Enhancement of the anti-inflammatory and anti-arthritic effects of theophylline by a low dose of a nitric oxide donor or non-specific nitric oxide synthase inhibitor.
OBJECTIVE
Although there are many new specific phosphodiesterase inhibitors with anti-inflammatory activity, none have yet reached the market because of their low therapeutic efficacy. Our study was aimed to evaluate the anti-inflammatory and anti-arthritic effect of an established phosphodiesterase inhibitor, theophylline, and to investigate the effect of the nitric oxide (NO) donor, sodium nitroprusside (SNP) or NO synthase inhibitor, L-N(G)-monomethyl arginine (L-NMMA) on its actions.


METHODS
The effects of theophylline alone and combined with SNP or L-NMMA on the pathogenesis of adjuvant-induced arthritis in rats were evaluated.


RESULTS
Prophylactic or therapeutic doses of theophylline significantly ameliorated the pathogenesis of adjuvant arthritis in rats as evidenced by a significant decrease in the arthritis index, hind paws volume, ankle joint diameter, fever, body weight loss and hyperalgesia in a dose-dependent manner. Inflammatory cellular infiltrate in synovium of ankle joint and pannus formation were also markedly inhibited. Interleukin-10 (IL-10) levels were significantly increased in arthritic rats given theophylline alone or in combination with either SNP or L-NMMA. Co-administration of a low dose of SNP or L-NMMA enhanced significantly the anti-inflammatory and anti-arthritic effect of theophylline. In contrast, a high dose of SNP counteracted the anti-inflammatory and anti-arthritic effects of theophylline.


CONCLUSIONS
These findings confirm the anti-inflammatory and anti-arthritic activities of theophylline and suggest a new approach to enhance the anti-inflammatory and anti-arthritic effects of theophylline would be to administer it in combination with a low dose of a NO donor or a non-specific NO synthase inhibitor.
Gomaa
Adel
A
Department of Pharmacology, Faculty of Pharmacy, Taibah University, Al-madinah Almunawwarah, KSA. a.gomma@aun.edu.eg
Elshenawy
Mohsen
M
Afifi
Noha
N
Mohammed
Eman
E
Thabit
Romany
R
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D016753:Interleukin-10 / Q000097:blood; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D016753:Interleukin-10; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D013806:Theophylline; D019001:Nitric Oxide Synthase