Lecture 2 OcSurface Pharm 120 PDF

Ocular Surface Diesease Treatment Options Pharmacology II Steroids Effect Potential side effects 96 Diane T. Adamczyk, OD, FAAO Copyright © 2024 80 -steroid: can increase IOP and potential to cause cataract with chronic use 80 Ocular Surface Diesease Treatment Options Pharmacology II Topical cortico...

Ocular Surface Diesease Treatment Options Pharmacology II Steroids Effect Potential side effects 96 Diane T. Adamczyk, OD, FAAO Copyright © 2024 80 -steroid: can increase IOP and potential to cause cataract with chronic use 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 -topical steroids for dry eye there is moderate to low certainty of evidence so it may or may not help 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 -steroids are used with commonalty to treating with DE -basically steroids show some potential helping with DE 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 -big molecule, immunosuppressant -used in systemic disease à has a lot of side effects but for topical use you don’t see the side effects in topical use bc it stays on the ocular surface and doesn’t go into systemic circulation -the difference in each cyclosporine is that is has diff vehicles 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 -T-cell activation is for inflammation so it inhibits t-cell activation of the lymphocytes and inhibits apoptosis of the conjunctival epithelial. cells -know highlighted -this cyclosporine is going after the calcineurin nuclear factor. You have your T-cell receptor come in and combines with the ligand causing Ca release. Calcineurin is part of the process and it continues on and you get activation of T-cell. -the cyclosporine comes in and interferes with calcineurin in order to inhibit T-lymphocyte activation 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 -words to the diagram in previous slide -arrow is where the cyclosporine comes in and interferes with the process -so if you’re dealing with topical or oral cyclosporine, the pathway or process is the same the only diff is with topical you want the cyclosporine to stay on the ocular surface - 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 -if your taking the oral version systemically you can see high amounts go in the colon, illum, kidney, liver but topically it rarely gets in -cyclosporine doesn’t go thru the cornea very well bc it has multiple layers 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 -don’t get these side effects with topical cyclosporine 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 keratoconjunctivitis 0.1% Ophthalmic Solution (Vevye) 107 Diane T. Adamczyk, OD, FAAO Copyright © 2024 88 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 -cyclosporine is lipophilic so it’s easily able to get thru the corneal epithelium but isn’t getting thru the barrier of the stroma so it stays on the ocular surface -for what we are treating, we do want the med to stay in the ocular surface so its good its not going thru the stroma 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 -first cyclosporine to come out was restasis -delivered better as an emulsion 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 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 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 -doesn’t take effect right away so put pt on steroid to help pt right away so they’re getting some effect -does take a while for it to take effect -after a while, you want to take the pt off steroid -takes a significant amount of time for improvement to be seen 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 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 -if pt has an active infection you don’t want pt on restasis or steroids 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 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 -burning occurs with any drops 97 Ocular Surface Diesease Treatment Options Pharmacology II 119 Diane T. Adamczyk, OD, FAAO Copyright © 2024 98 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 -cyclosporine is a relatively safe drug to use bc it doesn’t get into the systemic system -also discussed how cyclosporine acclimates and goes after the calcium/calcineurin and its affect on the mechanism with the activation of T-cells -cyclosporine's come in diff vehicles and diff concentrations and by alternating the vehicle, the efficacy of the drop and its delivery is changed - 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 -higher concentration than restasis so it’ll be a better drug -nanomicellar technology is used which is the vehicle that is delivering the drug by using very small molecules that come in a wide variety of different forms -the molecule has a hydrophilic outer core and is protecting the hydrophobic core -this makes it easier for the drug to get thru the corneal epithelium and the stroma -this drug is shown to work better than restasis bc you see improvement as early as one month vs restasis that takes 1 month to reduce symptoms, 3 months to see improvement and 6 months to see significant improvement bc it has a diff delivery system 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 The drug is entrapped between the hydrophilic and hydrophobic tail 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 -restasis vehicle is emulsion (oil and water) so its not a solution but this is formulated as a solution so the vehicle for cequa is the solution that contains the nanomicellar technology 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 103 103 Ocular Surface Diesease Treatment Options Pharmacology II 2019 127 Diane T. Adamczyk, OD, FAAO Copyright © 2024 104 104 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 -restasis vehicle came from an artificial tear and took years for FDA to approve bc people didn’t know if it was the cyclosporine or the vehicle that was improving the ocular surface -later discovered that the cyclosporine is working 105 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 106 -questioned if cyclosporine can be used for vernal KC -amongst the simplest is seasonal allergic conjunctivitis then GPC then vernal then atopic keratoconjunctivitis -in seasonal, you won’t get any disruption to the ocular surface meaning there won’t be damage or scarring but when you get GPC or vernal or atopic you start to get changes to the structure and also have an effect on the cornea and it can effect sight -atopic KC doesn’t respond to steroids thats why its steroid resistant -if you get epithelial HSV you don’t want to use steroids but if its stromal HSV then you want to use steroids 106 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 107 -verkazia is another cyclosporine and is an emulsion à higher concentration than restasis and cequa -shows nice results when treated vernal -inhibits t-cell proliferation 107 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 108 -did a study on vernal KC and did a comparison between twice a day (blue) and 4 times a day (yellow) to figure out what’s the best dosaging -study supports the 4 times a day gives a better end result -2 times a day also works well but doesn’t give optimal result 108 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 Perflurobutylpentane à seen in miebo also but is the vehicle in this instance – No anti-microbial preservatives, oils or surfactants – No associated pH or osmolarity 133 Efficacy after 4 weeks ADR: instillation site reactions causes pain, temporary decrease in VA Diane T. Adamczyk, OD, FAAO Copyright © 2024 109 109 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 Key point conclusion: 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 110 - 110 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 111 -most studies say that no matter what the virtue of the mechanism there is, the T-cells will naturally take time despite how good the delivery system may be -however vevye is showing a little more of a speed up and seeing a more faster response so with this particular drug delivery, the effication was much faster compared to the other cyclosporine's 111 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 112 -when used as miebo it nicely coats the eye, doesn’t cause much blurring bc of the way it interacts with the surface of the eye so its more tolerable for the pt - 112 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 113 -works different than cyclosporine as it is a anti-inflammatory 113 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 LFA1= Lymphocyte function-associated antigen-1 138 Diane T. Adamczyk, OD, FAAO Copyright © 2024 114 -LFA-1 is attached to t-cell then you need ICAM which needs to partner with LFA-1 and that’s what will start the inflammatory cascade -lifitegrast is an antagonist and prevents the LFA and ICAM from partnering up which prevents tcell activation and the whole sequence of events from happening -can you use 2 different drugs to treat a pt aka the cyclosporine and the lifitegrast and the answer is yes but from a clinical POV you usually start with one or the other because they have diff mechanisms 114 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 115 115 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 116 -dysgeusia is the biggest complain with lifitegrast 116 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 117 117 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 118 -arrow is impt à lifitegrast is known to be fast working compared to cyclosporine's such as restasis that takes 3 months to show improvement and cequa that shows improvement in 1 months time 118 Ocular Surface Diesease Treatment Options Pharmacology II Other Treatments 144 Diane T. Adamczyk, OD, FAAO Copyright © 2024 119 119 Ocular Surface Diesease Treatment Options Pharmacology II Other Treatment Considerations Avenova Mucolytics Hormones Tetracycline Nutritional 145 Diane T. Adamczyk, OD, FAAO Copyright © 2024 120 120