A Review of the Mechanism of Action of Cyclosporine A: The Role of Cyclosporine A in Dry Eye Disease and Recent Formulation Developments

References

• Farrand KF, Fridman M, Stillman IO, Schaumberg DA. Prevalence of diagnosed dry eye disease in the United States among adults aged 18 years and older. Am J Ophthalmol. 2017;182:90–98. doi:10.1016/j.ajo.2017.06.033
   PubMed Web of Science ®Google Scholar
• Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II epidemiology report. Ocul Surf. 2017;15(3):334–365. doi:10.1016/j.jtos.2017.05.003
   PubMed Web of Science ®Google Scholar
• de Oliveira RC, Wilson SE. Practical guidance for the use of cyclosporine ophthalmic solutions in the management of dry eye disease. Clin Ophthalmol. 2019;13:1115–1122. doi:10.2147/OPTH.S184412
   PubMed Web of Science ®Google Scholar
• McDonald M, Patel DA, Keith MS, Snedecor SJ. Economic and humanistic burden of dry eye disease in Europe, North America, and Asia: a systematic literature review. Ocul Surf. 2016;14(2):144–167. doi:10.1016/j.jtos.2015.11.002
   PubMed Web of Science ®Google Scholar
• Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15(3):276–283. doi:10.1016/j.jtos.2017.05.008
   PubMed Web of Science ®Google Scholar
• Fahmy RM, Aldarwesh A. Correlation between dry eye and refractive error in Saudi young adults using noninvasive Keratograph 4. Indian J Ophthalmol. 2018;66(5):653–656. doi:10.4103/ijo.IJO_1103_17
   Web of Science ®Google Scholar
• Nichols JJ, Ziegler C, Mitchell GL, Nichols KK. Self-reported dry eye disease across refractive modalities. Invest Ophthalmol Vis Sci. 2005;46(6):1911–1914. doi:10.1167/iovs.04-1294
   Web of Science ®Google Scholar
• Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol. 2002;86(4):418–423. doi:10.1136/bjo.86.4.418
   PubMed Web of Science ®Google Scholar
• Lopes NLV, Gracitelli CPB, Chalita MR, de Faria NVL. Ocular surface evaluation after the substitution of benzalkonium chloride preserved prostaglandin eye drops by a preservative-free prostaglandin analogue. Med Hypothesis Discov Innov Ophthalmol. 2019;8(1):52–56.
   PubMedGoogle Scholar
• Giannaccare G, Bernabei F, Pellegrini M, et al. Bilateral morphometric analysis of corneal sub-basal nerve plexus in patients undergoing unilateral cataract surgery: a preliminary in vivo confocal microscopy study. Br J Ophthalmol. 2020. doi:10.1136/bjophthalmol-2019-315449
   Web of Science ®Google Scholar
• He Y, Li J, Zhu J, Jie Y, Wang N, Wang J. The improvement of dry eye after cataract surgery by intraoperative using ophthalmic viscosurgical devices on the surface of cornea: the results of a consort-compliant randomized controlled trial. Medicine (Baltimore). 2017;96(50):e8940. doi:10.1097/MD.0000000000008940
   Web of Science ®Google Scholar
• Ishrat S, Nema N, Chandravanshi SCL. Incidence and pattern of dry eye after cataract surgery. Saudi J Ophthalmol. 2019;33(1):34–40. doi:10.1016/j.sjopt.2018.10.009
   PubMed Web of Science ®Google Scholar
• Lee SY, Wong TT, Chua J, Boo C, Soh YF, Tong L. Effect of chronic anti-glaucoma medications and trabeculectomy on tear osmolarity. Eye (Lond). 2013;27(10):1142–1150. doi:10.1038/eye.2013.144
   Web of Science ®Google Scholar
• Lee JH, Song IS, Kim KL, Yoon SY. Effectiveness and optical quality of topical 3.0% diquafosol versus 0.05% cyclosporine A in dry eye patients following cataract surgery. J Ophthalmol. 2016;2016:8150757. doi:10.1155/2016/8150757
   PubMed Web of Science ®Google Scholar
• Periman LM, Perez VL, Saban DR, Lin MC, Neri P. The immunological basis of dry eye disease and current topical treatment options. J Ocul Pharmacol Ther. 2020;36(3):137–146. doi:10.1089/jop.2019.0060
   PubMed Web of Science ®Google Scholar
• Baudouin C, Messmer EM, Aragona P, et al. Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction. Br J Ophthalmol. 2016;100(3):300–306. doi:10.1136/bjophthalmol-2015-307415
   PubMed Web of Science ®Google Scholar
• Geerling G, Baudouin C, Aragona P, et al. Emerging strategies for the diagnosis and treatment of meibomian gland dysfunction: proceedings of the OCEAN group meeting. Ocul Surf. 2017;15(2):179–192. doi:10.1016/j.jtos.2017.01.006
   PubMed Web of Science ®Google Scholar
• Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438–510. doi:10.1016/j.jtos.2017.05.011.
   PubMed Web of Science ®Google Scholar
• Baudouin C, Irkec M, Messmer EM, et al. Clinical impact of inflammation in dry eye disease: proceedings of the ODISSEY group meeting. Acta Ophthalmol. 2018;96(2):111–119. doi:10.1111/aos.13436
   PubMed Web of Science ®Google Scholar
• Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013;32(1):19–41. doi:10.3109/08830185.2012.748052
   PubMed Web of Science ®Google Scholar
• Zhang X, Qu Y, He X, et al. Dry eye management: targeting the ocular surface microenvironment. Int J Mol Sci. 2017;18(7):1398. doi:10.3390/ijms18071398
   PubMed Web of Science ®Google Scholar
• Contreras-Ruiz L, Masli S. Immunomodulatory cross-talk between conjunctival goblet cells and dendritic cells. PLoS One. 2015;10(3):e0120284. doi:10.1371/journal.pone.0120284
   PubMed Web of Science ®Google Scholar
• Lallemand F, Schmitt M, Bourges JL, Gurny R, Benita S, Garrigue JS. Cyclosporine A delivery to the eye: a comprehensive review of academic and industrial efforts. Eur J Pharm Biopharm. 2017;117:14–28. doi:10.1016/j.ejpb.2017.03.006
   PubMed Web of Science ®Google Scholar
• Du S, Hiramatsu N, Hayakawa K, et al. Suppression of NF-kappaB by cyclosporin a and tacrolimus (FK506) via induction of the C/EBP family: implication for unfolded protein response. J Immunol. 2009;182(11):7201–7211. doi:10.4049/jimmunol.0801772
   Web of Science ®Google Scholar
• Gao J, Sana R, Calder V, et al. Mitochondrial permeability transition pore in inflammatory apoptosis of human conjunctival epithelial cells and T cells: effect of cyclosporin A. Invest Ophthalmol Vis Sci. 2013;54(7):4717–4733. doi:10.1167/iovs.13-11681
   PubMed Web of Science ®Google Scholar
• Cholkar K, Patel A, Vadlapudi AD, Mitra AK. Novel nanomicellar formulation approaches for anterior and posterior segment ocular drug delivery. Recent Pat Nanomed. 2012;2(2):82–95. doi:10.2174/1877912311202020082
   PubMedGoogle Scholar
• Kuwano M, Ibuki H, Morikawa N, Ota A, Kawashima Y. Cyclosporine A formulation affects its ocular distribution in rabbits. Pharm Res. 2002;19(1):108–111. doi:10.1023/A:1013671819604
   PubMed Web of Science ®Google Scholar
• Luo L, Li DQ, Doshi A, Farley W, Corrales RM, Pflugfelder SC. Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Invest Ophthalmol Vis Sci. 2004;45(12):4293–4301. doi:10.1167/iovs.03-1145
   PubMed Web of Science ®Google Scholar
• Li DQ, Chen Z, Song XJ, Luo L, Pflugfelder SC. Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2004;45(12):4302–4311. doi:10.1167/iovs.04-0299
   PubMed Web of Science ®Google Scholar
• Chen Y, Chauhan SK, Saban DR, Sadrai Z, Okanobo A, Dana R. Interferon-gamma-secreting NK cells promote induction of dry eye disease. J Leukoc Biol. 2011;89(6):965–972. doi:10.1189/jlb.1110611
   PubMed Web of Science ®Google Scholar
• Coursey TG, Bohat R, Barbosa FL, Pflugfelder SC, de Paiva CS. Desiccating stress-induced chemokine expression in the epithelium is dependent on upregulation of NKG2D/RAE-1 and release of IFN-gamma in experimental dry eye. J Immunol. 2014;193(10):5264–5272. doi:10.4049/jimmunol.1400016
   Web of Science ®Google Scholar
• Brocker T. Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells. J Exp Med. 1997;186(8):1223–1232. doi:10.1084/jem.186.8.1223
   Web of Science ®Google Scholar
• Lemos MP, Fan L, Lo D, Laufer TM. CD8alpha+ and CD11b+ dendritic cell-restricted MHC class II controls Th1 CD4+ T cell immunity. J Immunol. 2003;171(10):5077–5084. doi:10.4049/jimmunol.171.10.5077
   Web of Science ®Google Scholar
• Zhang X, Volpe EA, Gandhi NB, et al. NK cells promote Th-17 mediated corneal barrier disruption in dry eye. PLoS One. 2012;7(5):e36822. doi:10.1371/journal.pone.0036822
   PubMed Web of Science ®Google Scholar
• Zhou D, Chen YT, Chen F, et al. Critical involvement of macrophage infiltration in the development of Sjogren’s syndrome-associated dry eye. Am J Pathol. 2012;181(3):753–760. doi:10.1016/j.ajpath.2012.05.014
   Web of Science ®Google Scholar
• Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. doi:10.3389/fimmu.2014.00491
   PubMed Web of Science ®Google Scholar
• Schaumburg CS, Siemasko KF, De Paiva CS, et al. Ocular surface APCs are necessary for autoreactive T cell-mediated experimental autoimmune lacrimal keratoconjunctivitis. J Immunol. 2011;187(7):3653–3662. doi:10.4049/jimmunol.1101442
   PubMed Web of Science ®Google Scholar
• Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol. 2009;147(2):198–205e191. doi:10.1016/j.ajo.2008.08.032
   PubMed Web of Science ®Google Scholar
• Kothari P, Pestana R, Mesraoua R, et al. IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages. J Immunol. 2014;192(1):349–357. doi:10.4049/jimmunol.1301906
   Web of Science ®Google Scholar
• Nicolle P, Liang H, Reboussin E, et al. Proinflammatory markers, chemokines, and enkephalin in patients suffering from dry eye disease. Int J Mol Sci. 2018;19(4):1221. doi:10.3390/ijms19041221
   PubMed Web of Science ®Google Scholar
• Gollmer K, Asperti-Boursin F, Tanaka Y, et al. CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway. Blood. 2009;114(3):580–588. doi:10.1182/blood-2009-01-200923
   Web of Science ®Google Scholar
• Marsland BJ, Battig P, Bauer M, et al. CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells. Immunity. 2005;22(4):493–505. doi:10.1016/j.immuni.2005.02.010
   PubMed Web of Science ®Google Scholar
• Ji YW, Seo Y, Choi W, et al. Dry eye-induced CCR7+CD11b+ cell lymph node homing is induced by COX-2 activities. Invest Ophthalmol Vis Sci. 2014;55(10):6829–6838. doi:10.1167/iovs.14-14744
   Web of Science ®Google Scholar
• Kodati S, Chauhan SK, Chen Y, et al. CCR7 is critical for the induction and maintenance of Th17 immunity in dry eye disease. Invest Ophthalmol Vis Sci. 2014;55(9):5871–5877. doi:10.1167/iovs.14-14481
   PubMed Web of Science ®Google Scholar
• Chen T, Guo J, Yang M, et al. Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression. Blood. 2004;103(2):413–421. doi:10.1182/blood-2003-07-2412
   PubMed Web of Science ®Google Scholar
• Coursey TG, Gandhi NB, Volpe EA, Pflugfelder SC, de Paiva CS. Chemokine receptors CCR6 and CXCR3 are necessary for CD4(+) T cell mediated ocular surface disease in experimental dry eye disease. PLoS One. 2013;8(11):e78508. doi:10.1371/journal.pone.0078508
   Web of Science ®Google Scholar
• Dohlman TH, Chauhan SK, Kodati S, et al. The CCR6/CCL20 axis mediates Th17 cell migration to the ocular surface in dry eye disease. Invest Ophthalmol Vis Sci. 2013;54(6):4081–4091. doi:10.1167/iovs.12-11216
   Web of Science ®Google Scholar
• Chauhan SK, El Annan J, Ecoiffier T, et al. Autoimmunity in dry eye is due to resistance of Th17 to Treg suppression. J Immunol. 2009;182(3):1247–1252. doi:10.4049/jimmunol.182.3.1247
   PubMed Web of Science ®Google Scholar
• García-Posadas L, Contreras-Ruiz L, Soriano-Romaní L, Dartt DA, Diebold Y. Conjunctival goblet cell function: effect of contact lens wear and cytokines. Eye Contact Lens. 2016;42(2):83–90. doi:10.1097/ICL.0000000000000158
   Web of Science ®Google Scholar
• Pflugfelder SC, De Paiva CS, Moore QL, et al. Aqueous tear deficiency increases conjunctival interferon-gamma (IFN-gamma) expression and goblet cell loss. Invest Ophthalmol Vis Sci. 2015;56(12):7545–7550. doi:10.1167/iovs.15-17627
   Web of Science ®Google Scholar
• Zhang X, Chen W, De Paiva CS, et al. Interferon-gamma exacerbates dry eye-induced apoptosis in conjunctiva through dual apoptotic pathways. Invest Ophthalmol Vis Sci. 2011;52(9):6279–6285. doi:10.1167/iovs.10-7081
   PubMed Web of Science ®Google Scholar
• Zhang X, De Paiva CS, Su Z, Volpe EA, Li DQ, Pflugfelder SC. Topical interferon-gamma neutralization prevents conjunctival goblet cell loss in experimental murine dry eye. Exp Eye Res. 2014;118:117–124. doi:10.1016/j.exer.2013.11.011
   Web of Science ®Google Scholar
• Ko BY, Xiao Y, Barbosa FL, de Paiva CS, Pflugfelder SC. Goblet cell loss abrogates ocular surface immune tolerance. JCI Insight. 2018;3(3). doi:10.1172/jci.insight.98222
   Web of Science ®Google Scholar
• Marko CK, Menon BB, Chen G, Whitsett JA, Clevers H, Gipson IK. Spdef null mice lack conjunctival goblet cells and provide a model of dry eye. Am J Pathol. 2013;183(1):35–48. doi:10.1016/j.ajpath.2013.03.017
   Web of Science ®Google Scholar
• Li XQ, Zhang ZL, Tan WF, Sun XJ, Ma H. Down-regulation of CXCL12/CXCR4 expression alleviates ischemia-reperfusion-induced inflammatory pain via inhibiting glial TLR4 activation in the spinal cord. PLoS One. 2016;11(10):e0163807. doi:10.1371/journal.pone.0163807
   Web of Science ®Google Scholar
• Enriquez-de-Salamanca A, Castellanos E, Stern ME, et al. Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease. Mol Vis. 2010;16:862–873.
   PubMed Web of Science ®Google Scholar
• Bushley KE, Raja R, Jaiswal P, et al. The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster. PLoS Genet. 2013;9(6):e1003496. doi:10.1371/journal.pgen.1003496
   PubMed Web of Science ®Google Scholar
• Borel JF, Feurer C, Magnee C, Stahelin H. Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology. 1977;32(6):1017–1025.
   PubMed Web of Science ®Google Scholar
• Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev. 2006;4:Cd005161.
   Google Scholar
• RESTASIS® (cyclosporine ophthalmic emulsion) 0.05% for topical ophthalmic use. Full prescribing information. Irvine, CA: Allergan; 2017.
   Google Scholar
• Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575–628. doi:10.1016/j.jtos.2017.05.006
   PubMed Web of Science ®Google Scholar
• Kymionis GD, Bouzoukis DI, Diakonis VF, Siganos C. Treatment of chronic dry eye: focus on cyclosporine. Clin Ophthalmol. 2008;2(4):829–836.
   Google Scholar
• Ambroziak AM, Szaflik J, Szaflik JP, Ambroziak M, Witkiewicz J, Skopinski P. Immunomodulation on the ocular surface: a review. Cent Eur J Immunol. 2016;41(2):195–208. doi:10.5114/ceji.2016.60995
   PubMed Web of Science ®Google Scholar
• Meyer S, Kohler NG, Joly A. Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF-kappaB activation. FEBS Lett. 1997;413(2):354–358. doi:10.1016/S0014-5793(97)00930-7
   PubMed Web of Science ®Google Scholar
• Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47(2–3):119–125. doi:10.1016/S0162-3109(00)00192-2
   PubMed Web of Science ®Google Scholar
• Matsuda S, Moriguchi T, Koyasu S, Nishida E. T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A. J Biol Chem. 1998;273(20):12378–12382. doi:10.1074/jbc.273.20.12378
   Web of Science ®Google Scholar
• Ames P, Galor A. Cyclosporine ophthalmic emulsions for the treatment of dry eye: a review of the clinical evidence. Clin Investig (Lond). 2015;5(3):267–285. doi:10.4155/cli.14.135
   Google Scholar
• Bang SP, Yeon CY, Adhikari N, et al. Cyclosporine A eyedrops with self-nanoemulsifying drug delivery systems have improved physicochemical properties and efficacy against dry eye disease in a murine dry eye model. PLoS One. 2019;14(11):e0224805. doi:10.1371/journal.pone.0224805
   PubMed Web of Science ®Google Scholar
• Demir T, Godekmerdan A, Balbaba N, Turkcuoglu P, Ilhan F, Demir N. The effect of infliximab, cyclosporine A and recombinant IL-10 on vitreous cytokine levels in experimental autoimmune uveitis. Indian J Ophthalmol. 2006;54(4):241–245. doi:10.4103/0301-4738.27948
   Google Scholar
• Ghasemi H, Djalilian A. Topical calcineurin inhibitors: expanding indications for corneal and ocular surface inflammation. J Ophthalmic Vis Res. 2019;14(4):398–399. doi: 10.18502/jovr.v14i4.5435
   Web of Science ®Google Scholar
• Davis G. The Evolution of Cataract Surgery. Mo Med. 2016;113(1):58–62.
   PubMedGoogle Scholar
• Salomao MQ, Ambrosio R Jr., Wilson SE. Dry eye associated with laser in situ keratomileusis: mechanical microkeratome versus femtosecond laser. J Cataract Refract Surg. 2009;35(10):1756–1760. doi:10.1016/j.jcrs.2009.05.032
   PubMed Web of Science ®Google Scholar
• Kanellopoulos AJ. Incidence and management of symptomatic dry eye related to LASIK for myopia, with topical cyclosporine A. Clin Ophthalmol. 2019;13:545–552. doi:10.2147/OPTH.S188521
   PubMed Web of Science ®Google Scholar
• Iaccheri B, Torroni G, Cagini C, et al. Corneal confocal scanning laser microscopy in patients with dry eye disease treated with topical cyclosporine. Eye (Lond). 2017;31(5):788–794. doi:10.1038/eye.2017.3
   PubMed Web of Science ®Google Scholar
• Napoli PE, Braghiroli M, Iovino C, Demarinis G, Fossarello M. A study of refractory cases of persistent epithelial defects associated with dry eye syndrome and recurrent corneal erosions successfully treated with cyclosporine A 0.05% eye drops. Drug Des Devel Ther. 2019;13:2001–2008. doi:10.2147/DDDT.S207453
   PubMed Web of Science ®Google Scholar
• Napoli PE, Mangoni L, Gentile P, Braghiroli M, Fossarello M. A panel of broad-spectrum antivirals in topical ophthalmic medications from the drug repurposing approach during and after the coronavirus disease 2019 era. J Clin Med. 2020;9(8):2441. doi:10.3390/jcm9082441
   PubMed Web of Science ®Google Scholar
• Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 study group. Ophthalmology. 2000;107(4):631–639. doi:10.1016/S0161-6420(99)00176-1
   PubMed Web of Science ®Google Scholar
• Stonecipher KG, Torkildsen GL, Ousler GW 3rd, Morris S, Villanueva L, Hollander DA. The IMPACT study: a prospective evaluation of the effects of cyclosporine ophthalmic emulsion 0.05% on ocular surface staining and visual performance in patients with dry eye. Clin Ophthalmol. 2016;10:887–895. doi:10.2147/OPTH.S101627
   PubMed Web of Science ®Google Scholar
• IKERVIS® (ciclosporin ophthalmic emulsion) 1 mg/mL, for topical ophthalmic use. Full prescribing information. Evry, France: Santen SAS; 2015.
   Google Scholar
• Leonardi A, Van Setten G, Amrane M, et al. Efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe dry eye disease: a multicenter randomized trial. Eur J Ophthalmol. 2016;26(4):287–296. doi:10.5301/ejo.5000779
   PubMed Web of Science ®Google Scholar
• CEQUATM (cyclosporine ophthalmic solution 0.09%). Full prescribing information. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.; 2018.
   Google Scholar
• Vaishya RD, Khurana V, Patel S, Mitra AK. Controlled ocular drug delivery with nanomicelles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014;6(5):422–437. doi:10.1002/wnan.1272
   PubMed Web of Science ®Google Scholar
• Cholkar K, Gilger BC, Mitra AK. Topical, aqueous, clear cyclosporine formulation design for anterior and posterior ocular delivery. Transl Vis Sci Technol. 2015;4(3):1. doi:10.1167/tvst.4.3.1
   PubMed Web of Science ®Google Scholar
• Goldberg DF, Malhotra RP, Schechter BA, Justice A, Weiss SL, Sheppard JD. A Phase 3, randomized, double-masked study of OTX-101 ophthalmic solution 0.09% in the treatment of dry eye disease. Ophthalmology. 2019;126(9):1230–1237. doi:10.1016/j.ophtha.2019.03.050
   PubMed Web of Science ®Google Scholar
• Malhotra R, Devries DK, Luchs J, et al. Effect of OTX-101, a novel nanomicellar formulation of Cyclosporine A, on corneal staining in patients with keratoconjunctivitis sicca: a pooled analysis of Phase 2b/3 and Phase 3 studies. Cornea. 2019;38(10):1259–1265. doi:10.1097/ICO.0000000000001989
   PubMed Web of Science ®Google Scholar
• Smyth-Medina R, Johnston J, Devries DK, et al. Effect of OTX-101, a novel nanomicellar formulation of Cyclosporine A, on conjunctival staining in patients with keratoconjunctivitis sicca: a pooled analysis of Phase 2b/3 and 3 clinical trials. J Ocul Pharmacol Ther. 2019;35(7):388–394. doi:10.1089/jop.2018.0154
   PubMed Web of Science ®Google Scholar
• Tauber J, Schechter BA, Bacharach J, et al. A Phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease. Clin Ophthalmol. 2018;12:1921–1929. doi:10.2147/OPTH.S175065
   PubMed Web of Science ®Google Scholar
• Sheppard J, Kannarr S, Luchs J, et al. Efficacy and safety of OTX-101, a novel nanomicellar formulation of Cyclosporine A, for the treatment of keratoconjunctivitis sicca: pooled analysis of a Phase 2b/3 and Phase 3 study. Eye Contact Lens. 2020;46(Suppl 1):S14–s19. doi:10.1097/ICL.0000000000000636
   PubMed Web of Science ®Google Scholar
• Weiss SL, Kramer WG. Ocular distribution of cyclosporine following topical administration of OTX-101 in New Zealand White Rabbits. J Ocul Pharmacol Ther. 2019;35(7):395–402. doi:10.1089/jop.2018.0106
   PubMed Web of Science ®Google Scholar
• Mandal A, Gote V, Pal D, Ogundele A, Mitra AK. Ocular pharmacokinetics of a topical ophthalmic nanomicellar solution of Cyclosporine (Cequa®) for dry eye disease. Pharm Res. 2019;36(2):36. doi:10.1007/s11095-018-2556-5
   PubMed Web of Science ®Google Scholar
• Pinheiro R, Panfil C, Schrage N, Dutescu RM. Comparison of the lubricant eyedrops Optive®, Vismed Multi®, and Cationorm® on the corneal healing process in an ex vivo model. Eur J Ophthalmol. 2015;25(5):379–384. doi:10.1089/jop.2015.0054
   Web of Science ®Google Scholar
• Schuerer N, Stein E, Inic-Kanada A, et al. Implications for ophthalmic formulations: ocular buffers show varied cytotoxic impact on human corneal-limbal and human conjunctival epithelial Cells. Cornea. 2017;36(6):712–718. doi:10.1097/ICO.0000000000001199
   Web of Science ®Google Scholar
• Abidi A, Shukla P, Ahmad A. Lifitegrast: a novel drug for treatment of dry eye disease. J Pharmacol Pharmacother. 2016;7(4):194–198. doi:10.4103/0976-500X.195920
   PubMed Web of Science ®Google Scholar
• Chao W, Belmonte C, Benitez Del Castillo JM, et al. Report of the Inaugural Meeting of the TFOS i(2) = initiating innovation Series: targeting the Unmet Need for Dry Eye Treatment. Ocul Surf. 2016;14(2):264–316. doi:10.1016/j.jtos.2015.11.003
   PubMed Web of Science ®Google Scholar
• Xiidra® (lifitegrast ophthalmic solution) 5%, for topical ophthalmic use. Full prescribing information. Lexington, MA: Shire; 2016.
   Google Scholar
• Perez VL, Pflugfelder SC, Zhang S, Shojaei A, Haque R. Lifitegrast, a novel integrin antagonist for treatment of dry eye disease. Ocul Surf. 2016;14(2):207–215. doi:10.1016/j.jtos.2016.01.001
   PubMed Web of Science ®Google Scholar
• Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010;12(3):348–360. doi:10.1208/s12248-010-9183-3
   PubMed Web of Science ®Google Scholar
• Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol. 2000;118(11):1489–1496. doi:10.1001/archopht.118.11.1489
   PubMedGoogle Scholar
• Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol. 2002;120(3):330–337. doi:10.1001/archopht.120.3.330
   PubMedGoogle Scholar
• Jerkins GW, Pattare GR, Kannarr SR. A Review of Topical Cyclosporine A Formulations-A Disease-Modifying Agent for Keratoconjunctivitis Sicca. Clin Ophthalmol. 2020;14):481–489. doi:10.2147/OPTH.S228070.
   PubMed Web of Science ®Google Scholar