Aspirin, diclofenac, diflunisal, ibuprofen and indomethacin were given orally or intravenously to fasted or fed rats. The resulting gastric and intestinal damage was assessed using standard methods. The same drugs were administered to rats with biliary fistulas, and the fraction of drug excreted in bile was quantified using HPLC methods. We found that gastric damage occurred only in the fasted animals and was found to be dose-dependent and related to the amount (r = 0.871) and solubility (r = 0.909) of the individual drug. As far as acute gastric toxicity is concerned, neither the potency of a drug as an inhibitor of cyclo-oxygenase nor the fraction of unchanged or conjugated agent excreted in bile appeared to be relevant. Secondly, ulcerations of the small intestine occurred in fed animals only. The degree of damage was related to the amount of unchanged or conjugated drug excreted in bile and cyclo-oxygenase inhibitory potency (r = 0.873). The administered dose (within the range investigated) and drug solubility appeared not to contribute to intestinal toxicity. It is concluded that, in the rat, acute gastric and intestinal toxicity of non-steroidal anti-inflammatory drugs are due to different mechanisms. Whereas gastric toxicity is strongly influenced by the amount of drug dissolved under the pH conditions in the stomach, intestinal toxicity appears to depend on biliary excretion and enterohepatic circulation of a drug as well as on its potency as an inhibitor of prostaglandin synthesis.

Objectives-To investigate the relation with a case-control study between symptomatic osteochondrosis or spondylosis of the lumbar spine and cumulative occupational exposure to lifting or carrying and to working postures with extreme forward bending. Methods-From two practices and four clinics were recruited 229 male patients with radiographically confirmed osteochondrosis or spondylosis of the lumbar spine associated with chronic complaints. Of these 135 had additionally had acute lumbar disc herniation. A total of 197 control subjects was recruited: 107 subjects with anamnestic exclusion of lumbar spine disease were drawn as a random population control group and 90 patients admitted to hospital for urolithiasis who had no osteochondrosis or spondylosis of the lumbar spine radiographically were recruited as a hospital based control group. Data were gathered in a structured personal interview and analysed using logistic regression to control for age, region, nationality, and other diseases aVecting the lumbar spine. To calculate cumulative forces to the lumbar spine over the entire working life, the MainzDortmund dose model (MDD), which is based on an overproportional weighting of the lumbar disc compression force relative to the respective duration of the lifting process was applied with modifications: any objects weighing >5 kg were included in the calculation and no minimum daily exposure limits were established. Calculation of forces to the lumbar spine was based on self reported estimates of occupational lifting, trunk flexion, and duration. Results-For a lumbar spine dose >9×10 6 Nh (Newton×hours), the risk of having radiographically confirmed osteochondrosis or spondylosis of the lumbar spine as measured by the odds ratio (OR) was 8.5 (95% confidence interval (95% CI) 4.1 to 17.5) compared with subjects with a load of 0 Nh. To avoid diVerential bias, forces to the lumbar spine were also calculated on the basis of an internal job exposure matrix based on the control subjects' exposure assessments for their respective job groups. Although ORs were lower with this approach, they remained significant. Conclusions-The calculation of the sum of forces to the lumbar spine is a useful tool for risk assessment for symptomatic osteochondrosis or spondylosis of the lumbar spine. The results suggest that cumulative occupational exposure to lifting or carrying and extreme forward bending increases the risk for developing symptomatic osteochondrosis or spondylosis of the lumbar spine. (Occup Environ Med 2001;58:735-746)

Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.

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