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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.

Pharmacokinetics and Efficacy of Topically Applied Nonsteroidal Anti-Inflammatory Drugs in Retinochoroidal Tissues in Rabbits

“…Earlier studies showed that the IC 50 of bromfenac was 0.0864 µM for COX-1 and 0.0112 µM for COX-2. The IC 50 of amfenac was 0.138 µM for COX-1 and 0.00177 µM for COX-2, [23] and it was also 0.25 µM for COX-1 and 0.15 µM for COX-2 [24]. Walters et al reported that the IC 50 was affected by the exposure time and/or the species from which the COX enzymes were obtained [23].…”

Topical Nonsteroidal Anti-Inflammatory Therapy in Ophthalmology

“…However, the analysis of NSAID-associated corneal events should implicate the exact diagnosis and reason for treatment, knowledge of concurrent topical and general drug therapy and the diagnosis of any other ocular disease in each case. Dry eyes or the concurrent use of topical corticosteroids or antibiotics might be identified as possible cofactors of other causes that lead to severe corneal damage using topical NSAIDs [140, 141, 142, 143, 144, 145]. For this reason NSAIDs should be applied at least under special awareness of such potential cofactors.…”

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“…In the eye, nepafenac is converted by intraocular tissue hydrolases into amfenac, an active derivative that is more potent [13,14]. Inflammatory process involves many mediators such as prostaglandin, leukotrienes, vascular endothelial growth factor and interleukins.…”

“…Inflammatory process involves many mediators such as prostaglandin, leukotrienes, vascular endothelial growth factor and interleukins. Antiinflammatory effects of NSAIDs are mainly by inhibition of Cyclooxygenase (COX) activity which reduces prostaglandin production [14,15]. By blocking prostaglandin synthesis which is one of the inflammatory mediators, NSAIDS are shown to be effective in inhibiting the blood-retinal barrier breakdown thus reducing vascular hyperpermeability [11,13,16].…”