ADVANTAGE OF PROTECTING MITOCHONDRIAL FUN CTIONS IN CYCLOSPORINE-A THERAPY

The use of cyclosporin A is often limited by its nephrotoxicity. This dose-dependent toxicity can occur in all kinds of transplantation and is reversed with drug withdrawal. Cyclosporin A induces a vasoconstric tion leading to an increase of renal vascular resistance and a reducti on of glomerular filtration. Histochemical studies show mitochondrial alterations and an excess of cytosolic and mitochondrial calcium leadi ng to a decrease of ATP synthesis. Two strategies can be evoked for li miting cyclosporin-A-induced nephrotoxicity. First, the use of drugs c ounteracting the vasoconstriction has been proposed. Second, drugs act ing by restoration of ATP synthesis could also be of interest. For exa mple, calcium channel blockers may be used for limiting the Ca2+ fluxe s into cells. Another way to protect ATP synthesis is to inhibit the c yclosporin-A-induced increase of mitochondrial Ca2+ concentrations. Tr imetazidine has shown its efficiency in vitro for protecting mitochond ria against these modifications of Ca2+ homeostasis and is under clini cal evaluation.