New orally effective chromone derivatives for the treatment of asthma

Augstein, J.; Cairns, Hugh; Hunter, Deborah J.; Lee, T. B.; Suschitzky, John L.; Altounyan, R. E. C.; Jackson, D.M.; Mann, J. S.; Orr, T. S. C.; Sheard, Philip W.

doi:10.1007/bf01966850

Cited by 43 publications

(18 citation statements)

References 8 publications

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“…The initial hypothesis that inhibition of immunologically induced histamine release from human lung fragments in vitro may provide a better predictive model of drug activity in asthma than animal models has proved false. In the clinic, AH 7725, tixanox, ICI 74917 and doxantrazole are at best of comparable efficacy to sodium cromoglycate in bronchial provocation tests, but appear to be inferior in the treatment of asthma (Assem, Evans & McAllen, 1974;Brogden et al, 1974;Poppius & Stenius, 1977 (Augstein et al, 1977;Ellul-Micallef & French, 1979). Clinical information is not yet available for M&B 22948 and RU 31156.…”

Section: Methodsmentioning

confidence: 99%

THE ACTIVITY OF SODIUM CROMOGLYCATE ANALOGUES IN HUMAN LUNG in vitro: A COMPARISON WITH RAT PASSIVE CUTANEOUS ANAPHYLAXIS AND CLINICAL EFFICACY

Church

Gradidge

1980

British J Pharmacology

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1 Eleven analogues of sodium cromoglycate have been tested for their ability to suppress histamine release induced by anti-IgE from passively sensitized human lung fragments in vitro. 2 With the exception of WY 16922, which released histamine at high concentrations, all inhibited histamine release in a linear dose-related manner. 3 The analogues were 30 to 1500 times more potent than sodium cromoglycate. However, their regression slopes of activity upon log-concentration were only one-third as steep as that for sodium cromoglycate, indicating a possible difference in their mechanism of action. 4 In comparison with sodium cromoglycate, the analogues were more potent in human lung than in rat passive cutaneous anaphylaxis (PCA); there was no quantitative correlation between potencies in the two tests. 5 The human lung model is not predictive of anti-asthmatic activity in man as the six analogues tested clinically are less effective than sodium cromoglycate. 6 These results throw doubt on the use of models of mast cell degranulation in the search for anti-allergic drugs and, possibly, on the relative importance of mast cell degranulation in the pathogenesis of asthma.

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Section: Methodsmentioning

confidence: 99%

THE ACTIVITY OF SODIUM CROMOGLYCATE ANALOGUES IN HUMAN LUNG in vitro: A COMPARISON WITH RAT PASSIVE CUTANEOUS ANAPHYLAXIS AND CLINICAL EFFICACY

Church

Gradidge

1980

British J Pharmacology

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“…Proxicromil has been reported to inhibit anti-IgEinduced release of histamine from human basophils [2]. Therefore, the effect of proxicromil, RHC 3024, DSCG and other antiallergic agents in this model was investigated.…”

Section: Effect Of Rhc 3024 and Dscg On Anti-ige-induced Release O F mentioning

confidence: 99%

“…Its clinical effectiveness has been attributed to its activity as an inhibitor of IgE-mediated release of bronchospastic mediators from mast cells both in vitro and in vivo [12,16,27], Since DSCG is ineffective orally, the search has been con tinued for an orally effective inhibitor of mediator re lease. Several new inhibitors of mediator release have been discovered and are in various stages of develop ment [2,5,8,9,15,19,35,36]. Three widely used in vitro models for the discovery of new inhibitors of the immunologic and/or non-immunoiogic release of histamine are: (a) rat peritoneal mast cells, (b) guinea pig lung slices and (c) human basophils [9].…”

Section: Introductionmentioning

confidence: 99%

RHC 3024: Antiallergic Activity in vitro and Comparison with Disodium Cromoglycate and Other Antiallergic Agents

Khandwala¹,

Coutts²,

Dally-Meade³

et al. 1983

Int Arch Allergy Immunol

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Abstract. RHC 3024 has been investigated for its antiallergic activity in three in vitro models of anaphylaxis. We have also compared its activity profile in these models with that of disodium cromoglycate (DSCG) and other antiallergic agents. As an inhibitor of antigen-induced release of histamine from rat mast cells RHC 3024 was 4 times more potent than DSCG. In the same model the activity profile of RHC 3024 was identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, reversibility of the inhibition, tachyphylaxis and cross-tachyphylaxis to each other and inability to inhibit histamine release stimulated by Ca++ ionophore, dextran/phosphatidyl serine and compound 48/80. Both drugs had no effect in the other two models, IgG|-mediated histamine release from guinea pig lung and anti-IgE-induced histamine release from human basophils. We conclude: (1) RHC 3024 is a potent inhibitor of mediator release with a me chanism of action similar to that of DSCG, M&B 22,948, PRD-92-Ea and AH-7725 and (2) the in vitro activity profiles of proxicromil, doxantrazole, ICI 74,917 and WY-16,922 are different from DSCG and RHC 3024.

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“…Sodium cromoglycate, 5,5'-[(2-hydroxy-1,3-propane)bis(oxy)]bis[4-oxo-4H-l-benzopyran-2-carboxylic acid], disodium salt (VIII), 6,7,8,9-tetrahydro-5-hydroxy-4-oxolo propyl-4H-naphtho(2,3-6)pyran-2-carboxylic acid, sodium salt (IX), 5-(hydroxypropoxy)-4-oxo-4H-l-benzopyran-2-carboxylic acid, sodium salt (X), 6,8-di(l,l-dimethylethyl)-4-oxo-4H-l-benzopyran-2-carboxylic acid, sodium salt (XI) and 8-allyl-5-(3-methylbutoxy)-4-oxo-4H-l-benzopyran-2-carboxylic acid, sodium salt (XII) were supplied by Fisons Ltd., Pharmaceutical Division, Loughborough, England. The structures and biological properties of VIII and IX have been described [19,20]. All the compounds, after con version to sodium salts where necessary, were made up to 1 mM in MCM.…”

Section: Antiallergic Compoundsmentioning

confidence: 99%

Glycosphingolipid Clustering and Mast Cell Degranulation

Curtain¹,

Looney²,

Smelstorius³

1981

Int Arch Allergy Immunol

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It was shown using spin-labelled probes that challenge of sensitized rat peritoneal mast cells results in clustering of sphingolipids located in the outer leaflet of the plasma membrane bilayer. This clustering is partially inhibited by antiallergic drugs of the chromone type. It is hypothesized that the sphingolipid clustering may be involved in the Ca⁺⁺ gate mechanism which is associated with anaphylactically-induced mast cell degranulation.

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New orally effective chromone derivatives for the treatment of asthma

Cited by 43 publications

References 8 publications

THE ACTIVITY OF SODIUM CROMOGLYCATE ANALOGUES IN HUMAN LUNG in vitro: A COMPARISON WITH RAT PASSIVE CUTANEOUS ANAPHYLAXIS AND CLINICAL EFFICACY

THE ACTIVITY OF SODIUM CROMOGLYCATE ANALOGUES IN HUMAN LUNG in vitro: A COMPARISON WITH RAT PASSIVE CUTANEOUS ANAPHYLAXIS AND CLINICAL EFFICACY

RHC 3024: Antiallergic Activity in vitro and Comparison with Disodium Cromoglycate and Other Antiallergic Agents

Glycosphingolipid Clustering and Mast Cell Degranulation

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