Comparison of the efficacy of indometacin farnesil and indometacin against various symptoms in adjuvant-induced knee-arthritis in dogs.
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Using subacute arthritis induced by inoculation of Freund's complete adjuvant into the knee-joint of beagles, the anti-inflammatory effect of indometacin farnesil (IMF) was observed and compared with that of indometacin (IND) . The side effects of both drugs were studied as well. The therapeutic efficacy of the two drugs was clarified through comparison of the efficacy rates against arthritis and those for side effects.<BR>Freund's complete adjuvant was injected into the knee-joints of the beagles 5 min before the initial administration of the test drugs. Thereafter, the test drugs were administered at 2 dose levels egivalent to clinical rates, once a day for 8 days. Local inflammatory symptoms such as pain, hyperthermia and swelling in the inflammatory lesions were monitored and the rectal temperature was measured during the experiment. Three hours after the final administration, PGE<SUB>2</SUB>, IND and IMF concentrations in the synovial fluid, and PGE<SUB>2</SUB>⋅I<SUB>2</SUB> and IND concentrations were measured in the pyloro-duodenum. The pyloroduodenum was also investi-gated histologically. Both IMF (30mg/kg) and IND (1.7mg/kg) reduced pain dose-dependently and were almost equipotent in analgesic activity on the 3rd day.<BR>Only IMF (30mg/kg) showed a significant ability to reduce the higher temperature in the inflamed joints (p<0.05) . IMF (30mg/kg) and IND (5.0mg/kg) were almost equipotent in anti-pyretic activity on both the 1st and 3rd days. A significant amount of IND, which might have come from the blood stream and/or result from the hydrolysis of IMF in the synovial fluid, and levels of PGE<SUB>2</SUB> lower than those of the control detected in the synovial fluids in both the IMF and IND groups, seem to indicate that the anti-inflammatory and analgesic effects are due to the tissue levels of IND, which inhibited the action of cyclooxygenase in the fluid.<BR>The side effects in the IND groups were very severe with bloody stool in one out of six and four out of six animals in the 1.7mg/kg and 5.0mg/kg groups, respectively, while no severe side effects were seen in either the IMF or control groups, except for mild anolexia and ref lexible vomiting. Ulcers and erosions with hemorrhage were seen in the pyloroduodenum and severe ulcers were observed in the IND 1.7mg/kg and 5.0mg/kg. These abnormalities were also confirmed in the histological examination. Similar reductions of PGE<SUB>2</SUB>⋅I<SUB>2</SUB> when compared with the control group were detected in the pyloroduodenum in both the IMF and IND groups but there was a significant difference in mucosal damage between them. It is therefore most likely that the inhibition of PGs syntheses by IND is not solely responsible for the mucosal damage and some other factors may be involved. In terms of anti-inflammatory effect, although IMF at 30mg/kg was weaker than IND at 5.0mg/kg, IMF had a similar effect or was a little stronger than IND at 1.7mg/kg. Even at the same effective dose, the frequency of side effects for IMF was much less for IND. These results indicate that IMF, a prodrug of IND, has a different action from IND, and is prefered since IMF would expect to cause lesser side effects associated with IND.
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