CONTINUOUS-INFUSION OF DL-ALPHA-DIFLUOROMETHYLORNITHINE AND IMPROVED EFFICACY AGAINST A RAT MODEL OF PNEUMOCYSTIS-CARINII PNEUMONIA

The rapid depletion of Pneumocystis carinii polyamines caused by in vi tro exposure to DL-alpha-difluoromethylornithine (DFMO; also called ef lornithine or Ornidyl) and the rapid repletion following removal of th is drug suggested that the in vivo efficacy of DFMO against P. carinii pneumonia (PCP) may be limited by troughs in drug concentration resul ting from the schedule of administration, This led to the prediction t hat, compared with the response to the standard animal protocol of adm inistering DFMO in drinking water, the response of a rat model of PCP to DFMO would be lessened by bolus administration and improved by cont inuous infusion, These predictions were confirmed, Intraperitoneal bol us administration of up to 3 g of DFMO kg of body weight(-1) was compl etely ineffective, although this dose has been shown to be effective w hen given in the drinking water, Conversely, continuous infusion impro ved the response against PCP seven- to ninefold over the response to d rinking water administration. These findings suggest that, compared wi th the standard clinical investigational protocol for treatment of PCP with DFMO given in four divided daily doses, continuous infusion comb ined with monitoring of drug concentrations in plasma may improve effi cacy and/or reduce the already low rate of adverse effects.