1 The effect of ketotifen was compared with that of clemastine and chlorpheniramine, known antihistamines, and sodium cromoglycate, a drug considered to have mast cell 'stabilizing' properties on histamine and allergen wealing reactions in human skin, in random order, double-blind, placebo controlled studies. 2 Ketotifen was significantly more potent in the inhibition of both histamine (P < 0.001) and allergen (P < 0.001) skin wealing reactions than either clemastine or chlorpheniramine. Sodium cromoglycate had no significant effect on either histamine or allergen skin wealing reactions in any of the concentrations tested. 3 However ketotifen, like clemastine, had a significantly greater inhibitory effect on histamine than on allergen induced weals (P < 0.001) and both drugs were shown to act as competitive antagonists of histamine. 4 Ketotifen has been shown to be a potent anti-histamine but there is no evidence from these in vivo studies to suggest that it has any additional inhibitory activity on release of mediators from mast cells in human skin.

Arterial plasma histamine concentrations were measured after exercise in 10 subjects with extrinsic atopic asthma, 10 who were non-atopic and non-asthmatic and seven who were atopic but non-asthmatic, by a single isotope radioenzymatic assay. Significantly higher plasma histamine concentrations were found in the asthmatic subjects before exercise than in the nonatopic controls (p < 0-05). The mean histamine concentration rose after exercise in all groups but the increased levels were not significantly different from pre-exercise values. Similarly, mean circulating basophil counts increased in all groups after exercise, and a highly significant correlation was found between basophil counts and whole blood histamine concentrations (p < 0.001). In vitro studies showed that there was a significant correlation between the number of basophils added to plasma samples and the concentrations of histamine subsequently detected. Although the mean concentrations of plasma histamine and whole blood histamine and number of basophils in the atopic control group were intermediate between those found in the atopic asthmatic and non-atopic controls, none of the differences was significant. Venous plasma histamine concentrations after exercise were measured in a further five subjects with extrinsic atopic asthma and five non-atopic, non-asthmatic subjects before and after exercise with the more sensitive and specific double isotope radioenzymatic assay. Concentrations of plasma histamine measured by this assay were about one tenth of those measured by the single isotope radioenzymatic assay. Although a small rise in mean plasma histamine concentration occurred in both groups after exercise there was no significant difference in these levels either between or within the groups. We find no evidence from these studies on measurement of peripheral blood histamine to support the hypothesis that mast cell mediator release is implicated in the pathogenesis of exercise induced asthma.Exercise induced asthma is a phenomenon which can be demonstrated in varying proportions of patients with both extrinsic atopic asthma and cryptogenic non-atopic asthma.' Several observations suggest that mast cells and their mediators may play a part in the pathogenesis. A short refractory period occurs after an episode of exercise induced asthma, during which exercise can no longer lead to airflow obstruction, suggesting the possibility of depletion of mediator stores from mast cells.2 Sodium cromoglycate, a drug thought to act by stabilising

Antisera to the IgG subclasses, 1, 2a, 2b, and 2c, induced histamine release from mast cells obtained from the peritoneal washings of Lister hooded rats. The maximum responses obtained with anti-IgG1 and anti-IgG2a were as great as that for anti-IgE (more than 60% histamine release). Cells from unresponsive Wistar rats which did not secrete appreciable amounts of histamine in response to any of the antisera, produced on active sensitization with ovalbumin a small but significant response on challenge with anti-IgG1 and anti-IgG2b as well as with anti-IgE. Passive sensitization with rat myeloma serum of mast cells from the unresponsive rats produced a large response on challenge with anti-IgE but no release to the anti-IgG group 2 subclasses. IgE myeloma serum (1:1000) neutralized the histamine-releasing activity on anti-IgE serum (87% inhibition) and the antisera to all subclasses of IgG. When the IgE in the myeloma serum was inactivated by heating, the response to the IgG antisera remained completely inhibited except for anti-IgG2a where some reversal was observed. When purified myeloma IgE (30 microgram/ml) was used in place of whole serum, marked inhibition (86%) of the response to anti-IgE was obtained leaving the responses to the IgE subclasses unaffected (except for IgG2a, which was 65% inhibited).

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