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Monitoring Stem Cell Research 
Cyclosporine has been the single most important factor associated 
with improved outcomes after organ transplantation over the past 
two decades. CyA binds to a cytosolic cell protein, cyclophilin (CyP). 
The CyA-CyP complex then binds to calcineurin and subsequently 
blocks interleukin-2 (IL-2) transcription. The binding of IL-2 to the IL- 
2 receptors on the surface of T lymphocytes is a key stimulant in 
promoting lymphocyte proliferation, activation, and ultimately 
allograft rejection. A review of the first decade of experience with 
heart transplantation revealed a total of 379 cardiac allograft 
recipients worldwide; actuarial survival rates in this cohort of 
patients at 1 year and 5 years were 56% and 31% respectively; the 
main causes of death being acute rejection and the side effects of 
immunosuppression. With the introduction and widespread use of 
CyA over the next decade, survival rates dramatically improved to 
85% and 75% at 1 and 5 years respectively. Similar results were 
obtained with other organ transplants, including kidney and lung. 
The major adverse effects of CyA are nephrotoxicity, 
hypertension, neurotoxocity and hyperlipidemia; less common side 
effects include hirsuitism, gingival hyperplasia and liver dysfunction. 
CyA nephrotoxicity can manifest as either acute or chronic renal 
dysfunction. It is important to note that a number of drugs commonly 
used in transplant patients, such as aminoglycosides, amphotericin B 
and ketoconazole can potentiate the nephrotoxicity induced by CyA. 
More than half the patients receiving CyA will require treatment for 
hypertension within the first year following transplantation. 
Corticosteroids also potentiate the side effects of CyA such as 
hypertension, hyperlipidemia and hirsuitism. Frequent monitoring 
of the serum level is essential to minimize the adverse effects. One of 
the major limitations of the original oil-based CyA formulation 
(Sandimmune) is its variable and unpredictable bioavailability. In the 
mid-90s Neoral was introduced, a new microemulsion formula of 
CyA, which has greater bioavailability and more predictable 
pharmacokinetics than Sandimmune. 
Tacrolimus 
Tacrolimus (FK506) is a macrolide antibiotic that inhibits T-cell 
activation and proliferation and inhibits production of other 
cytokines. The product of Streptomyces tsurubaensis fermentation, 
FK 506 was first discovered in 1984 and first used in clinical studies 
in 1988 at the University of Pittsburgh. While the mechanism of 
action of tacrolimus is similar to that of CyA, and comparative clinical 
trials have suggested similar efficacy, it has been suggested that 
some groups of patients may benefit from tacrolimus rather than CyA 
PRE -PUBLICATION VERSION 
