| Anti-rejection drugs given long-term in high doses in the long run result in considerable morbidity like cancer and atherosclerosis. It is a real art to preserve the organ with as little immunosuppressive therapy as possible. However, this therapy is counteracted by drug-transporting proteins in the membranes of the gut and the T-lymphocytes. They pump so to say the drugs effectively out of the cell (T-lymphocyte) or even the whole body (gut). This makes immunosuppressive therapy little efficient and expensive. One has to administer much since only part of the agents is effective. This particularly relates to treatments with a narrow therapeutic span like cancer chemotherapy and immunosuppressive therapy after transplantation; in fact one has to administer more than strictly needed, but too much results in severe side-effects. It must be taken into account that during viral or bacterial infections, which are common in each transplantation patient, the pumps will become considerably more active. It is assumed that this the reason that rejection is often preceded by viral (e.g. CMV) or bacterial infections. Possibly the anti-rejection treatment may be made much more effective by application of agents influencing the activity of drug pumps. By anticipating application during spells of infection two aims may be served: lower doses and thus less side-effects, and more effective treatment. As regards side-effects one should consider also the consequences of immunosuppressive therapy of hepatitis C. Presently, hepatitis C is one of the main indicators of liver tranplantation. High-dose immunosuppression has a very adverse effect since it stimulates virus replication. Especially for grafted hepatitis C patients it is important to keep the dose of immunosuppressive therapy as low as possible. In this project the influence of drug pumps on immunosuppressive agents in animal models and in grafted patients will be studied. |
