Multiple mediators are involved in the pathophysiology of allergic and inflammatory disorders. Drugs that affect the action of more than one mediator may, therefore, be particularly effective in these disorders. Two such mediators are
platelet-activating factor (PAF) and
histamine. From a structural series with documented
antihistamine activity,
Sch 37370 has been identified as a dual antagonist of PAF and
histamine. In vitro,
Sch 37370 selectively inhibits PAF-induced aggregation of human platelets (IC50 = 0.6 microM) and also competes with PAF binding to specific sites in membrane preparations from human lungs (IC50 = 1.2 microM).
Sch 37370 also blocks the binding of [3H]
pyrilamine to
histamine H1 receptors in rat brain membranes. In guinea pigs, orally administered
Sch 37370 is effective against
bronchospasm to
histamine (ED50 = 2.4 mg/kg), PAF (ED50 = 6.0 mg/kg) or
serotonin (ED50 = 9.6 mg/kg). In contrast, it only weakly antagonizes
methacholine-induced
bronchospasm (ED50 = 51 mg/kg) and is totally inactive at 50 mg/kg against
bronchospasm due to
leukotriene C4 or
substance P.
Sch 37370 blocks
hypotension in rats and a cutaneous reaction in monkeys induced by either PAF or
histamine, as well as PAF-induced
edema in the rat pleural cavity. In addition,
Sch 37370 blocks
bronchospasm induced by either
antigen in sensitized guinea pigs or
hyperventilation in nonsensitized guinea pigs.
Sch 37370 also inhibits
antigen-induced lung
eosinophilia in sensitized guinea pigs and a reverse passive
Arthus reaction in rats. Although
Sch 37370 is not the most potent PAF antagonist or
antihistamine, it is the first compound that combines these pharmacologically relevant activities and may offer important advantages over currently available
antihistamine therapies.