29 octubre 2010

Leishmaniasis, la epidemia de los pobres en Afganistán .

PD : Por recordar uno de los Farmacos que demostraron tener cierta actividad para combatir la Leishmaniasis ... era un Analogo del Kahalalide - F ... y que podría ser alguno de los Licenciados por Pharma Mar el año pasado a la Farmaceutica Medimetriks Pharmaceuticals, Inc. (Fairfield, NJ) ... veremos si puede llegar a buen puerto .

La OMS estima que 350 millones de personas están en riesgo de leishmaniasis. Anualmente la incidencia se estima de alrededor de 1 a 1.5 millón de casos de LC y 500 000 casos de LV. La prevalencia es de aproximadamente 12 millones de personas infectadas.

***************************

MAYO 2009 :

Kahalalide F, an antitumor depsipeptide in clinical trials, and its analogues as effective antileishmanial agents.
Cruz LJ, Luque-Ortega JR, Rivas L, Albericio F.

Institute for Research in Biomedicine, Barcelona Science Park, University of Barcelona, 08028-Barcelona, Spain.

Leishmaniasis is a human parasitic disease caused by infection by the protozoan Leishmania spp. Chemotherapy is currently the only treatment available, but its efficacy is increasingly challenged by the rising incidence of resistance and the frequent severe side effects associated with first-line drugs. Thus the development of leads with distinct mechanisms of action is urgently needed. A strategy often used for this purpose consists of assaying for leishmanicidal activity drugs formerly developed for other applications, such as amphotericin B (antifungal) or miltefosine (antitumor), among others, to profit from previous pharmacological and toxicological studies. Kahalalide F (KF) is a tumoricidal cyclic depsipeptide currently under phase II clinical trials for several types of cancer and psoriasis. Its mechanism of action has not been fully elucidated. Here we report the leishmanicidal activity of KF and its synthetic analogues at a micromolar range of concentrations. Its lethality is strongly linked to the alteration of the plasma membrane (PM) of the parasite based on (i) a rapid depolarization of the PM and uptake of the vital dye SYTOX Green upon its addition; (ii) evidence of severe morphological damage to the membrane of the parasite, as shown by transmission electron microscopy; and (iii) a rapid drop in the intracellular ATP levels, which correlates significantly with the leishmanicidal activity for active analogues, some of them with significant improvement of their therapeutic index with respect to the parental molecule. In addition to the basic knowledge obtained, this class of lethal mechanism is considerably less prone to the induction of resistance than classical drugs. All together, these observations foster further studies for the optimization of KF and its analogues as new anti-Leishmania leads with a new mode of action.