As with all types of solid organ transplantation, lifelong immunosuppression is required to prevent acute graft rejection. One of the most significant challenges of clinical transplantation is to maintain an adequate level of immunosuppression to prevent rejection while preserving adequate immunocompetence to avoid serious infectious complications. Since the mid 1980s, standard immunosuppression has employed a triple drug regimen consisting of cyclosporine (Sandimmune, SangCya), prednisone, and azathioprine (Imuran). The combination of these agents has resulted in superior graft and patient survival rates, has decreased the mortality from infectious complications, and has minimized the side effects of the individual agents. Recently, the newer immunosuppressive agents tacrolimus (Prograf) and mycophenolate mofetil (Cellcept) have been used in place of cyclosporine and azathioprine, respectively. In addition, some programs use induction therapy in the early postoperative period, employing cytotoxic antibody preparations targeted against the T lymphocytes. The most commonly used agents include OKT3, a murine monoclonal antibody, and polyclonal preparations such as antilymphocyte serum (ALS) and antilymphocyte globulin (ALG).
Cyclosporine remains one of the mainstays of immunosuppressive regimens. This fungal metabolite is a potent inhibitor of T-lymphocyte activity and interferes with the generation of interleukin 2 (IL-2). It is a lipophilic substance that is metabolized in the liver by the cytochrome P-450 system. Cyclosporine is usually taken twice daily, and doses are adjusted based on serial blood levels. Target trough levels vary depending on the specific laboratory assay used. Levels are maintained in the range of 300 to 400 ng/dL early after transplantation and then lowered to levels of approximately 150 ng/dL long term. The list of drugs that interact with cyclosporine (Table...56-2) continues to grow yearly, and careful consideration is required before adding or withdrawing medications for an individual patient. Such changes should always be made with the knowledge and input of the patient's transplant physician. Acute increases in cyclosporine levels may be associated with severe renal dysfunction, and acute decreases may result in the development of acute rejection.
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