Horizoe T, Nagakura N, Chiba K, Shirota H, Shinoda M, Kobayashi N, Numata H, Okamoto Y, Kobayashi S
Eisai Co., Ltd., Tsukuba Research Laboratories for Drug Discovery, Biology Unit 5, Ibaraki, Japan.
Inflamm Res. 1998 Oct;47(10):375-83. doi: 10.1007/s000110050347.
To investigate the effect of ER-34122, a novel pyrazole derivative, on 5-lipoxygenase (LOX) and cyclooxygenase (COX) metabolite production in vitro, ex vivo and in vivo.
In vitro, lysate of rat basophilic leukemia cells, the microsome fraction of sheep seminal vesicles, human polymorphonuclear leukocytes, human synovial cells, and human monocytes. Ex vivo and in vivo, male Balb/c mice or SD rats.
In ex vivo study, ER-34122 (0.03-1 mg/kg) was orally administered 1 h before withdrawal of blood samples. In carrageenin-induced paw edema, ER-34122 (3-100 mg/kg) and indomethacin (1-10mg/kg) were orally administered 1 h before carrageenin injection. In arachidonic acid-induced ear inflammation, ER-34122 (0.3-10mg/kg), zileuton (10-100mg/kg) and indomethacin (0.3-3mg/kg) were orally administered 1 h before arachidonic acid application.
5-Hydroxyeicosatetraenoic acid and other eicosanoids were determined by using an HPLC method and enzyme immunoassay, respectively. Rat hind paw edema and mouse ear edema were assessed by measuring paw volume and ear thickness, respectively. Myeloperoxidase (MPO) activity and eicosanoid content of the ear tissue were also determined.
ER-34122 inhibited both LOX and COX product generation in vitro, and ex vivo. ER-34122 and indomethacin inhibited carrageenin-induced paw edema formation. In the arachidonic acid-induced ear inflammation, ER-34122 inhibited inflammatory responses (edema formation and MPO accumulation) as well as eicosanoids (LTB4, LTC4 and PGE2) generation. A representative LOX inhibitor, zileuton, also inhibited these inflammatory responses, while a COX inhibitor, indomethacin, did not suppress them though it completely inhibited PGE2 generation.
The anti-inflammatory characteristics of ER-34122 are considered to be superior to those of COX inhibitors such as indomethacin, because in addition to its inhibitory activity on the COX pathway, ER-34122 inhibits LOX products generation, as revealed by the inhibition of edema formation or polymorphonuclear leukocyte infiltration in the arachidonic acid-induced ear inflammation model.
研究新型吡唑衍生物ER - 34122在体外、离体及体内对5 - 脂氧合酶（LOX）和环氧化酶（COX）代谢产物生成的影响。
体外实验使用大鼠嗜碱性白血病细胞裂解物、绵羊精囊微粒体部分、人多形核白细胞、人滑膜细胞和人单核细胞。离体及体内实验使用雄性Balb / c小鼠或SD大鼠。
在离体研究中，采血前1小时口服给予ER - 34122（0.03 - 1mg / kg）。在角叉菜胶诱导的爪肿胀实验中，角叉菜胶注射前1小时口服给予ER - 34122（3 - 100mg / kg）和吲哚美辛（1 - 10mg / kg）。在花生四烯酸诱导的耳炎症实验中，花生四烯酸应用前1小时口服给予ER - 34122（0.3 - 10mg / kg）、齐留通（10 - 100mg / kg）和吲哚美辛（0.3 - 3mg / kg）。
分别采用高效液相色谱法和酶免疫测定法测定5 - 羟基二十碳四烯酸和其他类花生酸。通过测量爪体积和耳厚度分别评估大鼠后爪肿胀和小鼠耳肿胀。还测定了耳组织的髓过氧化物酶（MPO）活性和类花生酸含量。
ER - 34122在体外和离体实验中均抑制LOX和COX产物的生成。ER - 34122和吲哚美辛抑制角叉菜胶诱导的爪肿胀形成。在花生四烯酸诱导的耳炎症中，ER - 34122抑制炎症反应（水肿形成和MPO积聚）以及类花生酸（白三烯B4、白三烯C4和前列腺素E2）的生成。代表性的LOX抑制剂齐留通也抑制这些炎症反应，而COX抑制剂吲哚美辛虽完全抑制前列腺素E2生成，但未抑制这些炎症反应。
ER - 34122的抗炎特性被认为优于吲哚美辛等COX抑制剂，因为在花生四烯酸诱导的耳炎症模型中，除了对COX途径的抑制活性外，ER - 34122还抑制LOX产物的生成，这可通过其对水肿形成或多形核白细胞浸润的抑制得以体现。
