Tacrolimus

A Clinical Study of 212 Patients A Unit of Myasthenia Gravis, Hospital General Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain Department of Surgery, Hospital General Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain Neurology Department, Hospital General Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain Address for correspondence: José M. Ponseti, Unit of Myasthenia Gravis, Department of Surgery, Hospital General Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129, E-08035 Barcelona, Spain. Voice: +34-93-2746000; fax: +34- 93- 2746224. jmponseti@vhebron.net and 5012jpb@comb.es Tacrolimus is a macrolide T cell immunomodulator that is used in myasthenia gravis (MG) patients to affect muscle contraction (ryanodine receptor by modulating intracellular calcium-release channels and increasing muscular strength), glucocorticoid receptors (increasing intracellular concentration of steroids and blocking the steroid export mechanism), and an increase in T cell apoptosis. In this study, we report the results of low-dose tacrolimus (0.1 mg/kg/day) treatment in 212 MG patients. There were 110 thymectomized, cyclosporine- and prednisone- dependent patients; 68 thymectomized patients who started tacrolimus early postoperatively (24 h after operation); and 34 patients over 60 years old with nonthymomatous generalized MG or in whom thymectomy was contraindicated. The mean follow-up time was 49.3 ± 18.1 months. Muscular strength showed an increase of 23% after 1 month of treatment and 29% at the end of the study. The acetylcholine receptor antibodies decreased significantly from a mean of 33.5 nmol/L at base line to 7.8 nmol/L at the final visit. In the thymectomy group with combined prednisone and tacrolimus stratified by histology of the thymus, the mean probability to attain complete stable remission at 5 years was 80.8% in patients with hyperplasia, 48.1% in thymic involution, and 9.3% in patients with thymoma. In 4.9% of patients, tacrolimus was withdrawn because of major adverse effects. Our results suggest that a low dose of tacrolimus is effective for MG and could be included to the armamentarium for this autoimmune disease. The present results should be interpreted considering the limitations of a retrospective clinical study. Confirmation of these results in randomized studies is desirable.

What is tacrolimus?

Tacrolimus was discovered in 1984 by a Japanese team headed by T. Goto, T. Kino and H. Hatanaka; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.^[1] Like cyclosporin, it was found in a soil fungus, although it is produced by a type of bacteria, Streptomyces tsukubaensis.^[2] The name tacrolimus is derived from 'Tsukuba macrolide immunosuppressant'.^[3]

The drug is owned by Astellas Pharma Inc., and is sold under the tradenames Prograf, Advagraf, and Protopic. It is sometimes referred to as FK-506 (Fermentek catalogue number 506). It was first approved by the Food and Drug Administration (FDA) in 1994 for use in liver transplantation; this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants.