Глазные лекарственные формы циклоспорина А в офтальмологии (обзор литературы)

Циклоспорин А (ЦСА) – это нейтральный липофильный гидрофобный циклический полипептид, представляющий собой метаболит грибов Tolypocladium inflatum и Beauveria nevus. Несмотря на широкое внедрение местных форм ЦСА в клиническую практику, его использование при воспалительных заболеваниях глазной поверхности и болезни сухого глаза до сих пор опирается на разрозненные исследования и эмпирический опыт без единой систематизированной оценки доказательной базы. Отсутствие структурированного обзора, сопоставляющего разные лекарственные формы ЦСА, их иммуномодулирующие эффекты, показания и ограничения, формирует выраженный научный и клинический пробел. Цель: систематизировать данные научной литературы эмпирических исследований ЦСА для местного применения как признанного эффективного средства терапии воспалительных форм заболеваний глазной поверхности и болезни сухого глаза. Материалы и методы. Использованы данные оригинальных исследований и обобщены опубликованные результаты наиболее значимых трудов, посвященных ЦСА, формы которого применяются в офтальмологии. Публикации отбирались методом сплошной выборки с использованием ключевых слов. В обзор вошли 93 работы из базы данных PubMed. Результаты. В офтальмологии ЦСА 0,05 % был первым доступным препаратом, одобренным для лечения болезни сухого глаза и зарегистрированным в РФ. Позднее для этих же целей появилась катионная эмульсия 0,1 %. По результатам проведенного анализа литературы были получены данные, что ЦСА, применяемый местно, усиливает слезопродукцию и защищает эпителий и бокаловидные клетки конъюнктивы. Его терапевтическое иммуномодулирующее действие связано со снижением HLA-DR, уровня цитокинов, маркеров апоптоза и конъюнктивальных Т-лимфоцитов. Выводы. ЦСА в офтальмологии должен использоваться для достаточно узкой, но сложной в лечении группы заболеваний глазной поверхности в комбинации с глюкокортикостероидами или отдельно в качестве стероидосберегающего препарата. Помимо тяжелых форм болезни сухого глаза с иммунным компонентом ЦСА целесообразно применять для контроля других форм T-опосредованных воспалительных состояний глазной поверхности, таких как отторжение трансплантата после кератопластики, весенний и атопический кератоконъюнктивит, кератит на фоне аутоиммунных заболеваний, поверхностный точечный кератит Тайгесона, дисфункция мейбомиевых желез.

1. Borel JF, Feurer C, Magnee C, Stahelin H. Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology. 1977;32:1017–1025.

2. Bushley KE, Raja R, Jaiswal P, Cumbie JS, Nonogaki M, Boyd AE, et al. The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster. PLoS Genet. 2013;9:e1003496. doi: 10.1371/journal.pgen

3. 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

4. Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplant ed patients. Cochrane Database Syst Rev. 2006:CD005161. doi: 10.1002/14651858.CD005161.pub2

5. Nussenblat RB, Palestine AG. Cyclosporine: immunology, pharmacology and therapeutic uses. Surv Ophthalmol. 1986;31:159–169. doi: 10.1016/0039-6257(86)90035-4

6. Belin MW, Bouchard CS, Phillips TM. Update on topical cyclosporin A: background, immunology, and pharmacology. Cornea. 1990;9:184–195.

7. Williams DL. A comparative approach to topical cyclosporin therapy. Eye. 1997;11:453–464. doi: 10.1038/eye.1997.126

8. De Smet MD, Nussenblat RB. Clinical use of cyclosporine in ocular disease. Int Ophthalmol Clin. 1993;33:31–45. doi: 10.1097/00004397-199303340-00005

9. Liu J. FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. Immunol Today. 1993;14:290– 295. doi: 10.1016/0167-5699(93)90048-P

10. Donnenfeld E, Pfl ugfelder SC. Topical ophthalmic cyclosporine: pharmacology and clinical uses. Surv Ophthalmol. 2009;54:321–338. doi: 10.1016/j.survophthal.2009.02.002

11. Foulks G. Topical cyclosporine for treatment of ocular surface disease. Int Ophthalmol Clin. 2006;46:105–122. doi: 10.1097/01.iio.0000212135.77675.6a

12. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47:119–125. doi: 10.1016/s0162-3109(00)00192-2

13. Fruman DA, Klee CB, Bierer BE, Burakoff SJ. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci USA. 1992;89:3686–3690. doi: 10.1073/pnas.89.9.3686

14. Halloran PF, Kung L, Noujaim J. Calcineurin and the biological effect of cyclosporine and tacrolimus. Transplant Proc. 1998;30:2167–2170. doi: 10.1016/s0041-1345(98)00577-6

15. Waldmeier PC, Zimmermann K, Qian T, Tintelnot-Blomley M, Lemasters JJ. Cyclophilin D as a drug target. Curr Med Chem. 2003;10:1485–1506. doi: 10.2174/0929867033457160

16. Du S, Hiramatsu N, Hayakawa K, Kasai A, Okamura M, Huang T, et al. Suppression of NF-kappa B by cyclosporin a and tacrolimus (FK506) via induction of the C/EBP family: implication for unfolded protein response. J Immunol. 2009;182:7201–7211. doi: 10.4049/jimmunol.0801772

17. Ames P, Galor A. Cyclosporine ophthalmic emulsions for the treatment of dry eye: a review of the clinical evidence. Clin Investig. 2015;5:267–285. doi: 10.4155/cli.14.135

18. Matsuda S, Moriguchi T, Koyasu S, Nishida E. T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SA-PK/JNK signaling pathways sensitive to cyclosporin A. J Biol Chem. 1998;273:12378– 12382. doi: 10.1074/jbc.273.20.12378

19. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science. 1999;284:339– 343. doi: 10.1126/science.284.5412.339

20. Li Y, Johnson N, Capano M, Edwards M, Crompton M. Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis. Biochem J. 2004;383:101–109. doi: 10.1042/BJ20040669

21. Gao J, Sana R, Calder V, Calonge M, Lee W, Wheeler LA, 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;54:4717–4733. doi: 10.1167/iovs.13-11681

22. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305:626–629. doi: 10.1126/science.1099320

23. Coster DJ, Shepherd WF, Fook TC, et al. Prolonged survival of corneal allografts in rabbits treated with cyclosporin A. Lancet. 1979;2:688–689. doi: 10.1016/s0140-6736(79)92082-8

24. 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

25. Hoffmann F, Wiederholt M. [Local treatment of corneal transplants in the human with cyclosporin A]. Klin Monbl Augenheilkd. 1985;187:92–96. doi: 10.1055/s-2008-1050995

26. Holland EJ, Olsen TW, Ketcham JM, et al. Topical cyclosporin A in the treatment of anterior segment inflammatory disease. Cornea. 1993;12:413–419. doi: 10.1097/00003226-199309000-00008

27. Lallemand F, Furrer P, Felt-Baeyens O, Gex-Fabry M, Dumont JM, Besseghir K, et al. A novel water-soluble cyclosporine A prodrug: ocular tolerance and in vivo kinetics. Int J Pharm. 2005;295:7–14. doi: 10.1016/j.ijpharm.2004.12.015

28. Wilson SE, Perry HD. Long-term resolution of chronic dry eye symptoms and signs after topical cyclosporine treatment. Ophthalmology. 2007;114:76–79. doi: 10.1016/j.ophtha.2006.05.077

29. Kymionis GD, Bouzoukis DI, Diakonis VF, et al. Treatment of chronic dry eye: focus on cyclosporine. Clin Ophthalmol. 2008;2:829–836. doi: 10.2147/opth.s1409

30. Tatlipinar S, Akpek EK. Topical ciclosporin in the treatment of ocular surface disorders. Br J Ophthalmol. 2005;89:1363–1367. doi: 10.1136/bjo.2005.070888

31. Sall K, Stevenson OD, Mundorf TK, et al. 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;107:631–639. doi: 10.1016/s0161-6420(99)00176-1

32. Barber LD, Pfl ugfelder SC, Tauber J, et al. Phase III safety evaluation of cyclosporine 0.1 % ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology. 2005;112:1790–1794. doi: 10.1016/j.ophtha.2005.05.013

33. Sall KN, Cohen SM, Christensen MT, et al. An evaluation of the efficacy of a cyclosporine-based dry eye therapy when used with marketed artificial tears as supportive therapy in dry eye. Eye Contact Lens. 2006;32:21–26. doi: 10.1097/01.icl.0000170599.57728.29

34. Vaishya RD, Khurana V, Patel S, Mitra AK. Controlled ocular drug delivery with nanomicelles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014;6:422–437. doi: 10.1002/wnan.1272

35. Cholkar K, Gilger BC, Mitra AK. Topical, aqueous, clear cyclosporine formulation design for anterior and posterior ocular delivery. Transl Vis Sci Technol. 2015;4:1. doi: 10.1167/tvst.4.3.1

36. 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;26:287–296. doi: 10.5301/ejo.5000779

37. Hoy SM. Ciclosporin ophthalmic emulsion 0.1 %: a review in severe dry eye disease. Drugs.2017 Nov;77(17):1909–1916. doi: 10.1007/s40265-017-0834-x

38. Boboridis KG, Konstas AGP. Evaluating the novel application of cyclosporine 0.1 % in ocular surface disease. Expert Opin Pharmacother. 2018;19:1027–1039. doi: 10.1080/14656566.2018.1479742

39. Pisella PJ, Labetoulle M, Doan S, Cochener-Lamard B, Amrane M, Ismail D, et al. Topical ocular 0.1 % cyclosporine A cationic emulsion in dry eye disease patients with severe keratitis: experience through the French early-access program. Clin Ophthalmol. 2018;12:289–299. doi: 10.2147/OPTH.S150957

40. Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II report executive summary. Ocul Surf. 2017;15:802–812. doi: 10.1016/j.jtos.2017.08.003

41. Stern ME, Gao J, Schwalb TA, et al. Conjunctival T-cell subpopulations in Sjogren’s and non-Sjogren’s patients with dry eye. Invest Ophthalmol Vis Sci. 2002;43:2609–2614.

42. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15:276–283. doi: 10.1016/j.jtos.2017.05.008

43. Strong B, Farley W, Stern ME, et al. Topical cyclosporine inhibits conjunctival epithelial apoptosis in experimental murine keratoconjunctivitis sicca. Cornea. 2005;24:80–85. doi: 10.1097/01.ico.0000133994.22392.47

44. Sheppard J, Kannarr S, Luchs J, Malhotra R, Justice A, Ogundele A, Darby C. 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 Jan;46 Suppl 1:14–19. doi: 10.1097/ICL.0000000000000636

45. Schultz C. Safety and effi cacy of cyclosporine in the treatment of chronic dry eye. Ophthalmol Eye Dis. 2014;6:37–42. doi: 10.4137/OED.S16067

46. Ambroziak AM, Szafl ik J, Szafl ik 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

47. The definition and classification of dry eye disease: Report of The Definition and Classification Subcommittee of The International Dry Eye Workshop (2007). Ocul Surf. 2007;5(2):75–92. doi: 10.1016/s1542-0124(12)70081-2

48. Stern ME, Gao J, Siemasko KF, et al. The role of the lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res. 2004;78:409–416. doi: 10.1016/j.exer.2003.09.003

49. Sullivan DA, Wickham LA, Rocha EM, et al. Androgens and dry eye in Sjogren’s syndrome. Ann NY Acad Sci. 1999;876:312– 324. doi: 10.1111/j.1749-6632.1999.tb07656.x

50. 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;107:967–974. doi: 10.1016/s0161-6420(00)00035-x

51. Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporin. Arch Ophthalmol. 2002;120:330–337. doi: 10.1001/archopht.120.3.330

52. Turner K, Pflugfelder SC, Ji Z, et al. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporin ophthalmic emulsion. Cornea. 2000;19:492–496. doi: 10.1097/00003226-200007000-00018

53. Byun YJ, Kim TI, Kwon SM, et al. Efficacy of combined 0.05 % cyclosporine and 1 % methylprednisolone treatment for chronic dry eye. Cornea. 2012;31(5):509–513. doi: 10.1097/ICO.0b013e31818c69ef

54. Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol. 2004;137:337–342. doi: 10.1016/j.ajo.2003.10.036

55. Dastjerdi MH, Hamrah P, Dana R. High-frequency topical cyclosporine 0.05 % in the treatment of severe dry eye refractory to twice-daily regimen. Cornea. 2009;28:1091–1096. doi: 10.1097/ICO.0b013e3181a16472

56. El-Asrar AM, Van Den Oord JJ, Geboes K, et al. Immunopathological study of vernal keratoconjunctivitis. Graefes Arch Clin Exp Ophthalmol. 1989;227:374–379. doi: 10.1007/BF02169416

57. El-Asrar AM, Tabbara KF, Geboes K, et al. An immunohistochemical study of topical cyclosporine in vernal keratoconjunctivitis. Am J Ophthalmol. 1996;121:156–161. doi: 10.1016/s0002-9394(14)70579-3

58. Bleik JH, Tabbara KF. Topical cyclosporine in vernal keratoconjunctivitis. Ophthalmology. 1991;98:1679–1684. doi: 10.1016/s0161-6420(91)32069-4

59. Ebihara N, Ohashi Y, Uchio E, et al. A large prospective observational study of novel cyclosporine 0.1 % aqueous ophthalmic solution in the treatment of severe allergic conjunctivitis. J Ocul Pharmacol Ther. 2009;25:365–372. doi: 10.1089/jop.2008.0103

60. Garrity JA, Liesegang TJ. Ocular complications of atopic dermatitis. Can J Ophthalmol. 1984;19:19–24.

61. Power WJ, Tugal-Tutkun I, Foster CS. Long-term follow-up of patients with atopic keratoconjunctivitis. Ophthalmology.1998;105:637–642. doi: 10.1016/S0161-6420(98)94017-9

62. Foster CS, Rice BA, Dutt JE. Immunopathology of atopic keratoconjunctivitis. Ophthalmology. 1991;98:1190–1196. doi: 10.1016/s0161-6420(91)32154-7

63. Hingorani M, Moodaley L, Calder VL, et al. A randomized, placebo controlled trial of topical cyclosporin A in steroid-dependent atopic keratoconjunctivitis. Ophthalmology. 1998;105:1715–1720. doi: 10.1016/S0161-6420(98)99043-1

64. Akpek EK, Dart JK, Watson S, et al. A randomized trial of topical cyclosporine 0.05% in topical steroid-resistant atopic keratoconjunctivitis. Ophthalmology. 2004;111:476–482. doi: 10.1016/j.ophtha.2003.05.035

65. Daniell M, Constantinou M, Vu HT, et al. Randomised controlled trial of topical cyclosporin A in steroid dependent allergic conjunctivitis. Br J Ophthalmol. 2006;90: 461–464. doi: 10.1136/bjo.2005.082461

66. Hingorani M, Calder VL, Buckley RJ, et al. The immunomodulatory effect of topical cyclosporin A in atopic keratoconjunctivitis. Invest Ophthalmol Vis Sci. 1999;40:392–399.

67. Pfister RR, Murphy GE. Corneal ulceration and perforation associated with Sjogren’s syndrome. Arch Ophthalmol. 1980;98:89–94. doi: 10.1001/archopht.1980.01020030091006

68. Kervick GN, Pflugfelder SC, Haimovici R, et al. Paracentral rheumatoid corneal ulceration. Clinical features and cyclosporine therapy. Ophthalmology. 1992;99:80–88. doi: 10.1016/s0161-6420(92)32006-8

69. Liegner JT, Yee RW, Wild JH. Topical cyclosporine therapy for ulcerative keratitis associated with rheumatoid arthritis. Am J Ophthalmol. 1990;109:610–612. doi: 10.1016/s0002-9394(14)70704-4

70. Nagra PK, Rapuano CJ, Cohen EJ, et al. Thygeson’s superficial punctate keratitis: ten years’ experience. Ophthalmology. 2004;111:34–37. doi: 10.1016/j.ophtha.2003.05.002

71. Pflugfelder SC, Karpecki PM, Perez VL. Treatment of blepharitis: recent clinical trials. Ocul Surf. 2014;12:273–284. doi: 10.1016/j.jtos.2014.05.005

72. Reinhard T, Sundmacher R. Topical cyclosporin A in Thygeson’s superficial punctate keratitis. Graefes Arch Clin Exp Ophthalmol. 1999;237:109–112. doi: 10.1007/s004170050204

73. 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;100:300–306. doi: 10.1136/bjophthalmol-2015-307415

74. Perry HD, Doshi-Carnevale S, Donnenfeld ED, et al. Efficacy of commercially available topical cyclosporine A 0.05 % in the treatment of meibomian gland dysfunction. Cornea. 2006;25:171–175. doi: 10.1097/01.ico.0000176611.88579.0a

75. Akpek EK, Merchant A, Pinar V, et al. Ocular rosacea: patient characteristics and follow-up. Ophthalmology. 1997;104:1863–1867.

76. Doan S, Gabison E, Gatinel D, et al. Topical cyclosporine A in severe steroid-dependent childhood phlyctenular keratoconjunctivitis. Am J Ophthalmol. 2006;141:62–66. doi: 10.1016/j.ajo.2005.08.035

77. Schechter BA, Katz RS, Friedman LS. Efficacy of topical cyclosporine for the treatment of ocular rosacea. Adv Ther. 2009;26:1–9. doi: 10.1007/s12325-009-0037-2

78. Arentsen JJ. Corneal transplant allograft reaction: possible predisposing factors. Trans Am Ophthalmol Soc. 1983;81:361– 402.

79. Hudde T, Minassian DC, Larkin DFP. Randomised controlled trial of corticosteroid regimens in endothelial corneal allograft rejection. Br J Ophthalmology. 1999;83:1348–1352. doi: 10.1136/bjo.83.12.1348

80. Hill JC, Maske R, Watson P. Corticosteroids in corneal graft rejection: oral versus single pulse therapy. Ophthalmology. 1991;98:329–333. doi: 10.1016/s0161-6420(91)32291-7

81. Perry HD, Donnenfeld ED, Acheampong A, et al. Topical cyclosporine A in the management of postkeratoplasty glaucoma and corticosteroid-induced ocular hypertension (CIOH) and the penetration of topical 0.5 % cyclosporine A into the cornea and anterior chamber. CLAO J. 1998;24:159–165.

82. Price MO, Price FW. Efficacy of topical cyclosporine 0.05 % for prevention of cornea transplant rejection episodes. Ophthalmology. 2006;113:1785–1790. doi: 10.1016/j.ophtha.2006.05.022

83. Poon A, Constantinou M, Lamoureux E, et al. Topical cyclosporin A in the treatment of acute graft rejection: a randomized controlled trial. Clin Experiment Ophthalmol. 2008;36:415–421.

84. Lelli GJ, Musch DC, Gupta A, et al. Ophthalmic cyclosporine use in ocular GvHD. Cornea. 2006;25:635–638. doi: 10.1097/01.ico.0000208818.47861.1d

85. Ogawa Y, Kuwana M. Dry eye as a major complication associated with chronic graft-versus-host disease after hematopoietic stem cell transplantation. Cornea. 2003;22:19–27. doi: 10.1097/00003226-200310001-00004

86. Ogawa Y, Yamazaki K, Kuwana M, et al. A signifi cant role of stromal fi broblasts in rapidly progressive dry eye in patients with chronic GvHD. Invest Ophthalmol Vis Sci. 2001;42:111–119.

87. Rao SN, Rao RD. Efficacy of topical cyclosporine. 0,05 % in the treatment of dry eye associated with graft versus host disease. Cornea. 2006;25:674–678. doi: 10.1097/01.ico.0000208813.17367.0c

88. Wang Y, Ogawa Y, Dogru M, et al. Ocular surface and tear functions after topical cyclosporine treatment in dry eye patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2008;41:293–302. doi: 10.1038/sj.bmt.1705900

89. Reynolds SA, Kabat AG. Therapeutic options for the management of early neurotrophic keratopathy: a case report and review. Optometry. 2006;77:503–507. doi: 10.1016/j.optm.2006.05.001

90. Zhao JC, Jin XY. Immunological analysis and treatment of Mooren’s ulcer with cyclosporin A applied topically. Cornea. 1993;12:481–488. doi: 10.1097/00003226-199311000-00004

91. Shimura M, Yasuda K, Fuse N, et al. Effective treatment with topical cyclosporin A of a patient with Cogan syndrome. Ophthalmologica. 2000;214:429–432. doi: 10.1159/000027538

92. Akpek EK, Ilhan-Sarac O, Green WR. Topical cyclosporin in the treatment of chronic sarcoidosis of the conjunctiva. Arch Ophthalmol. 2003;121:1333–1335. doi: 10.1001/archopht.121.9.1333

93. Рикс ИА. Применение циклоспорина при синдроме «сухого глаза». Офтальмологические ведомости. 2019;12(3):75– 82. doi: 10.17816/OV15853