Lethal Toxicity of NSAID in BRM Primed Mice

（1→3）-β-D-葡聚糖（β-glucan）是一种调节宿主免疫反应的生物反应调节剂（BRM）。然而，这种药物的副作用尚未得到广泛的研究。在这项研究中，我们发现β-葡聚糖和非甾体抗炎药吲哚美辛（IND）的组合在小鼠中诱导了致命毒性。经口给予IND（ICR小鼠多次给药;每天一次，共2周）的致死毒性在2周内为0/8（2.5 mg/kg）和5/8（5 mg/kg）（死亡/总数）。在用临床β-葡聚糖制剂sonifilan（250μg/小鼠，第0天单次腹腔注射）处理的小鼠中，毒性增强至3/8和8/8。单次口服导致致死毒性增强。在多次β-葡聚糖给药后第5 - 9天给予IND。对于其他β-葡聚糖，包括SSG、灰树花多糖、酵母聚糖A和zymocel，观察到类似的效果。对于各种微生物产品，如细菌和真菌的全细胞制剂、BCG和OK-432，也观察到类似的效果。各种小鼠品系（如C3 H/HeN、C3 H/HeJ、AKR/N、BALB/c、C57 BL/6、DBA/2、BALB/c nu/nu、KSN、WBB 6 F1）和各种NSAID（如阿司匹林、双氯芬酸和舒林酸）均显示出致死毒性。IND/β-葡聚糖处理的小鼠血清中IFN-γ、IL-6和CSF浓度显著升高。这些结果强烈表明，IND/BRM治疗通过失调细胞因子网络诱导小鼠死亡。

(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.