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

Abstract

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 micrograms or 13.1 micrograms/pleural cavity) and leukocyte count (ID30 = 83 or 230 micrograms); in the same conditions. Dex was more active (ID30 = 0.7 and 2.6 micrograms). All these steroids decreased PGE2 and LTC4/D4 contents in exudate fluids, respectively TP (50 micrograms/pleural cavity) by 28 and 63%; T (100 micrograms) by 33 and 31%; Dex (5 micrograms) by 43 and 40%. Local co-administration of RU 486 (50 micrograms) 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.

Direct inhibition of cyclooxygenase pathway in platelets by tixocortol 21-pivalate: comparison with related structures, steroidal and non steroidal anti-inflammatory drugs

“…These results differ from those reported with sulfide and sulfone derivatives of sulfinpyrazone which have been described as more potent than their parent compound [33]. In summary, TP, a 21-thiol derivative of cortisol, binds to dexamethasone receptors [11], its local anti-inflammatory activity can be reversed by the glucosteroid competitive antagonist RU486 [12,13]. It has also been found to possess significant and apparently direct inhibitory effect on cyclooxygenase pathway.…”

“…TP as other steroids, binds to dexamethasone receptor [11] and its anti-inflammatory effects are reversed by RU 486, a glucosteroid competitive antagonist [12,13]. Since 21 thioesters of glucosteroids represent a new chemical class of compounds with specific properties in terms of lack of systemic side effects [2] and metabolic behaviour [14], we have investigated its direct effect on arachidonic cascade, using rabbit washed platelets according to the procedure of Needleman et al [15].…”

New insight into dexamethasone activity in lymphoblast transformation of mouse thymocytes

“…modification of glucose or calcium transport, of interleukin synthesis or modification of interleukin receptors) and might be induced sequentially, in the presence of dex at least in part. In other respects, dex activity mediated partly through leukotriene synthesis inhibition might be involved, as recently reported [9], since esculetin is found in this test to inhibit proliferation at concentrations (IC50 = 25 ~M) usually required for inhibition in other cell types [10]. On one hand, the hypothesis that dex may switch on protein induction is supported by the fact that the dex effect lasts for 24 hr after its displacement from its receptor by RU 486.…”