Synergistic antiallergic activity of combined histamine H-1- and cysteinylleukotriene(1)-receptor blockade in human bronchus

Mast cell histamine (HA) and cysteinyl leukotrienes (CysLT) account for mos t of the early phase bronchospasm in asthma. However, activation of the smo oth muscle CysLT(1)-receptor plays a major role in asthmatic bronchospasms. CysLT-receptor antagonists or CysLT-synthesis inhibitors are efficacious i n asthma but do not completely abolish asthmatic bronchospasms. A recent cl inical study showed that combined antagonists loratadine (H-1) and zafirluk ast (CysLT(1)) were more effective against allergic bronchospasms than eith er drug alone. We examined the combined efficacy of H-1- and CysLT(1)-recep tor antagonists in allergic human bronchus. The H-1- and CysLT(1)-receptor antagonists chlorpheniramine (CTM; 1 muM) and MK-571 (0.03 muM), were teste d alone and in combination, against anti-human IgE antibody (Ab)-induced co ntractions of passively sensitized isolated human bronchus. Ab-induced alle rgic contractions were reduced 15% and 36% by CTM (1 muM) and MK-571 (0.03 muM), respectively. Combined CTM (1 muM) and MK-571 (0.03 muM) significantl y inhibited the Ab response by 87%. Mechanistic investigations in isolated human bronchus and cultured human cord blood mast cells suggest that H-1- a nd CysLT-receptor interactions likely occur at the airway smooth muscle lev el. CTM and MK-571 synergistically inhibited human allergic bronchospasm in the present in vitro model. The mechanism underlying this synergistic acti vity requires further investigation. (C) 2001 Elsevier Science Inc. All rig hts reserved.