This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cyclosporine and corticosteroids are frequently used drugs in transplant patients to prevent organ rejection. They are associated with a variety of adverse effects, which can shorten the live span of transplant organs and increase the cardiovascular risk of transplant patients. This can lead to premature loss of the transplanted organ or contribute to premature death of transplant patients. When given together both drugs can potentiate each other's negative effects. Although both drugs have been used for more than two decades, surprisingly the exact way in which they interact has never been systematically studied. We have designed a study to investigate the interaction of these two drugs in detail. We want to uncover the basic mechanisms that lead to their toxicity. Since the matter is too complex to be studied in real patients, we propose as a first step a study in healthy volunteers. Study participants will receive low doses of corticosteroids either alone or in combination with cyclosporine. Blood and urine will be collected at defined time points. The samples will then be analyzed in the laboratory to measure drug concentrations. Using complicated laboratory techniques we will also try to identify substances that could be used in the future as markers of drug toxicity. This could help to improve tolerability and safety of immunosuppressive drug therapy in the future.
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