Histamine and asthma: an appraisal based on specific H1-receptor antagonism.

H1-receptor antagonists have been utilized, following their initial chemical synthesis in 1933, both in the treatment of conditions in which histamine is considered to be of pathogenic importance and conversely to help elucidate the role of histamine in disease, through an evaluation of their influence on disease expression. While there is considerable indirect evidence to implicate histamine in the pathogenesis of asthma, a critical evaluation of H1-receptor antagonism in this condition has, until recently, proved difficult, as many of the early H1-receptor antagonists possessed additional actions, such as anti-cholinergic, local anaesthetic, alpha-adrenoceptor antagonistic and anti-serotonin activity. In addition, H1-receptor antagonists have been shown to have effects on mast cell function. In low concentrations in vitro, antihistamines have been found to inhibit immunologically stimulated mast cell mediator release, with the IC50 in the nanomolar to micromolar range, while at higher concentrations they induce histamine release. The potency of these drugs in producing such effects is unrelated to their H1-receptor blocking activity. Furthermore the sedative effects of these therapeutic agents limit the tolerable administrable dose and thus the degree of H1-receptor blockade achievable within the airways. The recent development of H1-receptor antagonists devoid of clinical sedative effects has enabled the administration of doses of H1-antihistamines which achieve a greater degree of H1-receptor blockade within the airways, thus permitting a better appraisal of the role of histamine in this condition. Furthermore, the receptor specificity of many of these agents has been focused such that terfenadine, astemizole, loratadine and cetirizine are devoid of anticholinergic activity and exhibit little alpha-antagonistic or anti-serotonin activity of clinical relevance. However, of these agents both loratadine and cetirizine possess additional actions likely to be of relevance to asthma. Pretreatment with loratadine has been shown to reduce the recovery of both histamine and prostaglandin D2 (PGD2) in nasal lavage fluid following nasal allergen challenge, a finding interpreted as indicative of in vivo mast cell stabilization, and cetirizine has been shown in vivo at therapeutic doses to inhibit allergen-induced eosinophil chemotaxis. Thus while both these agents offer the potential of an oral therapy for asthma based on an H1-receptor antagonist, their additional actions do not make them ideally suited to the exploration of the role of histamine in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)