title: Inhibition of leukotriene B4-induced CD11B/CD18 (Mac-1) expression by BIIL 284, a new long acting LTB4 receptor antagonist, in patients with rheumatoid arthritis.
abstract: BACKGROUND
  Leukotriene B4 (LTB(4)) has a key role in the pathophysiology of rheumatoid arthritis (RA).
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Rheumatologie und Physikalische Therapie, Schlossparkklinik, Heubnerweg 2, D-14059 Berlin, FRG.
authors.forename: R
authors.initials: R
authors.lastname: Alten
authors.forename: E
authors.initials: E
authors.lastname: Gromnica-Ihle
authors.forename: C
authors.initials: C
authors.lastname: Pohl
authors.forename: J
authors.initials: J
authors.lastname: Emmerich
authors.forename: J
authors.initials: J
authors.lastname: Steffgen
authors.forename: R
authors.initials: R
authors.lastname: Roscher
authors.forename: R
authors.initials: R
authors.lastname: Sigmund
authors.forename: B
authors.initials: B
authors.lastname: Schmolke
authors.forename: G
authors.initials: G
authors.lastname: Steinmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000578:Amidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002219:Carbamates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D020024:Leukotriene Antagonists / Q000627:therapeutic use*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D016177:Macrophage-1 Antigen / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D013997:Time Factors
chemical_list: D000578:Amidines; D002219:Carbamates; D020024:Leukotriene Antagonists; D016177:Macrophage-1 Antigen; D007975:Leukotriene B4; C424425:amelubant