Topical Ophthalmic Cyclosporine: Pharmacology and Clinical Uses

Cyclosporine A (CsA) is an immunomodulatory agent that primarily inhibits the proliferation and action of T cells. Systemic CsA has been used successfully in solid organ transplantation and noninfectious uveitis. Topical CsA with various formulations has been used in the field of ocular surface diseases since early 1980s. An ophthalmic emulsion 0.05% (Restasis, Allergan, Irvine, CA), was approved by the United States Food and Drug Administration in 2003 to treat dry eye syndrome. This article aims to evaluate the peer-reviewed published scientific literature and to define well-established uses of CsA eyedrops in the field of ocular surface diseases.

Clinical Review: Topical Ophthalmic Use of Cyclosporin A

Corneal transplantation is among the most successful solid organ transplants. However, despite low rejection rates of grafts in the ‘low-risk’ setting, rejection can be as high as 70% when grafted into ‘high risk’ recipient beds. Under normal homeostatic conditions, the avascular cornea provides a unique environment that facilitates immune and angiogenic privilege. An imbalance in pro-inflammatory, angiogenic and lymphangiogenic mediators leads to a breakdown in corneal immune privilege with a consequent host response against the donor graft. Recent developments in lamellar and endothelial keratoplasties have reduced the rates of graft rejection even more, while providing improved visual outcomes. The corneal layer against which an immune response is initiated, largely determines reversibility of the acute episode. While epithelial and stromal graft rejection may be treated with topical corticosteroids with higher success, acute endothelial rejection mandates a more aggressive approach to therapy due to the lack of regenerative capacity of this layer. However, current immunosuppressive regimens come with the caveat of ocular and systemic side effects, making prolonged aggressive treatment undesirable. With the advent of biologics, efficacious therapies with a superior side effect profile are on the horizon. In our review we discuss the mediators of ocular immune privilege, the roles of cellular and molecular immune players in graft rejection, with a focus on human leukocyte antigen and antigen presenting cells. Furthermore, we discuss the clinical risk factors for graft rejection and compare rates of rejection in lamellar and endothelial keratoplasties to traditional penetrating keratoplasty. Lastly, we present the current and upcoming measures of therapeutic strategies to manage and treat graft rejection, including an overview of biologics and small molecule therapy.

/pdf/corneal-allograft-rejection-immunopathogenesis-to-37lp2e5u72.pdf

Corneal Allograft Rejection: Immunopathogenesis to Therapeutics.

Purpose. To determine the ocular pharmacokinetics of cyclosporin A after topical ophthalmic administration. Methods. Radiolabled cyclosporin A in either a castor oil-in-water emulsion or a corn oil ointment was applied to the eyes of beagle dogs or albino rabbits using the following paradigms: (i) single doses of 0.2% emulsion to rabbits and dogs, (ii) single doses of 0.05%, 0.2%, or 0.4% emulsion to rabbits, (iii) multiple doses of 0.2% emulsion to dogs, (iv) single and multiple doses of 0.2% ointment to rabbits. The distribution of cyclosporin A was determined by measuring the distribution of radio-activity. Results. After a single dose, cyclosporin A was rapidly absorbed into the conjunctiva (C max : dogs, 1490 ng/g; rabbits, 1340 ng/g) and cornea (C max : dogs, 311 ng/g; rabbits, 955 ng/g). High concentrations (>300 ng/g) could be detected in the cornea up to 96 hours post-dose. Lower concentrations were found in the intraocular tissues, and systemic absorption was minimal. After multiple doses, th...

Distribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and beagle dogs.

Efficacy of Topical Cyclosporine 0.05% for Prevention of Cornea Transplant Rejection Episodes

Purpose: To evaluate the effect on intraocular pressure (IOP) of substituting topical Cyclosporine A 0.5% for topical corticosteroids in patients with postkeratoplasty glaucoma and corticosteroid-induced ocular hypertension (CIOH). We also sought to determine the penetration of topical 0.5% Cyclosporine A into the cornea and anterior chamber Methods: Topical Cyclosporine A 0.5% was prospectively substituted for topical corticosteroids in 47 patients (52 eyes) with postkeratoplasty glaucoma and CIOH in order to eliminate the IOP-elevating effect of topical corticosteroids, while maintaining protection against allograft rejection. Ten patients received 0.5% topical Cyclosporine before keratoplasty. Their corneal tissue and aqueous samples were evaluated by high pressure liquid chromatography for Cyclosporine levels. Results: Forty-eight of 52 eyes (92.3%) demonstrated a reduction of IOP at first followup (mean: -7.9 mmHg; range: -19 to +2). Mean followup was 10.3 months, ranging from 1 to 37 months. At last follow-up, mean IOP was -8.2 mm Hg. There were six allograft rejections, five of which were reversed with the reintroduction of topical corticosteroids. Graft clarity was maintained in 46 of 52 eyes (88%). The mean cornea Cyclosporine concentration was 3679 ng/gm (range: 1980 to 5520 ng/ gm) and aqueous humor mean concentration was 6.05 ng/mL (range: 0.4 to 15.5 ng/mL). Conclusions: Topical Cyclosporine A 0.5% may be substituted for topical corticosteroids to aid in the management of postkeratoplasty glaucoma and CIOH. However, the use of Cyclosporine in place of corticosteroids may be associated with an increased risk of immune rejections. The corneal penetration of topical Cyclosporine is excellent while the penetration into the anterior chamber is poor.

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.

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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.