Absence d'efficacité de la quinacrine dans le traitement des maladies à prions : possible explication à caractère pharmacologique

Given the epidemiological uncertainty of the prion diseases, there is an urgent need to discover and to develop antiprion therapeutics in humans. The efficacy of candidate molecules is predominantly tested in vitro in neuroblastoma cells. For several molecules, including quinacrine, a discrepancy has been observed between a proven antiprion action in vitro and its lack of clinical efficacy in the Creutzfeldt-Jakob disease. To further investigate the possible pharmacokinetic origin of the lack of clinical efficacy of quinacrine (and then predictable), we studied the quinacrine disposition both in vivo and in vitro. Ultimately, our experiment was aimed at determining the dosage regimen, which should be administered in vivo to obtain efficacious concentrations in the biophase. We used a model of naturally scrapie-affected ewes. First, we performed a standard clinical trial in scrapie-affected ewes and, we confirmed the absence of therapeutic benefit of quinacrine, as previously shown in humans. In in vitro experiments reproducing the princeps culture conditions in which 50% of antiprion action has been observed, namely a nominal quinacrine concentration of 300 nM, we re-evaluated the EC50 for the potential biophases of quinacrine effect. Quinacrine was assayed by HPLC. We showed that the actual extracellular and intracellular quinacrine neuroblastoma concentrations were 120 nM and 3700 nM, respectively. Quinacrine concentrations in cerebrospinal fluid concentrations and brain tissue, corresponding to the extracellular and intracellular biophases respectively, were measured in healthy ewes after quinacrine administration. The cerebrospinal fluid quinacrine concentrations (