Interaction studies of tilomisole, aspirin, and naproxen in acute and chronic inflammation with assessment of gastrointestinal irritancy in the rat.

The effect of combination NSAID therapy of tilomisole with aspirin or naproxen was studied in rats with carrageenan-induced paw edema and established adjuvant arthritis. Inflamed paws were measured using mercury plethysmography and the arthritic paws were X-rayed to determine any bony/soft tissue changes. The gastrointestinal tract was also examined for bleeding and ulceration. Tilomisole had a less potent acute anti-inflammatory effect than aspirin or naproxen, but produced no significant gastrointestinal damage. A significant reduction in anti-inflammatory activity was observed with the tilomisole/aspirin combination in acute inflammation. Only additive interactions were observed with the naproxen inhibition. In the established arthritis assay, a significant synergistic anti-inflammatory response, i.e. both inhibition of paw edema and bone erosion, was also observed with the 80 and 93% tilomisole/naproxen combinations. The gastric ulcerogenic effect of the combination paralleled its increased activity. The synergism between tilomisole and naproxen in this chronic arthritic model may be due to enhanced cyclooxygenase inhibitory activity. These drug interaction studies suggest possible interactions in human clinical trials of rheumatoid arthritis.

Quantit analysis: a quantal assay refinement.

A new tolerance distribution and inference procedure for quantal response assays is presented. This method is capable of fitting a wide variety of shapes of response curves. Specific cases of this new method include quantal response assay analyses based on the double exponential distribution, the logistic distribution (logit analysis), and the uniform distribution (linit analysis) in a limiting case. Computational techniques used to implement the likelihood procedures associated with this method are described. Comparisons are made for 22 sets of published data. These comparisons suggest that interval estimates of extreme dosages (e.g., ED95 and ED99) based on logit and probit analyses are, for the most part, either overly optimistic (too small) or overly pessimistic (too large). This interval estimation problem should be partially overcome by the added flexibility of the method introduced here.