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.

Targeted Disruption of Leukotriene B4 Receptors BLT1 and BLT2: A Critical Role for BLT1 in Collagen-Induced Arthritis in Mice

“…Several leukotriene antagonists and biosynthesis inhibitors have been used in clinical trials for human RA, but none have been approved for the treatment of RA (49,50). Although the elements of inflammatory response are similar, murine CIA has limitations in modeling human arthritis, including the absence of rheumatoid factor as well as lack of clear mechanisms for the initiation of disease in humans (5).…”

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…Pharmacological treatment with the BLT 1 R antagonist CP-105,696 reduced the histological signs of collagen-induced arthritis in the more arthritis-prone DBA/1J mice (Griffiths et al, 1995). In humans, oral administration of the BLT receptor antagonist amebulant (Birke et al, 2001) inhibits Mac-1 expression on neutrophils (Alten et al, 2004) (Dahlén, 2006). In addition, neutrophil recruitment to the airway is thought to be a major component of continuing inflammation and progression of chronic obstructive pulmonary disease (COPD), and the 46% of the neutrophil chemotactic activity in sputum derived from patients with COPD is inhibited by a BLT receptor antagonist (Woolhouse et al, 2002).…”

Leukotriene Receptor Antagonism and the Prevention of Extracellular Matrix Degradation During Atherosclerosis and In-Stent Stenosis

“…Nonstented rabbit carotid arteries were embedded in paraffin after paraformaldehyde fixation and used for immunohistochemical stainings with antibodies against ␣ SM -actin (Dako), Ki-67 (a nuclear proliferation marker, Immunotech), or RAM-11 (a marker of rabbit macrophage cytoplasm, Dako), as previously described. 18 …”

“…The latter concentration has previously been reported be sufficient to reach 100% inhibition of LTB 4 -induced Mac-1 expression on ex vivo stimulated neutrophils. 18 …”