CYCLOSPORINE - A REVIEW OF ITS PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES, AND THERAPEUTIC USE IN IMMUNOREGULATORY DISORDERS

Cyclosporin is a lipophilic cyclic polypeptide which produces calcium- dependent, specific, reversible inhibition of transcription of interle ukin-2 and several other cytokines, most notably in T helper lymphocyt es. This reduces the production of a range of cytokines, inhibiting th e activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppre ssive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has als o been evaluated in a large range of disorders where immunoregulatory dysfunction is a suspected or proven aetiological,factor, and this is the focus of the present review. In patients with severe disease refra ctory to standard treatment, oral cyclosporin is an effective therapy in acute ocular Behcet's syndrome, endogenous uveitis, psoriasis, atop ic dermatitis, rheumatoid arthritis, active Crohn's disease and nephro tic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a firs t line therapy in patients with moderate or severe aplastic anaemia wh o are ineligible for bone marrow transplantation, with the additional benefit of reducing platelet alloantibody titres. It may also be of co nsiderable therapeutic benefit in patients with primary biliary cirrho sis, particularly those with less advanced disease. Limited evidence s uggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-d ependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a number of indications. Furthermore, the d rug has shown some efficacy in a wide range of other, generally uncomm on disorders in which controlled clinical trials are lacking and/or ar e unlikely to be performed. Cyclosporin does not appear to be effectiv e in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in pat ients with type I (insulin-dependent) diabetes mellitus and should not be used in this indication. To avoid relapse after control of active disease, patients should receive cyclosporin maintenance therapy at th e lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should he discontinued in these patients once active disease is controlled. H ypertrichosis, gingival hyperplasia, and neurological and gastrointest inal effects are the most common adverse events in cyclosporin recipie nts, but are usually mild to moderate and resolve on dosage reduction. Changes in laboratory variables indicating renal dysfunction are rela tively common, although serious irreversible damage is rare. However, renal function monitoring is recommended, and cyclosporin dosage shoul d be reduced by 25 to 50% if serum creatinine increases > 30% above ba seline, with treatment discontinuation if creatinine does not return t o within 30% of baseline levels within 1 month. A large number of inte ractions between cyclosporin and other agents have been identified. In the treatment of immunoregulatory disorders, cyclosporin has generall y been reserved for use in patients with severe refractory disease and patients who have become steroid-dependent or, in patients with aplas tic anaemia, those with moderate or severe disease who are ineligible for bone marrow transplantation. Despite these limitations, cyclospori n appears to be a very effective agent in a number of recalcitrant dis orders where achieving adequate disease control is a major advance. Th is merits a trial of cyclosporin in these patients despite the careful monitoring required.