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Section IV - Autacoids Drug Therapy of Inflammation

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This chapter describes the physiological role and pathophysical consequences of histamine release and provides a summary of the therapeutic use of histamine H1-receptor antagonists. H2-receptor antagonists are discussed in detail in Chapter 37: Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux Disease in the context of prevention and treatment of peptic ulcers, their principal therapeutic application. The identity and role of H2- receptor subtypes are described briefly, as are the newly developed H3 agonists and antagonists, although none has been approved by the U.S. Food and Drug Administration (FDA) for clinical use to date | Over the past decade, the hypothesis that there may be a more selective and thus safer approach to controlling airway inflammation than glucocorticoid therapy has motivated much of the drug discovery effort in asthma research. In various stages of development are agents aimed at inhibiting certain cytokines, chemokines, or adhesion molecules and thereby selectively decreasing the influx of eosinophils and other leukocytes into the airways. Other approaches have targeted the atopic reaction for selective intervention. Monoclonal antibodies aimed at inhibiting the binding of immunoglobulin E (IgE) to receptors on mast cells and basophils are in clinical trials for asthma and other allergic diseases. These antibodies, in theory, would inhibit the immediate hypersensitivity reaction at its earliest stage, thus preventing allergic inflammation in the airways. Neuropeptide receptor antagonists, particularly antagonists at neurokinin receptors, are under development to inhibit neurogenic components of inflammation. These agents also may inhibit reflex activity in the airways. Another strategy to quell the inflammation associated with asthma and chronic obstructive pulmonary disease is to develop drugs that are isozyme-selective phosphodiesterase (PDE) inhibitors. The finding that the predominant PDEs in inflammatory cells are members of the PDE-IV family has led to the development of drugs that are PDE-IV–selective inhibitors. This type of drug may provide antiinflammatory actions without many of the side effects associated with nonselective PDE inhibitors such as