Oral bioavailability, efficacy and gastric tolerability of P2026, a novel nitric oxide-releasing diclofenac in rat.
The present study was designed to evaluate, P2026 [(2-((2-(nitrooxy)ethyl)disulfanyl)ethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate)], a novel NO (nitric oxide) donor prodrug of diclofenac for its ability to release NO and diclofenac, and whether P2026 provides advantage of improved activity/gastric tolerability over diclofenac. Oral bioavailability of P2026 was estimated from plasma concentration of diclofenac and nitrate/nitrite (NOx). Anti-inflammatory activity was evaluated in three different models of inflammation: acute (carrageenan-induced paw oedema), chronic (adjuvant-induced arthritis), and systemic (lipopolysaccharide-induced endotoxic shock). Gastric tolerability was evaluated from compound's propensity to cause gastric ulcers. P2026 exhibited dose-dependent diclofenac and NOx release. Similar to diclofenac, P2026 showed potent anti-inflammatory activity in acute and chronic model, whereas it improved activity in systemic model. Both diclofenac and P2026 inhibited gastric prostaglandin, but only diclofenac produced dose-dependent haemorrhagic ulcers. Thus, the results suggest that coupling of NO and diclofenac contribute to improved gastric tolerability while retaining the anti-inflammatory properties of diclofenac.
Pathan
Asif R
AR
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Karwa
Manoj
M
Pamidiboina
Venu
V
Deshattiwar
Jagannath J
JJ
Deshmukh
Nitin J
NJ
Gaikwad
Parikshit P
PP
Mali
Sunil V
SV
Desai
Dattatraya C
DC
Dhiman
Mini
M
Thanga Mariappan
T
T
Sharma
Somesh D
SD
Satyam
Apparao
A
Nemmani
Kumar V S
KV
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001169:Arthritis, Experimental / Q000188:drug therapy; D001682:Biological Availability; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D004008:Diclofenac / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D015232:Dinoprostone / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D011464:Epoprostenol / Q000096:biosynthesis; D005753:Gastric Mucosa / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D009566:Nitrates / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced
C553810:2-((2-(nitrooxy)ethyl)disulfanyl)ethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009566:Nitrates; D020030:Nitric Oxide Donors; D011355:Prodrugs; D004008:Diclofenac; D009569:Nitric Oxide; D011464:Epoprostenol; D015232:Dinoprostone