RESUMO
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.
Assuntos
Epilepsia , Proteínas de Neoplasias , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/uso terapêutico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/uso terapêutico , Epilepsia/tratamento farmacológico , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/uso terapêutico , Convulsões/tratamento farmacológico , Distribuição TecidualRESUMO
BACKGROUND: Low levels of AEDs can be secondary drug-drug interactions or related to irregular intake due to poor treatment adherence. This latter behavior is highly suspected in ambulatory pediatric epileptic patients when controls of AEDs are subtherapeutic. However, it cannot be considered for inpatients during long periods of hospitalization. A few isolated case reports have documented persistent low levels (PLL) of AEDs in hospitalized epileptic children, but no population study has currently been reported. OBJECTIVE: The aim of this study was to document the incidence of PLL of the most common AEDs - phenytoin (PHT), phenobarbital (PHB), valproic acid (VA), and carbamazepine (CBZ) - in pediatric epileptic in- and outpatients (PEP). METHODS: 21,040 plasma levels of the aforementioned AEDs from 3279 PEP were retrospectively analyzed. Plasma levels of AEDs were measured by an automated method using trademarked commercial kits with their corresponding quality control programs. Randomized samples were also controlled by HPLC methods. Only cases with more than 3 controls were included in the study. RESULTS: A high rate of PLL of PHT was detected in in- (71.7%) and outpatients (74.1%), while PLL of PHB, VA, and CBZ were detected in a lower proportion. Rates of PLL of PHT were similar in in- and outpatients. PLL of PHB was more commonly observed in outpatients while PLL of VA and CBZ were more frequently seen in inpatients. In some hospitalized patients receiving polytherapy, PLL of at least one AED were documented during a long time. DISCUSSION: Treatment non-adherence could be present in part of the outpatients, but cannot explain the PLL observed in a group of inpatients as described here. The recently described "pharmacokinetic hypothesis" of pharmaco-resistant epilepsy should be addressed in cases with AEDs-PLL, particularly in hospitalized cases. Perhaps, instead of stopping the subtherapeutic medication, the increasing doses of this AED and/or administration of inhibitors of CYP and P-glycoprotein, could help to achieve its therapeutic range, allowing a better pharmacologic effect and avoiding the development of more severe complications, such as status epilepticus or SUDEP.
Assuntos
Anticonvulsivantes/sangue , Quimioterapia Combinada , Epilepsia/sangue , Epilepsia/terapia , Adolescente , Assistência Ambulatorial , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Epilepsia/epidemiologia , Hospitalização , Humanos , Incidência , Lactente , Proibitinas , Estudos RetrospectivosRESUMO
Neuronal damage secondary to brain injuries such as cerebral hypoxia, seizures as well as neurodegenerative process, may include pro-inflammatory changes. The activation of a common mechanism related to survival or cell death, mediated by the stabilization and trans-activation of Hypoxia-Inducible Factor 1 (HIF-1), has been observed in these conditions. HIF-1 may induce over expression of P-glycoprotein, the product multidrug-resistance gene (MDR-1), both on blood-brain barrier as well as on the cerebral damaged cells, producing the refractoriness to therapeutic strategies for neuroprotection. However, in these same cells, HIF-1 can also induce the expression of erythropoietin receptor (Epo-R). Irrespective of its known properties on hematopoiesis, it was proposed that erythropoietin can trigger neuroprotective mechanisms mediated by Epo-R activation. Brain hypoxia, epilepsy, neurodegeneration and inflammation, can share the induction of Epo-R and several other growth factor receptors as well as signal transductions pathways after HIF-1 transactivation. Perhaps, the use of the intranasal route for the exogenous administration of Epo, (or other biological compounds) could help neuroprotection as well as to repair the brain areas damaged.
Assuntos
Epilepsia/tratamento farmacológico , Eritropoetina/uso terapêutico , Hipóxia Encefálica/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Epilepsia/fisiopatologia , Ácido Glutâmico/fisiologia , Humanos , Hipóxia Encefálica/fisiopatologia , Fator 1 Induzível por Hipóxia/fisiologia , Doenças Neurodegenerativas/fisiopatologia , Receptores da Eritropoetina/fisiologiaRESUMO
Epilepsy is a common neurological disorder. About one-third of epilepsy patients have a multidrug resistance (MDR) phenotype and develop refractory epilepsy (RE). Changes in the properties of the antiepileptic drugs (AEDs) targets resulting in reduced drug sensitivity, can't explain the MDR phenotype. This particular refractoriness is now attributed to overexpression of multidrug transporters in brain, leading to impaired access of AEDs to CNS targets, and it was documented in both human as well as in experimental models of RE. Single nucleotide polymorphism (SNP) identified in the MDR1-ABCB1 gene (C3435T/CC-genotype) is associated with increased intestinal expression of P-glycoprotein (P-gp) that affects levels of AEDs in plasma. The functional studies of P-gp using P-gp inhibitors could show the still unclear clinical impact of ABCB1 polymorphisms on AEDs resistance. Some drug-drug interactions previously believed to be cytochrome P450 (CYP) mediated are now also considered to be due to the modulation of multidrug-transporters. Because in certain cases pharmacoresistance can be overcome by add-on therapy, co-administered P-gp inhibitors could contribute to the effectiveness of AEDs treatment in RE. And in this regard, perhaps we can postulate to P-gp as a new clinical therapeutic target in multidrug-refractory epilepsy.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Interações Medicamentosas , Resistência a Medicamentos , Epilepsia/genética , Epilepsia/fisiopatologia , Regulação da Expressão Gênica , Humanos , Polimorfismo de Nucleotídeo ÚnicoAssuntos
Humanos , Masculino , Feminino , Encefalite , HIV , Transmissão Vertical de Doenças Infecciosas , HIV/fisiologia , HIV/patogenicidadeAssuntos
Humanos , Masculino , Feminino , Encefalite , HIV , Transmissão Vertical de Doenças InfecciosasRESUMO
It is estimated 20-25% of the epileptic patients fails to achieve good control with the different antiepileptic drugs (AEDs) treatments, developing refractory epilepsy (RE). Discovered first in cancer, the activity of P-glycoprotein (P-gp) and others ABC transporters as multidrug-resistance-associated proteins (MRPs) and breast cancer resistant protein (BCRP) are directly related with the refractoriness. We have observed the overexpression of these all transporters in the brain of patients with RE, and according with other authors, all these data suggests an active drug efflux from brain. Both constitutive and seizure induced brain P-gp overexpression was also suggested. As confirmation of these clinical evidences, different models of experimental epilepsy have demonstrated P-gp overexpression on blood brain barrier (BBB) and brain parenchyma cells, as astrocytes and neurons. In our model, early P-pg detection in vessel-related cells and later additional P-gp detection in neurons, correlated with the gradual loss of protective effect of phenytoin. The progressive neuronal P-gp expression, depending on intensity and time-constancy of seizure-injury, was in agreement with the development of "P-gp-positive seizure-axis" proposed by Kwan & Brodie, who also showed that the development of RE directly correlated with the number and frequency of seizures before initiation of drug therapy. P-gp expression in excretory organs suggests that P-gp have a central role in drug elimination. Persistent low levels of AEDs in plasma and P-gp brain overexpression in several RE pediatric patients were reported. We also observed in adult RE patients, an increased liver clearance of 99mTc-hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) (a P-gp substrate), and the surgically treated cases showed P-gp brain overexpression. These results suggest the systemic hyperactivity of P-gp in RE patients, including brain P-gp over-expression should be suspected when persistent subtherapeutic levels of AEDs in plasma are detected. P-gp neuronal expression described in both clinical and experimental reports indicates that additional mechanisms could be operative from seizure-affected P-gp-positive neurons, due to AEDs targets are expressed at membrane level. An alternative mechanism was demonstrated in P-gp-expressed cells that exhibit lower membrane potential (Deltapsi(0)=-10 to -20) compared to normal physiological Deltapsi(0) of -60 mV. Under this situation and irrespective to the P-gp pharmacoresistant property or type of drug treatment selected, P-gp-expressed neurons could increase their sensitivity to new seizures perhaps as an epileptogenic mechanism. The understanding of properties of these ABC transporters can offer new tools for better selection of more effective preventive or therapeutic strategies and avoid the invasive surgical treatments for RE.
Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Anticonvulsivantes/uso terapêutico , Resistência a Múltiplos Medicamentos/fisiologia , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/farmacologia , Animais , Anticonvulsivantes/sangue , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Resistência a Múltiplos Medicamentos/genética , Epilepsia/genética , Expressão Gênica/genética , Humanos , Fígado/metabolismo , Taxa de Depuração Metabólica , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Nitrilas/metabolismo , Compostos de Organotecnécio/metabolismo , Ratos , Distribuição TecidualAssuntos
Humanos , Feminino , Criança , Cefaleia , Fotofobia , Transtornos da Visão , Hipertensão Intracraniana/diagnósticoAssuntos
Humanos , Feminino , Criança , Cefaleia , Fotofobia , Hipertensão Intracraniana/diagnóstico , Transtornos da VisãoRESUMO
El linfoma primario del sistema nervioso central en pacientes pediátricos VIH positivos es poco frecuente. Se presenta un paciente, de siete años de edad, de sexo masculino, con síndrome de inmunodeficiencia adquirida, que desarrolló un linfoma decélulas B con localización leptomeníngea. El niño inició el cuadro con síntomas de alteración del sensorio, hipertensión endocraneana y amaurosis bilateral. El diagnóstico se efectuó por biopsia cerebral, inmunofenotipo de las células B del líquido cefalorraquídeo, además de PCR positiva para virus de Epstein Barr en el líquido. Realizó tratamiento con quimioterapia intratecal y sistémica. Mejoraron los síntomas durante quince meses y luego recidivó en la región talámica. Cumplió radioterapia craneo espinal y falleció cuatro meses después de la recidiva. En este artículo se realiza una revisión de la bibliografía sobre esta enfermedad, señalando el carácter excepcional de este paciente por tratarse de un linfoma localizado en forma exclusiva en el sistema nervioso central y, más precisamente, en la leptomeninges
Assuntos
Masculino , Criança , Linfoma de Células B , Linfoma não Hodgkin , Linfoma Relacionado a AIDS/complicações , Linfoma Relacionado a AIDS/diagnóstico , Linfoma Relacionado a AIDS/terapia , Meninges/patologia , Sistema Nervoso Central/patologia , Síndrome da Imunodeficiência Adquirida/complicaçõesRESUMO
El linfoma primario del sistema nervioso central en pacientes pediátricos VIH positivos es poco frecuente. Se presenta un paciente, de siete años de edad, de sexo masculino, con síndrome de inmunodeficiencia adquirida, que desarrolló un linfoma decélulas B con localización leptomeníngea. El niño inició el cuadro con síntomas de alteración del sensorio, hipertensión endocraneana y amaurosis bilateral. El diagnóstico se efectuó por biopsia cerebral, inmunofenotipo de las células B del líquido cefalorraquídeo, además de PCR positiva para virus de Epstein Barr en el líquido. Realizó tratamiento con quimioterapia intratecal y sistémica. Mejoraron los síntomas durante quince meses y luego recidivó en la región talámica. Cumplió radioterapia craneo espinal y falleció cuatro meses después de la recidiva. En este artículo se realiza una revisión de la bibliografía sobre esta enfermedad, señalando el carácter excepcional de este paciente por tratarse de un linfoma localizado en forma exclusiva en el sistema nervioso central y, más precisamente, en la leptomeninges(AU)
Assuntos
Masculino , Criança , Linfoma Relacionado a AIDS/complicações , Linfoma Relacionado a AIDS/diagnóstico , Linfoma Relacionado a AIDS/terapia , Meninges/patologia , Linfoma de Células B , Linfoma não Hodgkin , Sistema Nervoso Central/patologia , Síndrome da Imunodeficiência Adquirida/complicaçõesAssuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Infecções Oportunistas Relacionadas com a AIDS , Antibioticoprofilaxia , Síndrome da Imunodeficiência Adquirida/classificação , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/diagnóstico , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/terapia , VirosesRESUMO
El propósito de este trabajo es la presentación de tres niños con sindrome hipotónico (SH) debido a tres etiologías diferentes, todas con severa repercusión en su aparato bucal, y la descripción del tratamiento y del éxito terapéutico alcanzado (AU)
Assuntos
Humanos , Masculino , Feminino , Hipotonia Muscular/terapia , Distrofias Musculares/terapia , Sistema Nervoso Central/lesões , Síndrome de Prader-Willi/diagnóstico , Aparelhos Ativadores , Técnica de Expansão Palatina , Face/fisiopatologia , Boca/patologia , IncisivoRESUMO
El propósito de este trabajo es la presentación de tres niños con sindrome hipotónico (SH) debido a tres etiologías diferentes, todas con severa repercusión en su aparato bucal, y la descripción del tratamiento y del éxito terapéutico alcanzado