Synergistic antiallergic activity of combined histamine H1- and cysteinyl leukotriene1-receptor blockade in human bronchus.
Mast cell histamine (HA) and cysteinyl leukotrienes (CysLT) account for most of the early phase bronchospasm in asthma. However, activation of the smooth muscle CysLT1-receptor plays a major role in asthmatic bronchospasms. CysLT-receptor antagonists or CysLT-synthesis inhibitors are efficacious in asthma but do not completely abolish asthmatic bronchospasms. A recent clinical study showed that combined antagonists loratadine (H1) and zafirlukast (CysLT1) were more effective against allergic bronchospasms than either drug alone. We examined the combined efficacy of H1- and CysLT1-receptor antagonists in allergic human bronchus. The H1- and CysLT1-receptor antagonists chlorpheniramine (CTM; 1 microM) and MK-571 (0.03 microM), were tested alone and in combination, against anti-human IgE antibody (Ab)-induced contractions of passively sensitized isolated human bronchus. Ab-induced allergic contractions were reduced 15% and 36% by CTM (1 microM) and MK-571 (0.03 microM), respectively. Combined CTM (1 microM) and MK-571 (0.03 microM) significantly inhibited the Ab response by 87%. Mechanistic investigations in isolated human bronchus and cultured human cord blood mast cells suggest that H1- and CysLT-receptor interactions likely occur at the airway smooth muscle level. CTM and MK-571 synergistically inhibited human allergic bronchospasm in the present in vitro model. The mechanism underlying this synergistic activity requires further investigation.
Ruck
L M
LM
Allergy, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. lori.ruck@spcorp.com
Rizzo
C A
CA
Anthes
J C
JC
Eckel
S
S
Egan
R W
RW
Cuss
F M
FM
Hey
J A
JA
D000328:Adult; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology; D001986:Bronchial Spasm / Q000276:immunology / Q000517:prevention & control; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D007116:Immunization, Passive; D007073:Immunoglobulin E / Q000276:immunology; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D008565:Membrane Proteins; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects / Q000276:immunology; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene
D006634:Histamine H1 Antagonists; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011422:Propionates; D011804:Quinolines; D018077:Receptors, Leukotriene; D007073:Immunoglobulin E; C059141:verlukast; D017998:Leukotriene D4; D006632:Histamine; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor