Abstract
Topical cyclosporine has been used by veterinary ophthalmologists since 1989 for the treatment of ocular surface inflammatory disease and keratoconjunctivitis sicca (KCS). As well as ameliorating clinical signs of ocular surface lymphocyte-driven inflammation in the dog, cat and horse, topical cyclosporine significantly raises tear production in both normal and KCS-affected animals. A licensed ointment preparation of 0.2% cyclosporine, Optimmune (Schering-Plough), is now available for administration to dogs. In this paper we examine the mechanisms by which cyclosporine exerts both its immunomodulatory and its lacrimogenic actions. The pharmacokinetics of topical cyclosporine are examined to determine whether these effects are truly local or are influenced by generalised immunosuppression caused by systemic absorption of topically applied drug. The paper reviews the few side effects of cyclosporine preparations in the experience of veterinary ophthalmologists and the experimental evidence which appears to implicate the vehicle rather than the active agent cyclosporine as causing many of these effects. Given that topical cyclosporine has been so widely accepted as a valuable ophthalmic preparation in the veterinary world and licensed as such, it is surprising that human ophthalmologists have not employed the drug to the same extent for conditions from vernal keratoconjunctivitis to Sjögren's syndrome.
Similar content being viewed by others
Article PDF
References
Borel JF . Cyclosporine: historical perspectives. In: Kahan BD, editor. First international congress on cyclosporine. Orlando: Grune & Stratton, 1984: 3–13.
Borel JF, Feuer C, Gubler HU, Stahelin H . Biological effects of cyclosporin A: a new antilymphocyte agent. Agents Actions 1976; 6: 468–75.
Carne RY, Thiru S, McMaster P, Craddock GN, White DJG, Evans DB, et al. Cyclosporine A in patients receiving renal allografts from cadaveric donors. Lancet 1978; ii: 1323–7.
Sigal NH, Dumont FJ . Cyclosporin A, FK-506 and rapamycin: pharmacological probes of lymphocyte signal transduction. Annu Rev Immunol 1992; 10: 519–60.
Carne RY, White DJG, Pentlow BD, Rolles K, Syrakos T, Ohtawa T, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases and 2 livers. Lancet 1979; ii: 1022–36.
Bougneres PF, Carel JC, Castano L . Factors associated with early remission of type 1 diabetes in children treated with cyclosporine. N Engl J Med 1988; 318: 663–70.
Forre O, Bjerkhoel F, Salvessen CF . An open, controlled, randomised comparison of cyclosporine and azathioprine in the treatment of rheumatoid arthritis: a preliminary report. Arthritis Rheum 1987; 30: 88–92.
Nussenblatt RB, Rodrigues MM, Wacker WB, Cevario SJ, Salinas-Carmona MC, Gery I . Cyclosporin A: inhibition of experimental autoimmune uveitis in rats. J Clin Invest 1981; 67: 1228–31.
Nussenblatt RB, Rook AH, Wacker WB, Palestine AG, Scher I, Gery I . Treatment of intraocular inflammatory disease with cyclosporin A. Lancet 1983; ii: 235–8.
Bell TAG, Easty DL, McCullach KG . A placebo-controlled blind trial of cyclosporin-A in prevention of corneal graft rejection in rabbits. Br J Ophthalmol 1982; 66: 303–8.
Kana JC, Hoffman F, Buchen R, Krolik A, Wiederholt M . Rabbit corneal allograft survival following topical administration of cyclosporin A. Invest Ophthalmol Vis Sci 1982; 22: 686–90.
Zhao J-C, Jin X-Y . Immunological analysis and treatment of Mooren's ulcer with cyclosporine A applied topically. Cornea 1993; 12: 481–8.
BenEzra D, Peter J, Brodsky M, Cohen E . Cyclosporine eye drops for the treatment of severe vernal keratoconjunctivitis. Am J Ophthalmol 1989; 107: 160–6.
Holland EJ, Chan C, Kuwabara T, Palestine AG, Rowseg IJ, Nussenblatt RB . Immunohistologic findings and results of treatment with cyclosporine in ligneous conjunctivitis. Am J Ophthalmol 1989; 107: 160–6.
Liegner JT, Yee RW, Wild JH . Topical cyclosporine therapy for ulcerative keratitis associated with rheumatoid arthritis. Am J Ophthalmol 1990; 109: 610–2.
Holland EJ, Olsen TW, Ketcham JM, Florine C, Krachmer JH, Purcell JJ, et al. Topical cyclosporin A in the treatment of anterior segment inflammatory disease. Cornea 1993; 12: 413–9.
Emmel EA, Vermeij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR . Cyclosporine A specifically inhibits function of nuclear proteins involved in T cell activation. Science 1989; 246: 1617–20.
Banerji SS, Parsons JN, Tocci MJ . The immunosuppressant FK-506 specifically inhibits mitogen-induced activation of the IL-2 promoter and the isolated enhancer elements NFIL-2A and NF-AT1. Mol Cell Biol 1991; 11: 5074–87.
Liu J . FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. Immunol Today 1993; 14: 290–5.
Sigal NH, Dumont F, Durette P, Sierkierka JJ, Peterson L, Rich D, et al. Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A? J Exp Med 1991; 173: 619–28.
Clipstone NA, Fiorentino DF, Crabtree GR . Molecular analysis of the interaction of calcineurin with drug–immunophilin complexes. J Biol Chem 1994; 269: 26431–7.
McCaffrey PG, Perino BA, Soderling TR, Rao A . NF-ATp, a T lymphocyte DNA-binding protein that is a target for calcineurin and immunosuppressive drugs. J Biol Chem 1993; 268: 3747–52.
LeGrue SJ, Turner R, Weisbroth N, Dedman JR . Does the binding of cyclosporine to calmodulin result in immunosuppression? Science 1986; 234: 68–71.
Forrest MJ, Jewell ME, Koo GC, Sigal NH . FK-506 and cyclosporine A: selective inhibition of calcium ionophore induced polymorphonuclear leucocyte degranulation. Biochem Biopharmacol 1991; 42: 1221–8.
Shi YF, Shahai BM, Green DR . Cyclosporin A inhibits activation-induced cell death in T cell hybridomas and thymocytes. Nature 1989; 339: 625–6.
Kaswan RL, Martin CL, Chapman WL . Keratoconjunctivitis sicca: histopathological study of nictitating membrane and lacrimal glands from 28 canine cases. Am J Vet Res 1984; 45: 112–8.
Wieczorek R, Jakobiec FA, Sacks EH, Knowles DM . The immunoarchitecture of the normal human lacrimal gland: relevancy for understanding pathologic conditions. Ophthalmology 1988; 95: 100–9.
Jabs DA, Prendergast RA . Reactive lymphocytes in lacrimal gland and vasculitic renal lesions of autoimmune MRL/lpr mice express L3T4. J Exp Med 1987; 166: 1198–203.
Green K, Palmer SL, Bowen PA . Systemic cyclosporine increases tear flow in renal allograft recipients. Invest Ophthalmol Vis Sci 1994; 35: 2035.
Kaswan RL, Salisbury MA, Ward DA . Spontaneous canine keratoconjunctivitis sicca: a useful model for human keratoconjunctivitis sicca: treatment with cyclosporine eye drops. Arch Ophthalmol 1989; 107: 1210–6.
Reilly L, Beech J . Bilateral keratoconjunctivitis in a horse. Eq Vet J 1994; 26: 171–2.
Collins BK, Johnson PJ, Moore CJ, Collier LL, Shaw MS . Immune-mediated keratoconjunctivitis sicca in a horse. Vet Comp Ophthalmol 1994; 4: 61–5.
Williams DL, Hoey A, Smitherman P . The use of topical cyclosporine and dexamethasone in the treatment of canine chronic superficial keratitis: a comparison of therapeutic effects. Vet Rec 1995; 137: 635–9.
Watanbe-Fukunaga R, Brannan CI, Copeland NG, Jenkins A, Nagata S . Lymphoproliferative disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992; 356: 314–7.
Sato EH, Sulivan DA . Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sjogren' s syndrome. Invest Ophthalmol Vis Sci 1994; 35: 2632–42.
Dalavanga YA, Detrick B, Hooks JJ, Drosos AA, Moutsopoulos HM . Effect of cyclosporin A (CsA) on the immunopathological lesion of the labial salivary glands from patients with primary Sjogren' s syndrome. Ann Rheum Dis 1987; 46: 89–92.
Jabs DA, Lee B, Burek CL, Saboori AM, Prendergast RA . Cyclosporine therapy suppresses ocular and lacrimal gland disease in MRL/MP-lpr/lpr mice. Invest Ophthalmol Vis Sci 1996; 37: 377–83.
Jackson PA, Kaswan RL, Meredith RE, Barrett PM . Chronic superficial keratitis in dogs: a placebo controlled trial of topical cyclosporine treatment. Prog Vet Comp Ophthalmol 1991; 1: 269–75.
Mircheff AK, Warren DW, Wood RL, Tortoriello PJ, Kaswan RL . Prolactin localisation, binding and effects on peroxidase release in rat exorbital lacrimal gland. Invest Ophthalmol Vis Sci 1992; 33: 641–50.
Russell DH, Matrisian L, Kibler R, Larson DF, Poulos R, Magun BE . Prolactin receptors on human lymphocytes and their modulation by cyclosporine. Biochem Biophys Rev Commun 1984; 121: 899–906.
Kaswan RL, Salisbury MA, Mircheff AK, Glerow JP . Lacrimomimetic effects of cyclosporine. Invest Ophthalmol Vis Sci 1990; 31: 46.
Russell DH, Kibler R, Martrisian L, et al. Prolactin receptors on human T and B lymphocytes: antagonism of prolactin binding by cyclosporine. J Immunol 1985; 134: 3027–31.
Wera S, Belayew A, Martial JA . Rapamycin, FK506 and cyclosporine A inhibit human prolactin gene expression. FEBS Lett 1995; 358: 158–60.
Weingarten AJ, Ballard F, Jaffe J, Schwartz HJ . Ocular absorption and penetration following topical application of a 2% ointment prepared with a solution of cyclosporine in corn oil. Proc Eur Assoc Vet Pharmacol Ther, Edinburgh, August 1994.
Diaz-Llopis M, Menezo JL . Penetration of 2% cyclosporin eyedrops into human aqueous humour. Br J Ophthalmol 1988; 73: 600–3.
Bell TAG, Hunnisett AG . Cyclosporine A: tissue levels following topical and systemic administration to rabbits. Br J Ophthalmol 1986; 70: 852–5.
Nussenblatt RB, Dinning WJ, Fujikawa LS, Chan C-C, Palestine AG . Local cyclosporine therapy for experimental autoimmune uveitis in rats. Arch Ophthalmol 1985; 103: 1559–62.
Wiederholt M, Kossendrup D, Schultz W, Hoffmann F . Pharmacokinetics of topical cyclosporin A in the rabbit eye. Invest Ophthalmol Vis Sci 1986; 27: 519–24.
Kaswan RL . Intraocular penetration of topically applied cyclosporine. Transplant Proc 1988; 20: 650–5.
Mossteler MW, Gebbardt BM, Hamilton AM, Kaufman HE . Penetration of topical cyclosporine into the rabbit cornea, aqueous humour and serum. Arch Ophthalmol 1985; 103: 101–2.
Nussenblatt RB . The use of cyclosporine in ocular inflammatory disorders. Transplant Proc 1988; 20: 114–21.
Foets B, Misoten L, Van der Veeren P, Goosens W . Prolonged survival of allogenic corneal grafts in rabbits treated with topically applied cyclosporin A: systemic absorption and local immunosuppressive effects. Br J Ophthalmol 1985; 69: 600–3.
Saito H, Shimazaki J, Yang Y-H, Toda I, Fujishima H . Application of 0.05% cyclosporin A dissolved in alpha-cyclodextrin in human eyes. Invest Ophthalmol Vis Sci 1994; 35: 2879.
Pleyer U, Elkins B, Rlicken D, Lutz S, Grammer J, Chou J, et al. Ocular absorption of cyclosporin A from liposomes incorporated into collagen shields. Curr Eye Res 1994; 13: 177–81.
Alldredge OC, Krachmer JH . Clinical types of corneal transplant rejection: their manifestations, frequency, preoperative correlates and treatment. Arch Ophthalmol 1981; 99: 599–604.
Kana JS, Hoffmann F, Buchen R, Krolik A, Wiederholt M . Rabbit corneal allograft survival following topical administration of cyclosporin A. Invest Ophthalmol Vis Sci 1982; 22: 686–90.
Shepherd WFI, Coster DJ, Chin Fook T, Rice NSC, Jones BR . Effect of cyclosporin A on the survival of corneal grafts in rabbits. Br J Ophthalmol 1980; 64: 148–52.
Hunter PA, Wilhelmus KR, Rice NSC, Jones BR . Cyclosporin A applied topically to the recipient eye inhibits corneal graft rejection. Clin Exp Immunol 1981; 45: 173–9.
Newton C, Gebhardt BM, Kaufman HE . Topically applied cyclosporine in azone prolongs corneal allograft survival. Invest Ophthalmol Vis Sci 1988; 29: 208–15.
Milani JK, Pleyer U, Dukes A, Chou HJ, Lutz S, Rückert D, Schmidt KH, Mondino BJ . Prolongation of corneal allograft survival with liposome-encapsulated cyclosporine in the rat eye. Ophthalmology 1993; 100: 890–6.
Hill JC . Systemic cyclosporine in high risk keratoplasty. Ophthalmology 1994; 101: 128–33.
Williams DL . Histological and immunocytochemical analysis of canine chronic superficial keratitis. Invest Ophthalmol Vis Sci 1994; 35: 2016.
Jackson PA, Kaswan RL, Meredith RE, Barrett PM . Chronic superficial keratitis in dogs: a placebo-controlled trial of topical cyclosporine treatment. Prog Vet Comp Ophthalmol 1991; 1: 267–76.
Hill JC, Potter P . Treatment of Mooren's ulcer with cyclosporin A: a report of three cases. Br J Ophthalmol 1987; 71: ll–5.
Kuit PJ, Balen AThM, Stilma JS . Cyclosporin A in two cases of corneal peripheral melting syndrome. Doc Ophthalmol 1985; 59: 33–9.
Hoffman F, Widerholt M . Local treatment of necrotising scleritis with cyclosporin A. Cornea 1985; 4: 3–7.
Reed RA . Treatment of canine nictitans plasmacytic conjunctivitis with 0.2% cyclosporin ointment. J Small Anim Pract 1995; 36: 50–6.
Glaze MB, Crawford MA, Nachreiner RF, Casey HW, Nafe LA, Kearney MT . Ophthalmic corticosteroid therapy: systemic effects in the dog. J Am Vet Med Assoc 1988; 192: 73–5.
Crispin SM . Personal communication.
Reed RA, Barnett KC, Sansom J . Cyclosporin-responsive keratoconjunctivitis in the cat and horse. Vet Rec 1995; 137: 170–l.
Bleik JH, Tabbara KF . Topical cyclosporine in vernal keratoconjunctivitis. Ophthalmology 1991; 98: 1679–84.
Irani AM, Butrus SI, Tabbara KF, Schwartz LB . Human conjunctival mast cells: distribution of MCr and MCrc in vernal conjunctivitis and giant papillary conjunctivitis. J Allergy Clin Immunol 1990; 86: 34–40.
Kinai A, Alba RM, Takano T, Kopnayashi C, Nakajima A, Kurihara K, et al. The effect on the cornea of alpha-cyclodextrin vehicle for cyclosporine eye drops. Transplant Proc 1989; 21: 3150–2.
Beníttez del Catillo JM, del Aguila C, Duran S, Hernandez J, Sanchez JG . Influence of topically applied cyclosporin A in olive oil on corneal epithelial permeability. Cornea 1994; 13: 136–40.
Nasisse MP, Guy JS, Davidson MG, Susman WA, Fairley NM . Experimental ocular herpes virus infection in the cat. Invest Ophthalmol Vis Sci 1989; 30: 1758–68.
Boisjoly HM, Woog JJ, Pavan-Langston D, Oark NH . Prophylactic topical cyclosporine in experimental herpetic stromal keratitis. Arch Ophthalmol 1984; 102: 1804–7.
Meyers-Elliott RH, Chitjian PA, Billups CB . Effects of cyclosporine A on clinical and immunological parameters in herpes simplex keratitis. Invest Ophthalmol Vis Sci 1987; 28: 1170–80.
Salisbury MAR, Kaswan RL, Brown J . Microorganisms isolated from the corneal surface before and during cyclosporine treatment in dogs with keratoconjunctivitis sicca. Am J Vet Res 1995; 56: 880–4.
Kirland TN, Fierer J . Cyclosporine A inhibits Cocci-diodes immitis in vitro and in vivo. Antimicrob Agents Chemother 1983; 24: 921–4.
van Bijsterveld OP . Diagnostic tests in the sicca syndrome. Arch Ophthalmol 1988; 82: 10–4.
Laibovitz RA, Sotsh S, Andriano K, O'Connell M, Silverman MH . Pilot trial of cyclosporine 1% ophthalmic ointment in the treatment of keratoconjunctivitis sicca. Cornea 1993; 12: 315–23.
Gunduz K, Ozdemir O . Topical cyclosporin treatment of keratoconjunctivitis sicca in secondary Sjogren' s syndrome. Acta Ophthalmol (Copenh) 1994; 72: 438–42.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Williams, D. A comparative approach to topical cyclosporine therapy. Eye 11, 453–464 (1997). https://doi.org/10.1038/eye.1997.126
Issue Date:
DOI: https://doi.org/10.1038/eye.1997.126
Keywords
This article is cited by
-
Animal models of scarring control
Eye (2020)
-
Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease
Pharmaceutical Research (2019)
-
Augenbeteiligung bei atopischer Dermatitis
Der Ophthalmologe (2017)
-
A new look at dry eye disease and its treatment
Advances in Therapy (2000)