The influence of betahistine on the dynamics of the cutaneous hypersensitivity reaction in patients with grass pollen allergy.

Histamine has been well documented as an immune modulator, but the dynamics of a number of histamine receptor agonists and antagonists have not been similarly established. The aim of this study was to determine the effect of betahistine (an H3-receptor blocker with partial H1- and H2-agonism) on the dynamics of the cutaneous hypersensitivity reaction. The skin blister technique was used to collect inflammatory cells after intradermal (i.d.) administration of grass pollen antigen, histamine and betahistine to 11 atopic volunteers. In this open, cross-over study, volunteers were randomly allocated to five treatment protocols i.e. (a) histamine 1 microgram i.d.; (b) betahistine 57, 114 and 285 micrograms i.d.; (c) i.d. grass pollen antigen; (d) (c) plus oral betahistine; (e) (c) plus oral betahistine, cetirizine, (H1-blocker) and cimetidine (H2-blocker). Blister fluid containing cells were collected on microscope slides at 6 and 24 h after i.d. injections. The areas of the wheal and flare and of induration were measured, respectively, at 0.25, and, 1, 6 and 24 h. Combined oral therapy with cetirizine, cimetidine and betahistine reduced the area of grass pollen-induced induration significantly at all time periods, but caused a significant increase in eosinophil and neutrophil vacuolisation during the late phase reaction. This did not occur with orally administered betahistine alone. Intradermal betahistine induced significantly more neutrophil and eosinophil vacuolization than histamine and, in contrast to the latter, also mediated a concentration-dependent late phase induration. The results of this study suggest that the H3-receptor regulates a feedback system in conjunction with that previously proven for the H2-receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of histamine receptor antagonists on the dynamics of the cutaneous hypersensitivity reaction in patients infected with schistosoma haematobium.

The biphasic cutaneous hypersensitivity response elicited by intradermal administration of S. haematobium antigen to patients with schistosomiasis may be used as a model for drug effects on cell dynamics. As the effects of H1- and H2-blockade, and the possible involvement of H3-receptors, have not been elucidated, we have examined the effects of combinations of cetirizine, cimetidine and betahistine on the response of patients with confirmed schistosomiasis. The skin blister technique was used. After intradermal administration of antigen, blister fluid containing inflammatory cells was collected on microscope slides at 6 and 24 h, and a differential cell count was done; and the area of induration was measured at 0.25, 1, 6 and 24 h. These baseline tests were repeated after 3 days of pretreatment with cetirizine 20 mg/d, after the addition of cimetidine 1200 mg/d for 3 further days, and finally after adding on betahistine 32 mg/d for 3 days. Simultaneous H1- and H2-blockade with cetirizine plus cimetidine caused a significantly greater reduction in induration than cetirizine (H1-blockade) alone; the reductions from the baseline value were 70%, 78%, 89%, 97%, and 33%, 53%, 43%, 30%, at times 0.25, 1, 6 and 24 h, respectively. The triple combination with the addition of betahistine (H1- and H2-agonist and H3-antagonist) resulted in reductions of 37%, 63%, 95% and 97% at the same times. The most striking changes in cellular dynamics were a significant increase in eosinophil (6 h) and neutrophil (6 h) vacuolation, and enhancement of monocyte (24 h) and basophil (6 h) accumulation, when the betahistine was added.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cetirizine, ketotifen and chlorpheniramine on the dynamics of the cutaneous hypersensitivity reaction: a comparative study.

Allergic cutaneous challenge causes mast cell and basophil mediator release which recruit inflammatory cells to the site of antigen administration. This secondary cell infiltration and mediator release is responsible for the changes seen during the late phase of allergic diseases. In this randomised, double-blind, cross-over, placebo controlled study, it was demonstrated that, at steady-state drug concentrations, chlorpheniramine reduced the wheal-and-flare reaction by about 50% compared to the 75% reduction, on average, by cetirizine and ketotifen. Cetirizine significantly reduced eosinophil vacuolisation at all observation periods, i.e. 2,6,10 and 24 h, and also inhibited basophil accumulation significantly at 10 h (75% reduction), while chlorpheniramine had a negligible effect on these variables. These changes would indicate that the late phase reaction was modified, especially as eosinophil vacuolisation is known to correlate with late phase intensity, T-lymphocyte infiltration and subsequent tissue damage. It further supports previous speculation that cetirizine inhibit late histamine release by acting on basophils. The extent of induration in the late phase reaction did not differ significantly among the three treatments. Cetirizine and ketotifen, noticeably although not significantly, reduced eosinophil and lymphocyte recruitment. As these two antihistamines differ structurally and in regard to receptor specificity, it is possible that they exert their actions on other, unspecified, receptors.