Combination benefit of PEGylated soluble tumor necrosis factor receptor type I (PEG sTNF-RI) and dexamethasone or indomethacin in adjuvant arthritic rats.
OBJECTIVE
To determine the potential combination benefit receptor of treatment with PEGylated soluble tumor necrosis factor type I (PEG sTNF-RI) and dexamethasone (dex) or indomethacin (indo) in adjuvant arthritic rats.


METHODS
160 male Lewis Rats.


METHODS
PEG sTNF-RI, dex, indo.


METHODS
Rats with adjuvant arthritis were given daily oral dex (0.025 or 0.006 mg/kg) or indo (0.5 or 0.25 mg/kg) day 9-14, alone or in combination with PEG sTNF-RI (sc on days 9, 11, and 13 of arthritis). Efficacy was monitored by volume measurement of ankle joints, final paw weights and histologic evaluation with particular emphasis on bone lesions.


RESULTS
Treatment with 1 mg/kg PEG sTNF-RI alone resulted in 27% inhibition of final paw weights, dex alone (0.025 mg/kg) gave 25% inhibition and the combination resulted in 58% inhibition. Histologic evaluation of ankle joints demonstrated 48% inhibition of bone resorption with PEG sTNF-RI alone, 55% inhibition with dex alone and the combination treatment inhibited bone resorption by 100%. Inactive doses of PEG sTNF-RI (0.3 mg/kg) and dex (0.006 mg/kg) when combined resulted in 39% inhibition of paw swelling (AUC) and 39% inhibition of bone resorption. Combination treatment with indomethacin resulted in slight additive effects on inflammation parameters but no additive effects on bone resorption.


CONCLUSIONS
Combination therapy with PEG sTNF-RI and dexamethasone results in additive or synergistic effects depending on the dose. Combination therapy with indomethacin resulted in slight additive effects on paw swelling parameters, but no additive benefit on bone resorption. Data from these studies support the clinical investigation of the use of combination therapy of PEG sTNF-RI and dex or other corticosteroids in rheumatoid arthritis patients.
Bendele
A M
AM
BolderPATH, Inc., MCD Biology, University of Colorado, Boulder 80309, USA.
McComb
J
J
Gould
T
T
Frazier
J
J
Chlipala
E S
ES
Seely
J
J
Kieft
G
G
Wolf
J
J
Edwards
C K
CK
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy; D003907:Dexamethasone / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004487:Edema / Q000473:pathology; D005528:Foot / Q000473:pathology; D007213:Indomethacin / Q000627:therapeutic use*; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1; D011092:Polyethylene Glycols; D003907:Dexamethasone; D007213:Indomethacin