The anti-pyretic activity of alminoprofen (AP), a non-steroidal anti-inflammatory agent, and its mode of action were investigated in conscious febrile rabbits. A fever was evoked by i.v. injection of lipopolysaccharide (LPS), intracisternal (i.c.) injection of leukocytic pyrogen (LP) or i.c. injection of arachidonic acid (AA). The amount of PGE
2 or AP in the cerebrospinal fluid (CSF) after i.v. LPS was estimated using an RIA or HPLC method. AP (3 ?? 30 mg/kg, p.o.) dose-dependently inhibited the LPS (0.5 pg/kg, i.v.)-induced fever; AP, ibuprofen, indomethacin and pranoprofen had ED50 values of 9.64, 26.45, 4.41 and 11.91 mg/kg, p.o., respectively. PGE
2 in the CSF was markedly increased during the elevation of body temperature after i.v. LPS (0.5 μg/kg). AP (30 mg/kg, p.o.) markedly inhibited the increase in PGE
2 that was observed in the CSF during fever developed in response to i.v. LPS (0.5 μg/kg). The AP concentration in the CSF 2hr after AP (30 mg/kg, p.o.) was 2.86 × 10
-6 (1.15 ?? 4.57 × 10
-6) M, a concentration too low to inhibit PG synthesis. A dose-dependent fever was observed after i.c. LP (1 ?? 8 unit) or AA (10 ?? 100 pg). AP (30 mg/kg, p.o.) shifted the dose-response curves for the i.c. LP-induced fever to the right, but did not have any effect on the i.c. AA-induced fever. These results suggest that AP has a relatively potent anti-pyretic activity, and its mechanism of action involves competition with LP at a site in the CNS, but does not involve an inhibition of cyclooxygenase at a central site, which has been considered as an anti-pyretic mechanism of nonsteroidal anti-inflammatory drugs.
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