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TRANSDERMAL GLYCERYL TRINITRATE AS AN EFFECTIVE ADJUNCTIVE TREATMENT WITH ARTEMETHER FOR LATE-STAGE EXPERIMENTAL CEREBRAL MALARIA
Autor
Afiliación
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA / Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA / Fundação Oswaldo cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Malária. Rio de Janeiro, RJ, Brasil.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA / Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA.
La Jolla Bioengineering Institute. San Diego, California, USA / Fundação Oswaldo cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Malária. Rio de Janeiro, RJ, Brasil.
Resumen en ingles
Cerebral malaria (CM) is associated with low nitric oxide (NO) bioavailability, cerebrovascular constriction, occlusion, and hypoperfusion.
Administration of exogenous NO partially prevents the neurological syndrome and associated vascular pathology
in an experimental CM (ECM) mouse model. In this study, we evaluated the effects of transdermal glyceryl trinitrate in preventing
ECM and, in combination with artemether, rescuing late-stage ECM mice from mortality. The glyceryl trinitrate and/or artemether
effect on survival and clinical recovery was evaluated in C57BL/6 mice infected with P. berghei ANKA. NO synthase
(NOS) expression in mouse brain was determined by Western blots. Mean arterial pressure (MAP) and pial arteriolar diameter
were monitored using a tail-cuff blood pressure system and a cranial window preparation, respectively. Preventative administration
of glyceryl trinitrate at 0.025 mg/h decreased ECM mortality from 67 to 11% and downregulated inducible NOS expression
in the brain. When administered as adjunctive rescue therapy with artemether, glyceryl trinitrate increased survival from 47 to
79%. The adjunctive therapy caused a sustained reversal of pial arteriolar vasoconstriction in ECM mice, an effect not observed
with artemether alone. Glyceryl trinitrate induced a 13% decrease in MAP in uninfected mice but did not further affect MAP in
hypotensive ECM mice. Glyceryl trinitrate, when combined with artemether, was an effective adjunctive rescue treatment for
ECM. This treatment ameliorated pial arteriolar vasospasm and did not significantly affect MAP. These results indicate that
transdermal glyceryl trinitrate has potential to be considered as a candidate for adjunctive therapy for CM.
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