Korth C, Peters PJ Emerging pharmacotherapies for Creutzfeld-Jakob disease. Arch Neurol 2006;63:497-501. Neurological review. Antibodies are protective and heterocyclic small compounds have been proposed as antiprion drugs, leading to clinical trials. Notes from intro-- Variant CJD lasts longer, has younger onset, more psychiatric symptoms, occurs because of the lack of a bovine-human species barrier (which exists with humans and sheep), and concern exists about blood transfusions,organ donations in affected individuals. CJD occurs as sporadic, genetic, and infectious disease. PrP derives from a gene that is expressed by most cell types in the body, but especially CNS and lymphatic organs. After synthesis, PrP(c) (or cellular) is modified postranslationally to receive 2 N linked carbohydrate side chains and a glycosyl phosphatidylinositol membrane anchor, then is sent to the plasma membrane, where it sorts into cholesterol rich detergent resistant membranes (DRM) domains or so called lipid rafts. Membrane anchored PrP can adopt a pathological and infectious conformation PrP(Sc) (scrapie) by a mutation in its amino acid sequence either due to germline or somatic mutation. Once sufficient amount of PrP (sc) is present ("infectious dosage") normal PrP molecules are induced to adopt the PrP(sc) conformation. Cofactors like protein "x" may be essential. Once cascade starts, signal ensue that lead to neuronal death, and pathological hallmarks including plaques and vacuolation. Malluci et al (Science , 2003) showed that knocking out PrP during inoculation of prions, but before replication,could prevent/reverse vacuolization and halt neurological symptoms. Treatment ideas include 1. gene silencing by small RNA interfering targets of PrP expression. 2. Protecting/shielding PrP(c) from conversion by antibodies is proved in animals, but has the problem of constructing an antibody than can cross the blood brain barrier. 3. Destabilizing DRM which is needed for PrP conversion. Possibly statins or quinacrine. 4. Find a competitor to binding on the enzyme "x" which has yet to be identified, which may be necessary to conversion of PrP and misfolding. 5. Inactivating/shielding Prp(sc) so that it is conversion incompetent. Polyanions such as Congo red, dextran, heparin sulfate, and pentosan polysulfate. Pentosan polysulfate is used for cystitis and can be tried, especially if given intrathecally. 6. Conceptually, increase the degradation of the misfolded protein, which has a half life of 28 hours, but unfortunately, the degrading proteins are now unknown. 7. Preventing the neurotoxic effects of PrP(sc), but not known how. Heterocyclic antiprion compounds were identified in cell cultures including phenothiazine and acridine derivatives (quinacrine). Quinacrine was 10x more active than chlorpromazine.