期刊
ALLERGY
卷 55, 期 -, 页码 17-27出版社
MUNKSGAARD INT PUBL LTD
DOI: 10.1034/j.1398-9995.2000.00803.x
关键词
allergic diseases; azatadine; cetirizine; H-1-receptor antagonists; loratadine; mizolastine; terfenadine
资金
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI045583] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS [R01DC002714] Funding Source: NIH RePORTER
- NIAID NIH HHS [AI45583] Funding Source: Medline
- NIDCD NIH HHS [DC 02714] Funding Source: Medline
The primary mechanism of antihistamine action in the treatment of allergic diseases is believed to be competitive antagonism of histamine binding to cellular receptors (specifically, the H-1-receptors), which are present on nerve endings, smooth muscles, and glandular cells. This notion is supported by the fact that structurally unrelated drugs antagonize the H-1-receptor and provide clinical benefit. However, H-1-receptor antagonism may not be their sole mechanism of action in treating allergic rhinitis. On the basis of in vitro and animal experiments, drugs classified as H-1-receptor antagonists have long been recognized to have additional pharmacological properties. Most first-generation H-1-antihistamines have anticholinergic, sedative, local anaesthetic, and anti-5-HT effects, which might favourably affect the symptoms of the allergic response but also contribute to side-effects. These additional properties are not uniformly distributed among drugs classified as H-1-receptor antagonists. Azatadine, for example, inhibits in vitro IgE-mediated histamine and leukotriene (LT) release from mast cells and basophils. In human challenge models, terfenadine, azatadine, and loratadine reduce IgE-mediated histamine release. Cetirizine reduces eosinophilic infiltration at the site of antigen challenge in the skin, but not the nose. In a nasal antigen challenge model, cetirizine pretreatment did not affect the levels of histamine and prostaglandin D-2 recovered in postchallenge lavages, whereas the levels of albumin, N-tosyl-L-arginine methyl ester (TAME) esterase activity, and LTs were reduced. Terfenadine, cetirizine, and loratadine blocked allergen-induced hyperresponsiveness to methacholine. In view of the complexity of the pathophysiology of allergy, a number of H-1 antagonists with additional properties are currently under development for allergic diseases. Mizolastine, a new H-1-receptor antagonist, has been shown to have additional actions that should help reduce the allergic response. In animal models, mizolastine inhibits antigen-induced eosinophil infiltration into mouse skin and into the nasal cavity of guineapigs. Mizolastine also significantly inhibits antigen-induced neutrophil infiltration into the bronchoalveolar lavage fluids of guinea-pigs. In addition, it inhibits arachidonic acid-induced paw oedema in rats without affecting carrageenin-induced rat paw oedema, suggesting an effect on LT generation. In man, mizolastine inhibits early and late antigen-induced soluble intercellular adhesion molecule 1 (ICAM-1) levels in skin blisters. It also inhibits anaphylactic release of histamine from rodent mast cells, LTC4 and LTB4 release from mouse bone-marrow-derived mast cells, LTC4 release from rat intestinal mast cells, and 5-lipoxygenase activity of polymorphonuclear neutrophils of guinea-pig intestines and rat basophilic leukaemia cells. It is clear that a number of H-1-antihistamines have multiple effects on the allergic inflammatory response. It is equally clear that these antiallergic effects are not uniformly shared among all drugs of this class. The assessment of the clinical significance of these results and research regarding the parts of the molecules responsible for these activities are underway.
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