Randomised trialomania? The multicentre liver transplant trials of tacrolimus

摘要: In 1989-90 our group reported that tacrolimus (FK 506) could systematically control liver allograft rejection had been intractable despite conventional cyclosporin-based immunosuppression.1,2 The “rescued” patients were maintained on tacrolimus, and manifested no unique or unexpected toxicity. Consequently, a pilot trial was begun in which substituted for cyclosporin from the time of operation. By early 1990, nearly 200 liver, kidney, other kinds organ recipients who entered superior actuarial survival, lower requirement prednisone, better quality life than observed past experience.3,4 upgrading outlook after transplantation3 as obvious when succeeded azathioprine baseline immunosuppressant decade before.5 November, 1993, 1391 primary liver-transplant treated Pittsburgh with new drug.6 Only 35 (2·5%) crossed over to 15 these changed back supervened. The keystone management principle The drug user friendly. As all previous immunosuppressants,7-9 secret administration doses up limit imposed by drug's Dose-manoeuvrable prednisone adjuvant agents then added needed reverse rejection, given prophylactically. Because dose-limiting side-effects cyclosporin10 tacrolimus3,4,11,12 same (nephrotoxicity, neurotoxicity, diabetogenicity), organ-system-specific toxic manifestations be used first day treatment determine dose ceilings; occurrence helped establish floor. folly making invidious toxicity comparisons between scales tilted one way ratcheting down self-evident.12 only adverse effects exclusively but not dose-related hirsutism, gingival hyperplasia, facial brutalisation cyclosporin.10 It easy, it earlier cyclosporin,13 deduce meaning trough plasma blood concentrations (the plasma/blood ratio about 0·1) relate manifestations, preceding dose. When we realised overdosed, this corrected subsequent cases within few postoperative days hours responding clinical events flexible dosing. Nevertheless, lowered both starting intravenous oral January, 1990;12 subsequently reduced again.14 These important revisions matter what transplanted especially so because metabolism is more dependent good hepatic function. 12,15,16 addition, absorption little disturbed compared absence bile intestinal disorders. These details pharmacokinetics ranges, appropriate strategies, well worked through meetings organise multicentre trials March, 1990. 3 weeks later, data presented American Surgical Association (on April 5, 1990) manuscript published 5 months later eve trials.