Effect of S-diclofenac, a novel hydrogen sulfide releasing derivative, on carrageenan-induced hindpaw oedema formation in the rat.
S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester) is a novel derivative of diclofenac which, in vivo, undergoes enzymatic cleavage of its ester linkage to release hydrogen sulfide (H(2)S) along with the parent moiety, diclofenac. In this study the anti-inflammatory activity of S-diclofenac and diclofenac was studied in a carrageenan-evoked hindpaw oedema model in the rat. Drugs or vehicle were administered 3 h before carrageenan. Both drugs produced a dose-dependent anti-inflammatory effect in this model. However, S-diclofenac (ED(30), 14.2+/-0.6 micromol/kg) was more potent (P<0.05) than diclofenac (ED(30), 39.3+/-1.4 micromol/kg) as an inhibitor both of hindpaw swelling and in reducing the carrageenan-evoked rise in hindpaw myeloperoxidase activity reflecting tissue neutrophil infiltration (ED(50)s of 12.0+/-2.1 micromol/kg and 21.9+/-2.0 micromol/kg). Intraplantar carrageenan injection also significantly (P<0.05) increased hindpaw concentrations of prostaglandin E(2) (PGE(2)), nitrite/nitrate and H(2)S synthesizing activity measured at 6 h. Both S-diclofenac and diclofenac pretreatment reduced the carrageenan-induced rise in hindpaw PGE(2), nitrite/nitrate and H(2)S synthesizing activity. Whilst treatment with either drug produced similar inhibition of hindpaw PGE(2) and H(2)S synthesizing activity--S-diclofenac more effectively reduced hindpaw nitrite/nitrate concentration than did diclofenac. It is proposed that the enhanced anti-inflammatory effect of S-diclofenac relates to its ability to release H(2)S at the inflamed site. These data provide evidence for an anti-inflammatory effect of H(2)S.
Sidhapuriwala
Jenab
J
Department of Pharmacology, Cardiovascular Biology Research Group, Yong Loo Lin School of Medicine, National University of Singapore, 18 Medical Drive, Singapore, 117597, Singapore.
Li
Ling
L
Sparatore
Anna
A
Bhatia
Madhav
M
Moore
Philip K
PK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D002351:Carrageenan; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D006614:Hindlimb / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007267:Injections; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013871:Thiones / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
C520611:2-((2,6-dichlorophenyl)amino)benzeneacetic acid 4-(3H-1,2-dithiol-3-thione-5-yl)phenyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009566:Nitrates; D009573:Nitrites; D013871:Thiones; D004008:Diclofenac; D002351:Carrageenan; D009195:Peroxidase; D015232:Dinoprostone; D006862:Hydrogen Sulfide