calcimycin and timegadine

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arachidonic Acids; Auranofin; Calcimycin; Chemotaxis; Guanidines; Humans; Levamisole; Neutrophils; Penicillamine

Rat neutrophils isolated from 4-h reverse passive Arthus reaction (RPAR) pleural exudates actively metabolize arachidonic acid via cyclooxygenase and lipoxygenase. Utilizing this system, the effect of oral doses of nonsteroidal antiinflammatory drugs on the ability of these cells to produce HHT, 5-HETE, and LTB from exogenously added arachidonic acid has been investigated. In vitro and ex vivo, indomethacin and timegadine inhibit cyclooxygenase activity in rat pleural neutrophils. In vitro, timegadine is a lipoxygenase as well as a cyclooxygenase inhibitor. This dual inhibition is confirmed by the observation that ex vivo timegadine inhibits the production of lipoxygenase as well as cyclooxygenase metabolites. While indomethacin, a cyclooxygenase inhibitor, primarily inhibits edema formation, the inhibition of both pathways of arachidonic acid metabolism by timegadine is reflected in the drug's ability to reduce cellular influx as well as edema formation in the RPAR pleural cavity inflammatory reaction.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arthus Reaction; Calcimycin; Edema; Guanidines; Indomethacin; Inflammation; Leukocyte Count; Male; Neutrophils; Rats; Rats, Inbred Lew; Rats, Inbred Strains

Casein-elicited rat peritoneal polymorphonuclear leukocytes (PMNL) and rabbit platelets were prelabelled with [1-14C]arachidonic acid, and the effect of timegadine, a new anti-inflammatory agent, on the release and metabolism of arachidonic acid induced by A23187 (PMNL) and thrombin (platelets) was studied and compared with the effect of other compounds reported to affect these enzymatic mechanisms. Timegadine inhibited arachidonic acid release from both cells (IC50 = 2.7 X 10(-5) M), the lipoxygenase activity in PMNL (IC50 = 4.1 X 10(-5) M) and the cyclooxygenase activity in platelets (IC50 = 3.1 X 10(-8) M). By these mechanisms, PMNL leukotriene B4 formation was inhibited by 50% at 2.0 X 10(-5) M, platelet thromboxane B2 at 3.2 X 10(-8) M, and platelet 12-HETE at 4.9 X 10(-5) M. These effects might add to the understanding of the anti-inflammatory properties of timegadine.

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Autoradiography; Blood Platelets; Calcimycin; Caseins; Female; Guanidines; In Vitro Techniques; Leukotriene B4; Neutrophils; Rats; Rats, Inbred Strains