High incidence of persistent subtherapeutic levels of the most common AEDs in children with epilepsy receiving polytherapy

Czornyj, Liliana; Guido, Paulo Cáceres; Bramuglia, Guillermo F.; Rodiño, Alejandra; Feria-Romero, Iris; Lazarowski, Alberto

doi:10.1016/j.eplepsyres.2018.09.008

Cited by 12 publications

(6 citation statements)

References 57 publications

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“…In this population, PLLs of PHT were detected in inpatients (71.7%) and outpatients (74.1%), whereas PLLs of PHB, VA, and CBZ were also detected in a smaller proportion. In some patients, PLL of at least one ASM during long periods of hospitalization was documented as a dominant feature for four drugs evaluated 26 . This particular observation indicates that PLL is not only a compliance issue but should be considered as a pharmacokinetic change related to clinical conditions.…”

Section: Abc‐t In the Peripheral Mechanism Of Drug Resistance Epilepsymentioning

confidence: 84%

“…In some patients, PLL of at least one ASM during long periods of hospitalization was documented as a dominant feature for four drugs evaluated. 26 This particular observation indicates that PLL is not only a compliance issue but should be considered as a pharmacokinetic change related to clinical conditions. Unfortunately, some clinical epileptologists do not interpret these data as altered pharmacokinetic behavior but as a laboratory error and therefore decide to withdraw the drug found with PLL in plasma.…”

Section: Abc‐t In the Peripheral Mechanism Of Drug Resistance Epilepsymentioning

confidence: 99%

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Transporter hypothesis in pharmacoresistant epilepsies. Is it at the central or peripheral level?

2021

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The multidrug-resistance (MDR) phenotype is typically observed in patients with refractory epilepsy (RE) whose seizures are not controlled despite receiving several combinations of more than two antiseizure medications (ASMs) directed against different ion channels or neurotransmitter receptors. Since the use of bromide in 1860, more than 20 ASMs have been developed; however, historically ~30% of cases of RE with MDR phenotype remains unchanged. Irrespective of metabolic biotransformation, the biodistribution of ASMs and their metabolites depends on the functional expression of some ATP-binding cassette transporters (ABC-t) in different organs, such as the blood-brain barrier (BBB), bowel, liver, and kidney, among others. ABC-t, such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP-1), and breast cancer-resistance protein (BCRP), are mainly expressed in excretory organs and play a critical role in the pharmacokinetics (PK) of all drugs. The transporter hypothesis can explain pharmacoresistance to a broad spectrum of ASMs, even when administered simultaneously. Since ABC-t expression can be induced by hypoxia, inflammation, or seizures, a high frequency of uncontrolled seizures increases the risk of RE.These stimuli can induce ABC-t expression in excretory organs and in previously non-expressing (electrically responsive) cells, such as neurons or cardiomyocytes. In this regard, an alternative mechanism to the classical pumping function of P-gp indicates that P-gp activity can also produce a significant reduction in resting membrane potential (ΔΨ0 = −60 to −10 mV). P-gp expression in neurons and cardiomyocytes can produce membrane depolarization and participate in epileptogenesis, heart failure, and sudden unexpected death in epilepsy. On this basis, ABC-t play a peripheral role in controlling the PK of ASMs and their access to the brain and act at a central level, favoring neuronal depolarization by mechanisms independent of ion channels or neurotransmitters that current ASMs cannot control.

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Section: Abc‐t In the Peripheral Mechanism Of Drug Resistance Epilepsymentioning

confidence: 84%

Section: Abc‐t In the Peripheral Mechanism Of Drug Resistance Epilepsymentioning

confidence: 99%

Transporter hypothesis in pharmacoresistant epilepsies. Is it at the central or peripheral level?

2021

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“…y publicaciones de investigaciones (siempre asociadas a temas de farmacocinética y farmacología clínica, aunque no solo de antibióticos), observamos un incremento sostenido a lo largo del período evaluado (cantidad media de presentaciones por año, por período: 4 en 2007-2010 vs 7 en 2011-2020). En este sentido, el cambio más relevante se produjo en relación a la importancia, medida en términos del factor de impacto de las revistas en la que fueron publicados estos trabajos, correspondiendo los de la última etapa a revistas de mayor factor de impacto en relación al primer período (26)(27)(28)(29) . Asimismo, las actividades de formación de recursos humanos en ámbitos profesionales, incluyendo a universidades, sociedades científicas y demás instituciones de similar envergadura, también mostraron un incremento constante (cantidad media de actividades docentes por año, por período: 5 en 2007-2010 vs 11 en 2011-2020).…”

Section: Discussionunclassified

evaluación de desempeño del servicio de dosificación de precisión para vancomicina en un hospital pediátrico de nivel terciario

Guido

Licciardone

Riva

et al. 2022

Rev Fac Cien Med Univ Nac Cordoba

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Introducción: La dosificación de precisión a través del monitoreo de vancomicina basado en sus concentraciones plasmáticas (vancocinemia) es una práctica recomendada en el tratamiento de infecciones pediátricas de alta complejidad para aumentar la probabilidad de lograr una farmacoterapia segura y eficaz. Objetivo: Evaluar retrospectivamente las actividades y el desempeño relacionado a la optimización farmacoterapéutica basada en las vancocinemias (período 2007-2020) de un hospital pediátrico terciario. Métodos: Se analizaron las vancocinemias de pacientes pediátricos, estimándose indicadores de calidad asistencial y verificaciones analíticas, así como también aspectos relacionados a docencia e investigación. Se evaluó el desempeño predictivo de las concentraciones de vancomicina cuando se ajustaron los regímenes terapéuticos con un programa de optimización farmacocinética (BestDose v1.126) considerando el coeficiente de determinación (R2), el error porcentual absoluto medio (MAPE) y la raíz del error cuadrático medio (RMSE). Resultados: Se analizaron 13269 vancocinemias. El 70% fueron valles y el 81% pertenecieron a pacientes de Unidades de Cuidados Intensivos. El 40% de los valles se encontró dentro del margen terapéutico al ajustarse sin programa informático. Se realizaron 347 intervenciones farmacoterapéuticas, el 97% de las cuales fueron aceptadas por el médico tratante; el 75% de los valles posteriores al ajuste entraron en el margen terapéutico, valor significativamente mayor respecto al 40% de cuando el abordaje fue empírico (p=0.03). Los valores asociados al desempeño predictivo, (n subgrupo de pacientes = 91) fueron: R2=0.61, MAPE=28.16% y RMSE=3.3, mostrándose todos adecuados. Conclusión: Las actividades de monitoreo y farmacocinética clínica de vancomicina mostraron un buen rendimiento clínico.

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“…Lazarowski et al 34 , 35 , 36 reported subtherapeutic plasma levels of ASMs (PHT and phenobarbital) in patients with drug‐resistant epilepsy. This coincided with increased Pgp expression levels found in endothelial cells, astrocytes, and neurons from the resected brain tissue of the patients.…”

Section: A Broader Pharmacokinetic Perspective To Explain Drug‐resist...mentioning

confidence: 99%

The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug‐resistant epilepsy

Vázquez

Fagiolino

2021

Epilepsia Open

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High incidence of persistent subtherapeutic levels of the most common AEDs in children with epilepsy receiving polytherapy

Cited by 12 publications

References 57 publications

Transporter hypothesis in pharmacoresistant epilepsies. Is it at the central or peripheral level?

Transporter hypothesis in pharmacoresistant epilepsies. Is it at the central or peripheral level?

evaluación de desempeño del servicio de dosificación de precisión para vancomicina en un hospital pediátrico de nivel terciario

The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug‐resistant epilepsy

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