Anti-Inflammatory Drugs Amy J. Rankin Diplomate ACVO Associate Professor Ophthalmology Kansas State University

• • NSAIDs Corticosteroids

• Adrenal gland • – Zona fasciculata – Zona reticularis – Anti-inflammatory – Metabolic – Immune • Mineralocorticoids

– Zona glomerulosa www.news-medical.net – Electrolyte & water balance

Riviere & Papich, Veterinary Pharmacology & Therapeutics, 10th Ed Glucocorticoids • Anti-inflammatory – Inhibition of angiogenesis – Reduces leukocyte migration – Decreased capillary permeability – Decreases WBC degranulation • Effects on tissue regeneration – Decreased fibroblastic & collagen formation – Increased collagenolytic activity – Decreased wound healing

• Loewenberg et al.,Trends Molec Med, 2007

Loewenberg et al., Trends Molec Med, 2007

Glucocorticoids-Transrepression

• GC binds to receptor in cytoplasm • GC-receptor translocates to nucleus • Binds to negative GRE • Down regulation of pro-inflammatory proteins (IL-1 & IL-2) Glucocorticoids-Transrepression

• GC binds to receptor in cytoplasm • GC-receptor interacts with transcription factors (TF) NF- ĸβ, AP-1 • GC-receptor complex or TFs do not bind to pro- inflammatory GREs • Down regulation of pro-inflammatory and immune stimulation factors Glucocorticoids-Transrepression

• GC binds to receptor in cytoplasm • GC-receptor translocates to the nucleus • GC-receptor binds to nuclear coactivators – AP-1 • Inhibition of pro-inflammatory protein proteins Glucocorticoids-Transactivation

Stahn et al., Molecular and Cellular Endocrinology, 2007) • GC diffuses through cell membrane • GC binds to receptor in cytoplasm • GC-receptor translocates to nucleus • Binds to GC response element (GRE) in target gene • Up-regulation of anti-inflammatory, immunomodulatory, and metabolic processes

Non-genomic MOA

• High dose therapy • Rapid onset of clinical effects – Anti-inflammatory – Immunosuprression Non-genomic MOA

• GC interact with cellular membranes – Reduced Ca and Na transport across membranes of immune cells – Rapid immunosuppression

Non-genomic MOA

University of Tokyo

• GC-receptor binding causes protein complex dissociation so GC-receptor translocates to nucleus

• Heat shock proteins & kinases that are released mediate various rapid intracellular effects

• GC-receptor inhibits release of AA from plasma membrane via transcription-independent mechanism

Non-genomic MOA

• GC effects mediated by a membrane- bound GC receptor • Upregulation of membrane GC receptor during immunostimulation • GC-induced membrane bound GC receptor-mediated apoptosis

Anti-inflammatory Effects of Glucocorticoids • Inhibition – Pro-inflammatory transcription factors • AP-1 • NF- ĸβ • STAT – Expression of pro-inflammatory cytokines • IL1-6, IL 11-13, IL 16, & IL 17 • Interferon –γ • TNF • GM-CSF

Anti-inflammatory Effects of Glucocorticoids • Synthesis – Anti-inflammatory proteins • Lipocortin

– Inhibits phospholipase A2 • IL-10 • Annexin-1 • Mitogen-activated protein kinase phosphatase-1 – Decreased transcription of pro-inflammatory genes

Immunosuppressive Effects of Glucocorticoids • Decrease number and function of B &T cells – Inhibition of NF-ĸβ • Induction of TGF-β expression – Blocks cytokine synthesis and T-cell activation • Inhibition of humoral immunity – Decreased synthesis of IL-2 & IL-2 receptors • Inhibition of cell-mediated immunity – Inhibition of multiple interleukins (IL-1, IL-2, IL-3, IL-6) GC Side Effects • Systemic – Gluconeogenesis – Breakdown of muscle – Effects on psyche – Diabetogenic – Suppression of HPAA – Osteoporosis – PU/PD • Inhibition of ADH release and action

GC Side Effects

• Ophthalmic – Cataract – Ocular hypertension – Decreased wound healing – Potentiate infection – Corneal lipid deposition

GC-Induced Cataract

• Humans posterior subcapsular cataracts • Oral, topical, cutaneous, inhalation... • Dose and duration dependent • Children more sensitive • Reported prevalence 22% – 0-90% GC-Induced Cataract

• Not well documented in SA • Experimentally-induced cats – Topical NaP or – Subscapular cataracts after 40 days of therapy Zhan et al., Experimental Eye Research, 1992

Etiology of GC-Induced Cataract

• Etiology of GC-induced cataract – Unknown – Decrease in lens – Alterations in lens hydration • Modulation of NaKATPase – Aberrant posterior LEC migration – Alteration in ocular growth factors? GC Ocular Hypertension • Systemic, periocular, topical, inhalational routes... • High responder – 15 mmHg increase • Moderate responder – 6-15 mmHg increase

Phulke S et al., J Curr Glaucoma Practi 2017 Becker B, Invest Ophthalmol, 1965 Becker B & Chevette L, Am J Ophthalmol, 1964 Becker B & Hahnka L, Am J Ophthalmol, 1964

GC Ocular Hypertension

• Generally reversible • Risk factors in humans: – Glaucoma suspects (30%) – POAG patients (90%) – High myopia – History of refractive surgery – Bimodal age distribution (<10 years and older adults) – Diabetes mellitus – Genetics

Morales J & Good D, J Cataract Refract Surg, 1998 Podos SM et al., Am J Ophthalmol, 1966 Armaly MF, Arch Ophthalmol, 1963 Becker B, Am J Ophthalmol, 2971 Etiology of GC Hypertension

• Decrease in outflow facility • Accumulation of extracellular material in the TM • Increased expression laminin & myocilin TM cells • Activation of GC receptors in TM • Increased type IV collagen, heparin sulfate proteoglycan, fibronectin

Clark AF et al, Invest Opthalmol Vis Sci, 2001 Johnson et al., Arch Ophthalmol, 1997 Dickerson JE et al, Exp Eye Res, 1998 Tawara A et al., Glaucoma, 2008 GC Ocular Hypertension-Dogs

• Beagles with POAG – 2 weeks topical 0.1% dex QID – Mean IOP increase 5 mmHg – Returned to baseline within 1 week

• Normal dogs – Oral 3.3 mg/kg TID 5 weeks – No significant increase in IOP

Gelatt KN & Mackay EO, J Ocul Pharmacol Ther, 1998 Herring IP et al., Vet Ophthalmol, 2004 GC Ocular Hypertension Normal Cats – Topical 0.1% dex or 1% prednisolone TID for 4 weeks – Significant increase in IOP with 2-3 weeks – Mean IOP increase 4.5 mmHg greater than control cats – IOP values quickly returned to normal Bhattacherjee P et al., Arch Ophthalmol, 1999 – Topical 1% dex NaP BID or TID or 1% prednisolone BID – Significant increase IOP that was reversible Zhan G et al., Exp Eye Res, 1992

GC Ocular Hypertension - Cats

• 0.1% dexamethasone or 1% prednisolone BID • Normal cats (n=5) – 2/5 increased IOP compared to contralateral eye (maximum 6.4 mmHg) • Feline congenital glaucoma cats (n=11) – 8/11 increased IOP compared to contralateral eye (maximum 56 mmHg) • Mild 3 cats (<15 mmHg) • Moderate 2 cats (15-25 mmHg) • Marked 3 cats (>25 mmHg) • Values returned to baseline within 7-10 days

Gosling et al., Vet Ophthalmol, 2016 GC Ocular Hypertension

• Normal cows (Herford and Brahman X) • 1% prednisolone TID 7 wks • 100% of cows increased IOP after 3 weeks of therapy (maximum 15 mmHg)

• Normal sheep (Corriedale) • 0.5% prednisolone TID 3-4 wks • 100% of sheep increased IOP after 2 weeks (~16 mmHg difference) Gerometta R et al., Arch Ophthalmol, 2004 Gerometta R et al., Inves Ophthalmol Vis Sci, 2009 GC Ocular Hypertension - Cows • Normal cows (Herford and Brahman X) • 1% prednisolone TID • Altered gene expression in TM • Expression of 258 genes upregulated 187 genes downregulated in TM • Genes coding for cytoskeletal proteins, enzymes growth & transcription factors, immune response proteins

Danias J et al., Invest Ophthalmol Vis Sci, 2011 GC Corneal Wound Healing • Increase lytic action of collagenase • Delay wound healing • Decreased collagen deposition • Decreased stromal keratocyte proliferation • In vitro dexamethasone less cytopathic effect on cultured epithelial cells than prednisolone Hendrix DH et al., Vet Ophthalmol, 2002 GC Systemic Side Effects • Suppression of HHAA – Dogs 1% prednisolone QID 2 weeks • Adrenal suppression & liver changes – 0.1% dexamethasone QID OU • Mean 0.03mg/kg of body weight/day • Suppression of ACTH-stimulated – 2 subconjunctival injections 10 mg (3 weeks) • Iatrogenic Cushing's disease

Eichenbaum J et al., J Am Anim Hosp Assoc,1988 Roberts et al, Am J Vet Res, 1984 Glaze et al., J Am Vet Med Assoc, 1988 Regnier, Res Vet Sci, 1982 Murphy, J Am Animal Hosp Assoc, 1990 GC Systemic Side Effects

• Humans topical dexamethasone – Diabetics significant increase in BG at 1 month • Diabetic dogs topical 1% – No significant difference in BG curves, fructosamine or clinical scores between or prednisolone • Diabetic rats & humans subconjunctival injection dexamethasone – Increased BG

Bahr, Curr Eye Res, 2007 Rankin AJ et al., Proc ACVO, 2017 Faukushima, Eye, 2001 Fukushima, J Cataract Refract Surg, 2001 GC Side Effects

• Calcific band keratopathy – Humans & horses • Lipid keratopathy?? – Dogs • Bilateral exophthalmos – Calves parenteral dexamethasone – 30 mg/kg BID noted after 28 days

Berryhill et al., Vet Ophthalmol, 2017 Brooks, Equine Vet J, 2012 Taravella et al., Arch Ophthalmol, 1994 Townsend et al., Vet Ophthalmol, 2003 Minimize GC Side Effects

• Long-circulating liposomal GC • Selective GCR agonists (SERGAs) • Selective GCR modulators (SEGMs)

• Sustained action of • Decreased dose • Less frequent dosing interval Liposomal Glucocorticoids

• Liposomes – Phospholipid bilayer – GC in lumen – PEG polyethylene glycol • Modification of surface to increase stability and t1/2 • Medial applications – Cancer, RA, asthma, Parkinson’s dz... Liposomal Prednisolone

• Human colon carcinoma T-84 cell lines – Direct antiproliferative effect Lorente C et al., J Pharm Pharmacol, 2018

• Transgenic mice – Mouse mammary tumor virus – Inhibition of tumor growth Deshantri AK, et al., J Cont Release, 2016 • Therapeutic approach is not curative Selective GCR Modulators (SEGRMs) Selective GCR Agonists (SERGAs) SERGAMs • Promote a receptor conformation – Results in transrepression • Expectation – Efficacy of higher dosages – Safety profile of lower dosages of GC SEGRAMs • (PF-04171327) – Phase 2 randomized study – 10 and 25 mg improved signs in RA patients • Dagrocorat (PF-00251802) – Selective high-affinity partial agonist of GR – Potential for RA patients • (BOL-303242-X) – – Inflammatory skin disorders Stock T, et al., Int J Rheum Dis, 2017 Ripp et al., Clin Pharmacol Drug Del, 2018 Baiula & Spampinato, Inflamm Allergy Drug Targets, 2014 Fosdagrocorat Beagle Study

– Fed ad lib & or fosdagrocorat • Glomerulopathy • Increased urine volume, decreased SG • Body weight gain – Food restriction & prednisone or fosdagrocorat • Reduction in serum cortisol and eosinophils • Increased urine volume, decreased SG – Prednisone-treated dogs fed ad lib had more renal effects than fosdagrocorat-treated dogs

Radi et al., Int J Toxicol, 2018 Mapracorat • Phase II clinical trials • Topical ocular treatment – Allergic conjunctivitis – Reduces clinical symptoms – Decreases eosinophil recruitment – Decreases pro-inflammatory cytokine production – Induces a lower increase of IOP (dex) • Atopic dermatitis/psoriasis

Baiula & Spampinato, Inflamm Allergy Drug Targets, 2014 Selective GR Modulator (SEGRM)

Sundahl N et al., Pharmacology Therapeutics, 2015 Relative Potency

GC Effect MC Effect Duration Hydrocortisone 1 1 8 h Prednisone/ 4 0.8 16-36 h prednisolone 5 0 12-36 h Methylprednisolone 5 0 5 h 20 125 24 h Dexamethasone 25 0 36-54 25 0 36-54 h Ophthalmic Corticosteroids

• Ocular bioavailability – Corneal ulceration – Presence of uveitis

• Topical • Subconjunctival • Intravitreal • Systemic Ophthalmic Corticosteroids

• Blepharitis • Conjunctivitis • Keratitis • Anterior uveitis • Posterior uveitis • Episcleritis • Optic neuritis... Ophthalmic Formulations

Derivative Solubility Formulation Relative anti-inflammatory efficacy Prednisolone Lipid Suspension 50% 55% Ointment Alcohol Intermediate Suspension 40% (lipid) Ointment Phosphate Water Solution 30-45% 20% Bioavailability (ug/min/g) Anti-inflammatory Efficacy EPITHELIUM Intact Absent Intact Absent Pred acetate 2395 4574 51 53 1.0% Pred phosphate 1075 16338 28 47 1.0% Dex acetate 111 118 55 60 0.1% Dex alcohol 543 1316 40 42 0.1% Dex phosphate 1068 4642 19 22 0.1%

Adapted from Leibowitz Hm, Kupferman A. Use of corticosteroids in the treatment of corneal inflammation. Corneal Disorders: clinical diagnosis and management. 1984 Prednisolone

• Acetate has greater anti-inflammatory efficacy compared to phosphate • Acetate may have increased affinity for GR • Increasing concentration to 1.5 or 3% does NOT increase anti-inflammatory effect • Commercially available 1.0% and 0.125% Prednisolone Acetate 1%

Total # doses Decrease Corneal Inflammation (%) q4h 6 11 q2h 10 30 q1h 18 51 q30min 34 61 q15min 66 68 q1min for 5 minutes 90 72 each hour

Leibowitz HM & Kupferman A, Int Opthalmol Clin, 1980 Prednisolone Acetate-Dogs • Two pre-op protocols – TID 1 week before cataract surgery – 1 drop 3 times the evening prior to sx and 4 times the morning of surgery

– No difference in BAB disruption at day 2 or 9 post surgery – Higher incidence (60%) POH for 1 week group than 1 day group (18%)

McLean NJ, et al., JAVMA, 2012

Prednisolone Actetate-Cats

• BAB disruption with AC paracentesis • Laser flaremetry at 4, 8, 26 h • 1% prednisolone acetate reduced flare at 4, 8, and 26 h • 0.1% diclofenac reduced flare at 8 & 26 h • 0.1 dexamethasone reduced flare at 4 h

Rankin AJ, et al, AJVR, 2011 Dexamethasone • Anti-inflammatory efficacy of alcohol greater than sodium phosphate with or without intact corneal epithelium • Alcohol--suspension • Sodium phosphate--solution or ointment • In humans – Detectable in AH within 30 minutes – Peak levels btwn 90-120 minutes – Detectable levels in AH at 12 hours

Triamcinolone Acetonide Intravitreal Injection • Humans – Chronic uveitis, macular edema, proliferative diabetic retinopathy – Long duration of action (5-6 months) • Complications – Cataract (15-20%) – Ocular hypertension (40%) – Retinal – Infectious endophthalmitis (1:1000) Ozkiris A & Erkilic K, Can J of Ophthalmol, 2005 Jonas JB, Act Ophthalmol Scand, 2005 Torriglia A, et al., Bichem Pharmacol, 2010 Intravitreal Injection • Equine Yi NY et al., Vet Ophthalmol, 2008 – 10, 20, 40 mg vehicle-free triamcinolone – No overt toxicity normal eyes – Sustained drug concentration for 3 weeks – Bacterial contamination in 33.3% (4/12)

“Soft” Steroids

• 0.2% & 0.25% suspension/ointment • 1% suspension • 0.2 & 0.5% suspension/ointment • Lower propensity to increase IOP • Lack the anti-inflammatory efficacy of prednisolone and dexamethasone

Loteprednol Etabonate

• Normal cats • Topical dexamethasone, prednisolone, fluorometholone, rimexolone, loteprednol • IOP elevation least pronounced with loteprednol (highest with prednisolone and dexamethasone 4.5 ± 0.3mmHg) • IOP returned to baseline after discontinuation

Bhattacherjee et al., Arch Ophthalmol, 1999 Non-Steroidal Anti-Inflammatory Drugs

• • Released in tissue damage – COX-1, COX-2 (PGH synthase=COX) – – , , • Autacoids • Short lived

Praveen et al., J Pharm Pharmaceut Sci, 2008 Prostaglandins • Ocular effects – Miosis – Initial increase IOP followed by hypotony – Disruption of BAB – Vasodilation – Iris neovascularization – Corneal neovascularization • Produced by all ocular tissues (except lens) • PG receptors – Iris and ciliary body – Cat EP1 receptors iris sphincter and ciliary muscles FP receptors iris sphincter muscle Non-Steroidal Anti-Inflammatory Drugs

• COX-1 – Membrane bound – Endoplasmic reticulum – Constitutively in most tissues – Hemostasis, renoprotection, gastroprotection,

Non-Steroidal Anti-Inflammatory Drugs • COX-2 – Inducible • Stimulated by IL-1, TNF-α, LPS, and mitogens – Constitutive • Kidney, CNS, vascular endothelium, GIT, ovary, uterus, and ciliary body – Neoplastic cells – Production of pro-inflammatory PGs – Increase in COX-2 mRNA and protein production with inflammation • COX-2 not expressed in normal cat eyes • 16/44 eyes with uveitis expressed COX-2 in uvea

Sim et al., AJVR, 2018

NSAIDs

• 3500 yr ago • Willow leaves & bark • Salicyl alcohol – Colic, gout, fever... • 1875 – first synthetic NSAID • 1898 –

NSAIDs • Classification – Preferentially inhibit one isoform vs. the other – Inhibits isoenzyme by 50% Nonselectiv e COX COX-1 Preferential Selective COX-2 Inhibitors Inhibitors

Aspirin Indomethacin * Diclofenac Robenacoxicib* Carpforen

Selective COX-2 inhibitors COX-2 inhibition potency 5 to 30 fold greater than COX-1 * greater 50 fold potency for COX-2 inhibition

MOA NSAIDs

• COX-1 inhibition – Hydrogen bonding – Instantaneous – Competitively reversible (except for aspirin) • COX-2 inhibition – Covalent binding – Time dependent – Slowly reversible MOA NSAIDs • Similar active sites COX-1 & COX-2 • COX-2 • Substitution of valine for isoleucine - wider channel

COX in Tumor Development

• Chronic inflammation/infection – Human papilloma virus – cervical cancer – Hepatitis B & C viruses – hepatocellular carcinoma – Epstein-Barr virus – lymphoproliferative disorders – Helicobacter pylori – gastric neoplasia • Overexpression of COX-2 in tumors – Resistance to apoptosis – Angiogenesis – Promotion of tumor growth • Activation of NF- ĸβ • IL-1, IL-6, IL-8 TNF, VEGF-A COX in Tumor Development • High levels of COX-2 expression – Humans • Colorectal cancer, breast cancer, hepatocellular carcinoma, SCC of neck and head – Dogs • Nasal SCC, nasal carcinoma, renal carcinoma, transitional cell carcinoma, osteosarcoma – Horses • COX-1 and COX-2 significantly greater in equine corneas with SCC than control corneas • No significant difference in COX-1 or COX-2 eyelid or TEL SCC compared to control tissues McInnis CL, et al., AJVR, 2007 NSAIDs in Tumor Suppression

• Alter arachidonic acid metabolism – Increase AA available pathway – 15-LOX-1 • Induces apoptosis • Activation of p53 pathway • Alter gene expression – Increased NSAID Activated Gene (NAG-1) expression • Tumor growth inhibition • Increase apoptosis NSAIDs • Ophthalmic indications – Humans • Postoperative ocular inflammation – Diclofenac > > ketorolac > > flurbiprofen • Prevention of pseudophakic cystoid macular edema • Allergic conjunctivitis • Prevent intraoperative miosis cataract sx • Post refractive surgery (analgesia) • Decrease corneal sensitivity – Diclofenac > ketorolac > bromfenac > nepafenac

Duan et al., Graefes Arch Clin Exp Ophthalmol, 2017 et al., Cornea, 2015 NSAIDs • Ophthalmic indications – Veterinary medicine • Prevent intraoperative miosis cataract sx • Postoperative cataract surgery • Anterior uveitis • Analgesia ??? – Cats » Indomethacin, diclofenac and flurbiprofen » Decreased responsiveness of corneal nociceptors to chemical stimuli – Dogs Chen X, et al., IOVS, 1997 » Nonbrachycephalic dogs » Diclofenac and flurbiprofen did not reduce corneal sensitivity Dorbandt DM, et al., Vet Ophthalmol, 2017 Topical Ophthalmic NSAIDs

• Weak acids • pKa values 3.5-4.5 • Poorly water-soluble • Drops with pH 6-9 range comfortable

NSAIDs - Ocular Side Effects

• Humans – Transient ocular irritation – Impaired corneal sensation – Persistent epithelial defects Contact lens wear and dry eye – Superficial punctate keratitis Dr. Steven Soong – Stromal infiltrates – Exacerbation of bronchial asthma – Corneal melting

Corneal Complications

• More complications with generic diclofenac than Voltaren or Acular • 140 eyes – ~1/3 mild, 1/3 moderate, 1/3 severe complications • Voltaren or Acular – High doses of – Ocular comorbidities

Congdon, J Cataract Refract Surg, 2001 Corneal Complications NSAIDs • Shunting of AA to LOX – Leukotrienes • Neutrophil chemotaxis • Inhibition of wound healing • Aberrant expression MMP-1, MMP-2, & MMP-8 • Epithelial toxicity-preservatives – Generic diclofenac - Falcon • Vit E solubilizer may inhibit epithelial proliferation

Hargrave et al., Ophthalmology, 2002 Reviglio, et al., J Cataract Refract Surg, 2003 Mohamed-Noriega, et al., Case Rep Ophthalmol, 2016 Humans Cardiovascular Events • VIOXX ()-released 1999 – VIGOR Vioxx Gastrointestinal Outcomes Research 2000 – 4x-5x increased risk for MI for rofecoxib vs. – Misrepresentation of data (Merck & NE J Med) – Voluntarily withdrawn from market 2004 – Merck paid over $8.5 billion • USDA FDA Advisory Committee mtgs. 2005 & 2014 – NSAIDs increased risk of MI in high-risk individuals – Label for all NSAIDs (even OTC) highlight risk Human Cardiovascular Events • COX-2 inhibition – Decreased expression of pro-inflammatory PGs – Decreased expression of • Inhibits platelet activation – DOES NOT

• Decreased – Increased platelet aggregation

• Normal thromboxane A2 & decreased prostacyclin INCREASED platelet aggregation Flurbiprofen 0.03%

• Good intraocular penetration within 2 hr in humans • Undetectable in AH within 7.25 hr in humans • Not ocularly metabolized • Approximately 10% of dose enters the anterior chamber in rabbits

Ellis et al., J Ocul Pharmacol, 1994 Tang-Liu et al., J Pharmacokinet Biopharm, 1984 Flurbiprofen 0.03% • Cats QID 14 days flurbiprofen and diclofenac – Flurbiprofen reached higher plasma conc. longer duration – No clinically significant changes in renal parameters • Dogs – Reduced IOP-lowering effect of 20.41% – Greater inhibition of pilocarpine-induced BAB disruption than diclofenac – Increased IOP

Lanuza, et al., Vet Ophthalmol, 2016; Krohne SG, et al., AJVR, 1998; Pirie, et al., Vet Ophthalmol, 2011

Diclofenac 0.1% • Good intraocular penetration within 2.5 hr • Detectable in AH for 24 hr in humans • More effective in reducing ocular surface pain in humans than flurbiprofen • Greater inhibition of paracentesis induced BAB breakdown than flurbiprofen (dogs & cats) • Increased IOP in cats • Horses-diclofenac mitigated the drug induced discomfort of latanoprost and did not alter IOP

Ellis et al., J Ocul Pharmacol, 1994 Ward D, et al., Am J Vet Res, 1996 Rankin AJ, et al., Am J Vet Res, 2011 Toffelmire K, et al., Vet Ophthalmol, 2016 Ketorolac

• 0.4%, 0.45%, 0.5% • Strong COX-1 inhibitory activity • May be less toxic to corneal ep. than other NSAIDs (0.45% benzalkonium removed)

Xu, et al., Clin Ophthalmol, 2011 Bromfenac 0.09%

• Highly lipophilic due to bromine addition • Rabbits detectable in retinochoroid up to 24 hh after single application • Humans stable in AH up to 12 hours • Rats with ON crush injury

– Reduced retinal gliosis and PGE2 Baklayan et al., J Ocul Pharmacol, 2008 Waterbury et al., Curr Med Res Opin, 2006 Baklayan et al., Clin Ophthalmol, 2014 Marci et al., Int Ophthalmol, 2016 Rovere et al, IOVS, 2016

• Nepafenac – Rapid onset – Lipophilic – Reduced response of corneal nociceptors by acidic stimuli IOP

• Post op cataract sx – Elevated postop IOP in flurbiprofen and bromefenac – Bromfenac-treated eyes greater need for intervention for POH (52% vs 25%) NSAIDs and PCO • Normal lens does not express COX-2

• Postoperatively LEC express elevated COX-2

• COX-2 inhibition – Decreased migration – Decreased proliferation – Increased apoptosis Brookshire et al., Vet Ophthalmol, 2014 NSAIDs and PCO • -IOL/PA – Better initial inflammation control – Better initial control of PCO up to 12 weeks

• Bromfenac – Better long-term PCO control 56 weeks – Equally effective in controlling inflammation as PA