It is generally accepted that histamine is released in vivo when actively or passively sensitized fragments of lung, tracheobronchial strips, nasal polyps, or basophils are challenged with the appropriate allergen. In vivo, the blood level of histamine is increased during spontaneous or allergen-induced attacks of asthma. Moreover, at least in vivo, the asthmatic bronchi are hyperreactive to exogenous histamine, and thus, most likely to endogenous histamine as well. Yet, as repeatedly shown, the Hi blockers are ineffective in this disease. The negative reports with Hi blockers in asthma are surprising for two main reasons. First of all, the immediate response to skin tests or the symptoms of hay fever or urticaria, many times due to an IgE mediated reaction, are decreased by Hi blockers. Secondly, in the animal species in which histamine is an important mediator of anaphylaxis, experimental “asthma” can be decreased or prevented by pretreatment with appropriate doses of classic antihistamines.
One may explain the lack of activity of Hi blockers in (allergic) asthma by the overriding activity of chemical mediators other than histamine or the use of these competitive antagonists in insufficiently large doses. A review of the pertinent literature has disclosed that in the isolated studies claiming a beneficial effect of Hi blockers in asthma, especially in the prevention of allergen-induced asthma, large doses of these drugs had been given either intravenously or by inhalation. Read article: “Avoid Your Asthma & Allergy Triggers during Seasonal Changes“.
In a recent controlled study, chlorpheniramine maleate in a dose of 10 mg, intravenously, was shown to have mild bronchodilating effect in those asthmatic subjects with a moderate decrease in the ratio of forced expiratory volume in 1 sec/forced vital capacity (FEVi/FVC). Subsequently, other controlled studies confirmed that large aerosolized doses of chlorpheniramine or of another Hi blocker, clemastine, are able to dilate the bronchi.
The purpose of this study was to test the hypothesis that an Hi blocker, used in appropriate doses, could prevent allergen-induced asthma. In preliminary experiments, we have found that 10 mg chlorpheniramine, administered intravenously, would increase the tolerance to inhaled histamine two to four times, depending on the endpoint used, — A FEVi > 20 percent or —A > 10 percent respectively. As histamine is only one of the chemical mediators of anaphylaxis, we reasoned that in studying the effect of Hi blockers in antigen-induced asthma, we should resort to mild attacks of asthma, otherwise higher, potentially toxic intravenous doses of chlorpheniramine would have to be administered Moreover, we thought that the design of our study should fulfill other requirements as well: physiologically, the bronchoconstrictor agents should be nebulized in quantitative fashion; only airway responses of similar magnitude, reproducible, and obtained at comparable baseline levels, should be used in the study. Pharmacologically, the agents used to modulate the bronchoconstrictor responses should not dilate the bronchi; the effect of Hi blockers or any other modulating agents in drug or allergen-induced asthma should be expressed as a dose-ratio because this ratio allows a uniform, standardized assessment of the effect of the same agent against various types of bronchoconstrictor responses or of different agents with similar pharmacologic properties against the same bronchoconstrictor response.
For this study, we choose chlorpheniramine as the Hi blocker because milligram per milligram, it has less central, and possibly less anticholinergic, activity than diphenhydramine, the only other classic antihistamine available for intravenous use in the United States.