INHIBITION OF EX-VIVO NEUTROPHIL ACTIVATION BY ORAL LY293111, A NOVELLEUKOTRIENE B-4 RECEPTOR ANTAGONIST

1 The effects of orally administered LY293111 on ex vivo neutrophil Ma c-1 upregulation were determined in a total of 24 healthy male subject s within three study periods. 2 In the first period, eight volunteers received 60 mg LY293111 or placebo three times daily in 22 total doses over 8 days followed by a 1. week follow-up. The average ex vivo Mac- 1 response of the LY293111 group was 56% of the predose control (95% c onfidence interval (CI) 44.3 to 67.9%; P<0.01). The inhibitory effect was maximum at the end of dosing and had disappeared by day 14. 3 In t he second period, eight subjects received 120 mg LY293111 or placebo t hree times daily in 22 total doses over 8 days followed by a 1 week fo llowup. The average response of the LY293111 group was 70% of the pre- dose control (95% CI 59.7 to 81.0%; P<0.01). The inhibitory effect was maximum the day following the initial dose and continued throughout t he dosing period. 4 In the third period, eight subjects received 200 m g LY293111 or placebo twice daily in 15 total doses over 8 days follow ed by a 1 week follow-up. Mac-1 upregulation was 64% of pre-dose level s (95% CI 53.8 to 75.1%; P<0.01) over the course of the study period. The inhibition had disappeared 2 days following the final dose. Altern ate neutrophil stimulation by fMLP was not inhibited. 5 No statistical ly significant inhibition was observed for placebo-treated subjects. 6 No statistically significant differences were apparent between the ac tive dose regimens. 7 The results indicate that orally administered LY 293111 is pharmacologically active in humans. Results from this study may be useful in determining dose selection for efficacy trials.