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Antiedematous Effects of Combination Therapies With the Leukotriene Synthesis Inhibitor BAY X 1005 in the Archidonic Acid-Induced Mouse Ear Inflammation Test

Antiedematous Effects of Combination Therapies With the Leukotriene Synthesis Inhibitor BAY X 1005 in the Archidonic Acid-Induced Mouse Ear Inflammation Test

E R Burchardt, R Müller-Peddinghaus

Prostaglandins Leukot Essent Fatty Acids. 1997 Apr;56(4):301-6.

PMID: 9150376

Abstract:

The leukotriene synthesis inhibitor (LSI) BAY X 1005 was tested in the arachidonic acid (AA)-induced mouse ear inflammation test (AA-MEIT) alone and in combination with other representative anti-inflammatory compounds for antiedematous effects. When BAY X 1005 was used as a monotherapy, the ED50 (half-maximal effect) was observed at 5.1 mg/kg per os (p.o.) and at 0.8 microg for topical application. The maximal inhibition of edema formation was estimated to be 63% for p.o. application and 54% for topical application. Furthermore, experiments were carried out in which the animals were conditioned with a combination of the H1/5-HT receptor antagonists pyrilamine and methysergide in addition to treatment with BAY X 1005. This conditioning treatment alone, without BAY X 1005, resulted in a 45 +/- 13% reduction in edema formation. ED50 substance effects were observed at 5.3 mg/kg p.o. and at 0.02 microg per ear for topical application. The maximal inhibition of edema formation in the conditioned groups was 82% for the oral administration of BAY X 1005 and 72% for the topical application. To further characterize the antiinflammatory properties of BAY X 1005 in the conditioned and unconditioned AA-MEIT, BAY X 1005 was tested in combination with the nitric oxide (NO) synthase inhibitor L-NAME, with the cyclooxygenase inhibitor indomethacin, and in combination with both compounds. BAY X 1005 consistently exerted anti-inflammatory effects in the AA-MEIT. The effects of a combination of different inhibitors of inflammatory mediators were not simply additive in this model, as was demonstrated in the case of the combination of L-NAME and indomethacin where a smaller inhibition than with either substance alone was observed. In the conditioned model, a combination of BAY X 1005 with L-NAME or indomethacin, or with both compounds together was less effective than the monotherapy with BAY X 1005. Taken together, these data suggest that cyclooxygenase products and NO have little effect on edema formation in the conditioned and unconditioned AA-MEIT model and that their interaction with leukotrienes is of minor quantitative importance. Our results underline the complexity of the AA-MEIT model and provide a rationale for H1/5-HT-conditioning animals to compensate for peculiarities in the mouse-specific mediator spectrum and to recognize the importance of the leukotriene-specific inflammatory response.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP128253316	BAY-X-1005		128253-31-6	Price

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