A Method for Evaluating Anti-Allergic Drugs by Simultaneously Induced Passive Cutaneous Anaphylaxis and Mediator Cutaneous Reactions

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ABSTRACT-Effects of R[+]-8-{[1-[3,4-dimethoxyphenyl]-2-hydroxyethyl]amino}-3,7-dihydro-7-[2 methoxyethyl]-1,3-dimethyl-lH-purine-2,6-dione (MKS-492), a reported type III isozyme inhibitor of cyclic nucleotide phosphodiesterase, on antigen or platelet activating factor (PAF)-induced bronchoconstriction and allergic reactions in guinea pigs and rats were investigated. 1) MKS-492 inhibited antigen-induced bron choconstriction in guinea pigs. Aminophylline also inhibited the reaction. 2) MKS-492 inhibited PAF-in duced bronchoconstriction and inhibited the increase in airway responsiveness to histamine in guinea pigs, although aminophylline failed to affect these reactions. 3) MKS-492 relaxed guinea pig tracheal muscle in vitro more potently than aminophylline. 4) MKS-492 inhibited leukotriene B4 (LTB4)-induced airway eosinophilia in guinea pigs. 5) MKS-492 inhibited passive cutaneous anaphylaxis and mediator-induced skin reactions in rats more potently than aminophylline. Both drugs inhibited antigen and phospholipase A2 induced histamine release from guinea pig lung tissue. 6) MKS-492 inhibited PAF-induced 02 generation from guinea pig alveolar macrophages. These results indicate that MKS-492 is a more potent inhibitor of allergic bronchoconstriction and PAF or LTB4-induced inflammatory reactions in guinea pigs and the allergic cutaneous reactions in rats when compared to aminophylline.

“…PCA and cutaneous reactions caused by allergic chemi cal mediators were examined at the same time in the same rats (31). As allergic mediators, histamine, 5-HT and LTC4 were used.…”

Section: Pca and Cutaneous Reactionsmentioning

confidence: 99%

Effects of MKS-492 on Antigen-Induced Bronchoconstriction and Allergic Reaction in Guinea Pigs and Rats

Nagai

Sakurai

Iwama

et al. 1993

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“…PCA is one of the most important in vivo models of immediate hypersen sitivity in allergic cutaneous reactions. Rat or guinea pig dorsal skin and mouse ear are useful sites for studying PCA (11,13). Experimental allergic rhinitis has usually been induced by intranasal application of antigen in sensi tized animals, resulting in an increased nasal vascular permeability and intranasal resistance (16,20,21).…”

Section: Discussionmentioning

confidence: 99%

“…Mediator or mediator releaser-induced cutaneous reac tions in rats This experiment was carried out according to the previ ously described method (11,12). Briefly, male Wistar rats were injected intradermally into the shaved back with 0.1 ml of histamine (dihydrochloride, 20 ug/ml; Nacalai Tesque), 5-HT (creatinine sulfate, 0.5 pg/ml; Sigma), compound 48/80 (0.5 ug/ml, Sigma) or calcium iono phore A23187 (A23187, 50 ug/ml; Sigma).…”

Section: Antigensmentioning

confidence: 99%

Antiallergic Effects of ZCR-2060: Effect on Allergic Cutaneous Reactions and Rhinitis Models in Mice and Rats

Omata

Yoshida

et al. 1994

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ABSTRACT-The antiallergic action of 2-[2-[4-(diphenylmethyl)-1-piperadinyl]ethoxy]benzoic acid maleate (ZCR-2060) was investigated on allergic cutaneous reactions and nasal vascular permeability in mice and rats. ZCR-2060 markedly inhibited immediate allergic cutaneous reactions, including passive cutaneous anaphylaxis (PCA) in rats and mice; histamine-, compound 48/80 and calcium ionophore A 23187-induced cutaneous reactions in rats; and biphasic skin reactions mediated by monoclonal IgE anti body and epicutaneous challenge with antigen in mice, but did not affect 5-hydroxytryptamine-induced cutaneous reaction in rats. The antigen-induced nasal vascular permeability increase in actively and passive ly sensitized rats and histamine-induced nasal vascular permeability increase in rats (allergic rhinitis model) were clearly inhibited in a dose-dependent fashion by ZCR-2060. Moreover, ZCR-2060 significantly inhib ited antigen-induced anaphylactic histamine release from rat peritoneal mast cells and carrageenin-induced paw edema in rats. These results suggest that ZCR-2060 has antiallergic effects on allergic cutaneous reac tions and experimental rhinitis, probably due to histamine H,-receptor blockage and the inhibition of histamine release.

“…PCA and cutaneous reactions PCA and cutaneous reactions caused by allergic chem ical mediators were examined at the same time in the same rats (17,22). As allergic chemical mediators, his tamine (dihydrochloride, Nacalai Tesque, Kyoto, Japan), serotonin (creatinine sulfate, Merck, NJ, USA) and leukotriene C4 (LTC4; Wako, Osaka, Japan) were used.…”

Section: Antigen and Antiserummentioning

confidence: 99%

Mechanisms for Glucocorticoid Inhibition of Immediate Hypersensitivity Reactions in Rats

Miura

Inagaki

Yoshida

et al. 1992

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ABSTRACT-The inhibitory mechanisms of immediate hypersensitivity reactions by glucocorticoid (GC) were studied in rats. Homologous passive cutaneous anaphylaxis (PCA) mediated by IgE anti bodies and cutaneous reactions caused by histamine, serotonin and leukotriene C4 were elicited at the same time in the same rats. Three kinds of GC, hydrocortisone, prednisolone and dexamethasone, in hibited all these reactions significantly. Although mediator-induced cutaneous reactions were inhibited transiently around 2 hours after GC administration, inhibition of PCA was more potent and lasted long er. A time lag seemed to be essential for both inhibitions. IgE antibody-mediated histamine release in vivo in the rat peritoneal cavity was also inhibited by GC administration significantly, and the inhibition was long lasting when compared to those of the mediator-induced cutaneous reactions. Tyrosine amino transferase (TAT) activity in the rat liver increased significantly by GC administration, and the in creased TAT activity was completely abrogated by simultaneous administration of 5 mg/kg of cyclohex imide (CH). In the same experimental condition, although inhibition of histamine-induced cutaneous reaction by GC was completely abrogated, the inhibition of PCA elicited at the same time in the same rats was only partially attenuated. Furthermore, the same dose of CH little affected the dexamethasone inhibition of histamine release in the rat peritoneal cavity, although the increase of TAT activity in the liver of the same rats was completely abrogated. These results demonstrate that PCA is inhibited by GC through at least 2 mechanisms, inhibition of mediator release from mast cells and non-specific in hibition of vascular permeability increase caused by released mediators. Although the latter action of GC is dependent upon protein synthesis, the former seems to be mediated by a unique mechanism in dependent of protein synthesis.