1 Calculated from the 3 point regression of response on dose.
2 Calculated by the method of Litchfield and Wilcoxon.
than indomethacin and ibuprofen and of greater potency than aspirin and most other NSAIDs in the UV erythema assay .
Swingle and co-workers determined the chronic anti-inflammatory effects of nimesulide in the rat mycobacterial adjuvant-induced arthritis assay . The hind paw swellings in this assay were prevented in the established disease by nimesulide 0.2 mg/kg/d p.o. when given over the period of 14-30 days after induction of the disease . Higher doses of 0.6 and 1.8 mg/kg/d of nimesulide led to almost complete suppression of the disease  (Fig. 1).
Therapeutic effect of nimesulide (R-805) compared with phenylbutazone (PB) as established adjuvant-induced arthritis in rats. The animals were dosed orally with the drugs from day 14 after injection of the adjuvant on days as shown by the arrows. The mean values shown are from data of readings from 6 rats. The two highest doses of nimesulide (0.6 and 1.8 mg/kg/d) produced almost complete inhibition of adjuvant disease from day 18.*) Data significantly different from control P > 0.05. From . Reproduced with permission of the former Editor of Archiv Int Pharmacodyn (no longer in publication).
In comparison, phenylbutazone was about 10 times less potent. At a dose of 1.8 mg/kg/d nimesulide significantly reversed the body weight loss that occurs in adjuvant disease and improved the general 'state of health' of the animals .
These acute and chronic anti-inflammatory effects were largely confirmed in later studies by Tanaka et al. . These authors were using nimesulide as one of a number of comparator NSAIDs to determine the relative anti-inflammatory, analgesic and antipyretic effects of related novel sulphonanilide drug, T-614 (3-formylamino-7-methylsulphonylamino-6-phenoxy-4H-1-benzopyran-4-one) . A summary of the data of these authors are shown in Table 2.
Similar oral dose ranges for inhibition of carrageenan paw oedema in rats to those reported by Swingle et al.  and Tanaka et al.  have been reported by other workers [12-14].
The combined oral administration of nimesulide with aspirin did not show added anti-oedemic effects over that of the drugs alone in the carrageenan paw oedema assay in rats . This was notable even when relatively low doses of nime-sulide were given (0.7 or 2.0 mg/kg) with a fixed low dose of aspirin (60 mg/kg; a dose which causes only ~30% inhibition of oedema) . These data suggest that there is unlikely to be a limitation of effects due to reaching the upper range of the dose-response curve, but rather due to some pharmacological antagonism between the two drugs.
Intramuscular nimesulide 1.5-25 mg/kg has been found to produce a dose-related inhibition in carrageenan paw oedema in rats at 2 h (which is the time for peak plasma levels of nimesulide) as well as at 3 and 4 h post-treatment . The anti-oedemic effects of nimesulide were slightly greater than those from the same dose-range of diclofenac .
Topical nimesulide 50 mg in a 1% gel (of unknown pharmaceutical composition) applied to the top part of one of the paws of rats 1 h prior to sub-plantar injection of carrageenan produced a reduction of 71.2% in the paw swelling compared with the same dose of diclofenac which produced a reduction of 64.4% in the paw oedema . While there were no data on dose-response or pharmaco-kinetics of these drugs for comparison the results suggest that nimesulide gel has good anti-inflammatory effects.
In the carrageenan pleural oedema model in rats the ED50 values for inhibition of leucocyte infiltration and the ED30 value for reduction in pleural fluid are comparable for both nimesulide and indomethacin (Tab. 3) . In the carrageenan air pouch model both drugs appeared less potent ; this may be a reflection of the drug accumulation in the air pouch being less than that in the inflamed pleural cavity. The differences may account in part for the claim by Wallace and co-workers  that COX-2 inhibition may lead to limited anti-inflammatory effects.
The vascular permeability induced by i.p. acetic acid in rats and in the writhing test in mice was found to be inhibited to about the same extent as the anti-oedemic effects in the air pouch oedema in rats . The ED50 for the Evans blue pleural
Table 2 - Summary of acute oral anti-inflammatory effects of nimesulide in animal models (from )
Acute Paw Oedema in Rats Induced by: UV Erythema
MODEL Carrageenan Dose Kaolin Dextran Bromelain In Guinea Pigs
ED50 mg/kg (CI) mg/kg % Inhibition % Inhibition % Inhibition ED50 mg/kg (CI) after npur ± s.e.m @ 5 h (±s.e.m)@1h (± s.e.m) @ 1 h ^„„.„j««.
DRUG Single dose Two doses
Nimesulide 2.4 (0.95-6.3) 30 55.5 ±5.1* 28.8 ±2.1* 31.3 ±6.3* 4.5(1.7-12) 2.3(0.99-5.2)
Ibuprofen 25 (6.5-98) N/D N/D N/D 7.7(2.7-22) 7.8(3.4-18.0)
Indomethacin 1.9(0.75-4.9) 10 45.8 ± 7.0* 7.4 ± 1.2* 2.1 ± 3.6 2.8 (0.63-13) 1.3 (0.68-2.5)
Ratio-Nimesulide/ 1.3 1.2 3.9 14.9 1.6 1.8 Indomethacin
Nimesulide/ 0.096 N/D N/D N/D 0.6 0.3 Ibuprofen
CI = 95% confidence interval estimates.
* Statistically significant differences compared with control (p < 0.05). N/D = not determined.
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