WESTPORT, CT and LONDON (Reuters Health) Aug 13 - Acridine and phenothiazine derivatives inhibit the formation of pathogenic prion proteins and may even enhance their clearance from infected cells, investigators at the University of California at San Francisco report in the August 14th issue of the Proceedings of the National Academy of Sciences.
Dr. Stanley B. Prusiner and colleagues screened drugs known to penetrate the blood-brain barrier for their ability to inhibit pathogenic prion formation. They used as their model cultured neuroblastoma cells chronically infected with scrapie prions.
Chlorpromazine, promazine, and acepromazine at concentrations of 2 5M to 10 5M caused disappearance of the protein after 6-day treatments. The antimalarial agent quinacrine, a structural antecedent of the phenothiazines, was effective at doses as low as 200 nM.
What the inhibitors all had in common was a tricyclic structure with an aliphatic side chain extending from the middle ring moiety. Furthermore, since phenazine and phenothiazine did not act as prion inhibitors, the tricyclic scaffold alone must not be sufficient for antiprion activity, the researchers add.
Dr. Prusiner's team believes that quinacrine could be an immediate candidate for the treatment of patients dying of prion diseases. Even though less potent, the investigators posit that phenothiazines may be even more effective than quinacrine if they cross the blood brain barrier more efficiently. Another option would be use of the two types of drugs in combination.
Dr. R. Anthony Williamson, of the Scripps Research Institute in La Jolla, California, told Reuters Health, "It's a case of using well-known drugs for a different application."
He continued, "Their research has the advantage that it's using drugs that have already been through the Food and Drug Administration approval mechanisms. People know the pharmacokinetics and the toxicology of the drugs."
A spokesman for the Department of Health in London said experts from the National CJD Surveillance Unit are in close contact with Professor Prusiner over his research. "They have been having discussions about how it can be progressed. We are looking at the possibility of taking it forward it's a very encouraging piece of research."
But he stressed that there is currently no way of diagnosing vCJD until after death. This makes it difficult to be certain the drug is treating the disease and not another condition with similar symptoms.
Proc Natl Acad Sci USA 2001;98:9836-9841.
Comentario:
Es sorprendente, que a nuestro conocimiento, se haya descubierto y publicado, por vez primera, un artículo en donde se haya aniquilado la proteina prion. En este caso, del scrapie.
Aún faltará saber si será efectivo en humanos, y si actuará contra otras enfermedades por priones como Creutzfeldt-Jakob, Kuru, Insomnio Fatal Familiar, etc.
Estos medicamentos -quinacrina y clorpromazina- se utilizaron en células tumorales de neuroblastoma, infectadas por scrapie. Es dudoso si la efectividad se debió precisamente a no ser células normales.
Faltará que el Dr Prusiner y colegas, lo investiguen en humanos con enfermedad por priones.
De resultar efectivo, será un avance de gran importancia en la Neurología.
Estaremos al pendiente de próximas publicaciones a este respecto.
Quizá en forma "experimental" , pudiésemos indicarle a algún paciente con esta enfermedad, la cloropromazina . Lo más que le pudiese ocurrir, sería un incremento de la rigidez, la cual se podría corregiar con biperideno o cualquier otro anticolinérgico para síntomas extrapiramidales iatrogénicos.
De todas formas, es prudente esperar los resultados finales de esta investigación.
Atentamente Dr Hugo Navarrete Grupo de Estudio de Demencias Academia Mexicana de Neurología, A.C. Grupo Tijuana, B.C. hugon@telnor.net |
