Cyclosporine

Last fall, my neighbor Larry was told that his liver function was compromised, the aftermath of a bout of hepatitis when he was in college some 20 years ago. His liver is holding its own, but if it deteriorates, Larry's name could be added to the list of persons in the U.S. who need a liver transplant, a list of about 18,000.

That Larry and the more than 85,000 people in the U.S. who are waiting for an organ transplant have even a hope of surviving harkens back to the travel plans of two Sandoz employees.

In 1957, the Swiss pharmaceutical firm set up a program to search for new antibiotic drugs from fungal metabolites, and employees were requested to collect a plastic bag of soil from wherever they traveled. The bags were cataloged and queued to be screened. Two samples, one from Wisconsin and one from Norway, yielded Tolypocladium inflatum Gams, a fungus, in early 1970. An interesting compound isolated from the fungus turned out to have disappointing antibiotic properties, but in 1976 it was found to be a powerful immunosupressant. That drug, cyclosporine or cyclosporin A, a nonpolar cyclic oligopeptide, moved organ transplant from experiment to accepted medical procedure.

It was a case of good timing. Most of the surgical problems of allograft transplantation--within a species--had been resolved, and the problem of rejection had been identified as immunological. Organ transplant had been studied in animals and some humans, with unqualified success only when the donor and acceptor were identical twins; that is, genetically identical.

Researchers had pinpointed the proteins on the graft that are the principal targets of the immune response. And by comparing the proteins on the recipient and the organ--matching the donor and recipient--researchers found that they could slow, but not eliminate, rejection. Immunosuppression had been achieved with purine analogs and corticosteroids, and short-term successes were encouraging. But long-term survival was rare because the cost the body paid for maintaining immunosuppression was high.

When an organ from a donor--living or cadaveric--is placed in another person's body, the host's immune system sees it as an intruder and marshals an attack. This causes acute organ failure, which cyclosporine helps prevent. Immunosuppressive drug therapy is needed for the lifetime of the organ recipient, and that's problematic because, like many powerful drug regimens, the side effects are debilitating and can be life-threatening.

Cyclosporine acts by disrupting the signaling pathway used to activate T cells, a class of immune cells that attack and destroy diseased cells and other cells they recognize as foreign, including those of transplanted organs. Cyclosporine specifically inhibits calcineurin, a phosphatase that is required for T cell growth and proliferation.

Because cyclosporine suppresses the body's immune system, its use increases a patient's susceptibility to infections from bacteria, viruses, and fungi, as well as to some types of cancer. So although the drug helps keep a host's body from destroying the transplanted organ, it opens the door to other infections. Thus, cyclosporine and other immunosuppressive drugs must be administered as part of a suite of medications. Achieving and maintaining the delicate balance of medications--called maintenance immunosuppression--is a lifelong challenge. In addition, cyclosporine is nephrotoxic, so kidney function has to be monitored.

With further understanding of the mechanisms of immune response and of molecular manipulation, improved drugs have become available. Novartis (formerly Sandoz) in 1995 introduced a next-generation cyclosporine drug, Neoral, that it says is more bioavailable and delivers a more consistent dose. Tacrolimus is another immunosuppressant that is used to prevent organ rejection. The "cocktail" method has been found to be the most effective approach to immunosuppression; a variety of drugs that work in different ways on the immune system can be used in combinations and at different doses.

New approaches to preventing organ rejection include finding more selective immunosuppressive agents--for example, ones that don't affect the patient's ability to fight viral infections--and inducing tolerance of the transplanted organ by turning off the specific immune cells that attack the transplanted organ.

If Larry should need a liver transplant in the coming years, cyclosporine may not be prescribed for him, but whatever treatment he receives will have been developed from the body of knowledge that cyclosporine enabled.

Cyclosporin

Name
◾ Cyclosporin A

CAS Registry
◾ 59865-13-3

Other Names
◾ Sandimmune
◾ Neoral
◾ Gengraf
◾ ciclosporin

Introduced
1983, Sandoz (now Novartis)

Sales
$1.0 billion in 2004 for Reoral and SandImmune combined

Did you know that the development in the late 1960s of the concept of brain death as death--rather than cessation of circulation--increased dramatically the number of organs available for transplantation?