A major disadvantage of the early antiprion compounds like the polyanions was their inability to cross the blood-brain barrier and their relative failure to show antiprion effects when applied late in the incubation period in animal models of prion disease. In an effort to identify antiprion compounds with high blood-brain barrier permeability, approved drugs used in treating central nervous system diseases were screened for antiprion effects in a cell model of prion disease. This search resulted in identification of the heterocyclic compounds phenothiazine and acridine derivatives, with clear structure-activity relationships, as lead compounds for antiprion drug development.7 Quinacrine, the acridine derivative with the highest antiprion activity (median effective concentration, 300 nm) in cell culture, was 10 times more active than chlorpromazine, the highest antiprion phenothiazine derivative. Originally an antiparasitic drug, quinacrine was used for the treatment of malaria during World War II and, more recently, for treating giardiasis. The fact that quinacrine was an approved drug led to its immediate use for compassionate treatment of CJD patients. In parallel, animal experiments were started to further elucidate its mechanisms of action. In mice, results were ambiguous, with one group8 reporting extension of survival time by up to 25% with quinacrine therapy at a dosage of 37 mg/kg per day, while others5 reported failure to see antiprion effects or reported toxic effects after intrathecal application. Application of a combination therapy of quinacrine (150 mg/d intramuscularly) and chlorpromazine (100 mg/d intramuscularly) for 7 to 30 days in symptomatic ewes that had been naturally infected with scrapie did not show a significant extension of average survival times9; the authors of this study, however, raised the issue that intracerebral quinacrine concentrations might not have been high enough, even at subtoxic dosages, to reach antiprion-effective concentrations.