title: Oral bioavailability, efficacy and gastric tolerability of P2026, a novel nitric oxide-releasing diclofenac in rat.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Asif R
authors.initials: AR
authors.lastname: Pathan
authors.forename: Manoj
authors.initials: M
authors.lastname: Karwa
authors.forename: Venu
authors.initials: V
authors.lastname: Pamidiboina
authors.forename: Jagannath J
authors.initials: JJ
authors.lastname: Deshattiwar
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Deshmukh
authors.forename: Parikshit P
authors.initials: PP
authors.lastname: Gaikwad
authors.forename: Sunil V
authors.initials: SV
authors.lastname: Mali
authors.forename: Dattatraya C
authors.initials: DC
authors.lastname: Desai
authors.forename: Mini
authors.initials: M
authors.lastname: Dhiman
authors.forename: T
authors.initials: T
authors.lastname: Thanga Mariappan
authors.forename: Somesh D
authors.initials: SD
authors.lastname: Sharma
authors.forename: Apparao
authors.initials: A
authors.lastname: Satyam
authors.forename: Kumar V S
authors.initials: KV
authors.lastname: Nemmani
mesh_terms: 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
chemical_list: 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