Comparative effects of a glucocorticosteroid, theophylline and the peptido-leukotriene-antagonist CGP 45715A on antigen-induced early and late phase airway response and inflammatory cell influx in sensitised guinea pigs.
A novel model of allergic early and late-phase reaction in the airways of conscious guinea pigs was developed and the effect of established and novel antiasthmatic drugs on peak of immediate response, late phase response and associated inflammatory cell influx investigated. Guinea pigs were sensitised twice in adjuvant (50 mg/kg silica + 0.1 ml/kg Bordetella pertussis). Under cover of 10 mg/kg i.p. mepyramine guinea pigs exhibited still a pronounced immediate reaction. During a screening phase about 75% of guinea pigs demonstrated a late phase reaction of decrease of tidal volume between 4-10 h after ovalbumin inhalation. In a cross over study theophylline at 50 mg/kg p.o. (-1 h before ovalbumin) tended to attenuate not only the peak of the immediate reaction by about 69% (P>0.05, n = 12), but inhibited the airway late phase response significantly (P<0.05, 5-10 h, n = 12). Methylprednisolone (40 mg/kg p.o. 1 h before ovalbumin) did not inhibit the immediate response, but the late phase response. In contrast the cysteinyl-leukotriene antagonist CGP 45715A (Iralukast; 30 mg/kg p.o. 2 h before ovalbumin) neither interfered with the peak of the immediate, nor with the late phase response. When bronchoalveolar lavage by orotracheal route was performed 24 h after ovalbumin inhalation, total cell count, eosinophils, neutrophils, macrophages and lymphocytes were significantly increased in ovalbumin-controls compared to sham (n = 5; P<0.05). Methylprednisolone reduced significantly the antigen-induced increase of total cell count and eosinophil number. Neither theophylline nor the cysteinyl-leukotriene receptor antagonist attenuated the antigen-associated cell influx. The results do not provide evidence for a major role of cysteinyl-leukotrienes in the late phase response and inflammatory cell influx in this model.
Heuer
H O
HO
Department of Pharmacology, Boehringer Ingelheim Pharma KG, Ingelheim/Rhein, Germany. hubert.heuer@hmrag.com
Leon
I
I
Anderson
G P
GP
Jennewein
H M
HM
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001985:Bronchial Provocation Tests / Q000379:methods; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D018592:Cross-Over Studies; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D015289:Leukotrienes / Q000494:pharmacology*; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology*; D013997:Time Factors
D001578:Benzopyrans; D001993:Bronchodilator Agents; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D013806:Theophylline; C067425:iralukast; D008775:Methylprednisolone