Alten R, Gromnica-Ihle E, Pohl C, Emmerich J, Steffgen J, Roscher R, Sigmund R, Schmolke B, Steinmann G
Rheumatologie und Physikalische Therapie, Schlossparkklinik, Heubnerweg 2, D-14059 Berlin, FRG.
Ann Rheum Dis. 2004 Feb;63(2):170-6. doi: 10.1136/ard.2002.004499.
Leukotriene B4 (LTB(4)) has a key role in the pathophysiology of rheumatoid arthritis (RA).
To investigate the inhibition of ex vivo LTB(4)-induced Mac-1 (CD11b/CD18) expression in leucocytes of patients with RA by the new oral LTB(4) receptor antagonist BIIL 284.
The pharmacokinetics and inhibition of LTB(4)-induced Mac-1 expression of BIIL 284 were characterised in 26 adult patients with RA who were treated with BIIL 284 25 mg, 150 mg, or placebo given once a day for 14 days according to a double blind, randomised, parallel group design.
T(max) of BIIL 315 in plasma (main metabolite and active principle of BIIL 284 in plasma) was achieved about four hours after drug administration, and C(max,ss) and AUC(0-6h,ss) increased in proportion to the dosage. 100% inhibition of LTB(4)-induced MAC-1 expression was reached after two hours (150 mg) or four hours (25 mg), showing a statistically significant difference in comparison with placebo (p<0.005). A longlasting dynamic effect was seen consistently even when plasma concentrations declined to very low values 24 hours after administration. Secondary clinical efficacy end points remained unchanged probably owing to the short duration of treatment. Adverse events (AEs) were reported in 12 patients during the study. No serious AEs or laboratory AEs were seen.
Both the 25 mg and 150 mg doses of BIIL 284 safely and effectively inhibit Mac-1 expression on neutrophils; thus longer treatment with BIIL 284 may result in clinical benefit for patients with RA.
白三烯B4（LTB4）在类风湿关节炎（RA）的病理生理学中起关键作用。
研究新型口服LTB4受体拮抗剂BIIL 284对RA患者白细胞中离体LTB4诱导的Mac-1（CD11b/CD18）表达的抑制作用。
根据双盲、随机、平行组设计，对26例成年RA患者进行研究，患者接受BIIL 284 25mg、150mg或安慰剂治疗，每日一次，共14天，以表征BIIL 284的药代动力学及对LTB4诱导的Mac-1表达的抑制作用。
BIIL 315（BIIL 284在血浆中的主要代谢产物及活性成分）在给药后约4小时达到血浆中的T(max)，C(max,ss)和AUC(0-6h,ss)与剂量成比例增加。给药后2小时（150mg）或4小时（25mg）后，LTB4诱导的MAC-1表达被100%抑制，与安慰剂相比有统计学显著差异（p<0.005）。即使给药24小时后血浆浓度降至非常低的值，仍持续观察到长期的动态效应。次要临床疗效终点可能由于治疗时间短而保持不变。研究期间有12例患者报告了不良事件（AE）。未观察到严重AE或实验室AE。
25mg和150mg剂量的BIIL 284均能安全有效地抑制中性粒细胞上的Mac-1表达；因此，BIIL 284的长期治疗可能会给RA患者带来临床益处。
