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© Military Pharmacy and Medicine • 2012 • 4 • 46 – 50Review article(0.06 mg/mL) and octoxynol-40 (chemicallyinert detergent, also known as Triton X-100).Acular PF contains a 0,5% solution of ketorolac/tromethamine, without preservatives, i.e. benzalkoniumchloride and octoxynol-40; it isavailable as single use 0.4 mL vials (12 vials perpack). Acuvail (registered by US FDA in July2009 r.) contains a 0.45% solution of ketorolac/tromethamine without preservatives and withthe addition of carboxymethyl cellulose (CMC)which enhances the adhesion of drops to theconjunctiva and cornea [29, 30].Acular (0.5% Ophthalmic Solution) was approvedby the US FDA to be used after cataractsurgeries: 1 drop 4 times per day starting 24h after the procedure for 2 weeks. The officialindications of the drug include also the treatmentof itching that accompanies allergic conjunctivitis.Acular LS is officially registered foruse in reduction of ocular pain and burningafter cataract surgeries, while the newest product,Acuvail, is used in the treatment of painand inflammation after cataract removal. Thedrug may also be used to relieve ocular itchingdue to allergic conjunctivitis (dosage: 1drop — 0.25 mg of the drug 4 times a day) andto treat post-operative inflammation in patientsundergoing surgeries for cataract (1 drop 4times a day starting from the second day afterthe procedure for 2 weeks). According to themanufacturer, the strength of the anti-inflammatoryeffect of ketorolac is comparable to thatof 0.1% diclofenac.Pranoprofenα-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid or α-methyl-2-(5H-chromeno[2,3-b]pyridin-7-yl)propanoic acid [C 15 H 13 NO 3 ; MW255,27 g/mol] — a derivative of arylpropionic acid.Pranoprofen (an original product of Yoshitomi Pharmaceuticals,Osaka, Japan) is characterized by a stronganti-inflammatory and analgesic and a weaker antipyreticaction. It was taken by cooperating pharmaceuticalcompanies Yoshitomi and Senju (Osaka) to produceophthalmic drug under the name Niflan.Niflan (Senju, Osaka; the drug known outsideJapan under various names: Oftalar,Pranofen, Pranoflog, Pranox) — 0.1% eyedrops (1 mg pranoprofen/mL). The drug46 http://military.isl-journals.comwas registered in Japan in 1988 and is availableuntil now in some Asian and Europeancountries (Japan, China, Belgium, Italy,Portugal, Spain and Turkey). The drug doesnot possess US FDA registration and is notused in the US. In clinical studies beforeregistration, pranoprofen was shown to produceirritation of conjunctiva, the effect beingeventually eliminated using a combinationof components in future drug formulaof which boric acid appeared to be a crucialcomponent (it is worth of mention that boricacid occurs in formulas of many ophthalmicNSAIDs); other components include:polysorbat-80 and benzalkonium chloride(0.007% = 0.07 mg/mL) and disodium edetate[31].Therapeutic indications for Niflan include inflammationfollowing eye surgery, blepharitis,conjunctivitis and keratitis. Dosage: 1-2 drops 4xduring the day for a period necessary for completeresolution of the symptoms of inflammation.Fenoprofenα-methyl-2-(3-phenoxyphenyl)propionic acid[C 15 H 14 O 3 ; MW 242,27 g/mol] — a derivative ofarylpropionic acid.As mentioned before, fenoprofen ophthalmicdrops were tested in preclinical and clinicalstudies as an ophthalmic anti-inflammatoryand analgesic agent. Eye drops containing 1%solution of fenoprofen as hydrated sodium saltwere tested mostly for prevention of uveitis. Althoughthe efficacy of ophthalmic fenoprofenwas comparable to that of 1% dexamethazonein a rabbit uveitis model [32], the obtained resultswere not very encouraging and the studiesshowed no progress. No positive results werealso obtained in the clinical trials of 1% fenoprofensodium solution in patients with aphakiceyes and chronic cystoid macular edema [33].In consequence, fenoprofen was not introducedas an ophthalmic drug, although its dihydratecalcified form is registered in the US under thetrade name of Nalfon (fenoprofen calcium capsules,USP; 200 mg and 400 mg capsules; PedinolPharmacal, Inc.) for use in e.g. rheumatoidarthritis, osteoarthritis or acute gout episodes.
© Military Pharmacy and Medicine • 2012 • 4 • 47 – 50ConclusionPolish ophthalmologists have currently sixNSAID products at their disposal. Three productscontain diclofenac and, from medical standpoint,are practically identical (although it shouldbe mentioned that one of these products containsno preservative) and can be used interchangeably.One medication contains indomethacin — an activesubstance that has been known in medicalpractice for the longest time. The list is completedby two relatively new fenacs: nepafenac and bromfenac.In the Pharmindex–Okulistyka [Ophthalmology]2012 handbook, the latter two drugscontained in Nevanac and Yellox products areannounced in the part titled New registrations,although, to be exact, both were some time agothe pioneer drugs in the worldwide market ofophthalmic preparations.However, in Poland, Nevanac (nepafenac) andYellox (bromfenac) are new drugs, and thereforemost commonly referred to in current discussions,although the remaining compounds(mainly diclofenac products) are still extensivelyused in worldwide practice.However, let us focus on these two products thatare new to the Polish market. Nevanac containsthe active substance amfenac administered asa precursor compound, nepafenac. Yellox containsthe active substance bromfenac, whichdiffers from amfenac by a bromine atom in thebenzene ring. In other words, bromfenac is abrominated amfenac. The difference may seemsmall, but is a significant one in practical terms.Similarly to other halogens, i.e. fluorine, chlorineor iodine, the non-metal bromine modifiedthe properties of the structure it is boundto — for example, halogenated structures usuallypenetrate cell membranes better. In consequence,bromfenac, when administered intraconjunctivally,would easier/faster penetrateinto the eye than amfenac, which would affectthe concentrations achieved by both compoundsin ocular structures and fluids (cornea,aqueous humor, iris/ciliary body, uvea). Thus,bromfenac would faster reach higher concentrationsat target site (of potential or ongoing inflammation)compared to amfenac. However, itis not amfenac that is the ingredient of the Nevanacdrug — it is nepafenac, which is an amidederivative of amfenac, converted to amfenac inhttp://military.isl-journals.comJerzy Z. Nowak: Non-steroidal anti-inflammatory drugs (NSAIDs) in …ocular tissues by means of ubiquitous hydrolaseenzymes. Nepafenac is, by comparison, a poorPGHS inhibitor (IC 50 = 64 μM against COX-1),but it penetrates into ocular tissues faster thanamfenac; there it is transformed into amfenac,which is a highly active PGHS inhibitor (IC 50 =0.25 μM — COX-1 and 0.15 μM — COX-2) [22].To sum up these considerations, one might saythat the use of a prodrug formula in Nevanacfunctionally balances out the presence of bromineatom in the structure of bromfenac (Yellox). Istherefore the therapeutic efficacy of Yellox (aqueoussolution) and Nevanac (suspension) clinicallycomparable? Theoretically, yes, althoughophthalmologists should remember that everypatient is a non-fully-predictable individual whodoes not have to respond in the same mannereven to very similar drugs. This is due to the factthat drugs contain not only active substances,but also excipients which might have multidirectional,non-specific effects. With regard to thelatter, both Nevanac and Yellox contain benzalkoniumchloride (0.05%) and disodium edetatepreservatives, but differ in all other excipients:Nevanac contains mannitol, carbomer 974P, andtyloxapol, while Yellox contains boric acid, polysorbate80, and povidone. In addition, both compoundshave different pH values: 7.4 vs. 8.3 andslightly different (albeit comparable) osmolarity:305 vs. 300 mOsmol/kg.With reference to the discussion on nepafenacand bromfenac, one should also ask whether thediclofenac products (Dicloabac, Difadol 0.1%,Naclof) are therapeutically different from Yelloxand Nevanac? There is no definitive answer tothis question. In the author’s opinion, the newerfenacs have advantages over the older ones, butthe treatment success is determined by patient’sresponse, both in the terms of therapeutic activityand adverse events. The planned duration oftherapy and frequency of application may alsoprovide a hint when making therapeutic decisions,as both these parameters prefer safer drugs,i.e., in this case, the newer products. However, itmust also be stressed that the therapeutic, i.e.anti-inflammatory and analgesic effects will beachieved with all currently available ophthalmicNSAIDs. Short-term treatments are not as rigorousas long-term ones; the armory of drugs availablefor use over several or a dozen or so days isthus very wide.47
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