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Anti-inflammatory and Anti-arthritic Effects of a Novel Leflunomide Analogue, UTL-5b (GBL-5b)
Author(s) -
Jiajiu Shaw,
Ben Chen,
WenHsin Huang,
Lee Lee,
Dustin Zeng
Publication year - 2011
Publication title -
american journal of biomedical sciences
Language(s) - English
Resource type - Journals
ISSN - 1937-9080
DOI - 10.5099/aj110100031
Subject(s) - leflunomide , medicine , rheumatoid arthritis , in vivo , pharmacology , sepsis , arthritis , carrageenan , inflammation , edema , immunology , microbiology and biotechnology , biology
Rheumatoid arthritis (RA) is a common disease characterized by chronic inflammation and irreversible destruction of articular cartilage and bone. In this report, we examined the anti-inflammatory and anti-arthritic effects of a novel leflunomide analogue, UTL-5b (also known as GBL-5b), for potential RA treatment. Using a carrageenan-induced edema study in rats, UTL-5b exhibited a better anti-inflammatory effect as compared with leflunomide and its metabolite. The chronic efficacy of UTL-5b was examined using type II collagen-induced arthritis (CIA) mouse model. UTL-5b exerted an anti-arthritic effect in a dose-dependant manner with mice given 30 mg/kg exhibiting amelioration of disease early in the trial, but losing statistical significance over time. In contrast, mice treated with 60 mg/kg showed reduced clinical disease parameters early in the trial and these effects were sustained over the ten week trial period. Mechanistic studies indicate that UTL-5b is an inhibitor of TNF-α production in vivo. Oral administration of UTL-5b prior to i.p. injection with lethal dose of lipopolysaccharide (LPS)/D-galactosamine markedly reduced the levels of serum TNF-α and increased survival rates of animals from septic shock-induced death. Acute toxicity study using mice receiving increasing doses of UTL-5b showed that no animals were killed by UTL-5b at 2,000 mg/kg (LD(50) >2,000 mg/kg). Our studies show that UTL-5b represents a novel anti-inflammatory and anti-arthritic agent with potential therapeutic application for RA treatment.

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