Cyclosporin. 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 interleukin-2 and several other cytokines, most notably in T helper lymphocytes. This reduces the production of a range of cytokines, inhibiting the activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppressive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has also 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 refractory to standard treatment, oral cyclosporin is an effective therapy in acute ocular Behçet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Crohn's disease and nephrotic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a first line therapy in patients with moderate or severe aplastic anaemia who are ineligible for bone marrow transplantation, with the additional benefit of reducing platelet alloantibody titres. It may also be of considerable therapeutic benefit in patients with primary biliary cirrhosis, particularly those with less advanced disease. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a number of indications. Furthermore, the drug has shown some efficacy in a wide range of other, generally uncommon disorders in which controlled clinical trials are lacking and/or are unlikely to be performed. Cyclosporin does not appear to be effective in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in patients 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 the lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should be discontinued in these patients once active disease is controlled. Hypertrichosis, gingival hyperplasia, and neurological and gastrointestinal effects are the most common adverse events in cyclosporin recipients, but are usually mild to moderate and resolve on dosage reduction. Changes in laboratory variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare.(ABSTRACT TRUNCATED AT 400 WORDS)
Faulds
Diana
D
Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand.
Goa
Karen L
KL
Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand.
Benfield
Paul
P
Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand.
D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002986:Clinical Trials as Topic; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D004066:Digestive System Diseases / Q000188:drug therapy; D005128:Eye Diseases / Q000188:drug therapy; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy*; D009404:Nephrotic Syndrome / Q000188:drug therapy; D009422:Nervous System Diseases / Q000188:drug therapy; D012871:Skin Diseases / Q000188:drug therapy
D016572:Cyclosporine