USE OF CYCLOSPORINE-A IN EXPERIMENTAL SPINAL-CORD INJURY - DESIGN OF A DOSING STRATEGY TO MAINTAIN THERAPEUTIC LEVELS

Cyclosporin-A (CsA) is frequently used as an immunosuppressive agent i n experimental transplantations. CsA has been used in nervous tissue t ransplants in spinal cord injury (SCI). However, optimal results have not been obtained. This is likely due to the fact that SCI alters CsA pharmacokinetics and hence fixed dose regimens are not adequate. In th is study, several CsA dosing regimens were evaluated in Long-Evans fem ale rats subjected to a severe low thoracic (T8) SCI by the contusion method. Serum CsA concentrations were measured to determine which dosi ng regimen allowed CsA levels to be maintained within the therapeutic window. It was found that administration of 2.5 mg/kg/12 h intraperito neally during the first 2 days after SCI (acute phase) followed by 5 m g/kg/12 h orally thereafter (subacute and chronic phases) yields CsA c irculating levels within the therapeutic window, i.e., 0.120-0.275 mu g/mL. This dosing regimen represents a suitable alternative to fixed d osing to achieve an optimal CsA-induced immunosuppression in experimen tal models of SCI.