Lethal Toxicity of NSAID in BRM Primed Mice

NSAID 对 BRM 免疫小鼠的致死毒性

• 批准号: 10672059
• 负责人: OHNO Naohito
• 金额: $ 2.37万
• 依托单位: Tokyo University of Pharmacy and Life Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672059/
• 关键词: β-glucan; BRM; NSAID; Lethal toxicity; Indomethacin; Interferon-γ; Macrophage; マクロファージ; β-グルカン; Bグルカン

(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.

(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研究。在这项研究中，我们发现β-葡聚糖和非甾体类抗炎药吲哚美辛（IND）的组合会引起小鼠的致命毒性。口服 IND（对 ICR 小鼠多次给药；两周每天一次）的致死毒性在 2 周内分别为 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）治疗的小鼠中，毒性增强至3/8和8/8。单次口服会导致致死毒性增强。多次β-葡聚糖给药后第5至9天进行IND给药。其他 β-葡聚糖也观察到类似的效果，包括 SSG、灰树花多糖、zymosan A 和 zymocel。各种微生物产品也观察到类似的效果，例如细菌和真菌的全细胞制剂、BCG 和 OK-432。多种小鼠品系（例如 C3H/HeN、C3H/HeJ、AKR/N、BALB/c、C57BL/6、DBA/2、BALB/c nu/nu、KSN、WBB6F1）和各种 NSAID（例如阿司匹林、双氯芬酸和舒林酸）显示出致死毒性。 IND/β-葡聚糖治疗小鼠血清中的 IFN-γ、IL-6 和 CSF 浓度显着升高。这些结果强烈表明 IND/BRM 治疗通过细胞因子网络的失调而诱导小鼠死亡。

项目成果

N.Ohno, T.Miura, N.N.Miura, N.Chiba, M.Uchiyama, Y.Adachi, and T.Yadomae: "Inflammatory and Immunopharmacological activities of meta-periodate oxidized zymosan"Zent.bl.Bakteriol. 289. 63-77 (1999)

N.Ohno、T.Miura、N.N.Miura、N.Chiba、M.Uchiyama、Y.Adachi 和 T.Yadomae：“偏高碘酸氧化酵母聚糖的炎症和免疫药理学活性”Zent.bl.Bakteriol。

N, Ohno et al: "Inflammatory and immunophormacological activities of metaperiodate oxidized zymosan"Zent, bl. Bakteriol.. 289. 63-77 (1999)

N，Ohno 等人：“偏高碘酸氧化酵母聚糖的炎症和免疫学活性”Zent，bl。

T. Miura et al: "Antigen Specific response of murine immune system toward a yeast β-glucan preparation, zymosan"FEMS Immunol. Med. Microb.. 24. 131-139 (1999)

T. Miura 等人：“鼠免疫系统对酵母 β-葡聚糖制剂、酵母聚糖的抗原特异性反应”FEMS Microb.. 24. 131-139 (1999)

T.Miura, N.Ohno, N.N.Miura, Y.Adachi, S.Shimada, and T.Yadomae: "Antigen specific response of murine immune system toward a yeast β-glucan preparation, zymosan"FEMS Immunol.Med.Microb.. 24. 131-139 (1999)

T.Miura、N.Ohno、N.N.Miura、Y.Adachi、S.Shimada 和 T.Yadomae：“小鼠免疫系统对酵母 β-葡聚糖制剂、酵母聚糖的抗原特异性反应”FEMS Immunol.Med.Microb.. 24. 131-139 (1999)

A.Tsuzuki et al: "Interleukin 8 production of human leukocytes stimulated by triple or single helical conformer of an antitumos(1→3)-β-D-glucan preparation,sonifilan"Drg.Develop.Res.. 48. 17-25 (1999)

A.Tsuzuki 等人：“抗肿瘤 (1→3)-β-D-葡聚糖制剂 sonifilan 的三螺旋或单螺旋构象异构体刺激人白细胞产生白细胞介素 8”Drg.Develop.Res.. 48. 17-25 (1999)