Inhibition of Mediator Actions

Delineation of the role of a specific mediator in the bronchomotor response to a proinflammatory stimulus is usually obtained by the ability of a specific receptor antagonist to block the response. This process of identification is dependent on the antagonist's being applied in doses sufficient to block the receptor for the endogenously released mediator and selective for the receptor of the mediator at the applied doses. Specific antagonists have been developed or are currently being developed for many of the inflammatory cell-derived mediators possessing bronchoconstrictor or proinflammatory activity.

Histamine Antagonists. The first mediator to be implicated in the pathogenesis of asthma was histamine. Bronchoconstriction induced by histamine is inhibited by histamine H1-receptor antagonists, or so-called classical antihistamines. Drugs of this group include clemastine, chlorpheniramine, asternizole, and terfenadine. In general, antihistamines are administered orally for the treatment of a variety of allergic disease. However, aerosolized clemastine has been shown to cause bronchodilation in asthmatic subjects [71] and to inhibit antigen-induced bronchoconstriction [72]. Interestingly, the aerosol route of administration of the antihistamines appears to be more effective in eliciting bronchodilation than the oral route [73], an observation related, in part, to the limitation on oral dosage caused by the sedative actions of these drugs. The newer, nonsedating antihistamines (e.g., astemizole, cetirizine, loratadine), while effective in treating some allergic conditions, have proven to be of little benefit in the treatment of asthma when given orally [74]. No studies have been undertaken in which these agents were applied directly to the airways by inhalation.

Leukotriene Antagonists. The leukotrienes are metabolites of arachidonic acid generated de novo after inflammatory cell activation [69,75] and are potent bronchoconstrictors and proinflammatory agents (vide supra). The biological effects of the cysteinyl-leukotrienes (viz. C4, D4, and E4) and of leukotriene B4 are mediated via cysLTj and BLT receptors, respectively [69,76]. The development of potent, selective cysLT receptor antagonists, such as montelukast, pranlukast, and zafirlukast, have permitted a clearer understanding of the contribution of the cysteinyl leukotrienes to asthma. The efficacy of these drugs in relieving asthmatic bronchoconstriction is significant (indicating a role of cysteinyl leukotrienes in asthmatic airway obstruction) but inferior to inhaled b2-adrenoceptor agonists or inhaled corticosteroids [69,76]. As a result, they are often used in combination with other therapies [77]. These drugs are administered orally and exhibit relatively innocuous side effects [69]. This, together with their demonstrated clinical efficacy when administered orally, provides little impetus for the development of an inhalation formulation.

Platelet-Activating Factor Antagonists. Platelet-activating factor (PAF) is generated by a variety of inflammatory cells from membrane phospholipids under the actions of phospholiphase A2 and acetyl CoA-dependent acetyltransferase [78,79]. Interest in PAF was aroused by the observation that PAF administration mimicked many features characteristic of asthma, including bronchoconstriction, lung inflammation, and airways hyperreponsiveness [79]. The poor clinical efficacy of PAF antagonists, such as apafant (WEB2086) and foropafant (SR27417A), in preventing the symptoms of asthma [80,81] argues against a role for PAF in this disease and makes it unlikely that these agents will be developed for lung delivery.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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