Synergistic antiallergic activity of combined histamine H1- and cysteinyl leukotriene1-receptor blockade in human bronchus.

Abstract

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.

• Authors: L M Ruck, C A Rizzo, J C Anthes, S Eckel, R W Egan, F M Cuss, J A Hey
• Journal: Life sciences (Life Sci) Vol. 68 Issue 25 Pg. 2825-34 (May 11 2001) ISSN: 0024-3205 [Print] Netherlands
• PMID: 11432448 (Publication Type: Journal Article)

Chemical References

• Histamine H1 Antagonists
• Leukotriene Antagonists
• Membrane Proteins
• Propionates
• Quinolines
• Receptors, Leukotriene
• Immunoglobulin E
• verlukast
• Leukotriene D4
• Histamine
• cysteinyl leukotriene receptor 2
• leukotriene D4 receptor

Topics

• Adult
• Bronchi (drug effects, immunology)
• Bronchial Spasm (immunology, prevention & control)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Drug Synergism
• Female
• Histamine (pharmacology)
• Histamine H1 Antagonists (pharmacology)
• Humans
• Immunization, Passive
• Immunoglobulin E (immunology)
• In Vitro Techniques
• Leukotriene Antagonists (pharmacology)
• Leukotriene D4 (pharmacology)
• Male
• Mast Cells (drug effects)
• Membrane Proteins
• Middle Aged
• Muscle Contraction (drug effects, immunology)
• Muscle, Smooth (drug effects, immunology)
• Propionates (pharmacology)
• Quinolines (pharmacology)
• Receptors, Leukotriene