Amino acid metabolism characteristics of Banxia Baizhu Tianma Decoction in realizing drug withdrawal based on transcriptomic analysis / 中国中药杂志

This study aimed to demonstrate the effect of Banxia Baizhu Tianma Decoction(BBTD) on realizing withdrawal of anti-epileptic drugs and explore the relationship between BBTD and the amino acid metabolism by transcriptomic analysis in the rat model of epilepsy induced by lithium chloride-pilocarpine. The rats with epilepsy were divided into a control group(Ctrl), an epilepsy group(Ep), a BBTD & antiepileptic drug integrative group(BADIG), and an antiepileptic drug withdrawal group(ADWG). The Ctrl and Ep were given ultrapure water by gavage for 12 weeks. The BADIG was given BBTD extract and carbamazepine solution by gavage for 12 weeks. The ADWG was given carbamazepine solution and BBTD extract by gavage for the former 6 weeks, and then only given BBTD extract for the latter 6 weeks. The therapeutic effect was evaluated by behavioral observation, electroencephalogram(EEG), and hippocampal neuronal morphological changes. High-throughput sequencing was used to obtain amino acid metabolism-related differen-tial genes in the hippocampus, and the mRNA expression in the hippocampus of each group was verified by real-time quantitative polymerase chain reaction(RT-qPCR). The hub genes were screened out through protein-protein interaction(PPI) network, and Gene Ontology(GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed. Two ceRNA networks, namely circRNA-miRNA-mRNA and lncRNA-miRNA-mRNA, were constructed for ADWG vs BADIG. The experimental results showed that compared with those in Ep, rats in ADWG were significantly improved in the behavioral observation, EEG, and hippocampal neuronal impairment. Thirty-four amino acid metabolism-related differential genes were obtained by transcriptomic analysis, and the sequencing results were confirmed by RT-qPCR. Eight hub genes were obtained through PPI network, involving several biological processes, molecular functions, and signal pathways related to amino acid metabolism. Finally, the circRNA-miRNA-mRNA ternary transcription network of 17 circRNA, 5 miRNA, and 2 mRNA, and a lncRNA-miRNA-mRNA ternary network of 10 lncRNA, 5 miRNA, and 2 mRNA were constructed in ADWG vs BADIG. In conclusion, BBTD can effectively achieve the withdrawal of antiepileptic drugs, which may be related to the transcriptomic regulation of amino acid metabolism.

Detection of Carbamazepine and Its Metabolites in Blood Samples by LC-MS/MS / 法医学杂志

OBJECTIVES@#To establish a method for the detection of carbamazepine and its metabolites 10,11-dihydro-10,11-epoxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine in blood samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS).@*METHODS@#The blood samples were treated with 1-butyl-3-methylimidazolium hexafluorophosphate as an extraction solvent. The samples were extracted by ultrasound-assisted extraction and separated by ZORBAX Eclipse Plus C18, 95Å column. The mobile phase A aqueous solution containing 0.1% formic acid and 10 mmol/L ammonium acetate, and mobile phase B mixed organic solvent containing acetonitrile/methanol (Vacetonitrile∶Vmethanol=2∶3) were used for gradient elution at the flow rate of 1.00 mL/min. An electrospray ion source in positive mode was used for detection in the multiple reaction monitoring.@*RESULTS@#The linearities of carbamazepine and its metabolites 10,11-dihydro-10,11-epoxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine in blood samples were good within the corresponding range, with correlation coefficients (r) greater than 0.995 6. The limits of detection were 3.00, 0.40 and 1.30 ng/mL, respectively. The limit of quantitation were 8.00, 1.00 and 5.00 ng/mL, respectively. The extraction recoveries ranged from 76.00% to 106.44%. The relative standard deviations of the intra-day and inter-day precisions were less than 16%. Carbamazepine and its main metabolite 10,11-dihydro-10,11-epoxycarbamazepine were detected in blood samples of death cases with a mass concentration of 2.71 μg/mL and 252.14 ng/mL, respectively.@*CONCLUSIONS@#This method has high sensitivity and good selectivity, which is suitable for the detection of carbamazepine and its metabolites in blood samples, and can be used for carbamazepine-related forensic identifications.

Caracterización de pacientes con neuralgia del trigémino en un hospital mexicano, 2009-2019 / Characterization of patients with trigeminal neuralgia in a Mexican hospital, 2009-2019

Antecedentes: La neuralgia del trigémino (NT) es un dolor estereotipado, repetitivo y paroxístico, con prevalencia anual 4-13%. Objetivo: Describir características clínicas y terapéuticas de pacientes con diagnóstico de NT, División de Cuidados Paliativos, Clínica del dolor, Hospital "Dr. Manuel Gea González". Métodos: Estudio retrospectivo descriptivo. Revisión 91 expedientes, 1 enero 2009 a 31 diciembre 2019; se eliminaron 33 pacientes que abandonaron tratamiento, obteniendo muestra a conveniencia (61). Resultados: El sexo femenino fue más afectado 62.3% (38), comparado con el masculino 37.7% (23), relación 1.6 / 1. La edad media 60.2±16.8 años. La evolución previa a la atención tuvo una media: 17.6 meses. Las ramas del trigémino afectadas fueron: combinaciones rama izquierda 36.1% (22), rama derecha 27.9% (17), maxilar derecha 13.1% (8). Las causas secundarias fueron: 55.7% (35): postraumática 11, posherpética 7, compresión vascular 8, tumores 4, y disfunción temporomandibular 5. Las comorbilidades fueron: hipertensión arterial, diabetes mellitus tipo 2. Recibieron terapia farmacológica previa con antiinflamatorio no esteroideos 31.6% (37). Al ingreso la intensidad del dolor fue severa 96.7% (59), moderada 3.3% (2). Tratamiento intrahospitalario recibido fue carbamazepina 86.8% (53) y gabapentinoides 60.6% (37). Egresaron sin dolor 24.6% (15), con dolor leve 57.4% (35), dolor moderado 13.1% (8), y dolor severo 4.9% (3). Discusión: La NT fue más frecuente en mujeres, entre 50 y 70 años, similar a lo informado. El tiempo de inicio de síntomas y evaluación por especialista en algología fue prolongado. El tratamiento farmacológico indicado: carbamazepina, gabapentinoides, opioides y antidepresivos, apegados a Guías de Manejo Dolor Neuropático...(AU)

Assessment of carbamazepine acute toxicity in the cockle Cerastoderma edule through chemical, physiological and biochemical tools / Avaliação da toxicidade aguda da carbamazepina no berbigão Cerastoderma edule por meio de ferramentas químicas, fisiológicas e bioquímicas

The cockle Cerastoderma edule was exposed to four concentrations (5, 10, 20 and 70 µg L-1) of carbamazepine (CBZ). This anticonvulsant was found to alter the mussel behavior of by reducing its clearance rate (CR). Analysis of CBZ accumulation in tissues of C. edule was carried out using HPLC-UV after 48 or 96 hours of exposure. In addition, an overproduction of H2O2 by the bivalves was detected following exposure to CBZ but nitrite levels remained unchanged. Moreover, superoxide dismutase and catalase activities showed a significant increase in relation to their contact with CBZ. The activity of the biotransformation enzyme gluthatione-S-transferase did not change during exposure. Malondialdehyde (MDA) levels indicating cellular damage, increased when bivalves were exposed to 20 and 70 µg l-1 of carbamazepine for 96 h CBZ. The results also indicate that acetylcholinesterase activity (AChE) was inhibited in all CBZ concentrations during the 48 h exposure period. However, during the 96 h exposure period, AChE was only inhibited at the highest concentration. Further studies are needed now for more exploration of the toxicity of CBZ since it could be bioaccumulable throughout the food web and may affect non-target organisms.

O berbigão Cerastoderma edule foi exposto a quatro concentrações (5, 10, 20 e 70 µg L-1) de carbamazepina (CBZ). Este anticonvulsivante alterou o comportamento do mexilhão, reduzindo sua taxa de depuração (CR). A análise do acúmulo de CBZ nos tecidos de C. edule foi realizada por HPLC-UV após 48 ou 96 horas de exposição. Além disso, uma superprodução de H2O2 pelos bivalves foi detectada após a exposição à CBZ, mas os níveis de nitrito permaneceram inalterados. Além disso, as atividades de superóxido dismutase e catalase apresentaram aumento significativo em relação ao contato com CBZ. A atividade da enzima de biotransformação glutationa-S-transferase não se alterou durante a exposição. Os níveis de malondialdeído (MDA), indicando dano celular, aumentaram quando os bivalves foram expostos a 20 e 70 µg l-1 de carbamazepina por 96 h CBZ. Os resultados também indicam que a atividade da acetilcolinesterase (AChE) foi inibida em todas as concentrações de CBZ durante o período de exposição de 48 horas. No entanto, durante o período de exposição de 96 horas, a AChE foi inibida apenas na concentração mais alta. Mais estudos são necessários agora para uma maior exploração da toxicidade da CBZ, uma vez que pode ser bioacumulável em toda a cadeia alimentar e pode afetar organismos não alvo.

Assessment of carbamazepine acute toxicity in the cockle Cerastoderma edule through chemical, physiological and biochemical tools / Avaliação da toxicidade aguda da carbamazepina no berbigão Cerastoderma edule por meio de ferramentas químicas, fisiológicas e bioquímicas

The cockle Cerastoderma edule was exposed to four concentrations (5, 10, 20 and 70 μg L-¹) of carbamazepine (CBZ). This anticonvulsant was found to alter the mussel behavior of by reducing its clearance rate (CR). Analysis of CBZ accumulation in tissues of C. edule was carried out using HPLC-UV after 48 or 96 hours of exposure. In addition, an overproduction of H2O2 by the bivalves was detected following exposure to CBZ but nitrite levels remained unchanged. Moreover, superoxide dismutase and catalase activities showed a significant increase in relation to their contact with CBZ. The activity of the biotransformation enzyme gluthatione-S-transferase did not change during exposure. Malondialdehyde (MDA) levels indicating cellular damage, increased when bivalves were exposed to 20 and 70 μg l-¹ of carbamazepine for 96 h CBZ. The results also indicate that acetylcholinesterase activity (AChE) was inhibited in all CBZ concentrations during the 48 h exposure period. However, during the 96 h exposure period, AChE was only inhibited at the highest concentration. Further studies are needed now for more exploration of the toxicity of CBZ since it could be bioaccumulable throughout the food web and may affect non-target organisms.

O berbigão Cerastoderma edule foi exposto a quatro concentrações (5, 10, 20 e 70 μg L-¹) de carbamazepina (CBZ). Este anticonvulsivante alterou o comportamento do mexilhão, reduzindo sua taxa de depuração (CR). A análise do acúmulo de CBZ nos tecidos de C. edule foi realizada por HPLC-UV após 48 ou 96 horas de exposição. Além disso, uma superprodução de H2O2 pelos bivalves foi detectada após a exposição à CBZ, mas os níveis de nitrito permaneceram inalterados. Além disso, as atividades de superóxido dismutase e catalase apresentaram aumento significativo em relação ao contato com CBZ. A atividade da enzima de biotransformação glutationa-S-transferase não se alterou durante a exposição. Os níveis de malondialdeído (MDA), indicando dano celular, aumentaram quando os bivalves foram expostos a 20 e 70 μg l-1 de carbamazepina por 96 h CBZ. Os resultados também indicam que a atividade da acetilcolinesterase (AChE) foi inibida em todas as concentrações de CBZ durante o período de exposição de 48 horas. No entanto, durante o período de exposição de 96 horas, a AChE foi inibida apenas na concentração mais alta. Mais estudos são necessários agora para uma maior exploração da toxicidade da CBZ, uma vez que pode ser bioacumulável em toda a cadeia alimentar e pode afetar organismos não alvo.

Interchangeability among carbamazepine formulations: the impact over epilepsy patients

Abstract The treatment of epilepsy is complex and a matter of concern is the interchangeability among different formulations available for antiepileptic drugs. To evaluate the effects of interchangeability among carbamazepine formulations on patients with epilepsy. This is a prospective cohort study that included adult outpatients diagnosed with epilepsy and under pharmacological treatment with carbamazepine. Before switching the brand/manufacturer, the "Interchangeable Pharmaceutical Product in the Treatment of Epilepsies" questionnaire was applied. The questionnaires "Adverse Events Profile" and Quality of Life in Epilepsy-31, so as the plasma carbamazepine concentrations, were evaluated before and after the brand/ manufacturer switch. Physical-chemical tests aiming to assess tablets quality were performed in accordance with the Brazilian Pharmacopoeia 5th edition. The study population was composed by 14 patients (mean age: 44.6 years), with 10 of females. From those interviewed, 10 had no knowledge about the three antiepileptic drugs formulations available. The frequency of adverse event "problems with skin" incresead (p=0.023) and "upset stomach" decreased (p=0.041) after the changeover. The adverse events profile was associated with only two quality of life domains: "energy/fatigue" (p=0.048) and "total score" (p=0.018). Divergent results between generic and reference formulations were observed in purity-water test (reference: 1.96%, generic: 4.84%) and dissolution test, in which the generic formulation presented 66.27 to 85.77% of carbamazepine dissolved after the third level. Conclusions: Objective differences before and after the brand/manufacturer switch were not observed, in spite of patients' perceptions. Despite that, more studies in the field are necessary, especially on the interchangeability among generic antiepileptics, in order to better elucidate switching consequences on patients' life.

Reações cutâneas graves em crianças: como se comportam? / Severe cutaneous adverse reactions in children: how do they behave?

Introdução: As reações cutâneas graves a medicamentos (RCGM) compreendem um grupo de doenças caracterizadas por hipersensibilidade tardia a um ou vários tipos de fármacos. Por ser uma doença potencialmente fatal, o diagnóstico precoce, bem como o início do tratamento, são de suma importância. Objetivo: Analisar a evolução das RCGM em pacientes pediátricos acompanhados em dois hospitais da cidade de São Paulo, SP. Método: Trata-se de um estudo retrospectivo baseado na análise de prontuários de pacientes atendidos no período de 2002 a 2018 em dois hospitais da capital paulista. Resultados: Não houve diferença entre os sexos, prevaleceu a faixa etária dos adolescentes, e os medicamentos mais implicados com o desenvolvimento das lesões cutâneas foram os anticonvulsivantes, sendo os principais a carbamazepina e fenitoína, sem diferença entre eles, seguidos dos antibióticos betalactâmicos. No tratamento, todos os pacientes fizeram uso de corticoides sistêmicos e anti-histamínicos, sendo que oito pacientes também receberam imunoglobulina intravenosa e um recebeu ciclosporina. A taxa de mortalidade foi baixa e, em relação às complicações e sequelas, a autoimunidade foi a mais encontrada. Conclusão: Os casos de RCGM são eventos raros na faixa etária pediátrica, todavia de alta morbimortalidade e risco de sequelas. O diagnóstico e tratamento precoces contribuem para um melhor prognóstico, sendo de suma importância a identificação da medicação associada, bem como a retirada da mesma.

Background: Severe cutaneous adverse reactions (SCARs) comprise a group of diseases characterized by late hypersensitivity to one or more types of drugs. Because they are potentially fatal, early diagnosis and initiation of treatment are of paramount importance. Objective: To analyze the evolution of SCARs in pediatric patients followed up in two hospitals in São Paulo, SP, Brazil. Methods: This is a retrospective study based on the analysis of medical records of patients treated between 2002 and 2018 in two hospitals in the state capital. Results: There was no difference between sexes, and the age group of adolescents prevailed. Anticonvulsants were the drugs most implicated in the development of skin lesions, especially carbamazepine and phenytoin, with no difference between them, followed by betalactam antibiotics. During treatment, all patients used systemic corticosteroids and antihistamines; eight patients also received intravenous immunoglobulin and one received cyclosporine. The mortality rate was low, and regarding complications and sequelae, autoimmunity was the most commonly found. Conclusion: Cases of SCAR are rare events in the pediatric age group, but morbidity, mortality, and risk of sequelae are high. Early diagnosis and treatment contribute to a better prognosis, and identification of the associated medication as well as its withdrawal are extremely important.

Prevalence of Gingival Hyperplasia Induced by Anticonvulsants: A Systematic Review / Prevalência da Hiperplasia Gengival Induzida pelo uso de anticonvulsivantes: Revisão sistemática

Objective: Gingival hyperplasia (GH) is one of the side effects of anticonvulsant drugs. The aim of this study was to verify the prevalence of GH associated with the use of anticonvulsant, through a systematic review. Material and Methods: Systematic search was done at databases Pubmed and Embase between January 1984 and March of 2020 for identification of articles addressing the prevalence of GH associated with the use of anticonvulsant drugs. The methodological index for non-randomized studies (MINORS) was independently assessed for quality in the selected papers. Results: The search identified 4.471 references. Nine articles were selected and evaluated 632 participants. All of the studies included in the systematic review showed a low risk of bias. The anticonvulsants used by patients were carbamazepine, ethosuximide, phenytoin, primidone, phenobarbital, sodium valproate. The studies showed a correlation between different types of anticonvulsants and GH prevalence, with a range from 0% to 73%. Among the anticonvulsants used, phenytoin showed the greatest incidence of GH, varying between 15.61% and 73% in patients. Conclusion: In the analysis of the results obtained in the literature, it is possible to notice that the great majority of studies presented incidence of GH associated with anticonvulsant use. However, further studies are necessary to understand the anticonvulsant action mechanism inducing GH, as well as the prevention forms, given that GH is a significant side effect. (AU)

Objetivo: Hiperplasia gengival (HG) é um dos efeitos colaterais das drogas anticonvulsivantes. O objetivo deste estudo foi verificar a prevalência de HG associada ao uso de anticonvulsivantes, por meio de uma revisão sistemática. Material e Métodos: A busca sistemática foi realizada nas bases de dados Pubmed e Embase entre janeiro de 1984 e março de 2020 para identificação de artigos que abordassem a prevalência de HG associada ao uso de drogas anticonvulsivantes. Foi avaliado independentemente, o risco de viés através do "Methodological index for non-randomized studies" (MINORS), para análise da qualidade dos trabalhos selecionados. Resultados: A pesquisa identificou 4.471 referências. Nove artigos foram selecionados e avaliaram 632 participantes. Todos os estudos incluídos na revisão sistemática mostraram baixo risco de viés. Os anticonvulsivantes utilizados pelos pacientes foram carbamazepina, etossuximida, fenitoína, primidona, fenobarbital e valproato de sódio. Os estudos mostraram correlação entre os diferentes tipos de anticonvulsivantes e a prevalência de HG, com variação entre 0% a 73%. Entre os anticonvulsivantes utilizados, a fenitoína apresentou a maior incidência de HG, variando entre 15,61% e 73% em pacientes. Conclusão: Na análise dos resultados obtidos na literatura, é possível notar que a grande maioria dos estudos apresentou incidência de HG associada ao uso de anticonvulsivantes. No entanto, estudos adicionais são necessários para compreender o mecanismo de ação do anticonvulsivante para a indução da HG, bem como as formas de prevenção, dado que a HG é um efeito colateral significativo (AU)

Epilepsia no período gravídico-puerperal / Epilepsy in puerperal-pregnancy period

A epilepsia, doença cerebral caracterizada pela predisposição à geração de crises epilépticas, representa a patologia neurológica grave mais frequente na gravidez. Quando não acompanhada corretamente, possui um acentuado nível de morbimortalidade materno-fetal, sendo especialmente relacionada a riscos de convulsão materna na gestação e malformações fetais. Este artigo discute o acompanhamento da gestante epiléptica, trazendo recomendações de cuidados no período pré-concepcional, manejo durante o pré-natal, condução do trabalho de parto, peculiaridades no puerpério e tratamento de crises convulsivas, quando necessário. Serão abordados tanto aspectos de tratamento farmacológico quanto de monitoramento e orientações gerais, com o objetivo de contribuir para um suporte mais abrangente e adequado a esse grupo mais vulnerável de pacientes sob o cuidado do médico ginecologista-obstetra e neurologista.(AU)

Epilepsy, which is a brain disease defined for a greater predisposition for epileptic crisis, represents the most frequent neurological pathology during pregnancy. Without proper monitoring it is related to high morbidity and mortality to both mother and baby, especially due to the risks of mother seizure during pregnancy and fetus malformation. This article discusses about health care giving and follow-up for the epileptic pregnant women, pointing recommendations for preconception care, prenatal management, labor conduct, peculiarities in puerperium and treatment of convulsive crisis when needed. There will be approached pharmacological and non-pharmacological aspects, such as follow up exams and general orientations, having as a goal to contribute to an more abrangent and proper support of this more vulnerable group of patients under the care responsibility of obstetrician-gynecologist ad neurologist doctors.(AU)

Anatomical, radiological and clinical features of mesial temporal lobe epilepsy: two illustrated cases reports / Aspectos anatômicos, radiológicos e clínicos da epilepsia do lobo temporal mesial: relato ilustrado de dois casos

Mesial temporal lobe epilepsy is the most commom form of focal epilepsy in adults. Its clinical features include focal seizure, dysmnestic symptoms ­ such as déjà vu or jamais vu ­ and autonomic or psychic aura. We reported two cases of mesial temporal lobe epilepsy with similar clinical features, but with entirely different etiologies. Mesial temporal sclerosis contributes up to 70% of all mesial temporal lobe epilepsy cases and MRI usually shows reduced hippocampal volume and increased signal intensity on T2-weighted imaging. Incomplete hippocampal inversion has uncertain relation with epilepsy and is characterized by an atypical verticalized and medially positioned anatomical pattern of the hippocampus and also a deep collateral sulcus.

A epilepsia do lobo temporal mesial é a forma mais comum de epilepsia focal em adultos. Suas características clínicas incluem crises focais, sintomas dismnésicos - como déjà vu ou jamais vu - e aura autonômica ou psíquica. Relatamos dois casos de pacientes com epilepsia do lobo temporal mesial com manifestações clínicas semelhantes, mas com etiologias completamente diferentes. A esclerose mesial temporal contribui com até 70% de todos os casos de epilepsia do lobo temporal mesial e, geralmente, na ressonância magnética, apresenta atrofia do hipocampo e hipersinal na imagem ponderada em T2. A rotação incompleta do hipocampo possui uma relação incerta com a epilepsia e é caracterizada por alteração da estrutura interna do hipocampo, com um sulco colateral verticalizado e profundo.

Discinesia paroxística primaria kinesiogénica y no kinesiogénica: Reporte de 3 casos y revisión de la literatura / Paroxysmal Kinesiogenic Dyskinesia and Paroxysmal Non-Kinesiogenic Dyskinesia: Three Case Reports and a Review

Las discinesias paroxísticas son un grupo de entidades consistentes en paroxismos de diversos movimientos anormales de corta duración asociados o no a factores precipitantes. Suele afectar a sujetos jóvenes y la prevalencia es desconocida. La fisiopatología es incierta; se han identificado ciertas mutaciones que expliquen su origen. Clínicamente se pueden manifestar como ataques paroxísticos de movimientos de tipo coreoatetósico, distónicos o balísticos de corta duración y con preservación de la conciencia. Los estudios electrofisiológicos y de imagen suelen ser normales. Este grupo de trastornos del movimiento hacen parte del diagnóstico diferencial de las crisis epilépticas. El pronóstico suele ser bueno y el tratamiento es sintomático con anticonvulsivantes. Se presentarán tres casos de dos tipos de trastornos paroxísticos del movimiento y revisión de la literatura.

Paroxysmal dyskinesias are a group of entities consisting of paroxysms of diverse abnormal movements of short duration, associated or not with precipitating factors. It usually affects young subjects and its prevalence is unknown. The pathophysiology is uncertain; some mutations have been identified that explain their origin. Clinically, they can manifest as paroxysmal attacks of choreoathetosis, dystonic or ballistic movements of short duration and with preservation of consciousness. Electrophysiological and imaging studies are usually normal. This group of movement disorders are part of the differential diagnosis of epileptic seizures. Prognosis is usually good and the treatment is symptomatic with anticonvulsants. Three cases of two types of paroxysmal movement disorders and a review of the current literature are presented.

High Doses of Drugs Extensively Metabolized by CYP3A4 Were Needed to Reach Therapeutic Concentrations in Two Patients Taking Inducers / Dos pacientes que tomaban inductores necesitaron dosis altas de medicamentos metabolizados en gran medida por el CYP3A4 para alcanzar concentraciones terapéuticas

ABSTRACT Introduction: In the last 20 years of clinical practice, the senior author has identified these 2 rare cases in which the patients needed extremely high doses of drugs metabolized by CYP3A4 to reach and maintain serum therapeutic concentrations. Methods: The high metabolic ability of these 2 patients was demonstrated by the low concentration-to-dose ratios (C/D ratios) of several drugs metabolized by CYP3A4. Results: Case 1 was characterized by a history of high carbamazepine doses (up to 2,000 mg/day) and needed 170 mg/day of diazepam in 2 days to cooperate with dental cleaning. The high activity of the CYP3A4 isoenzyme was manifested by fast metabolism for quetiapine and diazepam, which took more than 1 year to normalize after the inducer, phenytoin, was stopped. Case 2 was also very sensitive to CYP3A4 inducers as indicated by very low C/D ratios for carbamazepine, risperidone and paliperidone. The carbamazepine (2,800 mg/day) and risperidone (20 mg/day) dosages for this second patient are the highest doses ever seen for these drugs by the senior author. Risperidone induction appeared to last for many months and metabolism was definitively normal 3 years after stopping carbamazepine. On the other hand, olanzapine C/D ratios were normal for induction. Conclusions: The literature has never described similar cases of very high doses of drugs metabolized by CYP3A4. We speculate that these 2 patients may have unusual genetic profiles at the nuclear receptor levels; these receptors regulate induction of drugs.

RESUMEN Introducción: Durante sus últimos 20 años de práctica, el último autor ha identificado estos 2 infrecuentes casos que necesitaban dosis extremadamente altas de medicaciones metabolizadas por el CYP3A4 para alcanzar y mantener concentraciones séricas terapéuticas. Métodos: La gran capacidad metabólica de estos 2 pacientes se demostró por los bajos cocientes entre concentración y dosis (C/D) de varias medicaciones metabolizadas por el CYP3A4. Resultados: El caso 1 se caracterizaba por una historia de altas dosis de carbamazepina (1.500 mg/día) y la necesidad de tomar 170 mg de diazepam en 2 días para facilitar una limpieza dental. La gran actividad de la isoenzima CYP3A4 se manifestó por una gran capacidad metabólica de quetiapina y diazepam, cuya normalización tardó más de 1 año tras la toma de un inductor, fenitoína. El caso 2 tambien era muy sensible a la inducción, lo cual se demuestra por los bajos cocientes C/D de carbamazepina, risperidona y paliperidona. Las dosis de carbamazepina (2.800 mg/día) y risperidona (20 mg/día) de este segundo paciente son las más altas nunca vistas por el último autor. La inducción de risperidona duró muchos meses y su metabolismo era normal 3 años después de interrumpir la carbamazepina. El cociente C/D de olanzapina era normal para la inducción. Conclusiones: Nunca se habían descrito casos similares de dosis tan altas de medicaciones metabolizadas por el CYP3A4. Se especula con que estos pacientes podrían tener unos perfiles genéticos inusuales en los receptores nucleares que regulan la inducción de medicamentos.

Antiphospholipid and Antinuclear Antibodies in Children with Idiopathic Epilepsy: A 2-Year Prospective Study

Adverse Skin Reactions with Antiepileptic Drugs Using Korea Adverse Event Reporting System Database, 2008–2017

Drug hypersensitivity reactions in Asia: regional issues and challenges

There are geographical, regional, and ethnic differences in the phenotypes and endotypes of patients with drug hypersensitivity reactions (DHRs) in different parts of the world. In Asia, aspects of drug hypersensitivity of regional importance include IgE-mediated allergies and T-cell-mediated reactions, including severe cutaneous adverse reactions (SCARs), to beta-lactam antibiotics, antituberculous drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast agents. Delabeling of low-risk penicillin allergy using direct oral provocation tests without skin tests have been found to be useful where the drug plausibility of the index reaction is low. Genetic risk associations of relevance to Asia include human leucocyte antigen (HLA)-B*1502 with carbamazepine SCAR, and HLA-B*5801 with allopurinol SCAR in some Asian ethnic groups. There remains a lack of safe and accurate diagnostic tests for antituberculous drug allergy, other than relatively high-risk desensitization regimes to first-line antituberculous therapy. NSAID hypersensitivity is common among both adults and children in Asia, with regional differences in phenotype especially among adults. Low dose aspirin desensitization is an important therapeutic modality in individuals with cross-reactive NSAID hypersensitivity and coronary artery disease following percutaneous coronary intervention. Skin testing allows patients with radiocontrast media hypersensitivity to confirm the suspected agent and test for alternatives, especially when contrasted scans are needed for future monitoring of disease relapse or progression, especially cancers.

Diagnóstico de encefalite límbica não paraneoplásica de etiologia imunomediada: estudo de caso e revisão de literatura / Diagnosis of immune-mediated non-paraneoplastic limbic encephalitis: case report and literature review

A encefalite límbica vem sendo descrita como um distúrbio neurológico raro, que afeta seletivamente as estruturas do sistema límbico. Clinicamente, é caracterizada como uma desordem neurológica debilitante, que se desenvolve como encefalopatia rapidamente progressiva, causada por inflamação encefálica. Objetivamos aqui relatar um caso de encefalite do sistema límbico de provável etiologia autoimune para melhor conhecimento da comunidade médica, bem como averiguar métodos diagnósticos deste quadro. Paciente do sexo masculino, 59 anos, admitido em nosso serviço com queixa de confusão mental. O exame clínico evidenciou desorientação, disartria, paresia e parestesia no hemicorpo esquerdo, dificuldade de marcha, desvio de rima e histórico de epilepsia há 2 anos. No estudo por ressonância magnética do crânio, foram observadas extensas lesões que acometiam a região mesial do lobo temporal direito, todo o hipocampo e giro para-hipocampal direito, estendendo-se pelo fórnix até a porção posterior do hipocampo esquerdo, substância branca do lobo frontal bilateral. Mediante os resultados da investigação complementar, o paciente foi tratado com pulsoterapia de metilpredinisolona por 5 dias, resultando na regressão parcial dos sintomas. Atualmente, o paciente se encontra em seguimento ambulatorial para acompanhamento. A encefalite límbica é uma doença rara, porém muito importante de ser investigada e diagnosticada precocemente, uma vez que a progressão da doença pode causar incapacidade e sequelas irreversíveis.

Limbic encephalitis has been described as a rare neurological disorder affecting the limbic system structures selectively. Clinically, it is characterized as a debilitating neurological syndrome that develops as a quickly progressive encephalopathy caused by brain inflammation. This paper reports a case of limbic encephalitis, probably of autoimmune etiology, aiming to improve the knowledge of the medical community, and to promote a debate on diagnosis methods for this pathology. The patient is male, 59 years old, and was admitted at our service complaining of mental confusion. The clinical examination showed disorientation, dysarthria, left hemiparesis and paresthesia, gait difficulties, light asymmetrical smile, and history of epilepsy 2 years ago. The magnetic resonance imaging of skull showed extensive lesions affecting the mesial region of the right temporal lobe, the entire hippocampus, and right parahippocampal gyrus, extending through the fornix to the posterior portion of the left hippocampus, white matter of bilateral frontal lobe. Based on the complementary investigation results, the patient was treated with intravenous methylprednisolone for five days. Currently, he is being followed in the outpatient's department. Although being rare, limbic encephalitis shall be investigated and diagnosed early because its progression can lead to disability and irreversible sequelae

Intoxicaciones agudas por medicamentos consumidos con fines de abuso / Acute poisoning due to medications used for abuse purposes

Introducción: El consumo de sustancias con fines de abuso y entre ellas los medicamentos, se ha incrementado a nivel mundial. Objetivo: Caracterizar a los pacientes atendidos por intoxicaciones agudas debido a medicamentos consumidos con fines de abuso. Métodos: El universo estuvo constituido por consultas de 961 pacientes, realizadas al servicio de información toxicológica de urgencia del Centro Nacional de Toxicología, durante el período 2010 al 2014. Fueron todas las intoxicaciones agudas por consumo de sustancias con fines de abuso. La serie incluyó 578 pacientes con intoxicaciones agudas con fines de abuso, donde el agente causal fueron los medicamentos. Se recopilaron los datos sociales y biológicos, formas de consumo, grupos farmacológicos, manifestaciones clínicas, aspectos de la toxicocinética y la toxicodinamia. Resultados: Los consumidores de medicamentos con fines de abuso, representaron el 60,14 por ciento de las consultas por consumo de sustancias con fines de abuso. El grupo etario de hasta 20 años fue el de mayor consumo (360 consultas; 62,28 por ciento) y el sexo masculino el más frecuente (447 pacientes; 77,3 por ciento). La combinación de medicamentos más alcohol fue la forma de consumo más empleada (292 consultas; 50,5 por ciento). La carbamazepina fue el medicamento más consumido (305 consultas; 52,7 por ciento). Conclusiones: Predominó la intoxicación aguda en el grupo etario de 10-20 años y del sexo masculino. La ingestión de medicamentos más alcohol, fue la forma de consumo más empleada. El grupo farmacológico más utilizado con fines no médicos, fue el de los anticonvulsivantes (carbamazepina), seguido de las benzodiacepinas y los opiáceos. Las manifestaciones clínicas que predominaron fueron del sistema neurológico, seguido del cardiovascular y el digestivo(AU)

ABSTRACT Introduction: The consumption of substances for the purpose of abuse, including drugs, has increased worldwide. Objective: To characterize patients treated for acute intoxications due to drugs consumed for abuse purposes. Methods: The universe was constituted by consultations of 961 patients, made to the emergency toxicology information service of the National Center of Toxicology, during the period from 2010 to 2014. They were all acute intoxications due to the consumption of substances for the purpose of abuse. The series included 578 patients with acute intoxications for abuse, where the causative agent was medication. We collected social and biological data, forms of consumption, pharmacological groups, clinical manifestations, aspects of toxicokinetics and toxicodynamics. Results: Consumers of medications for the purpose of abuse accounted for 60.14 percent of consultations for the consumption of substances for the purpose of abuse. The age group of up to 20 years consumed the most (360 consultations, 62.28 percent) and the most frequent was the male sex (447 patients, 77.3 percent). The combination of drugs plus alcohol was the most used form of consumption (292 consultations, 50.5 percent). Carbamazepine was the most commonly used medication (305 consultations, 52.7 percent). Conclusions: Acute intoxication predominated in the age group of 10-20 years and of the male sex. The ingestion of drugs plus alcohol was the most used form of consumption. The most used pharmacological group for non-medical purposes was the anticonvulsant group (carbamazepine), followed by benzodiazepines and opiates. The clinical manifestations that predominated were of the neurological system, followed by cardiovascular and digestive(AU)

Epilepsia en niños con hemiparesia congénita secundaria a infartos cerebrales vasculares perinatales / Epilepsy in children with congenital hemiparesis secondary to perinatal ictus

El objetivo fue describir la frecuencia, modo de presentación y características de la epilepsia en niños con hemiparesia congénita (HC). Estudio retrospectivo, descriptivo y multicéntrico, basado en la recolección de datos de las historias clínicas de pacientes de 0 a 19 años con HC secundaria a infarto perinatal en diferentes centros de la comunidad de Cataluña. Se incluyeron 310 niños (55% varones y 45% mujeres) de un total de 13 centros de Cataluña. Edad media del debut de las crisis fue de 2 ± 1 año. Presentaron epilepsia el 29.5% (n = 76), el subtipo vascular más frecuente fue el infarto presumiblemente perinatal (51.3%), seguido del accidente isquémico arterial neonatal (18.4%), infarto hemorrágico venoso periventricular (15.8%), infarto hemorrágico neonatal (10.5%) y trombosis venosa neonatal (3.9%). La semiología de las crisis más frecuente fue la focal motora en un 82%, seguida de las focales motoras con bilateralización secundaria en el 23%, focales discognitivas en 13.5%, generalizadas 2% y espasmos 6.5%. El 67.3% se controló con monoterapia y los fármacos empleados fueron el valproato, levetiracetam o carbamacepina. Se identificó el antecedente de estatus eléctrico durante el sueño en 3 pacientes, todos asociados a lesiones extensas que incluían al tálamo. Del total con epilepsia, el 35% debutaron con convulsiones neonatales en los primeros 3 días de vida. El 30% con accidente cerebrovascular perinatal y HC presentan riesgo de padecer epilepsia durante la infancia. Aquellos con infartos isquémicos tienen el riesgo más alto, por lo que requerirán un seguimiento dirigido a detectar precozmente la epilepsia e iniciar tratamiento.

The objective was to describe the frequency, mode of presentation and characteristics of epilepsy in children with congenital hemiparesis (CH). It is a etrospective, descriptive and multicenter study, based on the collection of data from the clinical records of patients from 0 to 19 years with CH secondary to perinatal infarction in different centers of the community of Catalonia. A total of 310 children were included (55% males and 45% females), from a total of 13 centers in Catalonia. Average age of onset of the crises was 2 ± 1 year. Epilepsy was present in 29.5% (n = 76), among which the most frequent vascular subtype was arterial presumed perinatal ischemic stroke (51.3%), followed by neonatal arterial ischemic stroke (18.4%), periventricular venous infarction (15.8%), neonatal hemorrhagic stroke (10.5%) and neonatal cerebral sinovenous thrombosis (3.9%). Semiology of the most frequent seizures was motor focal in 82%, followed by focal motor with secondary bilateralization in 23%, focal discognitive in 13.5%, generalized by 2% and spasms in 6.5%. The 67.3% were controlled with monotherapy and the drugs used were valproate, levetiracetam or carbamazepine. The antecedent of electrical status during sleep was identified in 3 patients, all associated with extensive lesions that included the thalamus. Of the total number of children with epilepsy, 35% began with neonatal seizu res in the first 3 days of life. The 30% of children with perinatal stroke and CH present a risk of epilepsy during childhood. Children with ischemic strock have the highest risk, so they will require a follow-up aimed at detecting prematurely the epilepsy and start a treatment.

Lamotrigine induced hypersensitivity syndrome in children: a case report / 北京大学学报(医学版)

Drug induced hypersensitivity syndrome (DIHS) is often manifested as severe systemic drug trans-reactions characterized by acute and extensive skin lesions (mostly measles-like rash), fever, enlargement of lymph nodes, multiple organ involvement (hepatitis, nephritis, and pneumonia), eosinophilia and mononucleosis,within 2-6 weeks of the application of sensitizing drugs. In the early stage of the lesion, macular papules or erythema multiforme were common, and in severe cases, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis were also common. Most of them developed after taking allergic drugs for 2-6 weeks (average: 3 weeks). Symptoms persisted after discontinuation of allergic drugs. It takes more than one month to alleviate, which may endanger life in severe cases. Documents report that the most common drugs causing DIHS are phenytoin sodium, carbamazepine and phenobarbital aromatic drugs. However, it was reported that phenobarbital sodium was the most common anticonvulsant among allergenic drugs in children, followed by antipyretics, analgesics and antibiotics, which may be related to the spectrum of childhood diseases and the particularity of the drug. Lamotrigine has been reported to cause DIHS in adults in China, but less in children. In order to improve the understanding of clinical diagnosis and treatment of DIHS in children, reduce misdiagnosis, missed diagnosis, and untimely treatment, and prevent the aggravation of the disease, we studied the case of a 4-year-old 7-month-old girl who presented with systemic erythematous papules, fever, hepatosplenomegaly, marked increase of white blood cells, marked decrease of anemia and platelets, abnormal liver function and coagulation routine after taking lamotrigine for one month due to epilepsy seizures. Now, according to the DIHS diagnostic criteria established by Registration of Severe Cutaneous Adverse Reactions Drug Review Group in 2007, plasma exchange was immediately given to replace the toxic metabolites in hemorrhagic plasma, and methylprednisolone was given intravenously for three days. At the same time, after symptomatic supportive treatments, such as loratadine and albumin, the condition gradually improved without recurrence. Through a case report of Drug reaction with eosinophilia and systemic symptoms in a child caused by lamotrigine, we can strengthen our understanding and improve the level of diagnosis and treatment of drug hypersensitivity syndrome in children. Lamotrigine can cause DIHS in children, which is very dangerous. Early diagnosis and early withdrawal of allergenic drugs, plasma exchange and glucocorticoid therapy are the key to treatment.