Inhibitors of
arachidonic acid (AA) metabolism and other pharmacologic agents were evaluated against ear
edema produced in mice by
tetradecanoylphorbol acetate (TPA) or AA. Drugs were administered orally and topically either 30 min prior to AA or 30 min after TPA, except for
steroids which were administered 2.5-3 hr prior to AA. Several
cyclooxygenase (CO) inhibitors including
indomethacin,
aspirin,
piroxicam and
timegadine were without effect when administered orally against either
irritant; the same drugs inhibited TPA
edema when they were administered topically. Mixed CO/
lipoxygenase (LO) inhibitors,
phenidone and
BW755C, were active orally against AA
edema (ED50S of 84 and 65 mg/kg, respectively) and against TPA
edema (ED50S of 235 and 88 mg/kg, respectively).
Phenidone was more active topically against AA
edema (ED50, 0.1 mg/ear) than
BW755C (ED50, 2.8 mg/ear); however,
BW755C was more active topically against TPA
edema (ED50, 0.2 mg/ear) than
phenidone (ED50, 0.6 mg/ear).
Methylprednisolone was very effective in the AA (oral ED50, 17 mg/kg; topical ED50, greater than 1 mg/ear) and TPA models (oral ED50, 4.3 mg/kg; topical ED50, 0.03 mg/ear.
MK-447 was topically and orally effective only in the TPA model. Not surprisingly, drugs were more effective topically than orally in both mouse ear
edema assays. The models were somewhat selective for CO and CO/LO inhibitors; however,
dapsone was orally effective in the ear models, and a number of mediator antagonists and CNS drugs, especially anti-psychotics, were topically active primarily against TPA
edema. These models may be useful for the detection of in vivo activity of CO/LO or 5-LO inhibitors.