Topical application of TPA to mouse skin causes oedema (2-6 h) neutrophil influx (3-24 h) and epidermal cell proliferation (24-48 h). Topical application of a cyclooxygenase inhibitor (indomethacin) dual cyclooxygenase and lipoxygenase inhibitors (phenidone and BW755C) a selective lipoxygenase inhibitor (AA861), protein synthesis inhibitors (cycloheximide and actinomycin D) or a glucocorticosteroid (prednisolone) inhibited oedema and neutrophil influx. Systemic administration of an inhibitor of microtubule assembly (colchicine) also prevented neutrophil influx and oedema. These results suggest that the inflammatory response to TPA depends on an interaction between a protein and products of arachidonic acid metabolism to produce a neutrophil dependent oedema. Epidermal cell proliferation was inhibited by topical administration of prednisolone, indomethacin, BW755C and cycloheximide but not systemically administered methotrexate. This suggests that inhibition of the early inflammatory response to TPA prevents the subsequent epidermal proliferation.

1 Old English (OE) rabbits produced more severe monoarticular arthritis (MAA) after sensitization and intra-articular challenge with ovalbumin than did either New Zealand White (NZW) or Dutch rabbits. NZW rabbits were better responders than Dutch rabbits. 2 The swelling of the joint in all three strains of rabbits was triphasic. There was an initial acute swelling which appeared to peak at 2-4 days after challenge. This was followed by a decrease in joint size, and then a secondary increase in size beginning 1-2 weeks after challenge. 3 An investigation of MAA in OE rabbits showed that there was an increase in E-type prostaglandins, total leucocyte counts and free acid phosphatase activity in the synovial fluid of the challenged joints at 6 h, 19 h, 47 h, 7 days and 46 days following challenge. There were also histopathological changes at these times. In addition, there was an increase in the surface temperature of both the challenged and non-challenged knees, and a rise in the body temperature.4 Prostaglandin levels peaked at 19 h and were equivalent to 19 ng E2 per joint. In a separate experiment, the prostaglandin present at 18 h was shown to be mainly E1. Maximum levels of prostaglandin appeared to coincide with maximum joint temperature, but preceded maximum joint swelling and a significant rise in both the number of inflammatory cells and the free acid phosphatase activity in the synovial fluid, all of which occurred at 47 hours. 5 Indomethacin, 7.5 mg/kg orally twice daily, almost completely inhibited the increase in prostaglandin levels in the challenged joints and produced a moderate reduction in joint swelling. It also reduced the increased surface temperature of both knee joints and the raised body temperature. However, indomethacin had no effect on the number of leucocytes present, the free acid phosphatase levels, or the histopathological changes in the joint. 6 The mean plasma level of indomethacin ranged from 0.5 to 3 Mg/ml at the time when the animals were killed. 7 Lysosomal enzymes may be more important than prostaglandins in rabbit MAA, and the lack of effect of indomethacin on joint histopathology may be due to its inability to prevent the release of these enzymes.

Established antigen-induced arthritis was produced in 264 out of 339 sensitized Old English rabbits 4-6 weeks after a single intra-articular injection of ovalbumin into one knee joint. Positive arthritis was diagnosed when the joint swelling at this time was greater than or equal to 2 mm. A positive correlation between established joint swelling and delayed hypersensitivity to ovalbumin injected intradermally 24 h prior to joint challenge was demonstrated. Groups of 5-10 arthritic rabbits were dosed orally with increasing or fixed doses of a range of drugs for a period of 3-7 weeks. Drug activity was measured on joint swelling intermittently during the test and on joint macroscopy, cell content of the synovial fluid and joint histopathology at the end of the experiment. Prednisolone sodium phosphate and ketoprofen were the most active compounds tested. Chloroquine diphosphate, cyclo phosphamide, indomethacin, naproxen, SKF 36914 and sudoxicam had some activity, while aspirin, levamisole, oxisuran and D(-)penicillamine had little or no activity.

A detailed evaluation has been made of the radiological changes occurring in the hindfeet of rats with adjuvant arthritis from 0 to 50 days after injection with Freund's Complete Adjuvant (FCA). The results were compared with concomitant foot swelling and the presence of histopathological abnormalities at the end of the experiment. In addition, the effects of oral administration of prednisolone and indomethacin administered either from one day before injection with FCA to 21 days afterwards, or from 21 to 35 days after injection with FCA, has been investigated on all these changes. The main radiological changes were osteoporosis of the tarsals and metatarsals, erosions of the tarsals and periosteal reactions in the metatarsals which were visible on day 10 and progressed up until 21-24 days after injection with FCA. Cystic fibrosis was noted in the metatarsals on day 14 and in the tibia, fibula and tarsals on day 21 and progressed to become the dominant abnormality by day 35. Cystic fibrosis and subsequent calcification, which was apparent on day 35, were the main features of the disease when the animals were killed on day 50. 10 and 30 mg/kg prednisolone and 0.3 and 3 mg/kg indomethacin both reduced the total X-ray score when administered either from day - 1 to 21, or from day 21-35, but did not at any time inhibit the osteoporosis or erosions. Their effect was mainly on preventing the cystic fibrosis and calcification which occurred later in the disease. Prednisolone and indomethacin also reduced the periosteal reaction when administered from one day before injection with FCA, but they were inactive in this respect when dosing was started on day 21 when the periosteal reaction was well established. Therefore, the results suggest that prednisolone and indomethacin inhibit the later sequelae of the disease and do not interfere with either the initial events or the disease process itself. There was a good correlation between the toal X-ray score, foot size and total histopathology score at the end of the experiment, and also an apparent correlation between total X-ray score and foot size throughout the experiment. Although this suggests that foot size is sufficient to indicate the overall reaction in adjuvant arthritis, X-ray analysis may detect clinically useful anti-rheumatoid activity which might not be evident from measurements of foot size alone.

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