title: Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I. Assessment of anti-inflammatory efficacy.
abstract: Nepafenac, the amide analog of 2-amino-3-benzoylbenzeneacetic acid (amfenac), was examined in preclinical models for its potential utility as a topical ocular anti-inflammatory agent. Diclofenac was selected as the reference compound. In contrast to diclofenac (IC50 = 0.12 microM), nepafenac exhibited only weak COX-1 inhibitory activity (IC50 = 64.3 microM). However, amfenac was a potent inhibitor of both COX-1 (IC50 = 0.25 microM) and COX-2 activity (IC50 = 0.15 microM). Ex vivo, a single topical ocular dose of nepafenac (0.1%) inhibited prostaglandin synthesis in the iris/ciliary body (85-95%) and the retina/choroid (55%). These levels of inhibition were sustained for 6 h in the iris/ciliary body and 4 h in the retina/choroid. Diclofenac (0.1%) suppressed iris/ciliary body prostaglandin synthesis (100%) for only 20 min, with 75% recovery observed within 6 h following topical dosing. Diclofenac's inhibition of prostaglandin synthesis in the retina/choroid was minimal. Nepafenac's inhibitory efficacy and longer duration of action was confirmed in a trauma-induced rabbit model of acute ocular inflammation monitoring protein or PGE2 accumulation in aqueous humor. Results warrant further assessment of nepafenac's topical ocular efficacy in the treatment of postoperative ocular pain, inflammation, and posterior segment edema.
authors.affiliation: Pharmaceutical Products Research, Alcon Research, Ltd., Fort Worth, Texas, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Gamache
authors.forename: G
authors.initials: G
authors.lastname: Graff
authors.forename: M T
authors.initials: MT
authors.lastname: Brady
authors.forename: J M
authors.initials: JM
authors.lastname: Spellman
authors.forename: J M
authors.initials: JM
authors.lastname: Yanni
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D005128:Eye Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010648:Phenylacetates / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis; D011817:Rabbits
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D010648:Phenylacetates; D011355:Prodrugs; D011453:Prostaglandins; D004008:Diclofenac; C014285:amfenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone