Evaluation of 5-lipoxygenase inhibitors, zileuton, A-78773 and ICI-D-2138 in an ionophore (A-23187)-induced pleural inflammation model in the rat.

Abstract

Intrapleural injection of A-23187 (10 micrograms), a calcium ionophore, elicited rapid increase in biosynthesis of prostaglandins and leukotrienes in a time-dependent manner. 6-Keto-prostaglandin-F1 alpha (6-KPA) was the principal cyclooxygenase product with modest increases in levels of thromboxane B2 and prostaglandin-E2. Orally administered indomethacin, a selective cyclooxygenase inhibitor, and three selective 5-lipoxygenase inhibitors, zileuton, A-78773 and ICI-D-2138 markedly attenuated respective arachidonate pathways with projected ED50 values of < 1-2 mg/kg. Furthermore, a single oral administration of either ICI-D-2138 or A-78773 (each 20 mg/kg, po) resulted in persistent inhibition of 5-lipoxygenase pathway for up to 24 hr. These results indicate zileuton, A-78773 and ICI-D-2138 to be potent and selective inhibitors of 5-LO and document the utility of A-23187-induced pleural inflammation in evaluating efficacy of inhibitors of arachidonic acid metabolism in vivo.

• Authors: T S Rao, J L Currie, A F Shaffer, P C Isakson
• Journal: Life sciences (Life Sci) Vol. 53 Issue 9 Pg. PL147-52 ( 1993) ISSN: 0024-3205 [Print] Netherlands
• PMID: 8394967 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Eicosanoids
• Leukotrienes
• Lipoxygenase Inhibitors
• Prostaglandins
• Pyrans
• Quinolones
• ICI D2138
• A 78773
• Calcimycin
• zileuton
• Hydroxyurea

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Calcimycin (pharmacokinetics)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Eicosanoids (biosynthesis)
• Hydroxyurea (analogs & derivatives, pharmacology)
• Leukotrienes (biosynthesis)
• Lipoxygenase Inhibitors (pharmacology)
• Male
• Pleurisy (chemically induced, drug therapy, enzymology)
• Prostaglandins (biosynthesis)
• Pyrans (pharmacology)
• Quinolones (pharmacology)
• Rats
• Rats, Sprague-Dawley