Local anti-inflammatory activities of tixocortol 21-pivalate, inhibition of prostaglandins and leukotrienes synthesis, in carrageenin-induced pleurisy. Reversion of effects by RU 486

- Since a direct effect of tixocortol pivalate (TP) has been described on cyclooxygenase pathway, local anti-inflammatory activities of some 21 thiol derivatives of steroids were investigated on the carrageenin-induced pleurisy model in comparison with dexamethasone (Dex) or other anti-inflammatory drugs. LTC4/D4 contents in pleural fluid were assayed by RIA as well as PGE2 levels to characterize the effects on arachidonate pathways. - After oral administration, TP was inactive up to 1 g/kg on exudate volume and leukocyte migration as expected for this strict local anti-inflammatory steroid contrary to Dex (ID50=0.05–0.41 mg/kg). - When administered locally, TP and tixocortol (T) exerted a dose dependent inhibitory activity on exudate volume (ID30=12.4 μg or 13.1 μg/pleural cavity) and leukocyte count (ID30=83 or 230 μg); in the same conditions, Dex was more active (ID30=0.7 and 2.6 μg). - All these steroids decreased PGE2 and LTC4/D4 contents in exudate fluids, respectively TP (50 μg/pleural cavity) by 28 and 63%; T (100 μg) by 33 and 31%; Dex (5 μg) by 43 and 40%. - Local co-administration of RU 486 (50 μg) with either TP, T or Dex reversed the anti-inflammatory effects of all steroids, indicating in these conditions a local activity through glucosteroid receptor occupancy.