| Research Abstract |
(1→3)-β-D-glucan (β-glucan) is a biological response modifier (BRM) that regulates host immune response. However, the side effects of this drug have not been extensively examined. In this study, we found that the combination of a β-glucan and a nonsteroidal anti-inflammatory drugs, indomethacin (IND), induced lethal toxicity in mice. Lethal toxicity of orally administered IND (multiple administration to ICR mice ; once a day of 2 weeks) was 0/8 (2.5 mg/kg) and 5/8 (5 mg/kg) (death/total) over 2 weeks. The toxicity was enhanced to 3/8 and 8/8 in mice treated with a clinical β-glucan preparation, sonifilan (250μg/mouse, single I.p. administration on day 0). Enhanced lethal toxicity resulted from a single p.o. administration of IND on day 5 to 9 after multiple β-glucans administration. A similar effect was observed for other β-glucans including,SSG,grifolan,zymosan A and zymocel. A similar effect was also observed for various microbial products, such as whole cell preparation of bacteria and fungi, BCG and OK-432. The lethal toxicity was shown by various strains of mice, such as C3H/HeN, C3H/HeJ, AKR/N, BALB/c, C57BL/6, DBA/2, BALB/c nu/nu, KSN, WBB6F1, and by various NSAIDs, such as aspirin, diclofenac, and sulindac. IFN-γ, IL-6 and CSF concentrations in sera of IND/β-glucan treated mice were significantly elevated. These results strongly suggest that IND/BRM treatment induces lethality in mice by mal-adjusting the cytokine network.
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