THE INHIBITORY EFFECTS OF ANTIRHEUMATIC DRUGS ON THE ACTIVITY OF HUMAN-LEUKOCYTE ELASTASE AND CATHEPSIN-G

The serine proteinases elastase and cathepsin G from polymorphonuclear granulocytes play a critical role in articular cartilage degradation, not only as proteolytic enzymes able to degrade the extracellular mat rix but also by additionally modulating the level of active matrix met alloproteinases, key enzymes of the proteolytic destruction of cartila ge during rheumatoid arthritis. The aim of our study was to examine wh ether antiinflammatory drugs and selected compounds inhibited elastase and cathepsin G, and also to determine whether it is necessary to use a highly purified elastase preparation to screen drugs for their abil ity to block the activity of this enzyme. Eglin C and the glycosaminog lycan-peptide complex DAK-16, at concentrations ranging from 10(-9) to 10(-4) M, dose-dependently inhibited elastase and cathepsin G while t he nonsteroidal anti-inflammatory drugs oxyphenbutazone, phenylbutazon e, sulfinpyrazone and diclofenac-Na required high concentrations to de monstrate some inhibitory effects on the activity of both enzymes. Non e of the other antiinflammatory drugs tested at a concentration of 10( -4) M such as acetylsalicylic acid, dexamethasone, indomethacin, ketop rofen, naproxen, oxaceprol, pirprofen and tiaprofenic acid demonstrate d any marked inhibitory activity on either of these proteinases. Only a few drugs, when dosed therapeutically, achieved synovial fluid conce ntrations sufficient to inhibit the activities of both proteinases. Th e antirheumatic drugs demonstrated similar inhibition profiles in puri fied or partially purified elastase preparations. Thus the leukocyte e xtract containing the partially purified elastase and cathepsin G whic h can be rapidly and easily prepared at low costs appears to be an eff icient mean of screening potentially new therapeutic agents for their ability to inhibit leukocyte elastase and cathepsin G.