Immunosuppressive agents organ transplantation

The efficacy of tacrolimus as a primary immunosuppressant for the prophylaxis of rejection and for rescue therapy following failure of conventional cyclosporin-based rejection prophylaxis has been demonstrated in numerous clinical studies in adults and pediatrics using various types of combination therapy since 1989. Tacrolimus is now well established not only as a primary immunosuppressant in organ transplantation but also an excellent rescue agent for patients experiencing posttransplant rejection while on cyclosporin-based regimens [44]. 

The induction agents are highly immunosuppressive and, when given prior to some organ transplants (e.g., kidney transplant), allow for significant reductions in acute rejection... 

MPA derivatives have replaced azathioprine as the antiproliferative agent of choice in most organ transplant centers. The MPA derivatives generally are considered to provide a more specific immunosuppressive effect compared with azathioprine. Mycophenolate mofetil and enteric-coated mycophe-nolic acid have similar safety and efficacy data in renal transplant recipients. 

Tissue/organ transplantation in which the donor is not genetically identical to the recipient (i.e. in cases other than identical twins). The recipient will mount an immune response against the transplanted tissue, culminating in tissue rejection unless immunosuppressive agents are administered. 

Cytotoxic agents Since proliferation of cells is essential for the immune response, agents that inhibit DNA synthesis have been used as immunosuppressive agents for many years. The first were used in the 1960s, particularly to prevent rejection of a transplanted organ, for example purine and pyrimidine analogues. These agents are not now used in autoimmune diseases but are stiU used in cancer chemotherapy (Chapter 21). 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

Basiliximab is a mouse/human chimeric monoclonal antibody with specificity and high affinity for the a-subunit of the IL-2 receptor. The antibody acts as an lL-2Ra antagonist and inhibits lL-2-mediated activation and proliferation of T l)unphocytes. It is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents like cyclosporin, azathioprine, mycophenolate mofetU... 

Allogeneic transplants For prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Gengraf and A/eora/have been used in combination with azathioprine and corticosteroids. Sanc//n n nne always is to be used with adrenal corticosteroids. Sandimmune a so may be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents. Because of the risk of anaphylaxis, reserve Sandimmune injection for patients who are unable to... 

Of major importance to blood level analysis are the type of assay used, the transplanted organ, and the other immunosuppressant agents being administered. 

The metabolism of ciclosporin is inhibited by diltiazem, verapamil, azole antifungal agents, erythromycin and clarithromycin with resultant potential for renal, hepatic and CNS toxicity. These interactions have been investigated as a cost saving device in organ transplant recipients, with the aim of using a lower dose of ciclosporin to achieve immunosuppression. 

By far the most important indication for the use of immunosuppressive agents nowadays is in organ transplantation. A second indication is the treatment of autoimmune diseases where immunosuppression has been shown to be effective. 

In recent years, the incidence and severity of human fungal infections have increased dramatically. The use of powerful immunosuppressive agents for cancer chemotherapy and for organ transplant, combined with the AIDS epidemic, has led to this significant increase. However, in healthy individuals, a normally functioning immune system tends to ward off fungal infections. 

Until the role of echinacea in immune modulation is better defined, this agent should be avoided in patients with immune deficiency disorders (eg, AIDS, cancer), autoimmune disorders (eg, multiple sclerosis, rheumatoid arthritis), and patients with tuberculosis. While there are no reported drug interactions for echinacea, some preparations have a high alcohol content and should not be used with medications known to cause a disulfiram-like reaction. In theory, echinacea should also be avoided in persons taking immunosuppressant medications (eg, organ transplant recipients). 

The initial organ transplantation was performed in 1933 when a kidney was transplanted from a cadaver. Total lymphoid irradiation was used for the immune suppression but the tissue was rejected and the patient eventually died. This was followed by the use of corticosteroids as immunosuppressive agents, but unfortunately steroids by themselves also did not produce positive results. In the early 1960s, cytotoxic agents were introduced for immune suppression these were followed by the use of a combination of cytotoxic agents and corticosteroids until the mid-1980s when cyclosporine was discovered by Borel. 

Because of the autoimmune basis of rheumatoid arthritis, various other drugs that affect the immune response are used on a limited basis. For instance, cyclosporine (Sandimmune), an immunosuppressant agent that is used to prevent rejection of organ transplants (see Chapter 37), is sometimes used to treat... 

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