Doxantrazole, an Antiallergic Agent Orally Effective in Man

J, Batchelor; Garland, L.G.; Green, A.F.; Hughes, David J.; Follenfant, M.J.; Gorvin, John H.; Hodson, H. F.; Tateson, J.E.

doi:10.1016/s0140-6736(75)93141-4

Cited by 50 publications

(14 citation statements)

References 13 publications

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“…If substantiated, however, the proposed mechanism of action of DSCG should lead to new strategies in the pharmacological research on asthma. Our recent data indeed demonstrate that other potential anti-asthmatics such as nedocromil (Cairns et al, 1985), doxanthrazole (Batchelor et al, 1975) and PRD-92-Ea (El Azab & Stewart, 1977), have the same cytoprotective capability as DSCG.…”

Section: And_jsupporting

confidence: 53%

Cytoprotective effects of disodium cromoglycate on rat stomach mucosa

Goossens

Reempts

Wauwe

1987

British J Pharmacology

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The cytoprotective effects of the anti‐asthmatic drug, disodium cromoglycate (DSCG), on gastric mucosal necrosis induced by ethanol in rats were studied. Subcutaneous, but not oral, DSCG prevented the formation of gastric lesions and this effect was dose‐dependent between 1.25 and 40 mg kg−1, with an ED50 value of 6.8 mg kg−1. Maximal cytoprotection occurred 15–30 min after DSCG treatment. Histological examination revealed that DSCG effectively protected the gastric mucosa against ethanol‐induced vascular congestion, haemorrhage, epithelial desquamation and mucosal oedema. Enhanced production of endogenous prostaglandins, which are known cytoprotective compounds, could not explain the mucosal protection. At a dose of 40 mg kg−1, DSCG did not change prostaglandin E2 or 6‐keto‐prostaglandin F1α concentrations in gastric mucosal tissue, although its cytoprotective activity was partially inhibited by prior treatment of the animals with indomethacin.

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Section: And_jsupporting

confidence: 53%

Cytoprotective effects of disodium cromoglycate on rat stomach mucosa

Goossens

Reempts

Wauwe

1987

British J Pharmacology

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“…DSCG-like agents are not effective in this model [1,9,37], The exceptions are IC1 74,917 and doxantrazole, which are reported to inhibit im munologic release of histamine from either actively or passively sensitized chopped guinea pig lung [4,5]. The activity of ICI 74,917 and doxantrazole in this model may be due to their ability to inhibit cyclic nu cleotide phosphodiesterase [5,10], We confirm that doxantrazole inhibits AIR from guinea pig lung. DSCG and other DSCG-like agents are ineffective in this in vitro model of anaphylaxis (table III).…”

Section: Histamine Release From Guinea Pig Lungmentioning

confidence: 54%

“…/(-Adrenergic agonists and cyclic nucleotide phosphodiesterase inhibitors have been shown to in hibit immunologic release of histamine from guinea pig lung [1,9,26]. DSCG-like agents are not effective in this model [1,9,37], The exceptions are IC1 74,917 and doxantrazole, which are reported to inhibit im munologic release of histamine from either actively or passively sensitized chopped guinea pig lung [4,5]. The activity of ICI 74,917 and doxantrazole in this model may be due to their ability to inhibit cyclic nu cleotide phosphodiesterase [5,10], We confirm that doxantrazole inhibits AIR from guinea pig lung.…”

Section: Histamine Release From Guinea Pig Lungmentioning

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%

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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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“…Doxantrazole is able to stabilize the mast cell membrane, thus inhibiting its degranulation, through still poorly understood mechanisms, despite its discovery in 1975. 24 One study by Sadeghi-Hashjin and colleagues 25 showed in isolated alveolar macrophages that doxantrazole was also a scavenger of free radicals. In our present study, such a mechanism appears unlikely because acetaldehyde has never been found associated with macrophage activation within the gut.…”

Section: Discussionmentioning

confidence: 99%

Impairment of the Intestinal Barrier by Ethanol Involves Enteric Microflora and Mast Cell Activation in Rodents

Ferrier

Bérard

Debrauwer

et al. 2006

The American Journal of Pathology

223

202

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Alcohol hepatic toxicity in heavy drinkers is associated with high endotoxin blood levels and increased intestinal permeability. Because endotoxins can cross damaged mucosa, we investigated the mechanisms through which ethanol impairs the colonic epithelium of rats submitted to acute alcohol intake. Colonic permeability to 51 Cr-ethylenediamintetraacetic acid was increased 24 hours after 3.0 g/kg ethanol intake (3.2 ؎ 0.2% versus 2.2 ؎ 0.2%) and was associated with significant endotoxemia. Antibiotics and doxantrazole (a mast cell membrane stabilizer) significantly inhibited the effect of ethanol. Two hours after intake, plasma concentrations of ethanol were twofold higher in antibiotictreated rats than in controls (155.8 ؎ 9.3 mg/dl versus 75.7 ؎ 7.6 mg/dl, P < 0.001). Lumenal concentrations of acetaldehyde were markedly increased after ethanol intake (132.6 ؎ 31.6 mol/L versus 20.8 ؎ 1.4 mol/L, P < 0.05) and antibiotics diminished this increase (86.2 ؎ 10.9 mol/L). In colonic samples mounted in Ussing chambers, acetaldehyde but not ethanol increased dextran flux across the mucosa by 54%. Doxantrazole inhibited the effect of acetaldehyde. This study demonstrates that an acute and moderate ethanol intake alters the epithelial barrier through ethanol oxidation into acetaldehyde by the colonic microflora and downstream mast cell activation. Such alterations that remain for longer periods could result in excessive endotoxin passage, which could explain the subsequent endotoxemia frequently observed in patients with alcoholic liver disease.

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Doxantrazole, an Antiallergic Agent Orally Effective in Man

Cited by 50 publications

References 13 publications

Cytoprotective effects of disodium cromoglycate on rat stomach mucosa

Cytoprotective effects of disodium cromoglycate on rat stomach mucosa

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

Impairment of the Intestinal Barrier by Ethanol Involves Enteric Microflora and Mast Cell Activation in Rodents

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