Fármacovigilancia de la carbamazepina en el Policlínico Marta Abreu. Santa Clara, 2022

Fundamento: en la práctica, el término estupefaciente se aplica a las especialidades farmacéuticas que contienen principios activos que actúan sobre el sistema nervioso central modificándolo y a las fórmulas magistrales con los mismos principios activos. Objetivo: caracterizar clínica y epidemiológicamente los pacientes que consumen carbamazepina en un área de salud del municipio de Santa Clara. Métodos: estudio descriptivo, transversal, en pacientes que consumen carbamazepina, pertenecientes al Policlínico Docente Marta Abreu, en el período del 1 de enero de 2021 al 1 de abril de 2022. Se incluyeron 209 pacientes y se midieron las siguientes variables: edad, sexo, número de pacientes según diagnósticos, número de pacientes según nuevos protocolos y tiempo de consumo del tratamiento. Resultados: predominó el grupo de edades de 51 a 60 con 43 pacientes (20,5 %), dentro de este grupo el sexo femenino (11,0 % del total); el diagnóstico predominante fue la epilepsia generalizada (93 pacientes). Predominó el sexo femenino, con 59 pacientes, y en ellas se encontró la mayor cantidad de expedientes vencidos, con un total de 16. Según nuevos protocolos, prevalecieron los pacientes con diagnóstico de neuralgia trigeminal, glosofaríngeo o facial (7 pacientes). En cuanto al tiempo de consumo predominaron los pacientes con igual diagnóstico a los anteriores y trastorno del comportamiento debido a enfermedad médica, ambos grupos con tratamientos de hasta tres años. Conclusiones: es importante el conocimiento sobre el uso y abuso de los estupefacientes así como mantener actualizado a todo el personal sanitario para lograr el óptimo control sobre estas sustancias.

Background: in practice, the term narcotic is applied to pharmaceutical specialties that contain active ingredients that act on the central nervous system, modifying it, and to master formulas with the same active ingredients. Objective: to characterize clinically and epidemiologically the patients who consume carbamazepine in a health area of the Santa Clara municipality. Methods: descriptive, cross-sectional study in patients consuming carbamazepine, belonging to the Marta Abreu Teaching Polyclinic, from January the 1st, 2021 to April the 1st, 2022. 209 patients were included and the following variables were measured: age, sex, number of patients according to diagnoses, number of patients according to new protocols and time of consumption of the treatment. Results: the age group from 51 to 60 predominated with 43 patients (20.5%), within this group the female sex (11.0% of the total); the predominant diagnosis was generalized epilepsy with a total of 93 patients. The female sex predominated with a total of 59 patients and in them the largest number of expired files was found, with a total of 16. According to new protocols, patients with a diagnosis of trigeminal, glossopharyngeal or facial neuralgia (7 patients) predominated. Regarding the time of consumption, patients with the same diagnosis as the previous ones and behavioral disorder due to a medical illness predominated, both groups with treatments of up to three years. Conclusions: knowledge about the use and abuse of narcotic drugs is important, as well as keeping all health personnel updated to achieve optimal control over these substances.

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.

Carbamazepine in the treatment of bipolar disorder: a systematic review / Carbamazepina no tratamento do transtorno bipolar: uma revisão sistemática

ABSTRACT Objective: Expand knowledge on the role and efficacy of carbamazepine (CBZ) in bipolar disorder (BD), based on original studies. Methods: The authors performed a systematic review of the scientific literature on the efficacy of CBZ in BD, using the PubMed/MEDLINE, Web of Science (ISI), and SciELO databases. The search terms were: ("carbamazepine") AND ("bipolar" OR "mania" OR "manic"). There was no restriction on the year of publication. Results: A total of 27 articles were selected. Among the selected articles, 14 evaluated the use of CBZ in the manic phase of BD, two in the depressive phase of BD, and 11 in the maintenance phase of BD. In the studies on the manic phase of BD, CBZ proved superior to placebo (PLA). As for the depressive phase of BD, there were two studies, both with small samples. In the maintenance phase, CBZ was inferior to lithium, and no studies compared CBZ to PLA. Conclusion: The results of the clinical studies suggest that CBZ is effective for the treatment of the manic phase. Regarding the treatment of acute depression and maintenance of BD, the results of the studies indicate that there is not enough data demonstrating the effectiveness of CBZ.

RESUMO Objetivo: Ampliar o conhecimento sobre o papel e a eficácia da carbamazepina (CBZ) no transtorno bipolar (TB), a partir de estudos originais. Métodos: Realizou-se uma revisão sistemática de literatura científica sobre a eficácia da CBZ no TB. Foram utilizadas as bases de dados PubMed/MEDLINE, Web of Science (ISI) e SciELO. Os termos de busca empregados foram: ("carbamazepine") AND ("bipolar" OR "mania" OR "manic"). Não houve restrição quanto ao período de publicação. Resultados: Foram selecionados 27 artigos. Entre os artigos selecionados, 14 avaliavam o uso da CBZ na fase de mania do TB, 2, na fase de depressão do TB e 11, na fase de manutenção do TB. A CBZ, nos estudos na fase de mania do TB, mostrou-se superior ao placebo (PLB). Em relação à fase de depressão no TB, havia dois estudos não controlados e com amostras pequenas. Quanto à fase de manutenção do TB, a CBZ foi inferior ao lítio, e não foram realizados estudos comparando com PLB. Conclusão: Os resultados dos estudos clínicos sugerem que a CBZ é eficaz para o tratamento da fase de mania. Em relação ao tratamento de depressão aguda e manutenção do TB, os resultados dos estudos indicam que não há dados suficientes que demonstrem a eficácia da CBZ.

Paroxysmal Hemicrania-Trigeminal Neuralgia (PH-Tic) syndrome with no structural lesion in a Brazilian woman: the first case-report / Síndrome de Neuralgia Paroxística Hemicrânia-Trigêmea (PH-Tic) sem lesão estrutural em mulher brasileira: primeiro relato de caso

Introduction: In Brazil there is only one case report of a patient diagnosed with Paroxysmal Hemicrania-Trigeminal (PH-Tic) syndrome reported, however it was observed in a patient with Chiari I malformation. Objective: Here, we describe the first case of primary PH-Tic syndrome in the country. Method: Case report. CARE guideline was used to guide the structuring of this article. This case report was approved by the ethics committee and has been registered under the protocol number 70705623.7.0000.5440 on "Plataforma Brasil". Results:A 72-year-old woman with a five-month history of headaches was admitted at our headache outpatient clinic. The pain was sharp, intense, localized in the periorbital and left temporal regions. Blood counts, liver, renal and thyroid function were normal, as well as brain magnetic resonance imaging. Despite using carbamazepine, the patient had pain in only the left side of the face. Indomethacin was added until the dose of 100 mg a day and resulted in improvement of headache frequency. Conclusion: PH-Tic should be hypothesized in patients with short-lasting headaches associated with facial pain that partially improve with carbamazepine or indomethacin.

Introdução: No Brasil há apenas um relato de caso de paciente com diagnóstico de síndrome Paroxística Hemicrania-Trigeminal (PH-Tic), porém foi observado em um paciente com malformação de Chiari I. Objetivo: Descrevemos aqui o primeiro caso de síndrome PH-Tic primária no país. Método: Relato de caso. A diretriz CARE foi utilizada para orientar a estruturação deste artigo. Este relato de caso foi aprovado pelo comitê de ética e registrado sob o número de protocolo 70705623.7.0000.5440 na "Plataforma Brasil". Resultados: Uma mulher de 72 anos com história de cefaleias há cinco meses foi internada em nosso ambulatório de cefaleias. A dor era aguda, intensa, localizada nas regiões periorbital e temporal esquerda. Os hemogramas, as funções hepática, renal e tireoidiana estavam normais, assim como a ressonância magnética cerebral. Apesar do uso de carbamazepina, o paciente apresentava dor apenas no lado esquerdo da face. A indometacina foi adicionada até a dose de 100 mg ao dia e resultou em melhora da frequência da cefaleia. Conclusão: O PH-Tic deve ser hipotetizado em pacientes com cefaleias de curta duração associadas a dores faciais que melhoram parcialmente com carbamazepina ou indometacina.

Drug rash with eosinophilia and systemic symptoms syndrome in an elderly man on carbamazepine � A jeopardising clinical entity

Drug rash with eosinophilia and systemic symptoms syndrome (DRESS) is a rare but serious hypersensitivity drug reaction most frequently associated with antiepileptics. We report a case of carbamazepine-induced DRESS syndrome in a 61-year-old man who was recently initiated on carbamazepine (6 weeks back) and presented with a history of acute febrile illness of 10 days duration. General examination showed multiple erythematous coalescent papules and rash over the body with relative sparing of the face with lymphadenopathy. Laboratory results revealed eosinophilia, atypical lymphocytosis, transaminitis, and negative serology for hepatitis. Registry of severe cutaneous adverse reactions (RegiSCAR) scoring system case is categorized as a definite case with a score of 7. Carbamazepine was discontinued and with the initiation of intravenous steroids; the transaminitis improved, fever and rashes resolved.

Efectos adversos severos de los estabilizadores del ánimo: revisión de la literatura

Introducción: El trastorno bipolar TB es una enfermedad crónica y recurrente, según el DSM 5 se clasifica en los subtipos: trastorno bipolar I, trastorno bipolar II, ciclotimia y categorías residuales de formas atípicas que no encajan en los subtipos antes mencionados. La prevalencia del TB tipo I es similar entre hombres y mujeres, mientras que el TB tipo II ocurre con mayor frecuencia en mujeres. Según la Encuesta nacional de salud mental la prevalencia estimada del trastorno bipolar tipo I en Colombia es del 1,9% en los hombres y del 0,6% en las mujeres, para un porcentaje total de 1,3%. La etiología de TB incluye factores genéticos, neuro bioquímicos, neuro anatómicos, así como médicos y ambientales. El tratamiento del trastorno bipolar se puede dividir en dos fases distintas: manejo de un episodio inicial y tratamiento a largo plazo para prevenir recaídas, los fármacos utilizados comúnmente son: litio, antipsicóticos y anticonvulsivantes. Los estabilizadores del estado del ánimo aceptados por la FDA son: litio, carbamazepina, divalproato, y lamotrigina. Una reacción adversa a medicamentos (RAM) se define como cualquier respuesta nociva y no intencionada a un medicamento, constituye una importante causa de morbimortalidad y de aumento de los costes sanitarios. Los sistemas de farmaco-vigilancia permiten la identificación y prevención de los riesgos asociados al uso de medicamentos. Metodología: Se realizó una búsqueda bibliográfica mediante la base de datos PubMed, utilizando términos MeSH. Los criterios de inclusión utilizados fueron: a) Artículos publicados entre el año 2016 y 2021, b) Idioma inglés o español, c) Población a estudio: pacientes con diagnóstico de trastorno bipolar según criterios del DSM. Resultados: Se encontró que los efectos adversos severos de los estabilizadores del estado del ánimo como la carbamazepina y el ácido valproico son variados, se pueden presentar manifestaciones cutáneas como el síndrome de Stevens-Johnson, necrólisis epidérmica tóxica; manifestaciones hematológicas como anemia aplásica y manifestaciones hepáticas como lo son la hepatotoxicidad e hiperamonemia.

SUMMARY Introduction: Bipolar disorder TB is a chronic and recurrent disease, according to DSM 5 it is classified into subtypes: bipolar I disorder, bipolar II disorder, cyclothymia and residual categories of atypical forms that do not fit into aforementioned subtypes. Prevalence of type I TB is similar between men and women, while type II TB occurs more frequently in women. According to the National Mental Health Survey, estimated prevalence of type I bipolar disorder in Colombia is 1.9% in men and 0.6% in women, for a total percentage of 1.3%. Etiology of TB includes genetic, neuro biochemical, neuro anatomical, as well as medical and environmental factors. Treatment of bipolar disorder can be divided into two phases: management of an initial episode and long-term treatment to prevent relapses, drugs normally used are: Lithium, antipsychotics and anticonvulsants. Mood stabilizers accepted by FDA are: Lithium, carbamazepine, divalproex, and lamotrigine. An adverse drug reaction (ADR) is defined as any harmful and unintended response to a drug, it constitutes a major cause of morbidity and mortality and increased healthcare costs. Pharma-covigilance systems allow identification and prevention of risks associated with use of drugs. Methodology: A graphic search was performed using PubMed database, using MeSH terms. Inclusion criteria used were: a) Articles published between 2016 and 2021, b) English or Spanish language, c) Study population: Patients with a diagnosis of Bipolar Disorder according to DSM criteria. Results: It was found that severe adverse effects of mood stabilizers such as carbamazepine and valproic acid are varied, skin manifestations such as Stevens-Johnson's syndrome, toxic epidermal necrolysis can occur; Hematological manifestations such as aplastic anemia and hepatic manifestations such as hepatotoxicity and hyperammonemia.

Introdução: O transtorno bipolar TB é uma doença crônica e recorrente, segundo o DSM 5 é classificada em subtipos: transtorno bipolar I, transtorno bipolar II, ciclo-timia e categorias residuais de formas atípicas que não se enquadram nos subtipos mencionados. A prevalência de TB tipo I é semelhante entre homens e mulheres, enquanto a TB tipo II ocorre com mais frequência em mulheres. De acordo com a Pesquisa Nacional de Saúde Mental, a prevalência estimada de transtorno bipolar tipo I na Colômbia é de 1,9% nos homens e 0,6% nas mulheres, para um percentual total de 1,3%. A etiologia da TB inclui fatores genéticos, neuro-bioquímicos, neuro-anatômicos, médicos e ambientais. O tratamento do transtorno bipolar pode ser dividido em duas fases distintas: manejo de um episódio inicial e tratamento de longo prazo para prevenção de recidivas, os medicamentos comumente utilizados são: lítio, antipsicóticos e anticonvulsivantes. Os estabilizadores de humor aceitos pela FDA são: lítio, carbamazepina, divalproex e lamotrigina. Uma reação adversa a medicamento (ADR) é definida como qualquer resposta prejudicial e não intencional a um medicamento, é uma das principais causas de morbidade e mortalidade e aumento dos custos de saúde. Os sistemas de farmacovigilância permitem a identificação e prevenção dos riscos associados ao uso de medicamentos. Metodologia: Foi realizada pesquisa bibliográfica na base de dados PubMed, utilizando termos MeSH. Os critérios de inclusão utilizados foram: a) Artigos publicados entre 2016 e 2021, b) Língua inglesa ou espanhola, c) População do estudo: Pacientes com diagnóstico de Bipolar Desordem de acordo com os critérios do DSM. Resultados: Verificou-se que os efeitos adversos graves dos estabilizadores do humor como a carbamazepina e o ácido valpróico são variados, podendo ocorrer manifestações cutâneas como a síndrome de Stevens-Johnson, podendo ocorrer necrólise epidérmica tóxica; Manifestações hematológicas como anemia aplástica e manifestações hepáticas como hepatotoxicidade e hiperamonemia.

Carbamazepine-induced hypersensitivity pneumonitis in a patient with neuromyelitis optica: A case report

A 36-year-old female with serum anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD) on carbamazepine (CBZ) therapy for paroxysmal tonic spasms (PTS) developed Type 1 respiratory failure. High-resolution computed tomography chest showed diffuse ground-glass opacities in both lungs predominantly in bilateral perihilar region sparing subpleural regions and predominantly upper lobes with a smooth interlobular septal thickening. A transbronchial lung biopsy was consistent with hypersensitivity pneumonitis and following withdrawal of the CBZ and treatment with steroids her respiratory symptoms resolved. After stopping CBZ, PTS recurred, which was successfully treated with lacosamide. This is the first described biopsy-proven case of CBZ-induced hypersensitivity pneumonitis in the NMOSD patient.

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.

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

Abstract The cockle Cerastoderma edule was exposed to four concentrations (5, 10, 20 and 70 g 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 g 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.

Resumo O berbigão Cerastoderma edule foi exposto a quatro concentrações (5, 10, 20 e 70 g 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 g 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.

Effects of levetiracetam combined with low-dose topiramate on bone and lipid metabolism in children with epilepsy / 中国基层医药

Objective:To investigate the efficacy of levetiracetam combined with low-dose topiramate on epilepsy and its effects on bone metabolism and lipid metabolism in children.Methods:A total of 108 children with epilepsy who received treatment in the First People's Hospital of Yongkang from August 2016 to December 2019 were included in this study. They were randomly allocated to study and control groups ( n = 54/group). The study group was treated with levetiracetam combined with low-dose topiramate. The control group was treated with carbamazepine combined with low-dose topiramate. Before treatment and half a year after treatment, serum alkaline phosphatase (ALP), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels, blood Ca 2+ and P 3- concentrations, and bone mineral density (BMD) were determined. Clinical efficacy was evaluated in each group. Results:Half a year after treatment, blood Ca 2+ concentration, blood P 3- concentration, and BMD in the study group were (2.41 ± 0.35) mmol/L, (1.57 ± 0.26) mmol/L, and (2.21 ± 0.52) g/cm2, respectively, which were significantly greater than those in the control group [(2.19 ± 0.27) mmol/L, (1.18 ± 0.15) mmol/L, (1.81 ± 0.38) g/cm, tca2+ = 4.20, tbloodP3- = 5.73, tBMD = 6.42, all P < 0.05). ALP level was significantly lower in the study group than in the control group [(129.78 ± 25.63) U/L vs. (181.55 ± 21.94) U/L, t = 15.39, P < 0.05). Half a year after treatment, TC, TG, and LDL-C levels in the study group were (4.38 ± 0.64) mmol/L, (1.71 ± 0.42) mmol/L, and (1.65 ± 0.32) mmol/L, respectively, which were significantly lower than those in the control group [(4.76 ± 0.83) mmol/L, (1.96 ± 0.45) mmol/L, (1.98 ± 0.34) mmol/L, tTC = 3.81, tTG = 4.14, tLDL-C = 5.58, all P < 0.05]. HDL-C level in the study group was significantly higher than that in the control group [(1.96 ± 0.38) mmol/L vs. (1.63 ± 0.27) mmol/L, tHDL-C = 7.39, P < 0.05]. Half a year after medication, clinical efficacy was significantly higher in the study group than that in the control group (94.44% vs. 81.48%, χ2 = 6.29, P < 0.05). Conclusion:Low-dose topiramate combined with levetiracetam is highly effective on epilepsy in children. The combined therapy has less impact on the levels of bone and lipid metabolism indicators and is suitable for clinical application.

Establishment of the method for simultaneous determination of levetiracetam and carbamazepine in human plasma / 中国药房

OBJECT IVE To e stablish the method for simultaneous determination of levetiracetam and carbamazepine concentrations in human plasma. METHODS After plasma samples were precipitated with methanol ，using carbamazepine-D 10 as the internal standard ，the concentrations of levetiracetam and carbamazepine were determined by high performance liquid chromatography-tandem mass spectrometry （HPLC-MS/MS）. The determination was performed on XBridge BEH C 18 column with methanol-0.1％ formic acid as mobile phase （gradient elution ）at the flow rate of 0.35 mL/min. The column temperature was set at 40℃，and sample size was 2 μL. With electrospray ion source，a multiple reaction monitoring mode was used for positive ion scanning；the detected ion pairs for quantitative analysis were m/z 171.3→126.3（levetiracetam），m/z 237.1→194.1（carbamazepine）， 247.1→204.1（internal standard ）. RESULTS The linear range of the concentrations of levetiracetam and carbamazepine were 0.5-50 and 0.2-20 μg/mL（r＝0.997 3 and 0.998 5），respectively；the lower quantitative limits were 0.5 and 0.2 μg/mL，respectively. RSDs of intra-day and inter-day were all no more than 10.00％. RE of intra-day and inter-day were within ±4.00％；the average extraction recoveries rate were 95.60％-105.00％；the average internal standard correction matrix factors were 98.40％-110.00％； RSDs of stability tests were all not higher than 5.60％. The concentrations of levetiracetam and carbamazepine in the plasma of 22 patients measured by this method were 3.36-40.90 and 3.64-9.93 μg/mL，respectively. CONCLUSIONS The established method for determining the concentration of levetiracetam and carbamazepine in human plasma is f ast，sensitive，accurate and stable ，and can be used for the monitoring of plasma concentration and pharmacokinetic study in epilepsy patients.

Síndrome de reacción a fármacos con eosinofilia y síntomas sistémicos inducido por carbamazepina de liberación prolongada: reporte de un caso

El síndrome de reacción a fármacos con eosinofilia y síntomas sistémicos es una reacción de hipersensibilidad a fármacos poco común, pero con una alta mortalidad, por ello se requiere un diagnóstico precoz y un manejo oportuno. Presentamos el caso de una mujer de 32 años con diagnóstico de epilepsia y trastorno esquizofreniforme orgánico, secundarios a encefalitis viral, y que ha recibido tratamiento con múltiples fármacos. Tres semanas después de añadir carbamazepina de liberación prolongada a su terapia habitual, la paciente presentó una erupción cutánea difusa tipo habón, edema facial, fiebre, linfadenopatía, leucocitosis con eosinofilia y elevación de las transaminasas. La administración de la carbamazepina fue suspendida, se administró antihistamínicos y glucocorticoides por vía oral, y la paciente mejoró.

The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but highly lethal drug hypersensitivity reaction. Thus, it requires an early diagnosis and timely management. We present the case of a 32-year-old female patient with a diagnosis of epilepsy and organic schizophreniform disorder, secondary to viral encephalitis, who was treated with multiple drugs. Three weeks after the addition of extended-release carbamazepine to her usual therapy, the patient presented a diffuse welt-type skin rash, facial edema, fever, lymphadenopathy, leukocytosis with eosinophilia and elevated transaminases. Carbamazepine administration was discontinued, antihistamines and glucocorticoids were administered orally, and the patient showed a remarkable improvement.

Current status and standardization conception of the testing quality of therapeutic drug monitoring samples / 中华检验医学杂志

Accurate determination of drug concentration in blood samples is a necessary prerequisite for therapeutic drug monitoring (TDM) and the implementation of precise drug treatment, and it is also one of the important tasks of clinical laboratories.TDM plays an important role in clinical treatment in immunosuppressants (cyclosporine A, tacrolimus), psychotropic drugs (valproic acid, carbamazepine) and other drugs that require monitoring of drug concentration. There are many types of methods used for TDM for the detection of drug concentration in blood samples. At present, only a few immuno-assay methods were approved for marketing with detection systems and kits, most methods used for TDM are high performance liquid chromatography or liquid chromatography-tandem mass spectrometry which belong to laboratory developed tests (LDTs). Detection of TDM samples has many problems, such as incomparable testing results and large bias between different testing systems, including the biasbetween both different methods and different laboratories using the same method. There are several reasons:(1) the traceability chain has not been established, (2) the methods have not yet been standardized, (3) the coverage of the EQA plan is insufficient, (4) the awareness of TDM laboratories to participate in the EQA plan is insufficient, (5) TDM standardization is still in its infancy. These problems restrict the clinical application of TDM and the development of related research work. In order to solve these problems, it is necessary to: (1) Establish a reference system to realize the traceability of the test results; (2) While gradually increasing the TDM EQA plan items, the Trueness evaluation plan should be carried out as soon as possible; (3) Standardized TDM sample testing Technology; (4) Strengthen laboratory management and establish a complete quality management system.

Two Cases Report of Trigeminal Neuralgia Successfully Treated with a Kampo Formulation Tokishigyakukagoshuyushokyoto / 日本東洋医学雑誌

The authors experienced two cases of trigeminal neuralgia successfully treated by a Kampo formulation tokishigyakukagoshuyushokyoto (TSG). Case 1 is 70-year-old woman who complained of severe pain on the right side of her face. She was administered carbamazepine. It was effective for the facial pain but she could not take it continuously because of side effect, namely ataxia. Therefore, we tried to administer TSG. This Kampo formulation proved effective, and her pain was controlled without carbamazepine. Case 2 is 69-year-old woman who complained of localized pain on the right side of her face. In this case TSG alone was effective.

Reporte de caso: purpura diseminada como primera manifestación de síndrome de dress / Case report: purpuriform lesions as the first manifestation of dress syndrome

RESUMEN El síndrome de DRESS es una reacción adversa severa a fármacos presentándose más comúnmente con anticonvulsivantes y antibióticos. Se estima que su mortalidad alcanza el 10%; clínicamente se presenta con fiebre, linfadenopatías, erupciones cutáneas morbiliformes y compromiso deórganos terminal. Las reacciones adversas cutáneas medicamentosas se presentan en más de la mitad de los pacientes que están recibiendo medicamentos sistémicos tales como la carbamazepina.

SUMMARY DRESS syndrome is a severe adverse reaction to medicament which is most commonly presentedwith anticonvulsants and antibiotics. It is estimated that the mortality reaches10%;clinically the patients presentit with fever, lymphadenopathies, morbilliform cutaneous eruptions and terminal organ involvement. Adverse skin reactions to medications occur in more than half of patients who have received systemic medications, such as anticonvulsants.

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.

Design and Synthesis of New Derivatives of (E)-3-(5-((phenylamino)methyl)-1,3,4-thiadiazol-2-yl)-2-styrylquinazolin-4(3H)-one for their Anticonvulsant Potential

Objective: The objective of the paper was to design and synthesize new derivatives of ((E)-3-(5-((substitutedphenylamino)methyl)-1,3,4-thiadiazol-2-yl)-2-styrylquinazolin-4(3H)-one and evaluated for their anticonvulsant potential. Materials and Methods: Various synthesis of (E)-3-(5-(substitutedaminomethyl)-1,3,4-thiadiazol-2-yl)-2-styrylquinazolin-4(3H)-one derivatives has been synthesized by reacting 2-substituted benzoxazin-4-one with (E)-2-(4-Substituedstyryl)-4H-benzo[d] [1,3]oxazin-4-one. All synthesized compounds have been characterized by the infrared, 1HNMR, and mass spectral analysis. Proposed compounds have been evaluated for anticonvulsant potential by subcutaneous pentylenetetrazole and maximal electroshock seizure model and compared with the reference drug phenytoin and carbamazepine. Neurotoxicity study of the synthesized compounds was also performed. Results and Discussion: The anticonvulsant evaluation of synthesized compound QNM-1, QNM-2, QNM-4, QNM-6, QNM-9, QNM-11, QNM-13, and QNM-15 has shown seizure protection at 100 mg/kg dose after 30 min and 4 h, so they have good onset of action as quickly reach brain and have prolonged action reveal that compound metabolized slowly. Whereas compound QNM-7, QNM-8, and QNM-12 were moderate active and reveal that their high concentration is required to cross blood brain barrier. Compounds QNM-3, QNM-5, QNM-10, and QNM-14 were less active. Compounds having chlorine, bromine, fluorine, and nitro in the phenyl moiety have shown good activity when attached to para group but the addition of meta and ortho group of the same may provide least active compounds and in last fluorine compounds have shown comparative less active compounds. Conclusion:The Pharmacological evaluation suggest that eight synthesized compounds have shown promising anticonvulsant potential and bulkier compounds can easily penetrate BBB to exert their effect.