OcSurface24_ho (1-16-24).pdf

Ocular Surface Diesease Treatment Options Pharmacology II Ocular Surface Disease Treatment Options Diane T. Adamczyk, OD,FAAO Pharmacology II 1 Diane T. Adamczyk, OD, FAAO Copyright © 2024 1 Ocular Surface Diesease Treatment Options Pharmacology II Dry Eye TFOS DEWS II (Tear Film and Ocular...

Ocular Surface Diesease Treatment Options Pharmacology II Ocular Surface Disease Treatment Options Diane T. Adamczyk, OD,FAAO Pharmacology II 1 Diane T. Adamczyk, OD, FAAO Copyright © 2024 1 Ocular Surface Diesease Treatment Options Pharmacology II Dry Eye TFOS DEWS II (Tear Film and Ocular Surface Dry Eye WorkShop II) global dry eye definition: “Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which E t  tear film instability and hyperosmolarity, i o  ocular surface inflammation and damage, and l o  neurosensory abnormalities play etiological roles.” g y The Ocular Surface 15 (2017) 276e283 (TFOS DEWS II Definition and Classification Report 2 Diane T. Adamczyk, OD, FAAO Copyright © 2024 2 Ocular Surface Diesease Treatment Options Pharmacology II The Vicious Circle of Dry Eye Disease (hyperosmolarity) The core mechanism of DED is tear hyperosmolarity. >>>It damages the ocular surface both directly and by initiating inflammation. The Ocular Surface 15 (2017) 438e510 (Pathophysiology Report) 3 Diane T. Adamczyk, OD, FAAO Copyright © 2024 3 Ocular Surface Diesease Treatment Options Pharmacology II The Vicious Circle of Dry Eye Disease (hyperosmolarity) In DED, tear hyperosmolarity: • Sets up a cascade of signaling events within surface epithelial cells • This leads to the release of inflammatory mediators and proteases. • Mediators and tear hyperosmolarity cause: • goblet cell and epithelial cell loss and • damage to the epithelial glycocalyx Damage is reinforced by inflammatory mediators from activated T-cells, recruited to the ocular surface. The net result is: • Punctate epitheliopathy and tear film instability >>> leads to tear film break-up. • This break-up exacerbates and amplifies tear hyperosmolarity>>> completes the Vicious Circle of events >>>> leads to ocular surface damage. The Ocular Surface 15 (2017) 438e510 (Pathophysiology Report) 4 Diane T. Adamczyk, OD, FAAO Copyright © 2024 4 Ocular Surface Diesease Treatment Options Pharmacology II The Vicious Circle of Dry Eye Disease (DED Forms) Two forms of DED are recognized: ADDE (Aqueous Deficient Dry Eye) and EDE (Evaporative Dry Eye). 1. In ADDE: • Tear hyperosmolarity results when lacrimal secretion is reduced • Normal evaporation from the eye is present 2. In EDE: • Tear hyperosmolarity osmolarity is caused by excessive evaporation from the exposed tear film • Normally functioning lacrimal gland is present The Ocular Surface 15 (2017) 438e510 (Pathophysiology Report) 5 Diane T. Adamczyk, OD, FAAO Copyright © 2024 5 Ocular Surface Diesease Treatment Options Pharmacology II Circle of Dry Eye Disease Ophthalmology 2017;124:S14-S19 10 Diane T. Adamczyk, OD, FAAO Copyright © 2024 6 Ocular Surface Diesease Treatment Options Pharmacology II Ocular Surface Disease • Treatment – Relieve Symptoms – Heal ocular surface – Prevent complications 12 Diane T. Adamczyk, OD, FAAO Copyright © 2024 7 Ocular Surface Diesease Treatment Options Pharmacology II Dry Eye Treatment • • • • • • Tear Supplements Tear Conservation Tear Stimulation Anti-inflammatory Nutrition Miscellaneous other 13 Diane T. Adamczyk, OD, FAAO Copyright © 2024 8 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation Artificial Tears Lubricants 14 Diane T. Adamczyk, OD, FAAO Copyright © 2024 9 Ocular Surface Diesease Treatment Options Pharmacology II Lubricants • • • • • • Dry eye Corneal abrasion Keratitis GPC, SLK, VKC Viral Others 15 Diane T. Adamczyk, OD, FAAO Copyright © 2024 10 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation • Polymer based artificial tears • Ideal artificial tear – Reproduce characteristics of natural tears 16 Diane T. Adamczyk, OD, FAAO Copyright © 2024 11 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • • • • • Water based + polymer Buffers Tonicity and pH Preservatives Nutrients 17 Diane T. Adamczyk, OD, FAAO Copyright © 2024 12 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Water based + polymer • • • • Buffers Tonicity and pH Preservatives Nutrients 18 Diane T. Adamczyk, OD, FAAO Copyright © 2024 13 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Polymer: – A compound formed by joining smaller molecules – Functions to • Enhance: – – – – – Viscosity Lubrication Retention time Tear stability Wettability • Decrease blink friction • Minimize surface tension – Polysaccharides are the most common polymers 19 Diane T. Adamczyk, OD, FAAO Copyright © 2024 14 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Polysaccharides include: – Mucilages • An artificial sticky paste used as a vehicle or excipient • Examples: – Methylcellulose (MC), hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC) – Dextrans • High molecular weight polymer of D-glucose 20 Diane T. Adamczyk, OD, FAAO Copyright © 2024 15 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Polysaccharides include: – Viscoelastic substances • Both viscous and elastic • Examples: – Sodium hyaluronate (500,000 x viscosity saline) – Chondroitin sulfate (350,000 x viscosity saline) – Vinyl Derivatives • Water soluble polymers • Increase viscosity • Examples: – Polyvinyl Alcohol (PVA) – Polyvinylpyrrolidone (PVP) • Wetting agent for CL Agents or gel solutions 21 Diane T. Adamczyk, OD, FAAO Copyright © 2024 16 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Water based + polymer • Buffers • Tonicity and pH • Preservatives • Nutrients 22 Diane T. Adamczyk, OD, FAAO Copyright © 2024 17 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Buffers – Resist a change in pH – Normal tear pH: 7.4 • Dependent on bicarbonates, proteins, phosphates, ammonium, others – Buffers include: • • • • • • Phosphate, Phosphate-acetate, Phosphate-citrate, Phosphate-citrate-bicarbonate, Borate, Sodium hydroxide 23 Diane T. Adamczyk, OD, FAAO Copyright © 2024 18 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Tonicity and pH – Tonicity: measure of effective osmolarity (hyper,hypo, iso tonic) – Tonicity and pH examples: • • • • Sodium chloride Potassium chloride Boric acid Ions 24 Diane T. Adamczyk, OD, FAAO Copyright © 2024 19 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Electrolytes – Maintain or lower osmolarity – Corneal epithelial metabolism or buffer system – Sodium chloride, potassium 25 Diane T. Adamczyk, OD, FAAO Copyright © 2024 20 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Water based + polymer • Buffers • Tonicity and pH • Preservatives • Nutrients 26 Diane T. Adamczyk, OD, FAAO Copyright © 2024 21 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Preservatives – Kill or inhibit microorganism growth – “First Generation*” • Bacteriostatic (cidal) • Includes: – – – – – Quaternary ammonium compounds (BAK*, polyquaternium) Mercurials (thimerosal*) Alcohols (chlorobutanol*) Esters of parahydroxybenzoic acid (methylparaben* and propylparaben*) EDTA* enhances quaternary ammonium base 27 Diane T. Adamczyk, OD, FAAO Copyright © 2024 22 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Preservatives – Potential ADR: • Epithelial toxicity (BAK) • Tear disruption (BAK) • Allergic reaction (thimerosal) – Possible solution to ADR: • Unpreserved unit dose packages – Discard 12 hours use 28 Diane T. Adamczyk, OD, FAAO Copyright © 2024 23 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Preservatives – Next Generation - formulations preserved in bottle: • Break down to nontoxic substances when exposed to light or ocular surface – Stabilized Oxychloro Complex: • Sodium chlorate + light > sodium chloride + water – Sodium Perborate: • Sodium perborate + water > H202 • Sodium perborate + eye > catalase decomposes to H20 + O2 29 Diane T. Adamczyk, OD, FAAO Copyright © 2024 24 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • • • • Water based + polymer Buffers Tonicity and pH Preservatives • Nutrients 30 Diane T. Adamczyk, OD, FAAO Copyright © 2024 25 Ocular Surface Diesease Treatment Options Pharmacology II Tear Supplementation: Artificial Tear Formulation • Nutrients – Vitamin A • Differentiation and maintenance of mucosal epithelium • Absence: loss of goblet cells, epithelial keratinizing metaplasia • Topical may help when goblet cells affected 31 Diane T. Adamczyk, OD, FAAO Copyright © 2024 26 Ocular Surface Diesease Treatment Options Pharmacology II 32 Diane T. Adamczyk, OD, FAAO Copyright © 2024 27 Ocular Surface Diesease Treatment Options Pharmacology II Various Artificial Supplements Various Formulations 33 Diane T. Adamczyk, OD, FAAO Copyright © 2024 28 Ocular Surface Diesease Treatment Options Pharmacology II 35 Diane T. Adamczyk, OD, FAAO Copyright © 2024 29 Ocular Surface Diesease Treatment Options Pharmacology II Systane lubricant family • Proprietary polymer HP-Guar (which chemically combines with borate in the pH environment of the eye to create a meshwork gel that helps to retain active lubricants on the ocular surface) • Systane COMPLETE • For all major forms of dry eye • Nano-droplet technology which helps retain lubricant on ocular surface 36 Diane T. Adamczyk, OD, FAAO Copyright © 2024 30 Ocular Surface Diesease Treatment Options Pharmacology II Artificial Tears • Thera Tears (ATF) – Hypotonic solution • Decreases osmolarity – Preservative free (unit dose) – Sodium perborate (preservative) • Dissociates to H2O2 • Then to oxygen and water by tear catalase – Electrolyte balance • restores conjunctival goblet cells and promotes healing – 2-6 gtts/QID x 3 mos 37 Diane T. Adamczyk, OD, FAAO Copyright © 2024 31 Ocular Surface Diesease Treatment Options Pharmacology II OTC Artificial Tears: Cochrane Review 2016 Quality of Evidence: low *Cannot propose 1 OTC artificial tear superior to another 38 Diane T. Adamczyk, OD, FAAO Copyright © 2024 32 Ocular Surface Diesease Treatment Options Pharmacology II Other Considerations 39 Diane T. Adamczyk, OD, FAAO Copyright © 2024 33 Ocular Surface Diesease Treatment Options Pharmacology II Eyesol® (perfluorohexyloctane based solution) • Used in : Vevye (cyclosporine ophthalmic solution) and Miebo • Formerly NOV03 • Proprietary water free technology • Preservative free ophthalmic drop 40 Diane T. Adamczyk, OD, FAAO Copyright © 2024 34 Ocular Surface Diesease Treatment Options Pharmacology II Miebo (Perfluorohexyloctane Ophthalmic Solution) • Miebo – Is 100% perfluorohexyloctane drop • No water, no preservative, no other ingredients – Spreads uniformly over ocular surface, forming protective surfactant layer, preventing evaporation and sensitizing osmolarity changes – Penetrates meibomian glands – Minimal visual disturbances because refractive index is similar to water (vs gels or ointments) – Dosage: QID – Prescription only 41 Diane T. Adamczyk, OD, FAAO Copyright © 2024 35 Ocular Surface Diesease Treatment Options Pharmacology II Miebo (Perfluorohexyloctane Ophthalmic Solution) • Perfluorohexyloctane: – Low surface tension = strong spreading properties/rapid spread oc surface • Facilitating small drop sizes • Interacting with the lipophilic layer of tears = prevent evaporation – Semifluorinated alkane liquid – Amphiphilic (hydrophobic and hydrophilic) – Nonaqueous liquid= microbial growth is not possible, therefore no need for preservative 42 Diane T. Adamczyk, OD, FAAO Copyright © 2024 36 Ocular Surface Diesease Treatment Options Pharmacology II MEIBO (Perfluorohexyloctane Ophthalmic Solution) • NOV03 (perfluorohexloctane) – Preservative free, sterile ophthalmic solution – Inert, anhydrous semifluorinated alkane – Dual mode of action affects abnormalities in: • Lipid layer • Meibomian glands – Rapidly spreads across ocular surface because of low surface/interfacial tension – Interacts with tear film lipophilic part • Forming layer at tear film-air interface • Results: prevention of evaporation of aqueous layer – Penetrates meibomian glands: interacts and dissolves the altered, viscous meibum in the glands • SEECASE study: – RCT: NOV03 (BID or QID) compared to Saline (BID or QID) – Findings/Conclusion: • NOV03 showed benefits for signs and symptoms favoring QID 43 Diane T. Adamczyk, OD, FAAO Copyright © 2024 37 Ocular Surface Diesease Treatment Options Pharmacology II Ophthalmic Drug Delivery • Lacrisert – Hydroxypropyl cellulose ophthalmic insert – Softens within 1 hour and dissolves in 14-18 hours – Blurred vision, FB sensation – Once (twice-if needed) a day http://www.lacrisert.com/ECP (accessed 1-18-2022) 44 Diane T. Adamczyk, OD, FAAO Copyright © 2024 38 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation 45 Diane T. Adamczyk, OD, FAAO Copyright © 2024 39 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation • Reduce evaporation – – – – – Ointment Environmental control Goggles, moisture chambers Humidifiers Tarsorrhaphy • Obstruction of lacrimal drainage system – Surgery, cautery, laser – Canalicular occlusion, Punctal plugs 46 Diane T. Adamczyk, OD, FAAO Copyright © 2024 40 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation: Reduce Evaporation • Ointments – Petrolatum, mineral oil, lanolin – Retard evaporation – Useful also: aqueous, mucin deficiency – Side effect: blurred vision – Bedtime use 48 Diane T. Adamczyk, OD, FAAO Copyright © 2024 41 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation: Lacrimal Occlusion Therapy Who do we Occlude? • Patients with: • Aqueous deficiency • Ocular surface problems • Neurotropic related (e.g. s/p refractive surgery) Who do we best consider not to Occlude? • Patients with inflammatory etiology to dry eye (at least initially) 49 Diane T. Adamczyk, OD, FAAO Copyright © 2024 42 Ocular Surface Diesease Treatment Options Pharmacology II 50 Diane T. Adamczyk, OD, FAAO Copyright © 2024 43 Ocular Surface Diesease Treatment Options Pharmacology II Take Home • Punctal plugs do not relieve inflammation – May result in retention of pro-inflammatory proteins – Leading to pooling in lower fornix – Result in ongoing damage and inferior corneal staining • Conclude: Suggest a benefit from earlier treatment or concurrent tx with anti-inflammatory agent (before or with punctal occlusion) THE OCULAR SURFACE / APRIL 2016, VOL. 14 NO. 2 53 Diane T. Adamczyk, OD, FAAO Copyright © 2024 44 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation • Lacrimal Occlusive Devices/Procedures – Temporary • Collagen rods • Extended dissolvable – Permanent • Silicone plugs – Intracanalicular – Freeman plug • Smart Plugs, Form Fit • Surgery/Cautery 54 Diane T. Adamczyk, OD, FAAO Copyright © 2024 45 Ocular Surface Diesease Treatment Options Pharmacology II Punctal Occlusion Temporary Short Term Collagen (Diagnostic) (< 1 Week) Temporary Extended Extend Dissolvable Polymer (2-6 months) Freeman Type (Multiple Varieties) (Multiple Sizes) (“Stopper”) Permanent Silicone Intracanular Herrick (Multiple Sizes) Other Intracanular Smart Plug Cautery or Laser Intracanular Form Fit 55 Diane T. Adamczyk, OD, FAAO Copyright © 2024 46 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation • Lacrimal Occlusive Devices/Procedures – Temporary • Collagen rods • Extended dissolvable – Permanent • Silicone plugs – Intracanalicular – Freeman plug • Smart Plugs, Form Fit • Surgery/Cautery 56 Diane T. Adamczyk, OD, FAAO Copyright © 2024 47 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation: Lacrimal Occlusion - Collagen • Lacrimal Occlusive Devices – Collagen rods • Dissolve 4- 7 days • 0.2-0.6 mm diameter • 1.75-2.0 mm long 57 Diane T. Adamczyk, OD, FAAO Copyright © 2024 48 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation • Lacrimal Occlusive Devices/Procedures – Temporary • Collagen rods • Extended dissolvable – Permanent • Silicone plugs – Intracanalicular – Freeman plug • Smart Plugs, Form Fit • Surgery/Cautery 59 Diane T. Adamczyk, OD, FAAO Copyright © 2024 49 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation: Temporary Synthetic Plugs • Lacrimal Occlusive Device: – Dissolve over extended time (2-6months) • Absorbable copolymers – Use: post surgical, dry eye – Examples: • UltraPlug Extended Wear Synthetic Absorbable Plug – E-Caprolactone-L-Lactide copolymer – Duration: 2-6 month • Extended Duration Absorbable Plug (Oasis) – Copolymer of glycolic acid and trimethylene carbonate – Duration: 3 months 60 Diane T. Adamczyk, OD, FAAO Copyright © 2024 50 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation • Lacrimal Occlusive Devices/Procedures – Temporary • Collagen rods • Extended dissolvable – Permanent • Silicone plugs – Intracanalicular – Freeman plug • Smart Plugs, Form Fit • Surgery/Cautery 61 Diane T. Adamczyk, OD, FAAO Copyright © 2024 51 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation: Lacrimal Occlusion - Silicone • Silicone based plugs – Types: • Intracanalicular (e.g. may vary=0.3-0.7) • Freeman (e.g. may vary=0.3-1) – Permanent, but can be removed • Intracanalicular – irrigation • Freeman - forceps – Contraindication: chronic dacryocystitis 62 Diane T. Adamczyk, OD, FAAO Copyright © 2024 52 Ocular Surface Diesease Treatment Options Pharmacology II Plugs included punctal, intracanalicular, and dissolving types 63 Diane T. Adamczyk, OD, FAAO Copyright © 2024 53 Ocular Surface Diesease Treatment Options Pharmacology II • Improvement (in ≥50%): in dry eye symptoms, ocular surface status, artificial tear use, CL comfort, TBUT • Complications – infrequent – – – – – Plug loss (most common = 40%) Epiphora (9%) Irritation (10%) Canaliculitis (most common in intracanalicular plugs = 8%) Tearing, discomfort, pyogenic granuloma, dacryocystitis (<4%) Ophthalmology 2015;122:1681-7 64 Diane T. Adamczyk, OD, FAAO Copyright © 2024 54 Ocular Surface Diesease Treatment Options Pharmacology II Abrasion Punctum Plug Partial plug extrusion AJO (4-05) Plug extrusion, with the plug firmly attached by a fibrovascular band originating from the canaliculus. Ophthal 108(2) Feb 2001 65 Diane T. Adamczyk, OD, FAAO Copyright © 2024 55 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation: Lacrimal Occlusion - Silicone • Silicone Punctal Occlusion in Dry Eye Patients – 50 patients/100 eyes – Findings: • 86% symptom free – Probability of plug loss • 1 mos: 17% • 3 mos: 36% • 6 mos: 37% – Plug retention • 63% probability (most lost 1st 3 mos) Am J Ophthal 2001;131:30-36 66 Diane T. Adamczyk, OD, FAAO Copyright © 2024 56 Ocular Surface Diesease Treatment Options Pharmacology II Ocular Drug Delivery Punctal Plug DEXTENZA (dexamethasone ophthalmic insert) indicated for: *Treatment of ocular inflammation and pain following ophthalmic surgery. *Treatment of ocular itching associated with allergic conjunctivitis. 67 Diane T. Adamczyk, OD, FAAO Copyright © 2024 57 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation • Lacrimal Occlusive Devices/Procedures – Temporary • Collagen rods • Extended dissolvable – Permanent • Silicone plugs – Intracanalicular – Freeman plug • Smart Plugs, Form Fit • Surgery/Cautery 68 Diane T. Adamczyk, OD, FAAO Copyright © 2024 58 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation: Lacrimal Occlusion • Lacrimal Occlusive Devices – Smart Plugs • Thermodynamic hydrophobic acrylic polymer (“smart polymer”) • Rigid at room temperature – Soft and flexible elastomer gel at or above 33oC • 20 second transformation 69 Diane T. Adamczyk, OD, FAAO Copyright © 2024 59 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation:Lacrimal Occlusion • Lacrimal Occlusive Devices – Smart Plugs • One size fits all – Conforms to patient punctum • • • • • • No inserter needed Body temperature moldable Can’t see after insert Cannot be rubbed out No foreign body sensation Remove: probe, irrigate 70 Diane T. Adamczyk, OD, FAAO Copyright © 2024 60 Ocular Surface Diesease Treatment Options Pharmacology II Form Fit (Oasis) • Form Fit : one size fits all plug • Made of a hydrogel material – Contact tear film: expands into a soft, pliable, gelatinous material. • Once inserted into the punctum: – Hydrates over 10 minutes – Increases in size until fills the vertical canalicula • Removable by irrigation 71 Diane T. Adamczyk, OD, FAAO Copyright © 2024 61 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation • Lacrimal Occlusive Devices/Procedures – Temporary • Collagen rods • Extended dissolvable – Permanent • Silicone plugs – Intracanalicular – Freeman plug • Port System, Smart Plugs, Form Fit • Surgery/Cautery 72 Diane T. Adamczyk, OD, FAAO Copyright © 2024 62 Ocular Surface Diesease Treatment Options Pharmacology II Tear Conservation: Lacrimal Occlusion Therapy • Cautery and laser – Often not permanent Cautery 73 Diane T. Adamczyk, OD, FAAO Copyright © 2024 63 Ocular Surface Diesease Treatment Options Pharmacology II Punctal Occlusion Temporary Short Term Collagen (Diagnostic) (< 1 Week) Temporary Extended Extend Dissolvable Polymer (2-6 months) Freeman Type (Multiple Varieties) (Multiple Sizes) (“Stopper”) Permanent Silicone Intracanular Herrick (Multiple Sizes) Other Intracanular Smart Plug Cautery or Laser Intracanular Form Fit 74 Diane T. Adamczyk, OD, FAAO Copyright © 2024 64 Ocular Surface Diesease Treatment Options Pharmacology II Tear Stimulation 75 Diane T. Adamczyk, OD, FAAO Copyright © 2024 65 Ocular Surface Diesease Treatment Options Pharmacology II Tear Stimulation • Oral Pilocarpine HCL (Salagen) – Parasympathomimetic with muscarinic secretagogue effect • Cholinergic stimulation improves lacrimation and salivation – 5mg PO QID • May take 6 weeks for response • Used in: – Sjogren Syndrome – Radiation induced xerostomia 76 Diane T. Adamczyk, OD, FAAO Copyright © 2024 66 Ocular Surface Diesease Treatment Options Pharmacology II Tear Stimulation • Pilocarpine HCL (Salagen) – Side effect: • Sweat (most common) • Nausea • Flush 77 Diane T. Adamczyk, OD, FAAO Copyright © 2024 67 Ocular Surface Diesease Treatment Options Pharmacology II Neurostimulation of Tear Production • Neurostimulation: application of electromagnetic energy or chemical stimulus to specific anatomic targets 78 Diane T. Adamczyk, OD, FAAO Copyright © 2024 68 Ocular Surface Diesease Treatment Options Pharmacology II Neurostimulation on tear production • • Activated afferent sensory nerves in the cornea and conjunctiva – > stimulate efferent parasympathetic and sympathetic nerves innervating the lacrimal gland – >trigger release of water, electrolytes and protein to ocular surface Stimulation of the anterior ethmoidal nerve (part of ophthalmic branch of trigeminal nerve) – > increase activity in the superior salivatory nucleus – > control of natural lacrimation 79 Diane T. Adamczyk, OD, FAAO Copyright © 2024 69 Ocular Surface Diesease Treatment Options Pharmacology II Lacrimal Function Unit Nasolacrimal Reflex Lacrimal gland (main & accessory), Goblet cells, Meibomian gland Postganglionic fibers via Lacrimal Nerve Parasympathetic fibers (via VII CN) to Pterygopalatine ganglion Superior Salivatory Nucleus Efferent Pathway 80 Diane T. Adamczyk, OD, FAAO Copyright © 2024 70 Ocular Surface Diesease Treatment Options Pharmacology II Enhanced Tearing by Electrical Stimulation of Anterior Ethmoid Nerve. IOVS 2017 83 Diane T. Adamczyk, OD, FAAO Copyright © 2024 71 Ocular Surface Diesease Treatment Options Pharmacology II iTear100 device Increases tear production Neurostimulation via small oscillating tip ◦ This stimulates the external branch of the anterior ethmoidal nerve (on the side of the nose) ◦ Which then then stimulates the lacrimal gland to produce tears Use BID for 30 seconds each side Increase in tear production immediately after stimulation ◦ Increase in pre-stimulation Schirmer at each visit 14- 30 days Adverse events: 1-2% dizziness and light headedness 85 Diane T. Adamczyk, OD, FAAO Copyright © 2024 72 Ocular Surface Diesease Treatment Options Pharmacology II 87 Diane T. Adamczyk, OD, FAAO Copyright © 2024 73 Ocular Surface Diesease Treatment Options Pharmacology II PostStimulation: higher Schirmer score Ocular Surface Disease Index decreases PreStimulation Study Conclusion: Safety and efficacy of the iTear device in this study support its indication for treating DED 88 Diane T. Adamczyk, OD, FAAO Copyright © 2024 74 Ocular Surface Diesease Treatment Options Pharmacology II TYRVAYA (varenicline solution) nasal spray • • • • Selective nicotinic acetylcholine agonist Nasal spray – Oral varenicline used for smoking cessation Pharmacologic neurostimulation: stimulates trigeminal parasympathetic pathway via the nose, resulting in increased basal tear film production – Binds to nicotinic acetylcholine receptor on trigeminal nerve in anterior nasal cavity – Activation stimulates tear secretion from meibomian glands, lacrimal glands and goblet cells (comprising lacrimal functional unit) Exact mechanism – unknown 89 Diane T. Adamczyk, OD, FAAO Copyright © 2024 75 Ocular Surface Diesease Treatment Options Pharmacology II TYRVAYA (varenicline solution) nasal spray • Preservative free • BID • Improved Schirmer and dryness score • ADR: 82% sneezing • 5-16% cough, throat irritation, nose irritation 90 Diane T. Adamczyk, OD, FAAO Copyright © 2024 76 Ocular Surface Diesease Treatment Options Pharmacology II TYRVAYA (varenicline solution) nasal spray • • • Do not spray too deep and avoid spraying into your sinuses Insert the tip of the nasal spray just past the nasal opening. Aim the tip out towards your ear on the same side of the nostril you’re spraying into. Ensure proper tongue placement Press your tongue to the roof of your mouth. Avoid inhaling deeply Breathe gently as you press and release the applicator, just misting the inside of your nostril. The medication will absorb into the wall of the nose where the nerve is located. 92 Diane T. Adamczyk, OD, FAAO Copyright © 2024 77 Ocular Surface Diesease Treatment Options Pharmacology II TYRVAYA (varenicline solution) nasal spray • Purpose: efficacy and safety of varenicline nasal spray for DED • RCT, double masked • Over 4 weeks improved tear production and improved patient reported symptoms of DED – Improvement in Schirmer of 10mm or more (significant) – Improvement Eye Dryness Score (nominal) • Avoids painful drop instillation, ease of administration, 93 Diane T. Adamczyk, OD, FAAO Copyright © 2024 78 Ocular Surface Diesease Treatment Options Pharmacology II Anti-inflammatory Drugs Steroids Cyclosporine (Restasis, Cequa, Verkazia) Lifitegrast (Xiidra) Other 95 Diane T. Adamczyk, OD, FAAO Copyright © 2024 79 Ocular Surface Diesease Treatment Options Pharmacology II Steroids • Effect • Potential side effects 96 Diane T. Adamczyk, OD, FAAO Copyright © 2024 80 Ocular Surface Diesease Treatment Options Pharmacology II Topical corticosteroids for dry eye Author’s conclusions on topical steroids: • Overall moderate to very low certainty evidence • Small to moderate symptom relief beyond lubricants • Small to moderate degrees of symptom relief beyond CsA • Less certain about the effects on improved tear film quality or quantity • Evidence of adverse effects: – Uncertain on IOP elevation – Uncertain on cataract formation or progression (based on short term use) 97 Diane T. Adamczyk, OD, FAAO Copyright © 2024 81 Ocular Surface Diesease Treatment Options Pharmacology II Topical corticosteroids for dry eye Implications for Practice (use of Topical Corticosteroids for Dry Eye): • Likely provide small to moderate improvement in symptoms compared with artificial tears (moderate certainty evidence) – May provide small to moderate improvement in symptoms as compared with cyclosporine A (low certainty evidence) • Evidence supports steroid anti-inflammatory effects on corneal staining scores over lubricants (moderate certainty evidence) – But not over cyclosporine A (low certainty evidence) • Little to no effect on tear quality or production: – TBUT (low certainty evidence) and Schirmer's test (low certainty evidence) • Evidence is very uncertain regarding the effects on tear osmolarity, risk of elevated intraocular pressure, or risk of cataract formation 98 Diane T. Adamczyk, OD, FAAO Copyright © 2024 82 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine • • A cyclic undecapeptide produced by fungi Immunosuppressant • Cyclosporine 0.05% Ophthalmic emulsion (Restasis) – FDA approved for dry eye disease 2003 – FDA approved generic February 2022 Cyclosporine 0.09% (Cequa) – FDA approved 2018 Cyclosporine 0.1% (Verkazia) – FDA approved VKC June 2021 • • 101 Diane T. Adamczyk, OD, FAAO Copyright © 2024 83 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine • Mechanism of action – Inhibit activation of T lymphocytes – Inhibit apoptosis (programmed cell death) • In the eye: reduced apoptosis of conjunctival epithelial cells – Calcineurin/nuclear factor for T cell activation is affected 102 Diane T. Adamczyk, OD, FAAO Copyright © 2024 84 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine • T-cell receptor activated by ligand > • Release of calcium> Cyclosporine cyclophilin A complex • Calcium stimulates phosphatase binds to Calcineurin and Inhibits dephosphorylation calcineurin> • Which dephosphorylates the phosphorylated form of nuclear factor for T cell activation (NF-AT)> • Dephosphorylated NF-AT migrates to nucleus and stimulates transcription of for IL-2 et al 103 Diane T. Adamczyk, OD, FAAO Copyright © 2024 85 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine • Immunomodulary agent • Systemic cyclosporine: potential serious adverse reactions – Topical can lead to plasma levels, but < toxic levels vs systemic 104 Diane T. Adamczyk, OD, FAAO Copyright © 2024 86 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine (Systemic Therapy) • Side Effects – – – – – – – Nephrotoxicity occurs in 25-75% of patients Mild to moderate hypertension Gingival hyperplasia Mild to moderate hypertrichosis 35-50% reversible liver toxicity with high doses Paresthesias with hand tremors GI symptoms including nausea and vomiting 106 Diane T. Adamczyk, OD, FAAO Copyright © 2024 87 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine (Topical) • Immunomodulator with anti-inflammatory effects – Anti-inflammatory • Prevents T cells from releasing cytokines • Treats underlying inflammation and improves tear volume production • 0.05% Ophthalmic Emulsion (Restasis) • 0.09% Ophthalmic Solution (Cequa) • 0.1% Ophthalmic Emulsion (Verkazia)=Vernal • 0.1% Ophthalmic Solution (Vevye) 107 Diane T. Adamczyk, OD, FAAO Copyright © 2024 88 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine (Topical) • Cyclosporine is Lipophilic – Hydrophilic corneal stroma is a penetration barrier for CsA • Penetration into the Eye is Very Limited • No Intraocular Adverse Effects 108 Diane T. Adamczyk, OD, FAAO Copyright © 2024 89 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.05% Ophthalmic • Hydrophobic nature >>> challenge to formulation • Emulsion: improves delivery – Castor oil, with glycerin, polysorbate 80, sodium hydroxide (pH) – Instill: cyclosporine partitions from oil droplets in emulsion into ocular surface tissue 109 Diane T. Adamczyk, OD, FAAO Copyright © 2024 90 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.05% (Restasis) (Topical) • • Indication: – To increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with KCS • ^Schirmer Best candidate – Moderate dry eye – Collagen vascular disease • Sjogren • RA • Lupus 111 Diane T. Adamczyk, OD, FAAO Copyright © 2024 91 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.05% Ophthalmic • Ocular mechanism in dry eyes: – In conjunctival biopsies: • Reduce activated T-lymphocytes • Reduce apoptotic cells – Reduce expression of proinflammatory cytokine (e.g. Interleukin) – Increase goblet cell densities in conjunctival epithelium – Restore normal architecture of lacrimal gland in dogs with dry eyes 112 Diane T. Adamczyk, OD, FAAO Copyright © 2024 92 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.05% (Restasis) (Topical) • Expectations – – – – 1 month: reduced symptoms 3 month: improvement 6 month: significant improvement >6 month: maintenance • taper for some • some: 1-2x/wk – Can use lubs also 113 Diane T. Adamczyk, OD, FAAO Copyright © 2024 93 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.05% (Restasis) (Topical) • Considerations: – No effect if diffuse loss of goblet cells • Ocular pemphigoid, • Steven Johnson Syndrome, • Chemical burns – Must have some response on Schirmer 2 • If < 3 mm wet with nasal stimulation, lacrimal gland beyond restoring 114 Diane T. Adamczyk, OD, FAAO Copyright © 2024 94 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.05% (Restasis) (Topical) • Contraindication: ocular infection • Dosage: BID – Unit dose • Milky • Expensive 116 Diane T. Adamczyk, OD, FAAO Copyright © 2024 95 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.05% (Restasis) • Results: – Improvement in conjunctival staining And SPK – Subjective measures of dry eye also show improvement – ^goblet cell number 117 Diane T. Adamczyk, OD, FAAO Copyright © 2024 96 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.05% (Restasis) • Side Effects – – – – – – – Ocular burning (17%) Mild ocular hyperemia Epiphora Eye pain FB sensation Itching Blur 118 Diane T. Adamczyk, OD, FAAO Copyright © 2024 97 Ocular Surface Diesease Treatment Options Pharmacology II 119 Diane T. Adamczyk, OD, FAAO Copyright © 2024 98 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.09% (CEQUA) • Indication: to increase tear production in keratoconjunctivitis sicca • Dosage: BID • Preservative free, single vial • ADR: pain on instillation (22%) 120 Diane T. Adamczyk, OD, FAAO Copyright © 2024 99 Ocular Surface Diesease Treatment Options Pharmacology II CEQUA (cyclosporine ophthalmic solution) 0.09% • • • • Highest FDA-approved concentration of cyclosporine A for Dry Eye (not vernal) – Vs Restasis (cyclosporine emulsion) 0.05% Nanomicellar technology – Prevents release of lipophilic molecule prior to penetration – Micelles=gelatinous aggregates of amphipathic (both hydrophobic and hydrophilic) molecules – Small size facilitates entry into corneal and conjunctival cells 12 weeks of treatment: improvement in Schirmer’s Some improvement as early as 1 month 121 Diane T. Adamczyk, OD, FAAO Copyright © 2024 100 Ocular Surface Diesease Treatment Options Pharmacology II Nanomicelle • Pharmaceutical carriers for solubilizing hydrophobic drugs • 10-100 nm • Entrap drug within hydrophobic core with corona of hydrophilic chains extending outward resulting in aqueous formulation • Lowers adverse side effects; improves drug penetration; minimize drug degradation 122 Diane T. Adamczyk, OD, FAAO Copyright © 2024 101 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.09% (CEQUA) • Nanomicelle formulation: hydrophobic agents entrap drug within the micelle structures, creating a clear aqueous solution • This formulation has a 10 fold increase in aqueous solubility 124 Diane T. Adamczyk, OD, FAAO Copyright © 2024 102 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine 0.09% (CEQUA) • Improvement observed as early as 28 days • This may result from higher ocular tissue concentration of cyclosporine with nanomicelle formulation 125 Diane T. Adamczyk, OD, FAAO Copyright © 2024 103 Ocular Surface Diesease Treatment Options Pharmacology II 2019 127 Diane T. Adamczyk, OD, FAAO Copyright © 2024 104 Ocular Surface Diesease Treatment Options Pharmacology II • Conclusion: • Evidence to treat dry eye: • Effect of CsA on ocular discomfort and ocular surface and tear film parameters (fluorescein staining, Schirmer's test, and TBUT) is inconsistent and • Sometimes may not be different from vehicle or artificial tears • May be an increase in adverse effects (particularly burning) • May increase the number of conjunctival goblet cells • But evidence does not support improvement in conjunctival mucus production • All published trials were short term and did not assess whether CsA has longer-term disease-modifying effects. 128 Diane T. Adamczyk, OD, FAAO Copyright © 2024 105 Ocular Surface Diesease Treatment Options Pharmacology II • Despite the widespread use of topical CsA to treat dry eye: evidence on the effect of CsA on ocular discomfort and ocular surface and tear film parameters (fluorescein staining, Schirmer's test, and TBUT) is inconsistent and sometimes may not be different from vehicle or artificial tears • May be an increase in adverse effects (particularly burning) • May increase the number of conjunctival goblet cells, but evidence does not support improvement in conjunctival mucus production • All published trials were short term and did not assess whether CsA has longer-term disease-modifying effects. 129 Diane T. Adamczyk, OD, FAAO Copyright © 2024 106 Ocular Surface Diesease Treatment Options Pharmacology II Cyclosporine A Studies for Topical Uses • Other considerations for use: – Vernal keratoconjunctivitis • Shield ulcer (VKC)-nonresponder – AKC (steroid resistant) – HSV stromal keratitis • Especially in steroid glaucoma, HS ulcers – Superior limbic keratitis – Contact lens intolerance 130 Diane T. Adamczyk, OD, FAAO Copyright © 2024 107 Ocular Surface Diesease Treatment Options Pharmacology II Verkazia (cyclosporine ophthalmic emulsion 0.1%) • • • • • • Use: vernal keratoconjunctivitis Emulsion – Positively charged nanodroplets of the cationic emulsion is attracted to the negatively charged cell membranes, resulting in increased residence time at the ocular surface Possible mechanism in VKC: – Inhibit TH2 proliferation and interleukin 2 production – Reduce levels of immune cells and mediators acting on ocular surface and conjunctiva QID Pregnancy/Lactation: no adequate data Single dose vials 131 Diane T. Adamczyk, OD, FAAO Copyright © 2024 108 Ocular Surface Diesease Treatment Options • • • • Pharmacology II Pediatric patients: 4-18 years Severe VKC (Grade 3 or 4) Randomized CsA 0.1% QID vs CsA BID vs vehicle QID Significant improvement signs and symptoms (photophobia, tearing, itching, mucous discharge) in high dose 132 Diane T. Adamczyk, OD, FAAO Copyright © 2024 109 Ocular Surface Diesease Treatment Options Pharmacology II Vevye (cyclosporine 0.1% ophthalmic solution) • • • • Vevye (formerly CyclASol) Use: tx of Dry Eye Disease Dosage: BID Solubilized in water free excipient – No anti-microbial preservatives, oils or surfactants – No associated pH or osmolarity • Efficacy after 4 weeks 133 Diane T. Adamczyk, OD, FAAO Copyright © 2024 110 Ocular Surface Diesease Treatment Options Pharmacology II Vevye (Cyclosporine 0.1% ophthalmic solution) Water-free cyclosporine eye drop, 0.1%, • Randomized, double-masked, vehiclecontrolled, clinical trial including • 834 study participants with moderate to severe DED • Fluorobutylpentane carrier of cyclosporine • The rapid onset and magnitude of improvements on the corneal epithelial damage are potential differentiators to existing therapies. 134 Diane T. Adamczyk, OD, FAAO Copyright © 2024 111 Ocular Surface Diesease Treatment Options Pharmacology II Vevye (cyclosporine 0.1% ophthalmic solution) (CyclASol) • Comparison effect on corneal staining: – CyclASol 0.1%: • Week 2 corneal stain/week 4 conjunctival stain – Cyclosporine A 0.05% emulsion: • After month 4-corneal stain – Cyclosporine 0.1% cationic emulsion: • After month 3-corneal stain – Cyclosporine A nanoemulsion: • Week 4 corneal stain/ week 8 conjunctival stain • Thought cyclosporine onset of effect might take months because of effect on T-cells, which depends on T-cell turnover rate. • However, cyclosporine A possess immediate T-cell independent anti-inflammatory mechanism (e.g. inhibition of conjunctival cell apoptosis and T cell apoptosis) 135 Diane T. Adamczyk, OD, FAAO Copyright © 2024 112 Ocular Surface Diesease Treatment Options Pharmacology II Vevye (cyclosporine 0.1% ophthalmic solution) (formerly CyclASol) • CyclASol 0.1% – Water free semifluorinated alkane (SFA) solution (Eyesol) – Improved tolerability and decreased visual disturbance compared to other formulations which involve surfactants and oils • Immediate effects in combination with enhanced local bioavailability – Novel water-free carrier and absence of ocular surface harming ingredients contribute to CYclASol’s early onset vs others 136 Diane T. Adamczyk, OD, FAAO Copyright © 2024 113 Ocular Surface Diesease Treatment Options Pharmacology II Lifitegrast (Xiidra 5%) • • • • • • • Use: treatment signs/symptoms of dry eye disease Approved July 2016 Lymphocyte function-associated antigen-1 (LFA-1) antagonist Is a tetrahydroisoquinoline derivative Dosage: BID Single dose container No data pregnant women 137 Diane T. Adamczyk, OD, FAAO Copyright © 2024 114 Ocular Surface Diesease Treatment Options Pharmacology II Lifitegrast (Xiidra) • Background: – Lymphocyte function-associated antigen-1 (LFA-1) • LFA-1 is a cell surface protein found on leukocytes – Intercellular adhesion molecule-1 (ICAM-1) • ICAM-1 overexpressed in DED corneal and conjunctival tissues – LFA-1/ICAM-1 interaction can contribute to formation of immunological synapse resulting in T-cell activation • Lifitegrast is antagonist to above process MHC=Major histocompatibility complex TCR=T cell Receptor APC=antigen presenting cells ICAM-1= Intercellular adhesion molecule-1 LFA 1= Lymphocyte function-associated antigen-1 138 Diane T. Adamczyk, OD, FAAO Copyright © 2024 115 Ocular Surface Diesease Treatment Options Pharmacology II Lifitegrast (Xiidra) • Mechanism of Lifitegrast action – Binds to the integrin lymphocyte functionassociated antigen-1 (LFA-1) – May inhibit T-cell adhesion to ICAM-1 – May inhibit secretion of inflammatory cytokines – Exact mechanism unknown 139 Diane T. Adamczyk, OD, FAAO Copyright © 2024 116 Ocular Surface Diesease Treatment Options Pharmacology II Lifitegrast (Xiidra) • Adverse reactions – – – – Burning Decreased VA Dry eye Dysgeusia (change in taste) 140 Diane T. Adamczyk, OD, FAAO Copyright © 2024 117 Ocular Surface Diesease Treatment Options Pharmacology II Lifitegrast (Xiidra) • Post hoc analysis from OPUS-2 and OPUS-3 • Results and conclusions: – Lifitegrast achieved meaningful improvement in all sign and symptom end points – Response especially in those with moderate to severe DED JAMA Ophthalmol. 2021;139(11):1200-1208 142 Diane T. Adamczyk, OD, FAAO Copyright © 2024 118 Ocular Surface Diesease Treatment Options Pharmacology II • Studies were over 12 week period • May see improvement as early as 2 weeks 143 Diane T. Adamczyk, OD, FAAO Copyright © 2024 119 Ocular Surface Diesease Treatment Options Pharmacology II Other Treatments 144 Diane T. Adamczyk, OD, FAAO Copyright © 2024 120 Ocular Surface Diesease Treatment Options Pharmacology II Other Treatment Considerations • • • • • Avenova Mucolytics Hormones Tetracycline Nutritional 145 Diane T. Adamczyk, OD, FAAO Copyright © 2024 121 Ocular Surface Diesease Treatment Options Pharmacology II Aveno (Hypochlorous acid 0.01%) • Hypochlorous acid 0.01% • Glass bottle - preserves the safety and efficacy of the pure HOCl (not compatible with plastic) • BID 146 Diane T. Adamczyk, OD, FAAO Copyright © 2024 122 Ocular Surface Diesease Treatment Options Pharmacology II 147 Diane T. Adamczyk, OD, FAAO Copyright © 2024 123 Ocular Surface Diesease Treatment Options Pharmacology II • Skin supports wide array of microorganisms • Hypochlorous acid is a natural antibacterial – Is produced naturally as an element of immune response – During oxidative burst, HOCL with other molecules are generated as WBC respond to pathogens in the body 148 Diane T. Adamczyk, OD, FAAO Copyright © 2024 124 Ocular Surface Diesease Treatment Options Pharmacology II • Hypochlorous acid – Compound is an oxidant that kills bacteria through protein and lipid peroxidation and/or halogenation – Part of ocular hygiene product to clean lids/lashes 149 Diane T. Adamczyk, OD, FAAO Copyright © 2024 125 Ocular Surface Diesease Treatment Options Pharmacology II Mucolytic Agents • Acetylcysteine (10%, 20%) – Softens mucous – Intracellular effect on goblet cells – Use: • Bronchopulmonary conditions • Filamentary keratitis, VKC, GPC (dilute to 2-5%) – Decrease viscosity – Sting 150 Diane T. Adamczyk, OD, FAAO Copyright © 2024 126 Ocular Surface Diesease Treatment Options Pharmacology II Other Treatments • Oral tetracycline – Posterior blepharitis --- inflammatory nature – Inhibit matrix metalloproteinases • Topical role for tetracycline?---to be determined 151 Diane T. Adamczyk, OD, FAAO Copyright © 2024 127 Ocular Surface Diesease Treatment Options Pharmacology II NUTRITIONAL CONSIDERATIONS 152 Diane T. Adamczyk, OD, FAAO Copyright © 2024 128 Ocular Surface Diesease Treatment Options Pharmacology II Nutrition Considerations • Dry Eye Inflammatory Component Considerations: – Omega 3 • May affect clotting time (decrease platelet aggregation)– therefore use with caution and appropriate comanagement (clotting time monitored) with patients on blood thinners – Flax seed oil - Reduces T lymphocyte proliferation 153 Diane T. Adamczyk, OD, FAAO Copyright © 2024 129 Ocular Surface Diesease Treatment Options Pharmacology II EPA=eicosapentaenoic acid TheraTears web site DHA=docosahexaenoic acid 154 Diane T. Adamczyk, OD, FAAO Copyright © 2024 130 Ocular Surface Diesease Treatment Options Pharmacology II Considerations When Taking Omega-3 Supplements • Cautions in patients with or taking: – Phenothiazines + Evening primrose oil (omega 6)  may lower seizure threshold and precipitate seizures – Blood thinners or aspirin + omega 3 and 6 (per PI)  reduces blood platelet aggregation – Flaxseed oil (omega 3) increases stool bulk and frequency, may cause intestinal blockage  not recommended in Bowel obstruction, irritable bowel syndrome, diverticular disease – Pregnancy category C per product information 155 Diane T. Adamczyk, OD, FAAO Copyright © 2024 131 Ocular Surface Diesease Treatment Options Pharmacology II Omega and Blood Thinning • EPA and DHA >3g/day may increase prothrombin time and risk of bleeding • Omega 3 may lower thromboxane A2 supplies in platelets and decrease clotting factor VII – EPA specifically inhibits platelet aggregation – Therefore can consider using only DHA as an option 156 Diane T. Adamczyk, OD, FAAO Copyright © 2024 132 Ocular Surface Diesease Treatment Options Pharmacology II Nutrition and the Eye • Suggested Use: total of four capsules daily, with meals (two capsules twice daily). 157 Diane T. Adamczyk, OD, FAAO Copyright © 2024 133 Ocular Surface Diesease Treatment Options Pharmacology II 158 Diane T. Adamczyk, OD, FAAO Copyright © 2024 134 Ocular Surface Diesease Treatment Options Pharmacology II Background: use of n-3 fatty acid supplements for DED treatment Methods: Each active capsule: ◦ 400 mg of EPA and 200 mg of DHA, ◦ for a total daily dose of 2000 mg of EPA and 1000 mg of DHA Each placebo capsule: ◦ 1000 mg of refined olive oil (68% oleic acid, 13% palmitic acid, and 11% linoleic acid) Active and placebo capsules contained: ◦ 3 mg of vitamin E (alpha-tocopherol), as an antioxidant, ◦ As well as masking flavor and lemon flavor 159 Diane T. Adamczyk, OD, FAAO Copyright © 2024 135 Ocular Surface Diesease Treatment Options Pharmacology II Methods • Each active capsule: – 400 mg of EPA and 200 mg of DHA, – for a total daily dose of 2000 mg of EPA and 1000 mg of DHA • Each placebo capsule: – 1000 mg of refined olive oil (68% oleic acid, 13% palmitic acid, and 11% linoleic acid) • Active and placebo capsules contained: – 3 mg of vitamin E (alpha-tocopherol), as an antioxidant, – As well as masking flavor and lemon flavor 160 Diane T. Adamczyk, OD, FAAO Copyright © 2024 136 Ocular Surface Diesease Treatment Options Pharmacology II 161 Diane T. Adamczyk, OD, FAAO Copyright © 2024 137 Ocular Surface Diesease Treatment Options Pharmacology II 162 Diane T. Adamczyk, OD, FAAO Copyright © 2024 138 Ocular Surface Diesease Treatment Options Pharmacology II 163 Diane T. Adamczyk, OD, FAAO Copyright © 2024 139 Ocular Surface Diesease Treatment Options Pharmacology II • Considerations – More patients in treated group vs placebo – Is the placebo truly a placebo? – Patients still using other treatments (how does that affect outcomes?) 164 Diane T. Adamczyk, OD, FAAO Copyright © 2024 140 Ocular Surface Diesease Treatment Options Pharmacology II Purpose DREAM Extension Study: Determine effects of continued vs discontinued use of omega-3 supplements (placebo = refined olive oil) Method: Those who received omega 3 supplement as part of the primary DREAM trial for 12 months, were then randomized for an additional 12 months to continue with the omega 3 supplements or be given a placebo 165 Diane T. Adamczyk, OD, FAAO Copyright © 2024 141 Ocular Surface Diesease Treatment Options Pharmacology II What is the difference? (Dream Extension 2020) 166 Diane T. Adamczyk, OD, FAAO Copyright © 2024 142 Ocular Surface Diesease Treatment Options Pharmacology II Conclusions • Findings: • No significant differences/similar findings between both groups: • Ocular Surface Disease Index score, conjunctival staining, corneal staining, • Results from 2 DREAM clinical trials does not support a beneficial effect of omega 3 supplementation on DED • Conclusion: Patients discontinuing use of omega 3 did not have significantly worse outcomes compared to those who continued using omega 3 supplements 167 Diane T. Adamczyk, OD, FAAO Copyright © 2024 143 Ocular Surface Diesease Treatment Options Pharmacology II 168 Diane T. Adamczyk, OD, FAAO Copyright © 2024 144 Ocular Surface Diesease Treatment Options Pharmacology II 169 Diane T. Adamczyk, OD, FAAO Copyright © 2024 145 Ocular Surface Diesease Treatment Options Pharmacology II Omega-3 and Omega-6 for DED Main Results: • Although much evidence was uncertain, long-chain omega-3 supplements may have little to no benefit relative to placebo on DE symptoms BUT did improve some clinical signs • Beneficial effect on symptoms when omega-3 supplements combined with standard dry eye tx (e.g. artificial tears, warm compresses, steroids) vs standard treatment alone • For combined omega-3 and omega-6 supplements, relative to placebo, no benefit for tear production, but small amount of improvement in tear stability • OVERALL: review suggest possible role for long-chain omega3 supplementation in managing DED, although evidence is uncertain and inconsistent 170 Diane T. Adamczyk, OD, FAAO Copyright © 2024 146 Ocular Surface Diesease Treatment Options Pharmacology II Note differences which can affect efficacy: • In doses • Sources of omega-3 E.g. Fish oil rich in EPA and DHA versus flaxseed oil which contains short chain ALA Nutrients 2020, 12, 952; doi:10.3390/nu12040952 171 Diane T. Adamczyk, OD, FAAO Copyright © 2024 147 Ocular Surface Diesease Treatment Options Pharmacology II Symptom Score Schirmer TBUT Fluorescein Stain Cornea Volume 38, Number 5, May 2019 Considerations: *Most studies very controlled (vs DREAM: allowed other Tx) *Variability in diet may affect results (location example) Conclusion: May recommend Omega 3 supplement for DED 172 Diane T. Adamczyk, OD, FAAO Copyright © 2024 148 Ocular Surface Diesease Treatment Options Pharmacology II 1000-3000 mg EPA/DHA per day (within therapeutic dosage) Caution above 3000mg EPA/DHA with elderly and blood thinners, hemophilia also Omega 3 Considerations Check bp on patients taking HT meds – high dose omega-3 may have hypotensive effect Omega 3 may lower blood pressure and may increase effect with bp meds Avoid fish or fish oil on day before to day after chemotherapy – has chemotherapy negating effect May take 3-6 months for maximum omega 3 blood level Obtain baseline omega 3 level prior to starting regimen 175 Diane T. Adamczyk, OD, FAAO Copyright © 2024 149 Ocular Surface Diesease Treatment Options Pharmacology II OTHER 176 Diane T. Adamczyk, OD, FAAO Copyright © 2024 150 Ocular Surface Diesease Treatment Options Pharmacology II Neurotrophic Keratitis • Neurotrophic keratitis: a degenerative corneal disease caused by damage of trigeminal innervation, resulting in reduction (hypoesthesia) or loss (anesthesia) of corneal sensitivity. – Corneal denervation can result in: • Reduction in lacrimal reflex/vitality and epithelial breakdown • Corneal edema, ulceration, melting, perforation – Corneal homeostasis is interplay between corneal nerves and epithelial cells mediated through production of trophic factors (e.g. neuromediators and nerve growth factor) 177 Diane T. Adamczyk, OD, FAAO Copyright © 2024 151 Ocular Surface Diesease Treatment Options Pharmacology II Neurotrophic Keratitis • Most common causes: – – – – – – Herpes keratitis, Chemical burns, Long-term use of contact lenses, Corneal surgery, Chronic severe blepharitis, Diabetes Signs of neurotrophic keratitis 178 Diane T. Adamczyk, OD, FAAO Copyright © 2024 152 Ocular Surface Diesease Treatment Options Pharmacology II Neurotrophic Keratitis • Treatment – D/C meds that can cause NK – Artificial tears – Corneal or scleral CL – Amniotic membrane – Tarsorrhaphy – Autologous serum with growth factors – Topical NGF (Cenegermin) Management of neurotrophic keratitis. www.co-ophthalmology.com Vol 32 (Number 4) July 2021 179 Diane T. Adamczyk, OD, FAAO Copyright © 2024 153 Ocular Surface Diesease Treatment Options Pharmacology II Oxervate (cenegermin-bkbj ophthalmic solution) 0.002% • 1st FDA approved treatment for neurotrophic keratitis • Escherichia coli derived recombinant form of human nerve growth factor • Structurally identical to nerve growth factor naturally produced by eyes • Mechanism of Action of Nerve Growth Factor: – Is an endogenous protein involved in the differentiation and maintenance of neurons – Acts through specific nerve growth factor receptors in the anterior segment of the eye – To support corneal innervation and integrity 180 Diane T. Adamczyk, OD, FAAO Copyright © 2024 154 Ocular Surface Diesease Treatment Options Pharmacology II Oxervate (cenegermin-bkbj ophthalmic solution) 0.002% • Dosage: one drop 6 times/day at 2 hour intervals for 8 weeks • No CL or other eye drops for at least 15 minutes • Adverse Effects: – Pain on instillation (16%). Ocular hyperemia, ocular inflammation, tearing, fb sensation, corneal deposits • Shipped directly to home (insulated packed with dry ice) • Refrigerate within 5 hours of delivery • Cost: Oxervate is around $25,418.76, 12% off the average retail price of $29,141.35 (1-30-22) – (on line 1-16-23: $70,000) 181 Diane T. Adamczyk, OD, FAAO Copyright © 2024 155 Ocular Surface Diesease Treatment Options Pharmacology II • Conclusion: Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate to severe NK 182 Diane T. Adamczyk, OD, FAAO Copyright © 2024 156 Ocular Surface Diesease Treatment Options Pharmacology II SUMMATION 183 Diane T. Adamczyk, OD, FAAO Copyright © 2024 157 Ocular Surface Diesease Treatment Options • • • Etiology Lubricants (the components) Lacrimal Occlusion – – – • Ocular Surface Review Collagen/Extended dissolvable/Silicone /Smart Plug Adverse effects Candidates Tears Stimulation – – – • Pharmacology II Pilocarpine, Cevimeline, Diquafosol iTear 100 Tyrvaya (varenicline) Anti-inflammatory – – Steroids Cyclosporine 0.05% (Restasis) • • Emulsion Expectations (1 month-dec symptoms, 3 months - improvement, 6 months - maintenance) – Cyclosporine 0.09% (Cequa) • • • Nanomicelle Improvement as early as 28 days – Cyclosporine 0.1% (Verkazia) – Cyclosporine 0.1% (Vevye) – Lifitegrast (Xiidra) Other – – – Miebo (perfluorohexyloctane ophthalmic solution) Mucolytics/Hormones/Nutrition (Omega 3) Oxervate 184 Diane T. Adam