Yamamoto N, Sakai F, Yamazaki H, Nakahara K, Okuhara M
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
Eur J Pharmacol. 1996 Oct 24;314(1-2):137-42. doi: 10.1016/s0014-2999(96)00537-7.
FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5-1-c] [1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate) is a low molecular weight inflammatory cytokine inhibitor that inhibits the production of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor-alpha (TNF-alpha) in human monocytes stimulated with lipopolysaccharide, and in human lymphocytes stimulated with phytohemagglutinin-M. FR167653 inhibited these cytokines in a dose-dependent manner (IC50 values were 0.84, 0.088, 1.1 microM and 0.072, respectively). However, FR167653 did not inhibit even at 10 microM interleukin-6 production by human monocytes, and the production of interleukin-2 and interferon-gamma by human lymphocytes. We evaluated the effect of FR167653 on lipopolysaccharide-induced disseminated intravascular coagulation in rats. FR167653 (0.032-0.32 mg/kg/h for 4 h, intravenous infusion) markedly improved thrombocytopenia and plasma coagulation parameters in a dose-dependent manner, but not leukopenia in this mode. Plasma interleukin-1 and TNF-alpha levels were elevated by lipopolysaccharide administration and the treatment with FR167653 (0.31 mg/kg/h for 4 h) inhibited the increased plasma interleukin-1 (100.0%) and plasma TNF-alpha (89.2%) levels. These results suggest that interleukin-1 and TNF-alpha may play a pivotal role in the pathogenesis of DIC. FR167653 can act as a protective drug in lipopolysaccharide-induced DIC, and this protection is due to an inhibition of increased plasma interleukin-1 and TNF-alpha.
FR167653（1-[7-(4-氟苯基)-1,2,3,4-四氢-8-(4-吡啶基)吡唑并[5-1-c][1,2,4]三嗪-2-基]-2-苯基乙二酮硫酸单水合物）是一种低分子量炎性细胞因子抑制剂，可抑制脂多糖刺激的人单核细胞以及植物血凝素-M刺激的人淋巴细胞中白细胞介素-1α、白细胞介素-1β和肿瘤坏死因子-α（TNF-α）的产生。FR167653以剂量依赖性方式抑制这些细胞因子（IC50值分别为0.84、0.088、1.1微摩尔和0.072）。然而，FR167653即使在10微摩尔时也不抑制人单核细胞产生白细胞介素-6，以及人淋巴细胞产生白细胞介素-2和干扰素-γ。我们评估了FR167653对大鼠脂多糖诱导的弥散性血管内凝血的影响。FR167653（0.032 - 0.32毫克/千克/小时，静脉输注4小时）以剂量依赖性方式显著改善血小板减少症和血浆凝血参数，但在此模式下对白细胞减少症无改善作用。脂多糖给药会使血浆白细胞介素-1和TNF-α水平升高，而用FR167653（0.31毫克/千克/小时，4小时）治疗可抑制血浆白细胞介素-1（100.0%）和血浆TNF-α（89.2%）水平的升高。这些结果表明白细胞介素-1和TNF-α可能在弥散性血管内凝血的发病机制中起关键作用。FR167653可作为脂多糖诱导的弥散性血管内凝血的保护药物，这种保护作用是由于抑制了血浆白细胞介素-1和TNF-α水平的升高。
