Curso: histria da descoberta de frmacos

“New drugs for Chagas disease treatment: From basic science to clinical trials”
Julio A. Urbina1
1Venezuelan Institute for Scientific Research
Chagas disease, a systemic parasitosis caused by the Kinetoplastid protozoon
Trypanosoma cruzi, remains the largest parasitic disease burden in the American
continent and is now spreading to non-endemic areas due to intra and international
migrations. Specific chemotherapy and treatment coverage of this condition are
unsatisfactory due to the toxicity and limited efficacy of currently available drugs
(nifurtimox and benznidazole), as well as controversies on the relevance of specific
treatment in chronic patients. Recent studies have concluded, in contrast to long-held
views on the autoimmune origin of the pathological manifestations of the chronic stage of
the disease, that the persistence of parasites is the key factor underlying the sustained
inflammatory responses that lead to these characteristic lesions. As a consequence, there
is growing consensus that this condition should be treated as an infectious, not
autoimmune, disease and that specific treatment should be offered to all seropositive
patients, independently of the stage of the disease.
Currently, the most promising approaches to new anti-T. cruzi drugs are: (a) ergosterol
biosynthesis inhibitors (EBI), particularly novel triazole derivatives acting on the parasite’s
CYP51 (sterol C14
-demethylase) such as posaconazole and E-1224, a pro-drug of
ravuconazole, which are currently undergoing Phase 2, poof-of-concept, clinical trials in
Latin America and Spain, (b) amiodarone, an antiarrhythmic drug recently shown to have
also potent anti-T. cruzi activity and to act synergistically with CYP51 inhibitors, (c)
inhibitors of cruzipain, the main cysteine protease of T. cruzi, (d) EBIs acting on squalene
synthase and (e) combination therapies such as benznidazole, nifurtimox or amiodarone
associated with EBIs or combinations of EBIs acting at different steps of the pathway.
Finally, a major stumbling block for the evaluation of new drugs, or the true efficacy of
currently available drugs, is the lack of validated biomarkers of response to antiparasitic
drugs and parasitological cure in chronically infected individuals. To address this issue
several novel approaches are being advanced, including qualitative and quantitative PCR,
specific biomarkers of cardiac compromise, hypercoagulability biomarkers, non-
conventional serology and specific anti-T. cruzi T cell responses.

Julio A. Urbina, Ph.D.

Urbina recibió el titulo de Licenciado en biofísica de la Universidad Central de Venezuela (UCV, Caracas, Venezuela) in 1970 y de Ph.D. en química del Massachusetts Institute of Technology (Cambridge, Massachusetts, EUA) en 1975. De 1975 a 2006 se desempeño como Profesor de Biofísica y Fisicoquímica en la UCV y entre 1991 y 2005 fue también jefe del Laboratorio de Química Biológica del Instituto Venezolano de Investigaciones Científicas (IVIC, Caracas, Venezuela). En 1997 fue nombrado Fellow de la John Simon Guggenheim Foundation (New York, EUA), en 1997 recibió el premio Lorenzo Mendoza Fleury Prize en Ciencias Básicas de la Fundación Polar (Caracas, Venezuela), y de 2000 a 2005 fue Académico Internacional del Howard Hughes Medical Institute (Maryland, EUA). Urbina ha investigado durante mas de 35 años la bioquímica y fisiología de protozoarios patógenos y hongos, con el objetivo estratégico de desarrollar nuevos tratamientos específicos para las enfermedades causadas por esos organismos. Ha publicado 148 artículos en esa área, en revistas y libros arbitrados internacionalmente. Se desempeño en dos oportunidades (1981-1984, 1994-1999) como miembro del Consejo Superior del Consejo Nacional de Investigaciones Científicas (CONICIT) de Venezuela y ha sido asesor de la Organización Mundial de la Salud (OMS) y la Organización Panamericana de la Salud (OPS), así como miembro y Presidente del Consejo Científico Asesor de la Drugs for Neglected Diseases initiative (DNDi). Ha sido Profesor Visitante de numerosas universidades en Venezuela, Brasil, Argentina, Uruguay, España y Japón y actualmente es asesor científico de varias instituciones académicas y consultor de empresas farmacéuticas internacionales.


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