posted:
2016-12-16
First Post:
1999-11-03
Brief Title:
Antifolate Effectiveness in Arthritis
Sponsor:
University of Alabama at Birmingham
Organization:
University of Alabama at Birmingham
Study Overview
Official Title:
Mechanisms of Antifolate Efficacy in Arthritis
Status:
COMPLETED
Status Verified Date:
2013-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
Detailed 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 antifolatesantimetabolites that are effective in the treatment of human and animal 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 antifolatesantimetabolites that are effective in the treatment of human and animal arthritis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| NIAMS-035 | US NIH GrantContract | None | httpsreporternihgovquickSearchR29AR042674 |
| R29AR042674 | NIH | None | None |