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 decrease MMP activity and thereby lessen the radiologic severity of adjuvant arthritis.


METHODS
Rats with adjuvant arthritis were treated with either flurbiprofen (FBP) or tenidap (TDP), along with 4-dedimethylaminotetracycline (CMT-1), a potent MMP inhibitor. Indices of inflammatory severity and of radiologic destruction were assessed and compared to serum and bone levels of the MMP inhibitor.


RESULTS
Combination therapy with the MMP inhibitor plus either of the other drugs led to synergistic improvement in radiologic severity. For example, CMT-1 combined with TDP reduced radiologic severity 45% while decreasing collagenase and gelatinase activities by 61 and 72%, respectively, more than doubling bone CMT-1 levels (7.6 micrograms/g to 16.4 micrograms/g). FBP had similar effects.


CONCLUSIONS
MMP inhibitors need access to the arthritic joint to interact with their target enzymes. Concomitant antiinflammatory therapy is required to assure drug entry into the inflamed tissues.
Department of Chemistry, State University of New York/Old Westbury 11568, USA.
M K
MK
Leung
R A
RA
Greenwald
N S
NS
Ramamurthy
S A
SA
Moak
R
R
Koszulinski
D
D
Dieudonne
L M
LM
Golub
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005480:Flurbiprofen / Q000627:therapeutic use*; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D000078183:Oxindoles; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D013752:Tetracycline / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D000078183:Oxindoles; D011480:Protease Inhibitors; C053450:4-des-dimethylaminotetracycline; D005480:Flurbiprofen; C062866:tenidap; D017364:Collagenases; D018093:Gelatinases; D013752:Tetracycline