RESUMO
To ensure neuronal survival after severe traumatic brain injury, oxygen supply is essential. Cerebral tissue oxygenation represents the balance between oxygen supply and consumption, largely reflecting the adequacy of cerebral perfusion. Multiple physiological parameters determine the oxygen delivered to the brain, including blood pressure, hemoglobin level, systemic oxygenation, microcirculation and many factors are involved in the delivery of oxygen to its final recipient, through the respiratory chain. Brain tissue hypoxia occurs when the supply of oxygen is not adequate or when for some reasons it cannot be used at the cellular level. The causes of hypoxia are variable and can be analyzed pathophysiologically following "the oxygen route." The current trend is precision medicine, individualized and therapeutically directed to the pathophysiology of specific brain damage; however, this requires the availability of multimodal monitoring. For this purpose, we developed the acronym "THE MANTLE," a bundle of therapeutical interventions, which covers and protects the brain, optimizing the components of the oxygen transport system from ambient air to the mitochondria.
Assuntos
Lesões Encefálicas Traumáticas , Hipóxia Encefálica , Humanos , Hipóxia Encefálica/etiologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/terapia , Encéfalo , Oxigênio/uso terapêutico , Hipóxia/complicações , Circulação Cerebrovascular/fisiologia , Consumo de Oxigênio/fisiologiaRESUMO
Flavanones (-)-(2S)-5,4'-dihydroxy-7-methoxyflavanone (1) and (-)-(2S)-5,3',4'-trihydroxy-7-methoxyflavanone (2) were isolated from the extracts of Calceolaria thyrsiflora Graham, an endemic perennial small shrub growing in the central zone of Chile. The absolute configuration of these compounds was resolved by optical rotation experiments and in silico calculations. Three analogs (3, 4, and 5) were synthesized to do structure-activity relationships with the biological assays studied. Biological tests revealed that only flavanone 2 exhibited a moderate inhibitory activity against the methicillin-resistant strain S. aureus MRSA 97-77 (MIC value of 50 µg/ml). In addition, flavanone 2 showed a potent, selective, and competitive inhibition of 5-hLOX, which supports the traditional use of this plant as an anti-inflammatory in diseases of the respiratory tract. Also, 2 exhibited cytotoxic and selective effects against B16-F10 (8.07 ± 1.61 µM) but 4.6- and 17-fold lesser activity than etoposide and taxol.
RESUMO
We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC50) and kinetic assays of all the studied molecules (5⯵g/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl)-ethanone (K205; IC50â¯=â¯3.5⯵M; Kiâ¯=â¯4.8⯵M) and 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-nitrophenyl)-ethanone (K206; IC50â¯=â¯2.3⯵M; Kiâ¯=â¯0.7⯵M) were potent, selective, competitive and nonredox inhibitors of 5-hLOX. Antioxidant behavior was also assayed by DPPH, FRAP, and assessing ROS production, and those with antibacterial and antiproliferative properties relating to 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-chlorophenyl)-ethanone (K208) established it as the most interesting and relevant compound studied, as it showed nearly 100% inhibition of bacterial growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Finally, docking studies were done that helped to characterize how the inhibitor structures correlated to decreased 5-hLOX activity.
Assuntos
Antibacterianos/farmacologia , Benzoína/análogos & derivados , Benzoína/farmacologia , Inibidores de Lipoxigenase/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/metabolismo , Benzoína/síntese química , Domínio Catalítico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Meticilina/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacosRESUMO
Lipoxygenases (LOX) are enzymes that catalyze polyunsaturated fatty acid peroxidation and have a non-heme iron atom located in their active site. They are implicated in the arachidonic acid pathway and involved in inflammation, fever, pain production, and in the origins of several diseases such as cancer, asthma, and psoriasis. The search for inhibitors of these enzymes has emerged in the last years, and isoflavonoids have a broad spectrum of biological activity with low cytotoxicity. Our previous results have shown that isoflavonoids inhibited different LOX isoforms in vitro. For this reason, we studied the most important interactions that govern the potency and selectivity of some isoflavones and isoflavans toward different LOX isoforms using computational methods. The docking results have shown that all the molecules can be located in different zones in the LOX active site. Steered molecular dynamics indicated that selectivity was present at the cavity entry, but not at its exit. We also observed the correlation between the potential mean force and the best (HIR-303) and worst inhibitors (IR-213) in 5-LOX. Finally, structure-activity relationship (QSAR) studies showed a good correlation between theoretical IC50 values and experimental data for 5-LOX and 12-LOX with 96 and 95%, respectively, and a lower correlation for 15-LOX (79%). Conclusively, pharmacophore analysis showed that our proposed molecules should possess a donor-acceptor and aromatic centers to encourage interactions in the active site.
Assuntos
Isoflavonas/química , Inibidores de Lipoxigenase/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Humanos , Ligação de Hidrogênio , Isoflavonas/farmacologia , Inibidores de Lipoxigenase/farmacologia , Conformação Molecular , Ligação ProteicaRESUMO
During traumatic brain injury, intracranial hypertension (ICH) can become a life-threatening condition if it is not managed quickly and adequately. Physicians use therapeutic hyperventilation to reduce elevated intracranial pressure (ICP) by manipulating autoregulatory functions connected to cerebrovascular CO2 reactivity. Inducing hypocapnia via hyperventilation reduces the partial pressure of arterial carbon dioxide (PaCO2), which incites vasoconstriction in the cerebral resistance arterioles. This constriction decrease cerebral blood flow, which reduces cerebral blood volume and, ultimately, decreases the patient's ICP. The effects of therapeutic hyperventilation (HV) are transient, but the risks accompanying these changes in cerebral and systemic physiology must be carefully considered before the treatment can be deemed advisable. The most prominent criticism of this approach is the cited possibility of developing cerebral ischemia and tissue hypoxia. While it is true that certain measures, such as cerebral oxygenation monitoring, are needed to mitigate these dangerous conditions, using available evidence of potential poor outcomes associated with HV as justification to dismiss the implementation of therapeutic HV is debatable and remains a controversial subject among physicians. This review highlights various issues surrounding the use of HV as a means of controlling posttraumatic ICH, including indications for treatment, potential risks, and benefits, and a discussion of what techniques can be implemented to avoid adverse complications.
RESUMO
AIM: To review the most significant studies on the pathophysiology of hypoglycaemia and hyperglycaemia in neurocritical patients and the therapeutic interventions used to control them. DEVELOPMENT: Available evidence shows that hypoglycaemia and hyperglycaemia increase brain injury and aggravate the prognosis, but it fails to establish the most suitable levels of blood glucose. Intensive treatment with insulin, compared with more moderate regimes, has not improved the prognosis and leads to further episodes of hypoglycaemia. CONCLUSIONS: Hypoglycaemia must always be avoided. Intensive treatment to control hyperglycaemia does not offer any kind of advantages and increases the likelihood of hypoglycaemia; it therefore cannot be recommended in neurocritical patients. No evidence is available showing the optimal level of blood glucose or the most suitable insulin regime, although its use is generally indicated when blood glucose levels are higher than 180-200 mg/dL. The value of the pharmacological control of blood glucose levels to improve the prognosis remains uncertain.
Assuntos
Glicemia/análise , Encefalopatias/sangue , Lesões Encefálicas/sangue , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hipoglicemia/sangue , Hipoglicemia/tratamento farmacológico , Encefalopatias/complicações , Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Lesões Encefálicas/complicações , Lesões Encefálicas/metabolismo , Lesões Encefálicas/fisiopatologia , Estado Terminal , Glucose/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/fisiopatologia , Hipoglicemia/complicações , PrognósticoRESUMO
En los últimos tres años se ha logrado en Andalucía, España, un avance significativo en las medidas de actuación en el ataque cerebral agudo. Este avance está relacionado en primer lugar con una mayor participación y compromiso de los profesionales de la salud en sus diferentes áreas para dar respuesta coordinada al ataque cerebral. El PLACA es un plan autonómico que se viene desarrollando desde hace cinco años en Andalucía, contribuyendo así a esta respuesta unitaria con su planificación. Colabora un grupo central formado por expertos de distintas sociedades científicas, coordinados por el Plan Andaluz de Salud y dependiente de la Dirección General del Servicio Andaluz de Salud. En este artículo se presentan los avances conseguidos en los últimos tres años con este plan, así como los objetivos futuros. Actualmente se ha logrado implementar la terapia trombolítica hasta en 55% de los hospitales de la comunidad, con una previsión del 100% para 2010. El incremento del número de trombólisis en los dos últimos años ha sido de más del doble respecto del período anterior. Se expone el importante esfuerzo económico realizado en la divulgación, información de medidas preventivas, formación de profesionales y desarrollo de telemedicina. No obstante, se considera necesario seguir avanzando. Las importantes medidas previstas para los próximos años ayudarán a continuar esta lucha, tratando de dar una respuesta más operativa y rápida, prevenir, y tratar de detener este incremento esperado de incidencia en la población, al mismo tiempo que se analizan mejor los resultados de la actitud terapeútica realizada.
Assuntos
Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/terapia , Planos e Programas de Saúde/organização & administração , Terapia Trombolítica/instrumentação , Terapia Trombolítica , EspanhaRESUMO
En los últimos tres años se ha logrado en Andalucía, España, un avance significativo en las medidas de actuación en el ataque cerebral agudo. Este avance está relacionado en primer lugar con una mayor participación y compromiso de los profesionales de la salud en sus diferentes áreas para dar respuesta coordinada al ataque cerebral. El PLACA es un plan autonómico que se viene desarrollando desde hace cinco años en Andalucía, contribuyendo así a esta respuesta unitaria con su planificación. Colabora un grupo central formado por expertos de distintas sociedades científicas, coordinados por el Plan Andaluz de Salud y dependiente de la Dirección General del Servicio Andaluz de Salud. En este artículo se presentan los avances conseguidos en los últimos tres años con este plan, así como los objetivos futuros. Actualmente se ha logrado implementar la terapia trombolítica hasta en 55% de los hospitales de la comunidad, con una previsión del 100% para 2010. El incremento del número de trombólisis en los dos últimos años ha sido de más del doble respecto del período anterior. Se expone el importante esfuerzo económico realizado en la divulgación, información de medidas preventivas, formación de profesionales y desarrollo de telemedicina. No obstante, se considera necesario seguir avanzando. Las importantes medidas previstas para los próximos años ayudarán a continuar esta lucha, tratando de dar una respuesta más operativa y rápida, prevenir, y tratar de detener este incremento esperado de incidencia en la población, al mismo tiempo que se analizan mejor los resultados de la actitud terapeútica realizada.(AU)