P.1.g.035 The role of P-glycoprotein in central sedative effects of H1-antihistamines

Abstract

Medicinal chemical research in pulmonary and allergic diseases continues to focus on the role of leukotrienes (LTs) as major causative agents in bronchoconstriction, edema, and inflammation. Several potent orally active receptor antagonists and biosynthesis inhibitors have emerged as potential clinical candidates. In addition to eukotriene research, interest continues in selective phospholipase A2 inhibitors, non-sedating anti histamines, and phosphodi esterase inhibitors. This chapter discusses the above in detail. There are leukotrienes pharmacology and biochemistry of leukotrienes, synthesis of leukotrienes and related compounds, leukotriene receptor antagonists, inhibition of leukotrlene biosynthesis—phospholipases, xanthines and phosphodiesterase inhibitors, antihistamines and mediator release inhibitors. Recent studies show astemizole to blunt antigen-induced bronco-constriction in allergic asthmatics. Furthermore, both astemlzole and terfenadine were shown to be effective against exercise-induced asthma. Although the asthmatic response was not abolished in any of the studies cited, the results suggest that antihistamines (particularly the non-sedating agents) may have a role in the pharmacotherapy of bronchial asthma. The role of histamine in proucing the signs and symptoms of bronchial asthma was evaluated. Historically, H1-antihistamines have been only marginally effective in preventing antigen-induced bronchoconstriction, perhaps because the sedative effects of classical antihistamines limit their therapeutic utility, olr because histamine is not a primary mediator of allergic asthma. New topically and orally active MRIs continue to be reported, although the precise biochemical mechanism of action of this class of anti-allergic agents remains unknown. Nedocromil sodium and minocromil are topically active MRIs.