EFFECT OF PRANLUKAST, AN ORAL LEUKOTRIENE RECEPTOR ANTAGONIST, ON LEUKOTRIENE D-4 (LTD4) CHALLENGE IN NORMAL VOLUNTEERS

Background - There is increasing evidence to show that leukotrienes ar e important mediators in asthma. Leukotriene receptor antagonists prot ect against antigen and exercise challenges in patients with chronic a sthma. A study was undertaken to investigate the activity of the leuko triene receptor antagonist pranlukast (SB 205312, ONO-1078) in blockin g bronchoconstriction induced by leukotriene D-4 (LTD4) inhalation. Th e selectivity of pranlukast was evaluated using histamine challenge. M ethods - Pranlukast, 450 mg twice daily, was given to eight healthy no n-smoking men for five days in a randomised, double blind, placebo con trolled, crossover study. The specific airways conductance (sGaw) was measured before and after bronchial provocation with inhaled LTD4 at 3 .5 hours after the first dose and at 3.5 and 9.5 hours after the last dose of pranlukast on the morning of day 5. The concentration of LTD4 required to produce a fall in sGaw of 35% (PC35) was calculated. Subje cts also underwent a histamine challenge 3.5 hours after a single dose of pranlukast, 450 mg, or placebo. Results - A single dose of pranluk ast produced a 10.6 fold increase in PC(35)sGaw (95% confidence interv al (CI) 4.4 to 25.5; p<0.001) for LTD4 at 3.5 hours after dosing compa red with placebo. Three and a half hours after the morning dose of pra nlukast on day 5 the PC(35)sGaw for LTD4 was increased 25.9 fold (95% CI 10.8 to 62.2; p<0.001) and was still increased sevenfold (95% CI 2. 9 to 16.7; p<0.001) relative to placebo 9.5 hours after administration of the morning dose. No significant differences were noted for the PC (35)sGaw to histamine for pranlukast compared with placebo. Conclusion s - This study shows that pranlukast is a potent and selective LTD4 re ceptor antagonist in humans which blocks LTD4 challenge after initial and repeated administration when given twice daily for five days.