Indications/PharmacologyCyclosporine is a polypeptide agent first isolated from a fungus. The agentinterferes with interleukin synthesis by T lymphocytes and in so doing has been employed extensively inpeople following major organ transplantation to prevent immune rejection. Cyclosporine is extremelyhydrophobic and was originally compounded by pharmacists in virgin olive oil or purified corn oil for thetopical application to dogs with keratoconjunctivitis sicca. Topical cyclosporine is now commerciallyavailable as a 0.2% ointment (Optimmune®-Schering). The mechanism of action of cyclosporine in thetreatment of keratoconjunctivitis sicca is still not fully understood, although it has been employed in thetreatment of KCS in dogs for several years. It stimulates increased tear production in normal dogs and forthis reason it is thought to have a direct stimulatory effect on the tear gland. It may do this acting as aprolactin analog, fitting onto lacrimal prolactin receptors. Its interleukin blocking effects likely are themajor mechanism of action. Halting local inflammatory mediator production appears to arrest selfperpetuating lacrimal adenitis resulting in resumption of normal or improved tear production after severalweeks of therapy. Cyclosporine in the cornea, appears to have the ability to lessen granulation andpigment development. This property appears to be unrelated to its tear producing ability.
The reported success rate of alleviating the signs of KCS in dogs with treatment with cyclosporine is 75-85%. Some studies indicate that the higher the Schirmer value prior to starting therapy, the more likelythat the dog will be well managed with cyclosporine drops alone. Absolute sicca may be associated withextensive fibrosis of the tear glands, leaving little tissue for stimulation or repair.
Cyclosporine is effective in the management of German Shepherd Pannus or chronic superficial keratitisin the dog. This condition is an immune disease of the cornea and likely is interleukin mediated.
Cyclosporine may be preferred for the treatment of pannus because of the lack of systemic side effectsnoted in dogs with chronic topical administration of cyclosporine. Chronic topical corticosteroidtreatment is associated with biochemical changes in the blood of large and small dogs.
Cyclosporine has been tried in the management of the rare case of keratoconjunctivitis sicca in the cat.
Dry eye in cats is usually associated with herpes virus destruction of lacrimal epithelial cells and orstenosis of the ductules or openings of the ductules due to chronic viral conjunctivitis. Preliminary resultshave not been promising. Topical cyclosporine often aggravates ophthalmic herpes virus infections inpeople. Cyclosporine has not shown promising effects in the management of feline eosinophilic keratitis, a condition now thought to be related to chronic stromal herpes virus infection in cats.Suggested Dosages/Precautions/Adverse Effects - Cyclosporine is initiated generally as the first courseof therapy for confirmed dry eye cases in the dog. The topical half life of cyclosporine is about 8 hoursand most canine cases of KCS are managed with twice daily therapy with 0.2% ointment (Optimmune®).
Three times a day therapy has been employed during the initial phases of treatment in more difficult orslow responding cases. For some uncertain reason (reversal of lacrimal adenitis? reorganization oflacrimal epithelial cell function? formation of secretory granules? tear production) 3-8 weeks oftherapy are necessary before a dramatic increase in the Schirmer tear test becomes evident. Patients aregenerally maintained for life on cyclosporine ophthalmic once or twice daily depending on the response.
Discontinuation of therapy is usually associated with the return of clinical signs of KCS within a fewdays. Reinstitution of therapy at this time, is usually associated with an almost immediate return of tearproduction (versus the initial lag phase noted). This likely is related to the degree of inflammatory diseasenoted with short discontinuation of therapy versus that present initially, prior to the diagnosis of KCS.
If tear production is very low, cyclosporine is often used in combination with artificial tears during theinitial phases of therapy. Once tear production is improved, artificial tears can generally be removedcompletely or their frequency reduced in the treatment plan. After treatment is initiated, reevaluation oftear production in one month is recommended. If ulcerative keratitis complicates keratoconjunctivitissicca in the dog, more frequent evaluation is necessary. Cyclosporine, although an immunomodulatingagent, is considered safe in the face of ulcerative keratitis, with concurrent antibiotic therapy. Caution isadvised, however.
When cyclosporin is delivered topically, no systemic toxicity has been noted in dogs given this drugchronically. This is probably associated with the poor absorption of this drug across the GI tract andbecause it is delivered to the eye at very low concentrations which even if 100% absorbed, when dividedover the body weight of the dog is well below even the therapeutic dose. Advanced detection methodshave made it possible to measure trace levels of cyclosporine in the blood of dogs being topically treatedfor dry eye. The clinical implications of this finding is uncertain at this time.Dosage Forms/Preparations/FDA Approval Status - Optimmune® ointment is the approvedformulation of topical cyclosporine for the management of dry eye in dogs. Compounding of topicalcyclosporine drops was popular before the introduction, approval, and marketing of Optimmune®ointment. Clinicians persistently using compounded formulations of cyclosporine eye drops may beoutside of expected ethical and legal standards of practice except under very specific situations. The useof commercially available ophthalmic products instead of compounded medications is highlyrecommended. Optimmune® is first applied 2 or 3 times daily and frequency of daily application isadjusted based on clinical response.
Cyclosporine Ophthalmic Ointment 0.2%; Optimmune® (Schering-Plough); (Rx)