1 A series of cationic, lipophilic histamine H1-receptor antagonists, neuroleptics, antidepressants and monoamine oxidase inhibitors were tested for their effects on anti-IgE-induced histamine release from human lung fragments in vitro. 2 They had a biphasic effect: at low concentrations a dose-related inhibition of histamine release was observed whereas, at higher concentrations, the drugs liberated histamine even in the absence of antigen. 3 Mepyramine, a much less lipophilic drug than the others tested, was only weakly active on mast cells at pharmacological concentrations. 4 The potency of the drugs as release inhibitors was not related quantitatively to their histamine liberating potency. 5 There was no; correlation between activity on mast cells and histamine H1-receptor antagonism. 6 Mast cell stabilization may play a part in the activity of these drugs as anti-allergic agents.

Inhibition of histamine release from human lung in vitro by antihistamines and related drugs.

The definition of a role of any chemical mediator in a disease is reliant on the proof of three separate criteria. These are evidence of its generation in disease., reproduction of the symptoms ofthe disease by administration of exogenous mediator, and inhibition by specific mediator antagonists of the effects of the disease. With histamine, the first of these criteria to be addressed was the symptoms produced by administration of exogenous mediator. Implication of histamine as a mediator of asthma stemmed from tbe report by Dale and Laidlaw in 1919 [I] that intravenous infusion of histamine could reproduce the effects of systemic anaphylaxis, including bronchospasm, in the guinea-pig. This was soon supported by the studies of Weiss c/a/, in man, that infusion of histamine caused wheezing and symptoms of rhinitis [2,3]. Indeed, histamine-induced bronchospasm is now used routinely to quantify airways hyperresponsiveness in asthma. The demonstration of histamine release from allergen challenge of lung tissue in vitro by Schild et al. in 1951 [4] was presented as compelling evidence of release in allergic disease in man. However, it was almost 30 years before histamine assays were developed with sufficient sensitivity to detect histamine release in vivo. Under experimental conditions, elevations in plasma histamine levels have been demonstrated after early and late antigen-induced asthmatic reactions [5,6], exercise-induced astbma [7,8], waterinduced asthma [9] and following aspirin challenge in aspirin-sensitive asthmatics [10], but not after isocapnic hyperventilation [II]. Furthermore, several studies have demonstrated elevated baseline plasma histamine in stable asthma [12,13], the level of which may relate to the severity of the airways obstruction [14]. These data are consistent with the long recognized bronchodilator action of Hj-antihistamines [15], suggesting the presence of a background 'histamine tone' possibly due to a continuous release of histamine by activated mast cells or basophils.

The pharmacology and mechanisms of action of histamine H1-antagonists.

Ketotifen, a benzocycloheptathiophene, possesses asthma-prophylactic and antiallergic activities in a number of in vitro and in vivo systems: prevention of cutaneous and lung anaphylaxis in the rat and guinea pig; inhibition of dermal and bronchial antigen challenges in man; inhibition of mediator release from rat mast cells, human basophils, human neutrophils, and human and guinea pig chopped lung; reduction of human neutrophil activation induced by PAF-acether; functional antagonism of mediator effects in the guinea pig; blockade of H1-receptors and prevention and reversal of beta-adrenergic tachyphylaxis in the rat. These properties make ketotifen suitable for the long-term prophylaxis of bronchial asthma and for the prevention and treatment of other allergic disorders, such as allergic rhinitis and conjunctivitis, food allergy, and urticaria. Oral ketotifen (1 mg twice daily) is particularly convenient in the management of the multiple allergies often encountered in patients with atopy.

https://www.jacionline.org/article/0091-6749(85)90659-1/pdf

Immunologic and therapeutic aspects of ketotifen

The inhibition of immediate allergen or histamine induced airflow obstruction by inhaled ketotifen, clemastine, sodium cromoglycate, and placebo was studied in two groups of asthmatic subjects. Single doses of ketotifen (0.5 mg), clemastine (0.5 mg), sodium cromoglycate (20 mg), or placebo were administered by inhalation 45 minutes before bronchial provocation testing at weekly intervals, double blind and in random order. Inhalation of ketotifen and clemastine, but not sodium cromoglycate, caused an increase in the amount of histamine which had to be administered to cause a 20% fall in FEV1 from control levels (PD20-FEV1) compared with placebo. The PD20-FEV1 for allergen increased significantly after inhalation of clemastine and sodium cromoglycate. Clemastine, primarily an H1 receptor antagonist, inhibited airflow obstruction after inhalation of both histamine and allergen. Its inhibitory effect on allergen induced asthma did not differ significantly from that of sodium cromoglycate. Ketotifen, when inhaled in a single dose of 0.5 mg before bronchial provocation testing, showed potent antihistamine activity, but there was no evidence of any additional "antianaphylactic" activity.

https://thorax.bmj.com/content/thoraxjnl/39/5/345.full.pdf

Effect of antihistamines and antiallergic drugs on responses to allergen and histamine provocation tests in asthma.

One hundred thirty-eight children with chronic asthma, requiring daily treatment with bronchodilators, took part in a 7-month, double-blind, multicenter clinical study. Patients were randomized into two groups, and after a 1-month baseline, were administered Zaditen (ketotifen), 1.0 mg twice daily, or an identical placebo for a period of 6 months. After 10 weeks of receiving the study medication, bronchodilator use was reduced or stopped. In the Zaditen-treated group, 60% of the children taking theophylline were able to stop its use completely, compared to 34% of the patients taking placebo (p less than 0.05). Of the patients who were unable to stop taking theophylline, the Zaditen-and placebo-treated groups recorded average dosage reductions of 62% and 26%, respectively. These differences were statistically significant (p less than 0.05). Thus, a high percentage of patients in the placebo-treated group maintained asthma symptom control with theophylline, whereas most of the Zaditen-treated patients could stop using this medication. Although pulmonary function readings improved in both groups, those patients taking Zaditen demonstrated earlier improvement and greater changes from baseline. Significant differences (p less than 0.05) in favor of Zaditen were found for reduction of concomitant medications, patient's global evaluation, physician's clinical evaluations, incidence of emergency room visits for asthma, and upper respiratory tract infections. No unexpected side effects were observed. It is concluded that Zaditen is an effective medication for long-term control of asthma in children.

https://www.jacionline.org/article/0091-6749(89)90410-7/pdf

A Canadian multicenter study with Zaditen (ketotifen) in the treatment of bronchial asthma in children aged 5 to 17 years

A clinical trial was performed with a new substance (HC 20-511) derived from the cycloheptothiophene group used in the management of asthma. Twenty-four asthma patients were treated at random, with HC 20-511 or placebo or the antihistaminic substance, clemastin (Tavegyl). A statistical evaluation of the results unequivocally demonstrates good protection with a single dose of 2.0 mg or two times 1.0 mg for 3 days against a challenging antigen, compared with the placebo or the antihistaminic agent. Tolerance was excellent.

Anti-asthmatic properties of a new peroral drug (hc 20–511.)

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Anti-asthmatic properties of a new peroral drug (hc 20–511.)