Antiedematous effects of combination therapies with the leukotriene synthesis inhibitor BAY X 1005 in the archidonic acid-induced mouse ear inflammation test.
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.
Burchardt
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Bayer AG, Pharma Research Center, Institute for Cardiovascular and Arteriosclerosis Research, Wuppertal, Germany.
Müller-Peddinghaus
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016718:Arachidonic Acid / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004423:Ear; D004487:Edema / Q000188:drug therapy*; D005260:Female; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007213:Indomethacin / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008784:Methysergide / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011738:Pyrilamine / Q000494:pharmacology; D011804:Quinolines / Q000627:therapeutic use*; D012702:Serotonin Antagonists / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006634:Histamine H1 Antagonists; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D012702:Serotonin Antagonists; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D016718:Arachidonic Acid; D019001:Nitric Oxide Synthase; D011738:Pyrilamine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin; D008784:Methysergide