Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat.
OBJECTIVE
Gastrointestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains a significant clinical problem. Hydrogen makes an important contribution to mucosal defense, and NSAIDs can suppress its synthesis. In this study, we evaluated the gastrointestinal safety and anti-inflammatory effects of a novel "HS-NSAID" (ATB-337) that consists of diclofenac linked to a hydrogen sulfide-releasing moiety.


METHODS
The gastrointestinal injury-inducing effects of single or repeated administration of diclofenac versus ATB-337 were compared in rats, as were their effects on prostaglandin synthesis and cyclooxygenase-1 and -2 activities. The ability of these drugs to reduce carrageenan-induced paw edema and to elicit leukocyte adherence to the vascular endothelium (intravital microscopy) were also examined in rats.


RESULTS
Diclofenac (10-50 micromol/kg) dose-dependently damaged the stomach, while ATB-337 did not. Repeated administration of diclofenac caused extensive small intestinal damage and reduced hematocrit by 50%. ATB-337 induced >90% less intestinal damage and had no effect on hematocrit. Diclofenac, but not ATB-337, elevated gastric granulocyte infiltration and expression of tumor necrosis factor alpha, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1. ATB-337 inhibited cycloxygenase-1 and cyclooxygenase-2 activity as effectively as diclofenac. ATB-337 did not induce leukocyte adherence, whereas diclofenac did, and was more potent at reducing paw edema.


CONCLUSIONS
An HS-NSAID spares the gastric mucosa of injury despite markedly suppressing prostaglandin synthesis. This effect may be related to hydrogen sulfide-mediated inhibition of tumor necrosis factor-alpha expression and of the leukocyte adherence to vascular endothelium normally induced by cyclooxygenase inhibitors.
Wallace
John L
JL
Inflammation Research Network, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada. wallacej@ucalgary.ca
Caliendo
Giuseppe
G
Santagada
Vincenzo
V
Cirino
Giuseppe
G
Fiorucci
Stefano
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005744:Gastric Acid / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects*
C517770:ATB 337; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D010975:Platelet Aggregation Inhibitors; D004008:Diclofenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D006862:Hydrogen Sulfide