An aerosol spray that delivers the anti-rejection drug cyclosporine directly to transplanted lungs appears to target an important biological process that other immunosuppressant drugs, including oral cyclosporine, have not been demonstrated to do. At the XVIII International Congress of the Transplantation Society, researchers from the University of Pittsburgh today presented preliminary results from an ongoing clinical study indicating aerosol cyclosporine can hinder the pumping mechanism a cell uses to spit out anything deemed undesirable, including drugs.
Understanding this mechanism could help researchers and clinicians identify ways to improve the concentrations of drugs within cells, making them more efficient and therapeutic, reported Vera Donnenberg, M.S., a graduate student working with University of Pittsburgh lung transplant surgeons Bartley P. Griffith, M.D., and Kenneth McCurry, M.D.
P-glycoprotein (P-gp) is a biological pump that was first identified in studies of cancer patients. The mechanism is so powerful that it is believed to be responsible for some types of cancer drug resistance -- the more the cell is exposed to the drug the more active and effective the pump becomes. With transplant patients, the mechanism makes it so that only about one third to one quarter of anti-rejection drugs are absorbed. Clinicians must compensate for this fact by delivering higher doses, but not without a price. Immunosuppressants, such as cyclosporine and tacrolimus, can produce a number of unwanted side effects as well as make patients more susceptible to life-threatening infections and tumor growth.
"Because organ transplant patients must take a life-long regimen of drugs to protect their donor organs from immune system attack, we were curious what effect the long-term exposure of such drugs would be to P-gp activity. Furthermore, we wanted to determine if delivering the drug directly to the transplanted organ -- where immune system cells would be waging a front-line battle -- would hamper the pump in any way," explained the study's principal investigator, Gilbert J. Burckart, Pharm.D., professor of pharmacy and medicine at the University of Pittsburgh.
In their current study, researchers looked at the P-gp activity of T cells, immune system cells that anti-rejection drugs target in order to suppress their ability to attack the donor organ. For both the 11 patients randomized to receive aerosol cyclosporine and nine patients who received a placebo spray, they found the T cells infiltrating the donor lungs had much greater P-gp activity than did T cells in peripheral blood. But in patients who received aerosol cyclosporine, the activity was much less, and in fact was no different from 15 healthy control subjects.
The University of Pittsburgh is the only center engaged in a clinical study of aerosol cyclosporine, a concept that researchers originated there eight years ago. They are currently about half-way into a National Institutes of Health-funded four-year trial, whereby lung transplant recipients are randomized to receive either a placebo spray or cyclosporine aerosol spray along with their standard immunosuppressant therapy, which includes oral tacrolimus, plus steroids. The subjects in the P-gp study were drawn from this clinical trial.
The University of Pittsburgh's transplant programs are world-renowned for their cutting-edge research contributions and sheer volume of experience. Since 1981, with the arrival of transplant pioneer Thomas E. Starzl, M.D., Ph.D., more than 10,000 organ transplants have been performed at the University of Pittsburgh. In addition to having among the most active liver, intestine, kidney, pancreas, heart and lung transplant programs, UPMC also has established the uniquely successful Istituto Mediterraneo per I Trapianti e Terapie ad Alta Specializzazione (ISMETT). ISMETT is a partnership between the Italian government, Civico and Cervello hospitals in Palermo and the UPMC. Since last year, more than 18 livers and 13 living-related kidney transplants have been performed there.
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Lisa Rossi
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(August 27-31)
Alessandra Cattoi
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Journal
Transplantation Proceedings