Introduction: Certain novel H₁-receptor antagonists, such as tecastemizole, have been reported to exert anti-allergic activity that is independent of histamine receptor antagonism (Hefni, A. et al., 2002). In the present study, we have investigated the effects of tecastemizole on cutaneous responses, including passive cutaneous anaphylaxis (PCA) in the guinea pig.

Method: Male guinea pigs (Harlan, 350-450g) were shaved and sensitised by 0.1 ml intradermal (i.d.) injections of (10^-2 dilution) guinea pig anti-ovalbumin (OVA) serum. 24 h later, the animals (n=5 per group) were injected i.p. with vehicle (1% DMSO) or tecastemizole (0.1 or 1 mg kg^-1). 1 h later, animals were anaesthetised with urethane (1.5 g kg^-1) and Evans blue dye was injected via a foot vein. OVA (0.1 or 1 µg) was administered i.d. into the serum-pretreated sites and saline (control), histamine (0.3 or 0.6 µg) or bradykinin (1 µg) were administered i.d. into the remaining sites. 30 min later, the guinea pigs were killed by an overdose of urethane and the responses assessed from the diameter (mm) and intensity (grade 1-5) of the extravasated dye. Finally, the tracheas were removed and isometric contractile responses to histamine (10^-9 - 10^-3 M) were measured ex vivo. Results are expressed as mean ± S.E.M. and data were analysed by one-way ANOVA.

Results: Data for cutaneous responses to histamine were expressed as diameter x intensity. Histamine (0.3, 0.6 µg) responses (70 ± 16, 60 ± 10 respectively, in vehicle treated animals) were inhibited by tecastemizole 0.1 mg kg^-1 (35 ± 7, 46 ± 7; P<0.05) and tecastemizole 1 mg kg^-1 (19 ± 4, 24 ± 3; P<0.05).

Although tecastemizole (1 mg kg^-1) reduced the PCA response to the lower dose of OVA (0.1 µg) (16 ± 3 compared to 42 ± 13 vehicle treated animals) this reduction was not statistically significant. Tecastemizole had no effect on the higher dose of OVA (1 µg) or bradykinin (1 µg) induced responses. In the ex vivo tracheal preparations from pre-treated animals, histamine induced contractions (expressed as % the response to methacholine (1 µM)) were significantly reduced in those obtained from tecastemizole treated animals (At the maximum histamine dose (10-3 M), control: 93.6 ± 4.3, tecastemizole 0.1 mg kg^-1: 62.4 ± 7.3 and tecastemizole 1 mg kg^-1: 26.7 ± 11, P < 0.05).

Conclusion: Injection of antigen into the sensitised sites resulted in pronounced plasma leakage. The relative ineffectiveness of tecastemizole to inhibit PCA responses was not due to poor drug availability, since tecastemizole significantly inhibited histamine responses in the skin and in the ex vivo tracheal preparations. It is well established that histamine contributes to the PCA response (Woodward et al., 1985). Although other mediators are known to be involved (Weg et al., 1991), the present data do not, so far, indicate H1-independent anti-allergic effects of tecastemizole in guinea pig PCA responses.

Hefni, A. et al., 2002. Am J Resp Crit Care 165, A819.
Weg, V.B. et al., 1991. Eur J Pharmacol 204, 157-163.
Woodward, D.F. et al., 1985. Agents Actions 27, 121.

This abstract is funded by : Sepracor Inc.