Changing trends in the treatment of dry-eye disease

Expert Opinion on Investigational Drugs

Volumn 22, Issue 12, 2013, Pages 1581-1601

  Dogru, Murat ^a,c   Nakamura, Masatsugu ^b   Shimazaki, Jun ^a   Tsubota, Kazuo ^c  

^a TOKYO DENTAL COLLEGE   (Japan)

^b SANTEN PHARMACEUTICAL CO LTD   (Japan)

^c KEIO UNIVERSITY SCHOOL OF MEDICINE   (Japan)

Author keywords

Artificial eye drops; Autologous serum; Dry eye disease; Mucin secretagogues; Tear secretagogues

Indexed keywords

ANTIINFLAMMATORY AGENT; ANTIOXIDANT; ARTIFICIAL TEAR; CARBOMER; CORTICOSTEROID; CYCLOSPORIN A; DIQUAFOSOL; DIQUAS; ESSENTIAL FATTY ACID; FLUORESCEIN; GAMMA LINOLENIC ACID; GENTEAL; HYALURONIC ACID; LACTOFERRIN; LINOLEIC ACID; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; METHYLPREDNISOLONE; MIMD 3; MUCIN; PLACEBO; REBAMIPIDE; RGN 259; RX 10045; TETRACYCLINE; TETRACYCLINE DERIVATIVE; TETRYZOLINE; THYMOSIN BETA4; TOFACITINIB; TRANILAST; UNCLASSIFIED DRUG;

BLEPHARITIS; DISEASE SEVERITY; DRUG SAFETY; DRUG TOLERABILITY; DRY EYE; ENVIRONMENT; EVAPORATION; EVIDENCE BASED PRACTICE; GOBLET CELL; HISTOCOMPATIBILITY; HUMAN; HUMIDIFIER; HYGIENE; INTERFEROMETRY; IONTOPHORESIS; KERATOCONJUNCTIVITIS SICCA; LIFESTYLE MODIFICATION; MEIBOMIAN GLAND; MEIBOMIAN GLAND DYSFUNCTION; MEIBOMIANITIS; NONHUMAN; OSMOLARITY; PATHOGENESIS; PREVALENCE; REGENERATIVE MEDICINE; REVIEW; SCHIRMER TEST; SJOEGREN SYNDROME; TEAR FILM; TEAR FLOW; TREND STUDY; WARMING;

ANIMALS; DRY EYE SYNDROMES; HUMANS; OPHTHALMIC SOLUTIONS;

EID: 84887798602     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2013.838557     Document Type: Review

References (143)

1. Lemp MA, Baudouin C, Baum J, et al. The definition and classification of dry eye disease. report of the Definition and Classification Subcommittee of the International Dry Eye Work Shop (2007). Ocul Surf 2007;5:75-92
2. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003;136:318-26
3. Miljanovic B, Dana MR, Sullivan DA, Schaumberg DA. Prevalence and risk factors for dry eye syndrome among older men in the United States [ARVO #4293]. ARVO; 2007
4. Schein OD, Hochberg MC, Munoz B, et al. Dry eye and dry mouth in the elderly: A population-based assessment. Arch Intern Med 1999;159:1359-63
5. Schein OD, Munoz B, Tielsch JM, et al. Prevalence of dry eye among the elderly. Am J Ophthalmol 1997;124:723-8
6. Munoz B, West SK, Rubin GS, et al. Causes of blindness and visual impairment in a population of older Americans: The Salisbury Eye Evaluation Study. Arch Ophthalmol 2000;118:819-25
7. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol 2000;118:1264-8
8. Christen WG, Manson JE, Glynn RJ, et al. Low-dose aspirin and risk of cataract and subtypes in a randomized trial of US physicians. Ophthalmic Epidemiol 1998;5:133-42
9. Christen WG, Gaziano JM, Hennekens CH. Design of physicians. Health study II. A randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann Epidemiol 2000;10:125-34
10. Chia EM, Mitchell P, Rochtchina E, et al. Prevalence and associations of dry eye syndrome in an older population: The Blue Mountains Eye Study. Clin Experiment Ophthalmol 2003;31:229-32
11. McCarty CA, Bansal AK, Livingston PM, et al. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology 1998;105:1114-19
12. Lin PY, Tsai SY, Cheng CY, et al. Prevalence of dry eye among an elderly Chinese population in Taiwan: The Shihpai Eye Study. Ophthalmology 2003;110:1096-101
13. Lee AJ, Lee J, Saw SM, et al. Prevalence and risk factors associated with dry eye symptoms: A population based study in Indonesia. Br J Ophthalmol 2002;86:1347-51
14. Uchino M, Dogru M, Uchino Y, et al. Japan Ministry of Health study on prevalence of dry eye disease among Japanese high school students. Am J Ophthalmol 2008;146:925-9
15. Uchino M, Schaumberg DA, Dogru M, et al. Prevalence of dry eye disease among Japanese visual display terminal users. Ophthalmology 2008;115:1982-8
16. Lemp MA. Report of National Eye Institute/Industry Workshop on clinical trials in dry eyes. CLAO J 1995;21:221-32
17. Pflugfelder S, Geerling G, Kinoshita S, et al. Management and therapy of dry eye disease. report of the Management and Therapy Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf 2007;5:163-78
18. Tsubota K. New approaches in dry eye management: supplying missing tear components to the ocular surface epithelium. Volume 1 1st Annual Meeting of the Kyoto Cornea Club; Kugler, Amsterdam: 1997. p. 27-32
19. Barabino S, Rolando M, Camicione P, et al. Systemic linoleic and gamma-linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea 2003;22:97-101
20. Dogru M, Matsumoto Y, Yamamoto Y, et al. Lactoferrin in Sj€ogrens syndrome. Ophthalmology 2007;114:2366-7
21. Kawashima M, Kawakita T, Okada N, et al. Suppression of age related decline in tear functions by caloric restriction. 33rd Japan Cornea Conference; 19-21 February 2009; Osaka, Japan
22. Augustin AJ, Spitznas M, Kaviani N, et al. Oxidative reactions in the tear fluid of patients suffering from dry eyes. Graefes Arch Clin Exp Ophthalmol 1995;233:694-8
23. Kojima T, Wakamatsu TH, Dogru M, et al. Age-related dysfunction of the lacrimal gland and oxidative stress: Evidence from the Cu,Zn-superoxide dismutase-1 (Sod1) knockout mice. Am J Pathol 2012;180:1879-96
24. Wakamatsu TH, Dogru M, Matsumoto Y, et al. Evaluation of lipid oxidative stress status in Sj€ogren syndrome patients. Invest Ophthalmol Vis Sci 2013;54:201-10
25. Drouault-Holowacz S, Bieuvelet S, Burckel A, et al. Antioxidants intake and dry eye syndrome: A crossover, placebo-controlled, randomized trial. Eur J Ophthalmol 2009;19:337-42
26. Blades KJ, Patel S, Aidoo KE. Oral antioxidant therapy for marginal dry eye. Eur J Clin Nutr 2001;55:589-97
27. Pelit A, BagişT, Kayaselçuk F, et al. Tear function tests and conjunctival impression cytology before and after hormone replacement therapy in postmenopausal women. Eur J Ophthalmol 2003;13:337-42
28. Uncu G, Avci R, Uncu Y, et al. The effects of different hormone replacement therapy regimens on tear function, intraocular pressure and lens opacity. Gynecol Endocrinol 2006;22:501-5
29. Rocha EM, Mantelli F, Nominato LF, Bonini S. Hormones and dry eye syndrome: An update on what we do and dont know. Curr Opin Ophthalmol 2013;24:348-55
30. Foulks GN. The now and future therapy of the non-Sjogrens dry eye. Adv Exp Med Biol 1998;438:959-64
31. Lemp MA. The 1998 Castroviejo Lecture. New strategies in the treatment of dry-eye states. Cornea 1999;18:625-32
32. Lemp MA. Management of the dry-eye patient. Int Ophthalmol Clin 1994;34:101-13
33. Murube J, Murube A, Zhuo C. Classification of artificial tears. II: Additives and commercial formulas. Adv Exp Med Biol 1998;438:705-15
34. Murube J, Paterson A, Murube E. Classification of artificial tears. I: Composition and properties. Adv Exp Med Biol 1998;438:693-704
35. Pflugfelder SC. Advances in the diagnosis and management of keratoconjunctivitis sicca. Curr Opin Ophthalmol 1998;9:50-3
36. Tong L, Petznick A, Lee S, Tan J. Choice of artificial tear formulation for patients with dry eye: where do we start Cornea 2012;31:S32-6
37. Oechsner M, Keipert S. Polyacrylic acid/polyvinylpyrrolidone bipolymeric systems. I. Rheological and mucoadhesive properties of formulations potentially useful for the treatment of dry-eye-syndrome. Eur J Pharm Biopharm 1999;47:113-18
38. Bron AJ, Daubas P, Siou-Mermet R, Trinquand C. Comparison of the efficacy and safety of two eye gels in the treatment of dry eyes: lacrinorm and Viscotears. Eye 1998;12:839-47
39. Bron AJ, Mangat H, Quinlan M, et al. Polyacrylic acid gel in patients with dry eyes: A randomised comparison with polyvinyl alcohol. Eur J Ophthalmol 1998;8:81-9
40. Shimmura S, Goto E, Shimazaki J, Tsubota K. Viscosity-dependent fluid dynamics of eyedrops on the ocular surface. Am J Ophthalmol 1998;125:386-8
41. Argueso P, Herreras JM, Calonge M, et al. Analysis of human ocular mucus: Effects of neuraminidase and chitinase enzymes. Cornea 1998;17:200-7
42. Li Q, Dunn ET, Grandmaison EW, Goosen MFA. Applications and properties of chitosan. J Bioact Comp Polym 1992;7:370-97
43. Gipson IK, Hori Y, Argueso P. Character of ocular surface mucins and their alteration in dry eye disease. Ocul Surf 2004;2:131-48
44. Dentinger PJ, Swenson CF, Anaizi NH. Stability of famotidine in an extemporaneously compounded oral liquid. Am J Health Syst Pharm 2000;57:1340-2
45. Rieger G. Lipid-containing eye drops: A step closer to natural tears. Ophthalmologica 1990;201:206-12
46. Tiffany JM. Lipid-containing eye drops. Ophthalmologica 1991;203:47-9
47. Tsubota K, Monden Y, Yagi Y, et al. New treatment of dry eye: The effect of calcium ointment through eyelid skin delivery. Br J Ophthalmol 1999;83:767-70
48. Calonge M. the treatment of dry eye. Surv Ophthalmol 2001;45:227-39
49. Snibson GR, Greaves JL, Soper ND, et al. Precorneal residence times of sodium hyaluronate solutions studied by quantitative gamma scintigraphy. Eye 1990;4:594-602
50. Tsubota K, Yamada M. Tear evaporation from the ocular surface. Invest Ophthalmol Vis Sci 1992;33:2942-50
51. Bayoneted DA, Clinch T, Laibson PR. In vivo observation of tear dynamics using fluorophotometry. Arch Ophthalmol 1984;102:410-12
52. Shimmura S, Ono M, Shinozaki K, et al. Sodium hyaluronate acid eyedrops in the treatment of dry eyes. Br J Ophthalmol 1995;79:1007-11
53. Aeon M, Catacomb C. The effect of hyaluronic acid on corneal epithelial cell proliferation. Invest Ophthalmol Vis Sci 1993;34:2313-15
54. Shimmura S, Goto E, Shimazaki J, Tsubota K. Viscosity-dependent fluid dynamics of eyedrops on the ocular surface. Am J Ophthalmol 1998;125:386-8
55. Lerner LE, Schwartz DM, Hwang DG, et al. Hyaluronan and CD44 in the human cornea and limbal conjunctiva. Exp Eye Res 1998;67:481-4
56. Baudouin F, Brignole F, Dupas B, et al. Reduction in keratitis and CD44 expression in dry eye patients treated with a unique 0.18% sodium hyaluronate solution [abstract # 180]. Invest Ophthalmol Vis Sci 2001;42:S32
57. Entwistle J, Hall CL, Turley EA. HA receptors: Regulators of signalling to the cytoskeleton. J Cell Biochem 1996;61:569-77
58. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: The interaction between the ocular surface and lacrimal gland. Cornea 1998;17:584-9
59. Aragona P, Di Stefano G, Ferreri F, et al. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjogrens syndrome patients. Br J Ophthalmol 2002;86:879-84
60. Condon PI, McEwen CG, Wright M, et al. Double blind, randomized, placebo controlled, crossover, multicentre study to determine the efficacy of a 0.1% (w/v) sodium hyaluronate solution (Fermavisc) in the treatment of dry eye syndrome. Br J Ophthalmol 1999;83:1121-4
61. Gilbard JP, Rossi SR, Heyda KG. Ophthalmic solutions, the ocular surface, and a unique therapeutic artificial tear formulation. Am J Ophthalmol 1989;107:348-55
62. Ubels JL, McCartney MD, Lantz WK, et al. Effects of preservative-free artificial tear solutions on corneal epithelial structure and function. Arch Ophthalmol 1995;113:371-8
63. Jones BR, Voop HV. The management of keratoconjunctivitis sicca. Trans Ophthalmol Soc UK 1965;85:379-90
64. Yamada M, Kawai M, Mochizuki H, et al. Fluorophotometric measurement of the buffering action of human tears in vivo. Curr Eye Res 1998;17:1005-9
65. Yen MT, Monroy D, Pflugfelder SC. Punctal occlusion decreases tear production, clearance, and ocular surface sensation. Invest Ophthalmol Vis Sci 1990;40(Suppl):S980
66. Gilbard JP. Human tear film electrolyte concentrations in health and dry-eye disease. Int Ophthalmol Clin 1994;34:27-36
67. Gilbard JP, Rossi SR. An electrolyte-based solution that increases corneal glycogen and conjunctival goblet-cell density in a rabbit model for keratoconjunctivitis sicca. Ophthalmology 1992;99:600-4
68. Rieger G. Lipid-containing eye drops: A step closer to natural tears. Ophthalmologica 1990;201:206-12
69. Tiffany JM. Lipid-containing eye drops. Ophthalmologica 1991;203:47-9
70. Holly FJ. Tear film physiology. Am J Optom Physiol Opt 1980;57:252-7
71. Tiffany JM. The role of meibomian secretion in the tears. Trans Ophthalmol Soc UK 1985;104:396-401
72. Tiffany JM. The lipid secretion of the meibomian glands. Adv Lipis Res 1987;22:1-62
73. Mitsui T. Physiochemistry of the cosmetics. 1st edition. Nanzando; Tokyo: 1993. p. 128-56
74. Nagai K. Polyoxyethylene castor oil derivatives. In: Saito Y, editor. Handbook of pharmaceutical excipents. Japanese edition. The Pharmaceutical Society of Japan; Tokyo: 1986. p. 345-8
75. Goto E, Shimazaki J, Monden Y, et al. Low-concentration homogenized castor oil eye drops for noninflamed constructive meibomian gland dysfunction. Ophthalmology 2002;109:2030-5
76. Khanal S, Tomlinson A, Pearce EI, Simmons PA. Effect of an oil-in-water emulsion on the tear physiology of patients with mild to moderate dry eye. Cornea 2007;26:175-81
77. Lee SY, Tong L. Lipid-containing lubricants for dry eye: A systematic review. Optom Vis Sci 2012;89:1654-61
78. Murube J, Murube A, Zhuo C. Classification of artificial tears. II: Additives and commercial formulas. Adv Exp Med Biol 1998;438:705-15
79. Tripathi BJ, Tripathi RC. Cytotoxic effects of benzalkonium chloride and chlorobutanol on human corneal epithelial cells in vitro. Lens Eye Toxic Res 1989;6:395-403
80. Becquet F, Goldschild M, Moldovan MS, et al. Histopathological effects of topical ophthalmic preservatives on rat corneoconjunctival surface. Curr Eye Res 1998;17:419-25
81. Burstein NL. Corneal cytotoxicity of topically applied drugs, vehicles and preservatives. Surv Ophthalmol 1980;25:15-30
82. Macri A, Rolando M, Pflugfelder S. A standardized visual scale for evaluation of tear fluorescein clearance. Ophthalmology 2000;107:1338-43
83. Berdy GJ, Abelson MB, Smith LM, George MA. Preservative-free artificial tear preparations. Assessment of corneal epithelial toxic effects. Arch Ophthalmol 1992;110:528-32
84. Danjo Y, Hamano T. Observation of precorneal tear film in patients with Sj€ogrens syndrome. Acta Ophthalmol Scand 1995;73:501-5
85. Pflugfelder SC, Maskin SL, Anderson B, et al. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am J Ophthalmol 2004;138:444-57
86. Avunduk AM, Avunduk MC, Varnell ED, Kaufman HE. The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: A clinical and immunocytochemical study. Am J Ophthalmol 2003;136:593-602
87. Sainz De La Maza Serra M, Simón Castellvi C, Kabbani O. Nonpreserved topical steroids and lacrimal punctal occlusion for severe keratoconjunctivitis sicca. Arch Soc Esp Oftalmol 2000;75:751-6
88. Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sj€ogren syndrome. Ophthalmology 1999;106:811-16
89. Stevenson D, Tauber J, Reis BL. Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: A dose-ranging, randomized trial. The Cyclosporin A Phase 2 Study Group. Ophthalmology 2000;107:967-74
90. 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;107:631-9
91. Pflugfelder SC, De Paiva CS, Villarreal AL, Stern ME. Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factor-beta2 production. Cornea 2008;27:64-9
92. Brignole F, Pisella PJ, De Saint Jean M, et al. Flow cytometric analysis of inflammatory markers in KCS: 6-month treatment with topical cyclosporin A. Invest Ophthalmol Vis Sci 2001;42:90-5
93. Turner K, Pflugfelder SC, Ji Z, et al. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treatedwith cyclosporine ophthalmic emulsion. Cornea 2000;19:492-6
94. Kunert KS, Tisdale AS, Stern ME, et al. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: Effect on conjunctival lymphocytes. Arch Ophthalmol 2000;118:1489-96
95. Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm 2010;7:41
96. Ghoreschi K, Laurence A, OShea JJ. Janus kinases in immune cell signaling. Immunol Rev 2009;228:273-87
97. Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIB dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012;64:617-29
98. Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIB dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate alone. Arthritis Rheum 2012;64:970-81
99. Boy MG, Wang C, Wilkinson BE, et al. Double-blind, placebocontrolled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol 2009;129:2299-302
100. Busque S, Leventhal J, Brennan DC, et al. Calcineurin-inhibitor free immunosuppression based on the JAK inhibitor CP-690,550: A pilot study in de novo kidney allograft recipients. Am J Transplant 2009;9:1936-45
101. Liew SH, Nichols KK, Klamerus KJ, et al. Tofacitinib (CP-690,550), a Janus kinase inhibitor for dry eye disease: Results from a phase 1/2 trial. Ophthalmology 2012;119:1328-35
102. Huang JF, Yafawi R, Zhang M, et al. Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690,550) in patients with dry eye disease. Ophthalmology 2012;119:e43-50
103. Patane MA, Cohen A, From S, et al. Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: Results of a randomized clinical trial. Clin Ophthalmol 2011;5:633-43
104. Aronowicz JD, Shine WE, Oral D, et al. Short term oral minocycline treatment of meibomianitis. Br J Ophthalmol 2006;90:856-60
105. De Paiva CS, Corrales RM, Villarreal AL, et al. Apical corneal barrier disruption in experimental murine dry eye is abrogated by methylprednisolone and doxycycline. Invest Ophthalmol Vis Sci 2006;47:2847-56
106. Matsumoto Y, Shigeno Y, Sato EA, et al. The evaluation of the treatment response in obstructive meibomian gland disease by in vivo laser confocal microscopy. Graefes Arch Clin Exp Ophthalmol 2009;247:821-9
107. Nichols KK, Yerxa B, Kellerman DJ. Diquafosol tetrasodium: A novel dry eye therapy. Expert Opin Invest Drugs 2004;13:47-54
108. Nakamura M, Imanaka T. New treatment for dry eye: diquafosol tetrasodium. Jpn J Ocular Pharmacol 2011;25:42-6
109. Nakamura M, Imanaka T, Sakamoto A. Diquafosol ophthalmic solution for dry eye treatment. Adv Ther 2012;29:579-89
110. Fujihara T. A new eyedrops for dry eye: diquas ophthalmic solution 3%. Jpn J Ocular Pharmacol 2012;26:23-7
111. Matsumoto Y, Ohashi Y, Watanabe H, Tsubota K. The efficacy and safety of diquafosol ophthalmic solution in patients with dry eye syndrome: A Japanese phase 2 clinical trial. Ophthalmology 2012;119:1954-60
112. Takamura E, Tsubota K, Watanabe H, Ohashi Y. A randomized, double-masked comparison study of diquafosol versus sodium hyaluronate ophthalmic solutions in dry eye patients. Br J Ophthalmol 2012;96:1310-15
113. Yamaguchi M, Tsubota K, Watanabe H, Ohashi Y. The safety and efficacy of long-term treatment with 3% diquafosol ophthalmic solution for dry eye. J Eye 2012;29:527-35
114. Uchida M, Tabusa F, Komatsu M, et al. Studies on 2(1H)-quinolinone derivatives as gastric antiulcer active agents. 2-(4-Chlorobenzoylamino)-3- [2(1H)-quinolinon-4-yl]propi oni c acid and related compounds. Chem Pharm Bull 1985;33:3775-86
115. Urashima H, Okamoto T, Takeji Y, et al. Rebamipide increases the amount of mucin-like substances on the conjunctiva and cornea in the N-acetylcysteine-treated in vivo model. Cornea 2004;23:613-19
116. Urashima H, Takeji Y, Okamoto T, et al. Rebamipide increases mucin-like substance contents and periodic acid Schiff reagent-positive cells density in normal rabbits. J Ocul Pharmacol Ther 2012;28:264-70
117. Takeji Y, Urashima H, Aoki A, Shinohara H. Rebamipide increases the mucin-like glycoprotein production in corneal epithelial cells. J Ocul Pharmacol Ther 2012;28:259-63
118. Kinoshita S, Awamura S, Oshiden K, et al. Rebamipide (OPC-12759) in the treatment of dry eye: A randomized, double-masked, multicenter, placebo-controlled phase II study. Ophthalmology 2012;119:2471-8
119. Kinoshita S, Oshiden K, Awamura S, et al. A randomized, multicenter phase 3 study comparing 2% rebamipide (OPC-12759) with 0.1% sodium hyaluronate in the treatment of dry eye. Ophthalmology 2013;120:1158-65
120. Noble BA, Loh RS, MacLennan S, et al. Comparison of autologous serum eye drops with conventional therapy in a randomised controlled crossover trial for ocular surface disease. Br J Ophthalmol 2004;88:647-52
121. Kojima T, Ishida R, Dogru M, et al. The effect of autologous serum eye drops in the treatment of severe dry eye disease: A prospective randomized case-control study. AJO 2005;139:242-6
122. Lambiase A, Manni L, Bonini S, et al. Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol Vis Sci 2000;41:1063-9
123. Joo MJ, Yuhan KR, Hyon JY, et al. The effect of nerve growth factor on corneal sensitivity after laser in situ keratomileusis. Arch Ophthalmol 2004;122:1338-41
124. Esquenazi S, Bazan HEP, Bui V, et al. Topical combination of NGF and DHA increases rabbit corneal nerve regeneration after photorefractive keratectomy. Invest Ophthalmol Vis Sci 2005;46:3121-7
125. Jain P, Li R, Lama T, et al. An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and demonstrates therapeutic efficacy in a rat model of dry eye. Exp Eye Res 2011;93:503-12
126. Meerovitch K, Torkildsen G, Lonsdale J, et al. Safety and effcacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled phase 2 clinical trial in patients with dry eye. Clin Ophthalmol 2013;7:1275-85
127. Goldstein AL, Hannappel E, Kleinman HK. Thymosin beta4: Actin-sequestering protein moonlights to repair injured tissues. Trends Mol Med 2005;11:421-9
128. Sosne G, Qiu P, Kurpakus-Wheater M. Thymosin beta 4: A novel corneal wound healing and anti-inflammatory agent. Clin Ophthalmol 2007;1:201-7
129. Ho JH, Tseng KC, Ma WH, et al. Thymosin beta-4 upregulates anti-oxidative enzymes and protects human cornea epithelial cells against oxidative damage. Br J Ophthalmol 2008;92:992-7
130. Sosne G, Qiu P, Christopherson PL, Wheater MK. Thymosin beta 4 suppression of corneal NFkappaB: A potential anti-inflammatory pathway. Exp Eye Res 2007;84:663-9
131. Regenerx receives clinical study report for phase 2 dry eye trial. Available from: http://phx.corporate-ir.net/phoenix.zhtml c=144396&p= irolnewsArticle& ID=1645009&highlight= [Accessed 20 June 2012]
132. RGN-259 significantly improves signs and symptoms of severe dry eye in phase 2 clinical trial. Available from: http://phx.corporate-ir.net/phoenix. zhtml c=144396&p=irolnewsArticle& ID=1706893&highlight= [Accessed 5 January 2012]
133. Lee CH. Resolvins as new fascinating drug candidates for inflammatory diseases. Arch Pharm Res 2012;35:3-7
134. Li N, He J, Schwartz CE, et al. Resolvin E1 improves tear production and decreases inflammation in a dry eye mouse model. J Ocul Pharmacol Ther 2010;26:431-9
135. de Paiva CS, Schwartz CE, Gjorstrup P, Pflugfelder SC. Resolvin E1 (RX-10001) reduces corneal epithelial barrier disruption and protects against goblet cell loss in a murine model of dry eye. Cornea 2012;11:1299-303
136. Resolvyx announces positive data from phase 2 clinical trial of the resolvin RX-10045 in patients with dry eye syndrome. 2009.Available from: http://www. resolvyx.com/news-pubs/releases/082409. Asp
137. Ogawa Y, Dogru M, Uchino M, et al. Topical tranilast for treatment of the early stage of mild dry eye associated with chronic GVHD. Bone Marrow Transplant 2010;45:565-9
138. Bar-Yehuda S, Silverman MH, Kerns WD, et al. The anti-inflammatory effect of A3 adenosine receptor agonists: A novel targeted therapy for rheumatoid arthritis. Expert Opin Investig Drugs 2007;16:1601-13
139. Mabley J, Soriano F, Pacher P, et al. The adenosine A3 receptor agonist, N6-(3-iodobenzyl)-adenosine-5=-Nmethyluronamide, is protective in two murine models of colitis. Eur J Pharmacol 2003;466:323-9
140. Bar-Yehuda S, Rath-Wolfson L, Del Valle L, et al. Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment. Arthritis Rheum 2009;60:3061-71
141. Gadek TR, Burdick DJ, McDowell RS, et al. Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science 2002;295:1086-9
142. Keating SM, Clark KR, Stefanich LD, et al. Competition between intercellular adhesion molecule-1 and a small-molecule antagonist for a common binding site on the alpha1 subunit of lymphocyte function-associated antigen-1. Protein Sci 2006;15:290-303
143. Murphy CJ, Bentley E, Miller PE, et al. The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs. Invest Ophthalmol Vis Sci 2011;52:3174-80