Transplantation using cyclosporins

The first human kidney and bone marrow transplants using cyclosporine were reported in 1978. Oral or intravenous cyclosporine is an immunosuppressant for transplantation of these and other organs and investigations are underway for its possible use in a variety of autoimmune diseases including rheumatoid arthritis, severe psoriasis, and Crohn s disease. Dose-dependent nephrotoxicity (261—264) remains the primary limitation of the dmg and necessitates close monitoring of patients, including measurement of dmg levels in blood. Cyclosporine research has been reviewed (265—274). 

Schrem, H., Liick, R., Becker, T., Nashan, B., Klempnauer, J. Update on liver transplantation using cyclosporine. Transplant. Proc. 2004 36 2525-2531... 

Cohen Z, Silverman RE, Wassef R et al (1986) Small intestinal transplantation using cyclosporine. Report of a case. Transplantation 42 613-621... 

The mechanism of action of azathioprine as a cytotoxic drug is not different from the mechanism of action of other antimetabolites. Azathioprine is the primary drug used for transplants, especially for kidney transplants. Today, cyclosporine is used instead of azathioprine in many places. However, azathioprine is useful in combination with cyclosporine, and it is even preferred in certain cases. Synonyms of this drug are azumec, imuran, and others. 

Renal, cardiac, and hepatic transplant Mycophenolate is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants. Use mycophenolate concomitantly with cyclosporine and corticosteroids. 

Clinical Use. Cyclosporine (Neoral, Sandimmune) is one of the primary medications used to suppress immune function following organ transplantation.14 21 69 This medication can be used alone or combined with glucocorticoids, azathioprine, and other immunosuppressants to prevent the rejection of a kidney, lung, liver, heart, pancreas, and other organ transplants. 

Jonas, S., Rayes, N., Neumann, U., Neuhaus, R., Bechstein, W. O., Guckelberger, O., Tullius, S. G., Serke, S., and Neuhaus, P. De novo malignancies after liver transplantation using tacrolimus-based protocols or cyclosporine-based quadruple immunosuppression with an interleukin-2 receptor antibody or antithymocyte globulin. Cancer 1141-1150. 

Nonspecific immunosuppressive therapy in an adult patient is usually through cyclosporin (35), started intravenously at the time of transplantation, and given orally once feeding is tolerated. Typically, methylprednisone is started also at the time of transplantation, then reduced to a maintenance dose. A athioprine (31) may also be used in conjunction with the prednisone to achieve adequate immunosuppression. Whereas the objective of immunosuppression is to protect the transplant, general or excessive immunosuppression may lead to undesirable compHcations, eg, opportunistic infections and potential malignancies. These adverse effects could be avoided if selective immunosuppression could be achieved. Suspected rejection episodes are treated with intravenous corticosteroids. Steroid-resistant rejection may be treated with monoclonal antibodies (78,79) such as Muromonab-CD3, specific for the T3-receptor on human T-ceUs. Alternatively, antithymocyte globulin (ATG) may be used against both B- and T-ceUs. 

Calcineurin is involved in cardiac hypertrophy and in cognitive and behavioral defects in the brain. Inhibitors of calcineurin such as cyclosporine A and FK 506 are used clinically in transplant rejection and autoimmune diseases. 

The introduction of PP2B (calcinemin) inhibitors revolutionized kidney transplantation. Cyclosporine A and tacrolimus (FK506) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. Cyclosporine A was in use clinically long before its mechanism of action was elucidated. 

Cyclosporine is a cyclic polypeptide immunosuppressant typically used to prevent organ rejection in transplant patients. Its use is restricted to patients with fulminant or refractory symptoms in patients with active IBD. Significant toxicides associated with cyclosporine are nephrotoxicity, risk of infection, seizures, hypertension, and liver function test abnormalities.1,13,14... 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

FIGURE 52-2. Center-specific protocols may use RATG, an IL-2RA, or no induction therapy. In any situation, patients receive IV methylprednisolone prior to, during, or immediately following the transplant operation. The patient then will begin the maintenance immunosuppressive regimen. The center-specific protocol will specify which calcineurin inhibitor (cyclosporine or tacrolimus) is used in combination with mycophenolate mofetil or sirolimus with or without steroids. Patients then are monitored for signs and symptoms of rejection. 

Azathioprine was originally approved by the FDA in 1968 as an adjunct immunosuppressant for use in renal transplant recipients. It is available in oral and IV dosage forms.11 Prior to the advent of cyclosporine, the combination of azathioprine and corticosteroids was the mainstay of immunosuppressive therapy. Over the past 10 years, the use of azathioprine has declined markedly due in large part to the success of the MPA derivatives, which are more specific inhibitors of T cell proliferation. 

The immunosuppressant compound170 FK-506, similar in effect to cyclosporin A, the leading drug for use in immune system suppression to prevent rejection of transplanted organs171, has been labelled at carbon atoms 10, 16, 18, 21a, 24 and 26 by fermentative biosynthesis using sodium [l-14C]propionate as a precursor172. The same 13C-labelled positions were derived from [l-13C]propionate. FK-506 producing culture Streptomyces tsukubaenis no 9993 has been utilized in this biosynthesis (120 h incubation at 29 °C). 

Antibodies have and likely will find additional use in transplantation-related medicine. In general, cell-mediated immunological mechanisms are responsible for mediating rejection of transplanted organs. In many instances, transplant patients must be maintained on immunosuppressive drugs (e.g. some steroids and, often, the fungal metabolite cyclosporine). However, complications may arise if a rejection episode is encountered that proves unresponsive to standard immunosuppressive therapy. Orthoclone OKT-3 was the first monoclonal antibody-based product to find application in this regard. 

Koal et al. (2004) measured four immunosuppressants (cyclosporine A, tacrolimus, sirolimus, and everolimus) in whole blood samples from transplant recipients. The samples were treated first with a protein precipitation step. The supernatant was extracted with a Poros Rl/20 perfusion column (30 x 2.1 mm, 20 tm, Applied Biosystems, Darmstadt, Germany) online. A Luna phenyl hexyl column (2 x 50 mm, Phenomenex, Schaffenburg, Germany) was used for separation. The total run time was 2.5 min. The lower limit of quantitation was 10 ng/mL for cyclosporine A and 1 ng/mL for the other three analytes. 

Cyclosporine is an immunomodulating agent used mainly to inhibit rejection after transplantations and it has a narrow therapeutic interval. Grapefruit juice is a strong inhibitor of the cyclosporine metabolism (CYP 3A4) and increases the blood concentration of cyclosporine. This can lead to toxicity but can also be used to reduce the doses and decrease the costs of the cyclosporine treatment. 

After transplantation, immunosuppression must be used to prevent host rejection of the graft liver, usually with prednisone and tacrolimus or cyclosporine. Tacrolimus and cyclosporine are calcineurin inhibitors and require drug level monitoring because of a narrow therapeutic range and significant toxicity, including renal failure and neurotoxicity. 

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