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Cyclosporine, also called cyclosporin A (CsA) was the first discovered, and is the only commercially available drug, in the category of immunosuppressive drugs, cyclosporins. Cyclosporine is non-cytotoxic, it inhibits T helper cell activity and shifts the regulation of the immune response towards immune tolerance. Since T-cells orchestrate most chronic immune responses, cyclosporine has broad anti-inflammatory effects. Its original indication was to prevent rejection in organ transplantation patients; its systemic indications currently include many autoimmune disorders.
The first commercial ophthalmic cyclosporine was Optimmune®, a 0.2% cyclosporine ointment made by Schering Plough Animal Health. Optimmune® was approved in 1995 in the US for the treatment of canine KCS, and approved in Europe for KCS and pannus. Compounded ophthalmic cyclosporine drops have been commonly used in 1.0 - 2.0% concentrations in corn oil when Optimmune® was either commercially unavailable or owners were physically unable to apply an ointment. An aqueous suspension of 0.5% cyclosporine (Restasis® ) was developed by Allergan Pharmaceuticals for treatment of KCS in human patients, and is in phase III testing for FDA approval.
Topical cyclosporine has several beneficial effects in dry eye patients. One of these effects is to directly increase secretion of physiologic tears. Physiologic tears (as opposed to artificial tears) contain growth factors to regulate corneal cell turnover and healing, lysozyme and antibodies for infection control, and numerous nutritional elements required for the health of the avascular cornea. Topical CsA appears to facilitate lymphocytic apoptosis and suppress epithelial cell apoptosis, allowing regeneration of lacrimal gland tissue in dogs with KCS. Cyclosporine also restores conjunctival goblet cell mucin production. Topical CsA is an effective therapy for aqueous deficiency and for mucin deficiency dry eye disorders in dogs.
Approximately 80% of dogs with KCS will increase tearing when treated with topical CsA. A major determinate in the success or failure of the individual KCS patient appears to be the stage of KCS at which CsA treatment is initiated. The lacrimal glands in KCS become progressively atrophied over the course of the disease. Dogs with a Schirmer tear test (STT) of 0 mm/min often have complete atrophy of the lacrimal glands and cannot respond to CsA; early treatment of KCS is therefore advocated. Dogs with congenital aplasia of the lacrimal glands and dogs with neurologic etiologies of KCS are also unlikely to increase tearing with CsA. However, even in dogs where lacrimation cannot be restored with CsA, the anti-inflammatory effects on the cornea and conjunctiva, and the regulation of mucus production can be beneficial. The majority of KCS dogs require lifelong CsA treatment. Interruptions in therapy lead to relapse of KCS.
Topical CsA represents an important therapeutic addition for several autoimmune and immune mediated disorders of the ocular surface which were previously only responsive to corticosteroids. Dogs that receive chronic topical corticosteroids are in jeopardy of incurring a minor corneal abrasion which, under the influence of corticosteroids and collagenase activation, may progress to a melting stromal ulcer. Cyclosporine does not activate collagenase, hence its much safer for chronic use than corticosteroids, particularly in exophthalmic breeds susceptible to ocular injury.
Cyclosporine does not penetrate well into the inner eye and it is therefore seldom used to treat anterior uveitis. It reaches high concentrations in the cornea, conjunctiva, sclera and lids, where it is useful for suppressing chronic immune mediated disease. In the treatment of chronic superficial keratitis (pannus), nictitans plasmacytic conjunctivitis, and pigmentary keratitis, topical cyclosporine is effective whether used with topical corticosteroids or in place of corticosteroids. Anecdotal evidence suggests it is also useful in the treatment of nodular scleritis, diffuse scleritis, follicular conjunctivitis and atopic blepharoconjunctivitis.
• Suppression of systemic lymphoblastogenesis has been reported in small dogs treated with 2% topical cyclosporine, but not with 0.2% (Optimmune®), suggesting that lower concentrations are advisable, particularly in small animals.
• Ocular irritation reactions, including conjunctival hyperemia, periocular alopecia and blepharitis are common when topical cyclosporine is made from oral cyclosporine (Sandimmune®) but are rarely seen with Optimmune®. Ingredients in the oral solution such as alcohol and surfactants as well as higher concentrations of CsA contribute to the irritation response. Cats have a lower tolerance to this ocular irritation than do dogs.
• Experimentally, CsA induced exacerbations of ocular herpes in cats when used without concurrent virostatic agents.
• Unlike corticosteroids, cyclosporine does not induce collagenase and is therefore not contraindicated in the presence of corneal ulcers.
• Epiphora is an anticipated side effect of CsA in non-dry eye patients.
• The bioavailability of CsA is affected by the oil in which it is dissolved. Corn oil and castor oil are desirable vehicles; mineral oil is particularly undesirable. Cyclosporine is an extremely stable molecule, however stability of the ophthalmic preparation is limited by solubility, oxidation of the vehicle, and sterility.
Recommended frequency is usually twice daily, and can be adjusted more or less frequently to effect. For KCS, ophthalmic cyclosporine usually needs to be continued lifelong. For transient ocular surface disorders it may be used periodically as needed.
About the AuthorDr. Renee Kaswan is a Diplomate in the College of Veterinary Ophthalmologists and former professor of ophthalmology at the University of Georgia College of Veterinary Medicine, where she taught for 17 years.
She devotes her career to investigating the causes of KCS in man and dog, and developing cyclosporine ophthalmic as the first truly therapeutic agent to treat this common disease.
Renee is internationally distinguished as the 'Queen of Dog tears' and aspires to similar recognition in human ophthalmology with the eventual approval of Restasis.
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