Pairet M, van Ryn J, Schierok H, Mauz A, Trummlitz G, Engelhardt G
Boehringer Ingelheim Pharma KG, Biberach an der Riss, Germany.
Inflamm Res. 1998 Jun;47(6):270-6. doi: 10.1007/s000110050329.
Two structurally related compounds, meloxicam (Mel) and its structural 4'-isomer (4'-Mel), were compared to examine the role of a slightly different chemical structure on cyclooxygenase (COX) selectivity in in vitro and in vivo experimental models.
In vitro studies were performed using human whole blood obtained from healthy volunteers, in vivo studies were performed in rats.
A concentration-response curve was obtained in the whole blood assay for Mel, 4'-Mel, indomethacin, piroxicam and diclofenac. These were used to calculate the respective IC50 values of either prostaglandin E2 (PGE2) or thromboxane B2 (TxB2). Similarly, a dose-response curve was obtained for Mel, 4'-Mel and piroxicam when measuring in vivo prostaglandin production, anti-inflammatory activity and gastric tolerance to determine the dose resulting in a 50% reduction of the each parameter.
COX selectivity was investigated in vitro using a human whole blood assay. PGE2 synthesis in vivo was measured in inflammatory exudate, in the stomach and kidneys of rats. Anti-inflammatory effects were measured in an adjuvant arthritis model and gastric tolerance was tested in an ulcerogenicity model in vivo in rats.
In the human whole blood assay, the ratio of IC50 values for COX-1 vs. COX-2 inhibition was 13 for Mel and 1.8 for 4'-Mel. In inflammatory exudate in rats, Mel and 4'-Mel inhibited PGE2 synthesis to a similar extent, ID50 values approximately 0.3 mg/kg. In contrast, Mel was a weaker inhibitor of PG synthesis than 4'-Mel in the rat stomach and in the rat kidney. Paw swelling was reduced by 50% with 0.1 and 0.2 mg/kg for Mel and 4'-Mel, respectively, in the rat adjuvant arthritis model. Gastric tolerance (UD50) was 2.4 mg/kg for Mel and 0.4 mg/kg for 4'-Mel.
These data demonstrate that the in vitro and in vivo pharmacological profile of meloxicam is structurally dependent and that minor structural changes can lead to significant differences in the selectivity for COX-1 and COX-2 in vitro and to different profiles in vivo suggesting different therapeutic potential.
比较两种结构相关的化合物，美洛昔康（Mel）及其结构4'-异构体（4'-Mel），以研究在体外和体内实验模型中，略有不同的化学结构对环氧合酶（COX）选择性的作用。
体外研究使用从健康志愿者获得的人全血进行，体内研究在大鼠中进行。
在全血试验中获得美洛昔康、4'-美洛昔康、吲哚美辛、吡罗昔康和双氯芬酸的浓度-反应曲线。这些用于计算前列腺素E2（PGE2）或血栓素B2（TxB2）各自的半数抑制浓度（IC50）值。同样，在测量体内前列腺素产生、抗炎活性和胃耐受性时，获得美洛昔康、4'-美洛昔康和吡罗昔康的剂量-反应曲线，以确定导致各参数降低50%的剂量。
使用人全血试验在体外研究COX选择性。在大鼠的炎症渗出液、胃和肾脏中测量体内PGE2的合成。在佐剂性关节炎模型中测量抗炎作用，并在大鼠体内致溃疡模型中测试胃耐受性。
在人全血试验中，美洛昔康对COX-1与COX-2抑制的IC50值之比为13，4'-美洛昔康为1.8。在大鼠的炎症渗出液中，美洛昔康和4'-美洛昔康对PGE2合成的抑制程度相似，半数抑制剂量（ID50）值约为0.3mg/kg。相比之下，在大鼠胃和大鼠肾脏中，美洛昔康对PG合成的抑制作用比4'-美洛昔康弱。在大鼠佐剂性关节炎模型中，美洛昔康和4'-美洛昔康分别以0.1mg/kg和0.2mg/kg使爪肿胀减少50%。美洛昔康的胃耐受性（UD50）为2.4mg/kg，4'-美洛昔康为0.4mg/kg。
这些数据表明，美洛昔康的体外和体内药理学特征取决于结构，微小的结构变化可导致体外对COX-1和COX-2选择性的显著差异以及体内不同的特征，提示不同的治疗潜力。
