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Combination therapy with anti‐mediator drugs in allergic disease

Inflammatory mediators are local hormones that act via specific cell-surface receptors in an autocrine or paracrine manner to modulate the behaviour of inflammatory leucocytes and structural cells in inflamed tissues. The classical inflammatory mediators are the autacoids such as histamine, cysteinyl-leukotrienes (cys-LT), LTB4, prostanoids, bradykinin, and platelet-activating factor (PAF). Potent, selective, safe and long-acting compounds that inhibit the synthesis or block the receptors of individual autacoids have been developed over the last 20 years. The leukotriene (LT) modifiers (montelukast, pranlukast, zafirlukast, zileuton) have entered clinical practice for asthma, and the non-sedating H1 histamine antagonists (cetirizine, loratadine, terfenadine) are front-line therapies for allergic rhinitis and allergic skin disease. Potent inhibitors of prostanoid synthesis (NSAIDs) have been available for 100 years, but the new cycloxygenase-2-selective inhibitors (celecoxib, rofecoxib) may combat inflammation without the gastric and other adverse effects associated with traditional NSAIDs. Experimental antagonists of LTB4, PAF and the mast cell protease, tryptase, have also been investigated in clinical trials in asthma and other diseases, with mixed results. LT modifiers and other anti-mediator therapies have been shown to provide excellent clinical benefit in significant subgroups of patients. Many have advantages with respect to patient compliance and favourable adverse effect profiles compared to anti-inflammatory corticosteroids. The perception emerging from clinical trials is that anti-mediator monotherapies may be less efficacious than corticosteroids against the broad spectrum of inflammatory processes in allergic disease, arousing growing interest in the concept of combination therapy with two or more antimediator drugs, not only in asthma but also in inflammatory diseases of the nasal airway and skin. The paper from Professor Lipworth's group at Dundee University published in this issue of Clinical & Experimental Allergy [1] provides important evidence that combination therapy with two anti-mediator drugs, specifically a LT modifier and an H1 histamine antagonist, can provide additive and complementary anti-inflammatory outcomes that match those afforded by topical corticosteroids. This review will focus on clinical trials of anti-mediator cotherapy, particularly with combinations of LT modifiers and antihistamines, in the treatment of allergic asthma, exercise-induced bronchoconstriction, allergic skin disease (eczema, urticaria), and allergic rhinitis.