TENIDAP AND FLURBIPROFEN ENHANCE UPTAKE OF MATRIX METALLOPROTEINASE INHIBITOR 4-DEDIMETHYLAMINOTETRACYCLINE IN INFLAMED JOINTS OF ADJUVANT ARTHRITIC RATS

Objective. To identify a mechanism by which a matrix metalloproteinase (MMP) inhibitor might act synergistically with other agents to decrea se MMP activity and thereby lessen the radiologic severity of adjuvant arthritis. Methods. Rats with adjuvant arthritis were treated with ei ther flurbiprofen (FBP) or tenidap (TDP), along with 4-dedimethylamino tetracycline (CMT-1), a potent MMP inhibitor. Indices of inflammatory severity and of radiologic destruction were assessed and compared to s erum and bone levels of the MMP inhibitor. Results. Combination therap y with the MMP inhibitor plus either of the other drugs led to synergi stic improvement in radiologic severity. For example, CMT-1 combined w ith TDP reduced radiologic severity 45% while decreasing collagenase a nd gelatinase activities by 61 and 72%, respectively more than doublin g bone CMT-1 levels (7.6 mu g/g to 16.4 mu g/g). FBP had similar effec ts. Conclusion. MMP inhibitors need access to the arthritic joint to i nteract with their target enzymes. Concomitant antiinflammatory therap y is required to assure drug entry into the inflamed tissues.