Asthma is a complex syndrome characterized by variable obstruction to airflow, bronchial hyperresponsiveness, and inflammation. The initiation and propagation of airway inflammation arises from many factors, including mediators generated by resident airway cells and recruited leukocytes (1). Leukotrienes are biologically active fatty acids derived from the oxidative metabolism of arachidonic acid, an integral component of the cell membrane (2). A role for leukotrienes in the pathogenesis of asthma has been suggested by their biologic activities, which produce effects that mimic those of clinical asthma, and by the effects of either inhibition of leukotriene production (5-lipoxygenase inhibitors) or antagonism of leukotriene binding to cellular receptors (leukotriene D 4-receptor antagonists). The recent U.S. Food and Drug Administration (FDA) approval of a leukotriene-receptor antagonist, zafirlukast (Accolate), and a leukotriene synthesis inhibitor, zileuton (Zyflo), provides the first mediator-specific therapy for asthma. This review will consider the biochemistry of the leukotrienes, their biologic role in asthma, and the therapeutic potential of drugs that alter the production or action of leukotrienes, as well as provide guidelines for the use of leukotriene modifiers in patients with asthma. MECHANISMS OF MODIFICATION OF LEUKOTRIENE ACTION Two approaches have been developed to decrease the action of leukotrienes. One is to block leukotriene synthesis by en
Leukotrienes can be generated from a wide variety of cells including mast cells and eosinophils. The biological properties of these products include bronchial smooth muscle contraction, stimulation of mucous production, enhancement of vascular permeability, and recruitment of eosinophils. These properties can contribute significantly to the pathobiology of asthma. Recently, zafirlukast and montelukast, and zileuton, leukotriene D4 receptor antagonists and 5-lipoxygenase inhibitors, respectively, have been developed and are available for treating asthma. Studies have found these compounds modify bronchospasm with exercise, the pulmonary reaction to aspirin in sensitive subjects, and the airway response to inhaled antigen. Furthermore, in patients with chronic asthma, leukotriene modifiers improve airflow obstruction, decrease the need for rescue medication, and diminish symptoms. Moreover, these drugs can prevent asthma exacerbations. However, there is little evidence that these medications have potent anti-inflammatory activity. Nonetheless, leukotriene modifiers represent new, and effective, therapeutics in the treatment of asthma; at present, the positioning of these products in relationship to inhaled corticosteroids, for example, in the treatment of asthma has not been fully defined but will emerge with further study and use in the clinic setting.
Asthma screening through a Head Start program provides an effective means of targeting preschool-aged children from socioeconomic groups at high risk for asthma. Identification of children early in the disease course and those at high risk for asthma provides an ideal opportunity for the implementation of preventive and therapeutic interventions.
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