Elsevier

Clinics in Liver Disease

Volume 1, Issue 2, 1 August 1997, Pages 417-437
Clinics in Liver Disease

CYCLOSPORINE AND TACROLIMUS: The Mainstay of Immunosuppressive Therapy for Solid Organ Transplantation

https://doi.org/10.1016/S1089-3261(05)70278-6Get rights and content

The goal of immunosuppressive therapy is to achieve tolerance for the transplanted organ with minimum rates of complications and side effects. Cyclosporine and, more recently, tacrolimus have greatly contributed in improving the long-term survival of both patient and graft but their nonspecific immunosuppressive action and toxicity bring about problems such as infections, neoplasms, hypertension, hyperglycemia, decreased renal function, and neurotoxicity, representing a challenge to the transplant surgeon and physician. Nevertheless, better understanding of the action and metabolism and more experience in the use of these drugs have led to a better balance between efficacy and side effects and have delineated more precisely the role of the drugs in different clinical settings.

The pharmacologic characteristics of cyclosporine and tacrolimus, their side effects, complications, and methods of use are described in the first part of this article. A comparative analysis of the two drugs is outlined in the second part of the article. The analysis concentrates on the differences and similarities concerning efficacy and toxicity of cyclosporine and tacrolimus. The data reported are based on the results of historic studies such as the US and European multicenter trials and other single-center studies on specific issues. The last section is dedicated to a description of the immunosuppressive protocols used at our institution. The protocols represent the end result of a large clinical experience gained with more than 1300 liver transplants performed at our institution and the observations of other investigators. Each protocol is designed with the goal of matching the most efficacious immunosuppressive regimen to the needs of each patient, taking into account the pathology that brought the liver to failure, the clinical conditions at the time of and following the transplant, and the patient's age.

Section snippets

CYCLOSPORINE

Cyclosporine is a cyclic undecapeptide isolated from the soil fungi Cylindrocarpum Lucidum and Tolypocladium inflatum (Fig. 1). The metabolite cyclosporine is produced by fermentation, and its immunosuppressive properties were discovered by Borel in 1972.4 Cyclosporine acts by blocking the T lymphocytes1 response to transplanted antigens. T lymphocytes, after exposure to the antigens in the donor organ by the antigen-presenting cells, react with the production of interleukin (IL) 2, 3, and 4;

TACROLIMUS

Tacrolimus is the first drug specifically developed for antirejection therapy in solid organ transplantation. It was discovered in 1984 by Kino and Goto.20, 19 It is a hydrophobic macrolactam that is able to suppress the immune response with a mechanism of action similar to the one exerted by cyclosporine (see Figs 1,3). Tacrolimus binds to intracytoplasmic-binding proteins called FKBPs, of which the FKBS12 is the most important.5 The complex, tacrolimus–FKBS12, acts in a way similar to the

COMPARING CYCLOSPORINE AND TACROLIMUS

Cyclosporine has been the drug of choice for the prevention of graft rejection since its introduction in 1978. The discovery and clinical use of tacrolimus, first as rescue therapy in rejection refractory to steroid treatment, then as a first-line immunosuppressive agent, have added an essential tool to the armamentarium of the transplant surgeon and physician and opened the field of immunosuppressive therapy to different drug regimens, with more options to suit different clinical scenarios and

PROTOCOLS

The opportunity to choose between two different main immunosuppressive regimens—one cyclosporine- the other tacrolimus-based—has allowed our center to design protocols to match patients' clinical needs using the characteristics of the drugs and their efficacy versus toxicity, with the goal of obtaining the best immunosuppression with the least incidence of side effects and complications. With the exception of patients affected by hepatitis C and B, elderly patients over age 60, and patients

References (47)

  • D.G. Deschler et al.

    Posttransplantation lymphoproliferative disorder in patients under primary tacrolimus (FK 506) immunosuppression

    Arch Otolaryngol Head Neck Surg

    (1995)
  • European FK506 Multicentre Liver Study Group

    Randomised trial comparing tacrolimus (FK506) and cyclosporine in prevention of liver allograft rejection

    Lancet

    (1994)
  • J.J. Fung et al.

    FK506 in solid organ transplantation

    Ther Drug Monit

    (1995)
  • S. Hadley et al.

    Major infectious complications after orthotopic liver transplantation and comparison of outcomes in patients receiving cyclosporine or FK506 as primary immunosuppression

    Transplantation

    (1995)
  • P.C. Heistand et al.

    Pharmacological studies with norvaline2-cyclosporine (SDZ OG 37-325) in comparison with cyclosporine (Sandimmune): A summary

    Transplant Proc

    (1994)
  • D. Holt et al.

    The pharmacokinetics of Sandimmune Neoral: A new oral formulation of cyclosporine

    Transplant Proc

    (1994)
  • M.A. Hooks

    Tacrolimus, a new immunosuppressant—a review of the literature

    Ann Pharmacother

    (1994)
  • B.E. Jarrell et al.

    Cyclosporine

  • R.M. Jindal et al.

    Diabetogenicity of FK506 versus cyclosporine in liver transplant recipients

    Transplantation

    (1994)
  • M.W. Johnson et al.

    Hepatitis C viral infection in liver transplantation

    Arch Surg

    (1996)
  • T. Kino et al.

    Discovery of FK-506 and update

    Ann N Y Acad Sci

    (1993)
  • T. Kino et al.

    FK-506, a novel immunosuppressant isolated from a Streptomyces: II. Immunosuppressive effect of FK-506 in vitro

    J Antibiot (Tokyo)

    (1987)
  • G.B. Klintmalm

    De novo lymphoma after liver transplantation

    Clin Transplant

    (1992)

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    Address reprint requests to Goran Klintmalm, MD, PhD, FACS, Baylor University Medical Center, Transplantation Services, 3500 Gaston Avenue, Dallas, TX 75246

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    Copyright © 1997 W. B. Saunders Company. Published by Elsevier Inc. All rights reserved.