Immunosuppressive Drugs Help Extend Lives of Transplant Patients

"Immuno" is a form of the word "immune," as in the body's immune system, which attacks unwanted invaders in the body, such as viruses, bacteria and other foreign matter. "Suppression" is the act of inhibiting or restraining from a usual course of action.

So "immunosuppression" means, basically, inactivating the body's immune system.

For transplant recipients, this is vital. Without methods of immunosuppression -- drugs -- nearly all transplanted organs fail relatively quickly in their recipients' bodies. But advances in drug regimens enable many recipients to live a decade or longer.

One U.S. man, J. Tom Williams, underwent a kidney transplant in 1980 and lived until 1994. He even added a heart transplant in 1987 and lived for an additional seven years, thanks largely to use of cyclosporine, an immunosuppressive drug developed 30 years ago that continues to be vital to transplant recipients.

"Because of the transplants my dad received, he was given 14 extra years," says Mary Lynne Williams of Memphis, Tennessee. "He was able to see his two daughters grow up, and we were given memories that would not have been possible without his transplants."

Immunosuppression isn't perfect, however. While it can keep a recipient from rejecting a transplanted organ, it also leaves the body less able to fight off other maladies. Patients on immunosuppressants are at higher risk of developing cancer and infections. When Williams died, his donor heart and kidney were doing great, his daughter says. Other causes led to his death.

Available immunosuppressive drugs work best in the short-term. One-year survival rates for most organ and tissue transplants exceed 80 percent. But long-term survival has not improved significantly in the past two decades, according to the National Institute of Allergy and Infectious Diseases.

Another consideration in the use of immunosuppressive drugs is their common adverse side effects. Therefore, immunosuppression regimens often involve combinations of drugs to combat different mechanisms of organ rejection and balance the side effects.

Also note that different organs require varying levels of immunosuppression to maintain proper function. Hearts and lungs are the most difficult to maintain; kidneys are the easiest. In addition, immunosuppression is not required for transplants between identical twins, and it is not as crucial when donors and recipients are closely matched from the same family.

Nearly all organ transplant patients today rely on several immunosuppressive drugs.

The most common:

Cyclosporine (Neoral, Sandimmune): Discovered in 1970 and commercialized in 1983, this potent drug was a breakthrough therapy in aiding the body's acceptance of solid organ transplants. It remains one of the most frequently used anti-rejection medicines and usually is combined with prednisone, a steroid. Because of its strength, cyclosporine dosage needs to be closely monitored -- too much increases a host of side effects, and too little reduces its immunosuppressive effectiveness. The drug is taken every 12 hours in liquid or capsule form. The most common visible side effects are hair growth on the face or upper body and tremors in the hands.

Tacrolimus, or FK506 (Prograf): A newer alternative to cyclosporine, tacrolimus uses a similar method of action. It is recommended for patients who cannot take cyclosporine. Researchers are studying the drug to determine if it can be combined with lower doses of prednisone than cyclosporine to achieve the same immunosuppressive effects. Lower doses would reduce side effects and make the patient's regimen easier.

Sirolimus: The newest immunosuppressant on the market -- it received FDA approval in September 1999 -- sirolimus interferes with the second phase of T-cell activation rather than the first phase, as with cyclosporine and tacrolimus. Therefore, sirolimus is believed to be effective in combination with cyclosporine or tacrolimus in suppressing the immune system. It is also known as rapamycin. Currently, it is FDA approved only for short-term use after kidney transplantation. It is not approved for use by children younger than 13.

Mycophenolate mofetil (CellCept): Best used with other immunosuppressants such as cyclosporine, or tacrolimus and prednisone, mycophenolate works differently but likewise must be monitored closely to avoid uneven levels in the blood. The side effects: possible tremors, headache, heartburn, stomach upset and diarrhea. Doctors advise to avoid pregnancy or breastfeeding while taking the drug. It mainly is used for kidney and heart recipients.

Prednisone: A steroid, prednisone helps control a natural agent in the body that deals with the stress of infection and rejection. The body produces its own form of prednisone called cortisol. Cortisol helps the body deal with the stress caused by immune reactions. When prednisone is administered, the body produces less cortisol, so doctors taper doses of prednisone over time to allow the body to adjust and produce more cortisol.

Thymoglobulin: A rabbit-derived polyclonal antibody, Thymoglobulin went on the U.S. market in 1999. It is used in combination with other immunosuppressants to prevent acute rejection of transplanted kidneys. Side effects are similar to those of OKT3, but are usually less severe. When used in combination with other agents, Thymoglobulin (anti-thymocyte globulin, or ATG) generally reduces initial episodes of acute rejection by two to three days.

Daclizumab and basiliximab: FDA-approved in 1998, both agents are monoclonal antibodies used in combination with other drugs to delay rejection and reduce the incidence of severe acute rejection. Data from late-stage clinical testing showed that both agents improved results without increased side effects, according to Dr. Philip F. Halloran of the American Society of Transplantation. Both agents are used mainly in combination with prednisone and mycophenolate mofetil.

No "wonder drugs" appear on the horizon for their immunosuppressive capabilities, so research is centering on different combinations for use in different organ procedures. One drug that might be worth watching is ISA247, which successfully completed Phase I clinical trials and could enter Phase II trials later this year. Developed by Canadian company Isotechnika, ISA247 showed fewer toxic effects in first-round human testing and greater immunosuppression than cyclosporine in all clinical and preclinical tests to date, according to the company.

Homecare companies and home infusion services, such as provided by Apria Healthcare, are especially valuable when a transplant patient has a rejection reaction, which is the beginning of the body rejecting the donor organ. The service can provide a quick remedy through intravenous or injected drugs such as antibiotics, antivirals, antifungals or steroids.

Intravenous ganciclovir is the most common antiviral drug that Apria administers to transplant patients suffering from rejection reactions. It is used in about 80 percent of rejection reactions that Apria infusion manages, says Mike Rigas, PharmD, corporate director of infusion services for Apria Healthcare. To further control the rejection reaction until the normal immunosuppressive therapy is established, the patient's physician may add IV steroids to the regimen, Rigas says.

"If you do everything you're supposed to do with your immunosuppression regimen, and you're proactive with your physician when you don't feel good or feel right, you really should not need much of Apria's services after a transplant," Rigas says. "But almost every transplant patient has one or more rejection reactions per year."