Towards safer nonsteroidal anti-inflammatory drugs

More than one hundred years ago salicylic acid and its salts were introduced into the therapy of rheumatic diseases. Ninety years ago aspirin was discovered, and within the last forty years phenylbutazone, indomethacin, ibuprofen, the oxicams and many others were discovered. All of these drugs are acidic. They inhibit the prostaglandin synthetase, combine analgesic and anti-inflammatory activity and show side-effects mainly in the GI-tract, liver, bone-marrow, and kidney. Within the last twenty years, however, distinct relationships between effects and side-effects could be shown: 1. Rapid absorption beginning in the stomach goes along with intensive gastric-duodenal irritation and ulceration. 2. A high degree of enterohepatic circulation appears to be associated with ileal and jejunal ulcerations and perforations. 3. Intensive hepatic metabolisation may be related to enhanced hepatic damage. 4. Intensive intrarenal circulation of the active moiety may be related to kidney damage. These observations indicate that certain pharmacokinetic characteristics of distinct nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible, at least in part, for well-known side-effects. It is obvious that modifying the pharmacokinetics of the active principle may reduce specific types of side-effects. The clinical success of these attempts are limited but altogether promising.