The potential of active metabolites of antihistamines in the management of allergic disease.

Abstract

Since the discovery of histamine in the ®rst decade of the 20th century, there has been increasing evidence that this biogenic amine, synthesized predominantly in mast cells and basophils, is released in in ammatory processes and plays a key role in the pathogenesis of urticaria and allergic airway diseases, including asthma, rhinitis, and urticaria (1±3). Studies have demonstrated that histamine levels are signi®cantly increased in the bronchoalveolar lavage (BAL) of symptomatic asthmatics, compared with asymptomatic asthmatics (4, 5), and that allergen challenge leads to a marked increase in the levels of histamine in asthmatics (6, 7). Similarly, studies have demonstrated that allergen challenge also leads to signi®cant increases in the levels of histamine in the nasal secretions of patients with allergic rhinitis (8±10). A comparison of patients with chronic urticaria and healthy subjects has also demonstrated that the former release greater amounts of histamine, both spontaneously and after antigen provocation (11±13). In addition, some studies have demonstrated that the responsiveness of the skin to histamine is slightly increased in patients with urticaria (11). Mechanistic studies have demonstrated that the action of histamine arises from its interaction with one of at least three speci®c histamine receptors, H1, H2, and H3, located on various histamine-responsive target tissues. Interaction of histamine with the H1 receptor leads primarily to smooth-muscle contraction, vasodilatation and hypotension, increased vascular permeability with formation of tissue oedema, increased respiratory mucus secretion, and parasympathetic nerve stimulation (14, 15). These effects can subsequently lead to bronchial obstruction in asthma; nasal blockage, sneezing, itching, and discharge in rhinitis; and itchy skin wheals/ ares in urticaria. At the cellular level, histamine may also act on in ammatory cells and lead to release of mediators, such as leukotrienes and cytokines, and increased expression of class II antigens (HLA-DR) and ICAM-1 on epithelial cells (16, 17), effects which could, in turn, exacerbate the pathology and symptoms of allergic disease. In contrast, effects attributable to H2 receptors include augmentation of gastric acid secretion and increases in gastric and respiratory mucus secretion (14). H3 receptors have been implicated in autocrine regulation of histamine synthesis and release from nerve tissue (14).