Antianaphylactic agents. 1. 2-(Acylamino)oxazoles

Ross, William T.; Harrison, Roger G.; Jolley, Michael R.J.; Neville, M. C.; Todd, Alec; Verge, J. P.; Dawson, W.; Sweatman, W. J. F.

doi:10.1021/jm00190a011

Cited by 40 publications

(12 citation statements)

References 5 publications

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“…In contrast to the findings of Greenwood (1982) and Ross et al (1979), who used sensitized guinea-pig and human chopped lung preparations to study the effect of ketotifen on antigen-induced histamine and SRS-A release, we failed to find any inhibition of the antigen-induced mediator release by ketotifen. Apart from differences in immunization procedures, species used and experimental conditions, much higher ketotifen concentrations (10-4 mol 1-1) were used compared to the more appropriate concentrations (500 ngml-' = 1.18 x 10-6moI 1-P) in our experiments, which may explain this discrepancy.…”

Section: Discussioncontrasting

confidence: 52%

“…Although reversal and prevention of P-adrenoceptor-mediated tachyphylaxis (Bretz et al, 1983) might be a very relevant, additional factor for the anti-asthmatic activity of ketotifen in the clinical situation, it does not play a role in our present experiments. Taking into account the fact that ketotifen is a strong histamine Hi-receptor antagonist (Martin & Romer, 1978) and also exhibits functional SRS-A antagonism in vivo (Ross et al, 1979), and the finding in our experiments that ketotifen effectively inhibited the 5-HT induced bronchoconstriction without affecting the mediator re lease, it can be assumed that the bronchoprotective effect of ketotifen is mainly based on (multiple) receptor antagonism. …”

Section: Discussionmentioning

confidence: 98%

“…With regard to the preventive effect of ketotifen in bronchial asthma, several mechanisms have been suggested (see also Craps & Ney, 1984): inhibition of the antigen-induced release of histamine (Martin & Romer, 1978;Radermecker et al, 1980) and SRS-A (Ross et al, 1979;Greenwood, 1982); SRS-A (Ney et al, 1980) but not histamine HI- (Martin & R6mer, 1978;Martin & Baggiolini, 1981) receptor-antagonism; calcium antagonism (Lowe & Richardson, 1980) and prevention or reversal of decreased P-adrenoceptor sensitivity (Bretz et al, 1983). In contrast to the findings of Greenwood (1982) and Ross et al (1979), who used sensitized guinea-pig and human chopped lung preparations to study the effect of ketotifen on antigen-induced histamine and SRS-A release, we failed to find any inhibition of the antigen-induced mediator release by ketotifen.…”

Section: Discussionmentioning

confidence: 99%

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The effect of prednisolone and ketotifen on the antigen‐induced bronchoconstriction and mediator release in rat isolated lungs

Ottenhof

Ufkes

Rooij

1985

British J Pharmacology

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1 Using a new method for inducing IgE-mediated, systemic anaphylaxis in the rat both prednisolone and ketotifen had been shown previously to be effective in suppressing the bronchial anaphylaxis in vivo. In order to study the mode of action underlying their bronchoprotective effect, both agents were. also tested on the antigen-induced bronchoconstriction in rat isolated lungs in relation to the mediator release in the lung-effluent. 2 The presence of histamine, 5-hydroxytryptamine (5-HT) and SRS-A could be detected biologically in the lung-effluent during bronchoconstriction. Histamine and 5-HT were determined quantitatively by means of h.p.l.c. with fluorimetric detection, whereas SRS-A was determined using the guinea-pig ileum in a cascade set-up. 3 Although both prednisolone and ketotifen inhibited the antigen-induced bronchoconstriction effectively, it appeared that only prednisolone suppressed the release ofhistamine, 5-HT and SRS-A in the lung-effluent significantly, whereas ketotifen had no effect. 4 On account of these data it is suggested that the bronchoprotective effect of prednisolone is mainly based on inhibition of the release of the mediators involved, whereas the effect of ketotifen may be based on receptor antagonism.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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The effect of prednisolone and ketotifen on the antigen‐induced bronchoconstriction and mediator release in rat isolated lungs

Ottenhof

Ufkes

Rooij

1985

British J Pharmacology

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“…In a compari- son of the effects of ketotifen on anaphy laxis-induced mediator release from gui nea pig and human chopped lung, Ross et al [44] found that, whilst ketotifen inhibits leukotriene release in both species, its ac tivity in human lung is greater. Histamine release is also moderately inhibited in gui nea pig lung, but to a lesser extent in hu man lung.…”

Section: Mediator Releasementioning

confidence: 99%

Ketotifen: Current Views on Its Mechanism of Action and Their Therapeutic Implications

Craps

Ney²

1984

Respiration

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The mechanism of action of ketotifen in the prevention of bronchial asthma is discussed, the pathogenesis of the disease itself being taken as a starting point. The following biological effects of ketotifen may be relevant to its therapeutic activity: the inhibition of release of myotonic mediators, leukotrienes in particular, the inhibition of slow reactin ubstances-induced bronchoconstriction in vivo, calcium antagonistic properties, and the prevention or reversal of decreased β-adrenoceptor sensitivity. In asthmatic patients the prevention of bronchospasm due to mediator release and a progressive reduction of

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“…Both are H, an tihistamines and have been shown to pre vent antigen-mediated histamine release in a variety of animal experimental models Roemer, 1977, 1978;Awouters et al, 1977;Borgers et al, 1978]. Evidence for their antianaphylactic action on isolated human tissues is, however, sparse [Kumagai and Tomioka, 1978;Ross et al, 1979] or, in the case of oxatomide, lacking. The aim of the present study is to examine, on hu man cells and tissue (leukocytes and pas sively sensitized chopped lung), the ability of these new antiallergic drugs to inhibit an tigen-mediated histamine release.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Allergen-Mediated Histamine Release from Human Cells by Ketotifen and Oxatomide

Radermecker¹

1981

Respiration

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We have studied the ability of four H₁ antihistamines, ketotifen, oxatomide, clemastine and promethazine, and of disodium cromoglycate (DSCG) to inhibit in vitro histamine release mediated by antigen from passively sensitized human lung and from basophilic leukocytes. Anaphylactic histamine release from human leukocytes is inhibited in a comparable fashion by oxatomide, clemastine and promethazine at concentrations just below those inducing histamine release in the absence of antigen. Ketotifen causes a significantly weaker inhibition without inducing histamine release and DSCG is not at all active in this model. On human lung, oxatomide, clemastine and promethazine give a strong and similar inhibition which is linearly related to the dose. Ketotifen markedly differs in this respect, inhibiting according to a bell-shaped dose-response curve and at concentrations closely comparable to that of DSCG. Thus, we confirm that H₁ blockers, such as clemastine and promethazine, inhibit anaphylactic histamine release from baso-phils and human lung but only at high concentrations which may be cytoioxic. Oxatomide behaves very much like these antihistamines. Ketotifen, on the other hand, gives in both models a different pattern of inhibition, closely mimicking that of DSCG. This suggests that the antianaphylactic activity of ketotifen is not related to its H₁ blocker properties and that this effect may be relevant to its therapeutic activity

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Antianaphylactic agents. 1. 2-(Acylamino)oxazoles

Cited by 40 publications

References 5 publications

The effect of prednisolone and ketotifen on the antigen‐induced bronchoconstriction and mediator release in rat isolated lungs

The effect of prednisolone and ketotifen on the antigen‐induced bronchoconstriction and mediator release in rat isolated lungs

Ketotifen: Current Views on Its Mechanism of Action and Their Therapeutic Implications

Inhibition of Allergen-Mediated Histamine Release from Human Cells by Ketotifen and Oxatomide

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