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ANTIPROLIFERATIVE
AGENTS
Azathioprinekfk
| Representative Examples: | Mycophenolate Mofetil (CellCept®), Azathioprine (Imuran®), Sirolimus (Rapamune®) |
| Clinical Use: | Antiproliferative Agents are used in maintenance immunosuppression and treatment of rejection. |
| General Mechanism: | Antiproliferative Agents are drugs that work to block the proliferative phase of acute cellular rejection. They are an integral part of most immunosuppression regimens. |
Mycophenolate Mofetil
| Pharmacological Mechanism: | Mycophenolate Mofetil (MMF) is absorbed and rapidly hydrolyzed in the blood to its active form: MPA. MPA inhibits the key enzyme in the de novo pathway of purine biosynthesis, IMPDH1. Rapidly dividing cells, such as activated lymphocytes, depend on the de novo pathway for the production of purines necessary for RNA and DNA synthesis. In this way, activated lymphocytes are selectively inhibited since they are not allowed to proliferate once activated. |
| Side Effects: |
Side effects observed
with MMF use include:
|
| Representative Dose/Route: | MMF is normally taken orally, 1-1.5 g twice daily. An intravenous form is also available. |
Azathioprine
| Pharmacological Mechanism: | Azathioprine is rapidly hydrolyzed in the blood to 6-mercaptopurine. In this form (a purine analog and antimetabolite), it incorporates into the DNA, inhibiting nucleotide synthesis by causing feedback inhibition in the early stages of purine metabolism. This ultimately prevents mitosis and proliferation of rapidly dividing cells, such as activated B and T lymphocytes. Through this action, Azathioprine is able to block most T-cell functions and inhibit primary antibody synthesis. Azathioprine has little effect on established immune responses, and is therefore effective only in the prevention (not treatment) of acute rejection. |
| Side Effects: |
Side effects observed
with Azathioprine use include:
|
| Representative Dose/Route: |
Azathioprine is normally taken orally, at a rate of 1-2 mg/kg/day. An intravenous form is also available. Azathioprine is used as part of a triple immunosuppression regimen, along with prednisone and a calcineurin inhibitor. |
Sirolimus
| Pharmacological Mechanism: | Sirolimus is a highly potent macrolide antibiotic that has a chemical structure similar to Tacrolimus. Sirolimus binds to the same protein as Tacrolimus: FKBP-12. Instead of inhibiting Calcineurin as Tacrolimus does, this complex inhibits mTOR. This inhibition prevents the progression of T cells from the G1 to the S phase of the cell cycle by blocking signaling downstream of the IL-2 receptor. It therefore is able to block DTH immune reactions, CTL activity, and humoral responses directed against a transplanted organ. Because Cyclosporine and Sirolimus have different mechanisms, the combination of clinical combination of the two in an immunosuppression regimen results in effects that are synergistic. This drug is under Phase III clinical trials for kidney transplantation. |
| Side Effects: |
Side effects observed with Sirolimus use include:
|
| Representative Dose/Route: | Sirolimus is taken orally, at a recommended rate of 2-5 mg once a day. |
Corticosteriods Calcineurine Inhibitors Antiproliferative Agents Monoclonal Antibodies Polyclonal Antibodies
Other References
Side Effects Drug Efficacy