Manejo del estado epiléptico en niños: encuesta en hospitales pediátricos de la Ciudad Autónoma de Buenos Aires / Management of status epilepticus in childhood: a survey conducted at pediatric hospitals in the City of Buenos Aires

Introducción. El estado epiléptico constituye la emergencia neurológica más frecuente. Si bien la mortalidad en niños es baja, su morbilidad puede superar el 20 %. Objetivo. Conocer las pautas de manejo del estado epiléptico referidas por médicos pediatras que atienden esta patología en forma habitual. Población y métodos. Estudio descriptivo, transversal, basado en una encuesta a médicos de tres hospitales pediátricos monovalentes de gestión pública de la Ciudad Autónoma de Buenos Aires. Resultados. Se administraron 292 encuestas (la tasa de respuesta completa alcanzó el 86 %); el 77 % se administró a pediatras y el 16 %, a especialistas en cuidados intensivos. Un 47 % de los participantes refiere indicar la primera benzodiacepina en el tiempo correcto; el 56 % utilizar diazepam intrarrectal en ausencia de un acceso intravenoso; el 95 % elige lorazepam como benzodiacepina inicial en caso de contar con acceso intravenoso; el 58 % refiere iniciar la etapa de fármacos de segunda línea en tiempo adecuado; el 84 % opta por fenitoína como fármaco inicial de segunda línea, un 33 % no cronometra el tiempo durante el tratamiento. La adherencia global a las recomendaciones internacionales fue del 17 %. Conclusiones. Nuestro estudio advierte una baja adherencia referida de los pediatras a las guías internacionales, en particular en las decisiones tiempo-dependientes. También se observó mayor heterogeneidad en las conductas terapéuticas a medida que se avanza en el algoritmo de tratamiento.

Introduction. Status epilepticus is the most common neurological emergency. Although mortality in children is low, morbidity may exceed 20%. Objective. To evaluate the management of status epilepticus by pediatricians who usually treat this condition. Population and methods. Descriptive, cross-sectional study based on a survey administered to physicians from 3 pediatric hospitals in the City of Buenos Aires. Results. A total of 292 surveys were administered (complete response rate as high as 86%); 77% were administered to pediatricians and 16% to intensive care specialists. Forty-seven percent of the participants reported that they administer the first dose of a benzodiazepine within the correct timeframe; 56% use intrarectal diazepam when intravenous access is not available; 95% choose lorazepam as the initial benzodiazepine if an intravenous access is available; 58% initiate the administration of a second-line drug within the correct timeframe; 84% administer phenytoin as the first-choice, second-line drug; and 33% do not measure treatment time. Overall adherence to international recommendations was 17%. Conclusions. Our study highlights poor adherence of pediatricians to international guidelines, particularly in time-dependent decisions. Greater heterogeneity was observed in treatment approaches as the treatment algorithm progressed.

Produção de fumo e insônia: relato de caso sobre os determinantes socioeconômicos para o uso contínuo de benzodiazepínicos em uma zona rural no Sul do Brasil / Tobacco production and insomnia: case report on socioeconomic determinants of the continuous use of benzodiazepines in a rural area in southern Brazil / Producción de tabaco e insomnio: Reporte de caso sobre determinantes socioeconómicos del uso continuo de benzodiacepinas en una zona rural del sur de Brasil

Introdução: A fumicultura concentra-se sobretudo em áreas rurais do Sul do país. Reconhecidamente, as áreas rurais apresentam disparidades socioeconômicas, desigualdades no acesso geográfico, bem como dificuldade de retenção de profissionais na Atenção Primária à Saúde (APS). Apresentação do caso: Descrevem-se, neste artigo, as intersecções de determinantes socioeconômicos de saúde ao se abordar um paciente masculino, de 57 anos, em uso crônico de benzodiazepínicos para o tratamento de insônia. Ao se aprofundar a anamnese, os determinantes socioeconômicos que levaram ao desenvolvimento da insônia foram identificados como: dificuldades financeiras na produção de tabaco, preocupações excessivas com o trabalho e presença de depressão como comorbidade. Nesse sentido, ser produtor de tabaco e a relação com a empresa podem ser considerados determinantes socioeconômicos da saúde para o desenvolvimento de insônia. Conclusões: No contexto deste caso, a rotatividade de profissionais e a falta de criação de vínculo fez com que o paciente permanecesse cronicamente a tratar a insônia como benzodiazepínico, o que é proscrito. Assim, revelam-se a fragmentação do cuidado e a alta rotatividade de profissionais como determinantes socioeconômicos da saúde.

Introduction: Tobacco production is mainly concentrated in rural areas of the southern region of the country. Rural areas present socioeconomic disparities, inequalities in geographic access, and difficulties in retaining professionals in primary care. Mental health problems, such as insomnia, are common in clinical practice. Case presentation: This article describes the intersections of the social determinants of health when approaching a patient with chronic use of benzodiazepines for treatment of insomnia. By delving deep into anamnesis, the socioeconomic determinants that led to the development of insomnia were identified as: financial trouble with tobacco production, excessive concern about work and presence of depression as comorbidity. Conclusions: In this context, the turnover of health professionals and lack of doctor-patient relationship meant that the patient continued using benzodiazepines, which are not recommended for long-term treatment. Therefore, fragmented care and high professional turnover stand out as socioeconomic determinants of health.

Introducción: La producción de tabaco se concentra principalmente en las zonas rurales del sur del país. Se reconoce que las zonas rurales presentan desigualdades socioeconómicas, desigualdades en el acceso geográfico, así como dificultad para retener profesionales en Atención Primaria de Salud (APS). Los problemas de salud mental como el insomnio son comunes en la práctica clínica. Presentación de caso: Este artículo describe las intersecciones de los determinantes socioeconómicos de la salud al abordar a un paciente uso crónico de benzodiazepinas para el tratamiento del insomnio. Al profundizar la anamnesis, se identificaron los determinantes socioeconómicos que llevaron al desarrollo del insomnio como: dificultades económicas en la producción de tabaco, excesiva preocupación por el trabajo y la presencia de depresión como comorbilidad. En este sentido, ser productor de tabaco y la relación con la empresa pueden considerarse determinantes socioeconómicos de la salud para el desarrollo del insomnio. Conclusiones: En el contexto de este caso, la rotación de profesionales y la falta de vinculación hicieron que el paciente continuara crónicamente tratando el insomnio como una benzodiazepina, lo que no es recomendable. Así, la fragmentación de la atención y la alta rotación profesional se evidencia como un determinante socioeconómico de la salud.

Pharmacotherapy used for alcohol and cocaine use disorders in a CAPS-AD of Minas Gerais

Abstract Substance use disorder is one of the major social and public health problems in the world. The present study analyzed the pharmacoepidemiological profile of patients treated at the Psychosocial Treatment Center for Alcohol and Substance Use Disorders (CAPS-AD) for treatment of alcohol use disorders (AUD), cocaine use disorders (CUD) and concomitant alcohol and cocaine use disorders (A-CUD) in the city of Betim-MG. The study used quantitative and descriptive data and was based on the evaluation of medical records of patients attended from January to December 2016. After analyzing 295 medical records, the majority of study participants were male (83.7 %) with an average age of 46.26 for AUD, 28.88 for CUD and 34.29 for A-CUD. The most prescribed drugs for AUD were diazepam (54.1 %), thiamine (37 %), complex B vitamins (29.5 %), and disulfiram (2.7 %); for CUD, diazepam (26.9 %) and haloperidol (23.1 %). It should be noticed that although contraindicated by the guidelines, chlorpromazine (42.3 %, 25.3 %, 20.3 %) was prescribed for CUD, AUD, and A-CUD respectively. Knowing the pharmacoepidemiological profile of CAPS-AD patients is extremely important for making decisions regarding which medicines to make available to the population.

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.

Effects of Oral Diazepam or Inhalatory Nitrous OxideOxygen for Conscious Sedation During Third Molar Surgery: A Randomized Controled Trial, Split Mouth Design / Efectos del Diazepam Oral o la Inhalación de Óxido Nitroso-Oxígeno para la Sedación Consciente Durante la Cirugía del Tercer Molar: Un Ensayo Controlado Aleatorio, Diseño de Boca Dividida

ABSTRACT: Anxiety in dental surgery may lead to behavioral and physiological changes for the patient and constitute a frequent challenge for the oral surgeon. The objective of this study was to compare the effect of inhalatory nitrous oxide and oxygen (N2O/O2) with oral diazepam conscious sedation in vital signs of patients undergone third molar extraction. Outpatients who needed removal of partially impacted, bilateral lower third molars, during the period of one year, were included. Each patient underwent conscious sedation with either oral diazepam or inhalatory N2O/O2 on a randomized controlled trial, split-mouth design. Systolic and diastolic blood pressure, heart rate and oxygen blood saturation were the changes measured before, at the beginning and the end of the procedure. Also, surgical procedure duration was recorded. Data from vital signs were submitted to analysis of variance and the duration of the surgery to paired Student's t-test. Twenty-five healthy outpatients (13 women and 12 men) with a mean age of 21.6 years were studied. There was an increase in systolic and diastolic pressure and in heart rate in the beginning; these values decreased and stabilized at the end of the surgical procedure in both treatments (p < 0.001) being lower in N2O/O2 but without difference between treatments. The surgical procedure duration was lower and occurred an expected increase of oximetry under N2O/O2 sedation (p < 0.001). Both treatments were effective for the conscious sedation but N2O/O2 showed better outcomes, mainly in duration of the surgery.

RESUMEN: La ansiedad en la cirugía dentoalveolar puede conducir a alteraciones fisiológicas y de comportamiento en el paciente, constituyendo así un desafío frecuente para el cirujano maxilofacial. El objetivo de este estudio fue comparar el efecto del óxido nitroso inhalatorio con oxígeno (N2O/O2) y la sedación consciente oral con diazepam por médio de los signos vitales de pacientes sometidos a la extracción del tercer molar. Fueron incluídos pacientes ambulatoriales com necesidad de exodoncia de terceros molares inferiores bilaterales, parcialmente impactados, durante el período de un año. Cada paciente fue sometido a sedación consciente con diazepam oral o N2O/O2 por inhalación en un ensayo controlado aleatorio, diseño de boca dividida. La presión arterial sistólica y diastólica, la frecuencia cardíaca y la saturación de oxígeno en la sangre fueron medidos antes, al inicio y al final del procedimiento. Además, se registró la duración del procedimiento quirúrgico. Los datos de los signos vitales fueron enviados para análisis de varianza y la duración de la cirugía para la prueba t de Student pareada. Se estudiaron 25 pacientes ambulatorios sanos (13 mujeres y 12 hombres) con una edad media de 21,6 años. Al início hubo un aumento en la presión sistólica y diastólica y en la frecuencia cardíaca; estos valores disminuyeron y se estabilizaron al final del procedimiento quirúrgico en ambos tratamientos (p <0,001), siendo más bajos en N2O/ O2 pero sin diferencia entre los tratamientos. La duración del procedimiento quirúrgico fue menor y se produjo un aumento esperado de la oximetría bajo sedación con N2O/O2 (p <0,001). Ambos tratamientos fueron efectivos para la sedación consciente, pero el N2O/O2 mostró mejores resultados, principalmente en la duración de la cirugía.

Antinociceptive activity of Thyme (Thymus vulgaris L. ) and interactions with neurotropics and analgesics

The plant world represents an important source of potential therapeutic agents, but concomitant administration of herbal and conventional medications may result in interactions with subsequent beneficial or adverse effects. This study was designed to examine the analgesic effect of thyme tincture and thyme syrup, two commonly used thyme formulations, and their interactions with codeine, paracetamol, pentobarbital and diazepam in mice. The identification and quantification of thymol and carvacrol were carried out by GC/MS and GC/FID. The analgesic activity was studied using a hot plate method. Effects of thyme syrup on diazepam-induced motor coordination impairment in rotarod test and on pentobarbital-induced sleeping time were also determined. Thymol (175.3 µg/mL and 9.73 µg/mL) and carvacrol (10.54 µg/mL and 0.55 µg/mL) concentrations were measured in tincture and syrup, respectively. Thyme syrup and tincture exhibited effective analgesic activity in the hot plate pain model. Pretreatment with thyme formulations reduced analgesic activity of codeine, and potentiated the analgesic activity of paracetamol. Co-administration of thyme formulations has led to potentiation of diazepam and pentobarbital depressive central nervous system effects. Thyme formulations interacted with tested conventional drugs, probably through interference with their metabolic pathways and succeeding altered concentrations and pharmacological effects.

Spatiotemporal expression of RCAN1 and its isoform RCAN1-4 in the mouse hippocampus after pilocarpine-induced status epilepticus

Regulator of calcineurin 1 (RCAN1) can be induced by an intracellular calcium increase and oxidative stress, which are characteristic features of temporal lobe epilepsy. Thus, we investigated the spatiotemporal expression and cellular localization of RCAN1 protein and mRNA in the mouse hippocampus after pilocarpine-induced status epilepticus (SE). Male C57BL/6 mice were given pilocarpine hydrochloride (280 mg/kg, i.p.) and allowed to develop 2 h of SE. Then the animals were given diazepam (10 mg/kg, i.p.) to stop the seizures and sacrificed at 1, 3, 7, 14, or 28 day after SE. Cresyl violet staining showed that pilocarpine-induced SE resulted in cell death in the CA1 and CA3 subfields of the hippocampus from 3 day after SE. RCAN1 immunoreactivity showed that RCAN1 was mainly expressed in neurons in the shammanipulated hippocampi. At 1 day after SE, RCAN1 expression became detected in hippocampal neuropils. However, RCAN1 signals were markedly enhanced in cells with stellate morphology at 3 and 7 day after SE, which were confirmed to be reactive astrocytes, but not microglia by double immunofluorescence. In addition, real-time reverse transcriptase–polymerase chain reaction showed a significant upregulation of RCAN1 isoform 4 (RCAN1-4) mRNA in the SE-induced hippocampi. Finally, in situ hybridization with immunohistochemistry revealed astrocytic expression of RCAN1-4 after SE. These results demonstrate astrocytic upregulation of RCAN1 and RCAN1-4 in the mouse hippocampus in the acute and subacute phases of epileptogenesis, providing foundational information for the potential role of RCAN1 in reactive astrocytes during epileptogenesis.

Polifarmácia e cognição em pacientes com idade avançada / Polypharmacy and cognition in elderly patients

Objetivo: Avaliar a prevalência da polifarmácia e da prescrição de medicações inapropriadas, bem como suas associações com a capacidade cognitiva e funcional do idoso. Métodos: Estudo observacional transversal, no qual foram analisadas as medicações prescritas em 141 prontuários para pacientes acima de 50 anos, em associação com testes que quantificaram a capacidade funcional e cognitiva deles. Resultados: Observou-se média de 4,41 medicamentos por paciente, sendo que 0,41 deles foram considerados inapropriado, segundo o critério de Beers. Verificou-se também relação estatisticamente significativa quanto ao número de medicações e testes que mediam a capacidade funcional e cognitiva dos idosos. Conclusão: O aumento da polifarmácia e da prescrição de medicações potencialmente inadequadas acarretou significativa piora da capacidade cognitiva e funcional do idoso

Objective: To evaluate the prevalence of polypharmacy and of the prescription of inappropriate medications, as well as their associations with the cognitive and functional capacity of the elderly. Methods: Cross-sectional observational study which analyzed the drugs prescribed in 141 medical records for patients over 50 years of age, associated with tests that quantified their functional and cognitive capacity. Results: An average of 4.41 medications per patient was observed, and 0.41 were considered inappropriate according to the Beers criteria. There was also a statistically significant relation regarding the number of medications and tests that measure the functional and cognitive capacity of the elderly. Conclusion: The increase in polypharmacy and in the prescription of potentially inappropriate medications led to a significant impairment of the cognitive and functional capacity of the elderly

Drug interactions in maternal intensive care: prevalence, risk factors, and potential risk medications / Interações medicamentosas em terapia intensiva materna: prevalência, fatores e medicamentos de risco

ABSTRACT Objective: To characterize severe potential drug interactions in maternal intensive care, and to determine their frequency, risk factors and potential risk medications. Methods: An observational and longitudinal study conducted between December 2014 and December 2015 in a maternal intensive care unit. Clinical data were collected and severe potential drug interactions were identified on pregnant inpatients. The drug interactions were classified by type, prevalence and exposure rate. A multivariate logistic regression model was used to identify the severe potential drug interactions and the related drugs (p<0.05). Results: A total of 95.1% of patients were exposed to, at least, one potential drug interaction; in that, 91.7% 33.9% were related to, respectively, moderate and severe potential drug interactions. The patients were exposed, on average, on 69.2% of days they were in the intensive care unit. The main drugs involved in more severe drug interactions were magnesium sulfate, metoclopramide, propranolol and diazepam. Conclusion: The severe potential drug interactions were observed in almost all patients of the study, and, approximately one third of those interactions were related to greater severity and resulted in exposure during long hospital stay. The higher number of prescribed drugs and its previous use of medications at home increase the occurrence of severe potential drug interactions.

RESUMO Objetivo: Caracterizar as interações medicamentosas potenciais graves em terapia intensiva materna, e determinar sua frequência, os fatores e os medicamentos de risco associados à ocorrência dessas interações. Métodos: Estudo observacional e longitudinal executado entre dezembro de 2014 a dezembro de 2015, conduzido em uma unidade de terapia intensiva materna. Foram coletados dados clínicos e identificadas interações medicamentosas potenciais graves de gestantes admitidas. As interações medicamentosas foram caracterizadas quanto ao tipo, à prevalência e à taxa de exposição. Um modelo multivariado de regressão logística foi utilizado para identificação de fatores associados à ocorrência de interações medicamentosas potenciais graves e os medicamentos implicados (p<0,05). Resultados: Um total de 95,1% das pacientes foi exposto a, no mínimo, uma interação medicamentosa potencial, com 91,7% delas envolvidas com interações medicamentosas potenciais moderadas e 33,9% com as interações graves. As pacientes ficaram expostas, em média, em 69,2% dos dias que estiveram sob terapia intensiva. Os principais medicamentos implicados em interações medicamentosas de maior gravidade foram sulfato de magnésio, metoclopramida, propranolol e diazepam. Conclusão: As interações medicamentosas potenciais graves ocorreram na maioria das pacientes avaliadas. Aproximadamente um terço das interações foram graves e levaram à maior exposição por um longo período de internação. Maior número de fármacos prescritos e uso prévio domiciliar de medicamentos elevam a ocorrência de interações medicamentosas potenciais graves.

Segurança do paciente: potenciais interações medicamentosas favorecidas pela sobreposição de medicamentos aprazados pelo enfermeiro / Patient safety: potential drug interactions favored by overlapping of medications scheduled by nurses

A terapêutica medicamentosa tem predomínio no ambiente hospitalar, apresenta-se em um contexto com inúmeras possibilidades para incidentes e assim, mais desafiador para interceptar situações que comprometam uma assistência de qualidade. O enfermeiro possui a responsabilidade sobre o processo de medicação e ocupam papel essencial na detecção e prevenção das interações medicamentosas ao adequar os horários durante o aprazamento. Este estudo teve por objetivo investigar as potenciais interações medicamentosas favorecidas pela sobreposição de medicamentos aprazados por enfermeiros nas prescrições de pacientes em unidade de internação clínica. Trata-se de um estudo descritivo, transversal, de análise documental com abordagem quantitativa com 260 prescrições medicamentosas. Foram selecionadas, por conveniência, prescrições de pacientes adultos de duas unidades de internação clínica de um hospital universitário localizado no Rio de Janeiro durante o mês de setembro de 2019. Os dados foram analisados por meio de estatística descritiva através do Microsoft Excel e as potenciais interações medicamentosas foram identificadas por meio da ferramenta Drug Interactions (Medscape®). Foi aprovado pelo Comitê de Ética em Pesquisa, da referida instituição sob o parecer: 3.556.571. Foram 3066 doses analisadas com concentração de quatro horários (10h, 18h, 22h e 06h) evidenciando aprazamento institucional padronizado. A via oral foi a mais predominante (74%). Os motivos para a omissão de dose foram: 60,3% sem justificativas, 22,8% não havia o medicamento ou não era padronizado e em 5,3% das doses, o horário estava ausente e as principais classes envolvidas foram: aparelho digestivo e metabolismo (38,6%), anti-infecciosos gerais para uso sistêmico (15,9%) e sistema nervoso (15,3%). A taxa de erros de medicação foi 5,44. Quanto ao tipo de prescrição, houve predomínio de prescrições pré-digitadas (n=194, 74,61%), apenas 3 (1,15%) foram escritas à mão e 63 (24,23%) foram mistas. As interações medicamentosas potenciais com menor gravidade foram ácido valproico/ isoniazida e carbonato de cálcio/ aspirina ambos com 19,7%, com gravidade moderada foram lopinavir/ clonazepam (11,9%) e diazepam/ tramadol (7,3%) e com risco grave foram isoniazida/ omeprazol (12,3%) e com 2,8% rifampicina/ dexametasona. A equipe de enfermagem deve considerar o cuidado centrado no paciente com aprazamento mais próximo às necessidades individuais, inclusive na preservação do sono e evitando a sobreposição medicamentosa, comunicação verbal e escrita adequada, a utilização de bases de dados como ferramenta de apoio à decisão clínica, realização da dupla checagem, elaboração de um guia de aprazamento, bem como um ambiente reservado para sua realização e a configuração do processo de trabalho quanto à organização, distribuição e acondicionamento dos medicamentos de forma adequada.

Drug therapy is predominant in the hospital environment, presenting itself as a context subject to numerous incidents possibilities, therefore, it's more challenging to intercept situations that compromise the quality of care. The nurse is responsible for the medication process and plays an essential role in detecting and preventing drug interactions by the adjustment of the schedules during the scheduling. The aim of this study was to investigate the potential drug interactions favored by overlapping of medications scheduled by nurses in patients' prescriptions at a clinical inpatient unit. This is a descriptive cross-sectional study of document analysis, through a quantitative approach with 260 drug prescriptions. For convenience, the prescriptions selected were those from adult patients from two inpatient units of a university hospital located in Rio de Janeiro, during September 2019. Data were analyzed through descriptive statistics using Microsoft Excel, and the potential drug interactions were identified using the Drug Interactions tool (Medscape®). The present work was approved by the Ethics and Research Committee of the mentioned institution under the peer review: 3,556,571. There were 3066 analyzed doses, with a concentration of four hours (10h, 18h, 22h and 06h) showing standardized institutional schedule. The oral route was the most predominant (74%). The reasons for dose omission were: 60.3% without justification; in 22.8%, there was no medication, or it was not standardized; and, in 5.3% of doses, the time was absent. The main classes involved were: digestive tract and metabolism (38.6%), general anti-infectives for systemic use (15.9%) and nervous system (15.3%). The medication error rate was 5.44. Regarding the type of prescription, there was a predominance of preset prescriptions (n=194, 74.61%); only 3 (1.15%) were handwritten, and 63 (24.23%) were mixed. The potential drug interactions with lower severity were valproic acid/ isoniazid and calcium carbonate/ aspirin, both with 19.7%; those with moderate severity were lopinavir/ clonazepam (11.9%) and diazepam/ tramadol (7.3%); and the ones with severe risk were isoniazid/ omeprazole (12.3%) and rifampicin/ dexamethasone (2.8%). Nursing staff must consider patient-centered care by adopting a medication schedule closer to the patient's individual needs, including sleep preservation and avoiding drug overlap; a proper verbal and written communication; the use of databases as a clinical decision support tool; double checking; the elaboration of a scheduling guide, as well as a reserved environment for its accomplishment; and the configuration of the work process regarding the organization, the distribution and a proper packaging of the medications.

Síndrome de la persona rígida / Stiff-man syndrome

El síndrome de la persona rígida es un trastorno neurológico infrecuente y desconcertante, caracterizado por contractura progresiva, rigidez y espasmos dolorosos que afectan la musculatura axial, lo que imposibilita la deambulación del paciente. Se presenta un paciente masculino de 22 años de edad con manifestaciones clínicas y electromiográficas compatibles con esta entidad nosológica. El tratamiento descrito para la enfermedad no produjo mejoría de los síntomas. Con respecto a los casos descritos en la literatura científica, es el primer paciente con diagnóstico de síndrome de la persona rígida que ha recibido una dosis de diazepam de 500 mg diarios por vía oral sin efectos adversos y una dosis en bolo de propofol de 800 mg para lograr la relajación muscular(AU)

Stiff-Man Syndrome is an uncommon and disturbing neurological disorder characterized by progressive contracture, stiffness and painful spasms that affect the axial musculature, making it impossible for the patient to walk around. We present a 22-year-old male patient with clinical and electromyographic manifestations compatible with this nosological disease. The treatment described for the disease did not produce an improvement in symptoms. Regarding the cases described in the scientific literature, this is the first patient diagnosed with Stiff-Man Syndrome who has received a dose of diazepam of 500 mg daily orally without adverse effects and a bolus dose of 800 mg of propofol to achieve muscle relaxation(AU)

Oral lactate intensifies insulin toxicity during severe insulin-induced hypoglycemia in mice

ABSTRACT We investigated whether oral lactate could prevent seizures and deaths in mice with severe hypoglycemia induced by a high dose of insulin. For this purpose, mice were fasted for 15 h and then given an intraperitoneal injection of regular insulin (5.0 U/kg or 10.0 U/kg). Immediately after insulin injection, the mice received an oral dose of saline (control), glucose (5.5 mmol/kg), or lactate (18.0 mmol/kg). Glucose and lactate levels were measured in the blood and brain before and after the seizures began. Glucose and lactate delayed (p < 0.05) the onset of seizures associated with severe insulin-induced hypoglycemia. Elevated (p < 0.05) brain levels of lactate were associated with an absence of seizures in mice that received glucose or lactate, suggesting that lactate could prevent convulsions associated with severe insulin-induced hypoglycemia. However, the same oral dose of lactate that delayed the onset of convulsions also increased the mortality rate. In contrast, diazepam (3.0 mg/kg) prevented seizures and markedly decreased the frequency of death during severe insulin-induced hypoglycemia. The results demonstrated that in contrast to oral glucose, oral lactate intensifies insulin toxicity.

Interferência do TSPO sobre as vias de ativação de adipócitos da linhagem 3T3-L1 / Interference of TSPO upon the activation pathways of 3T3-L1 adipocytes

A obesidade está associada a um processo inflamatório crônico de baixa intensidade e representa um dos fatores de risco para o desenvolvimento de uma série de comorbidades. A proteína TSPO está envolvida em inúmeras funções celulares, incluindo biossíntese e transporte de esteróides, transporte de porfirinas, apoptose, biossíntese do heme, processos oxidativos e imunomodulação. Ademais, a presença e a função da proteína TSPO no tecido adiposo e na inflamação ainda não estão bem estabelecidas. Deste modo, o objetivo do presente estudo foi validar a expressão e função do TSPO durante a diferenciação de células 3T3-L1, e investigar se o tratamento de adipócitos 3T3-L1 com diazepam, um benzodiazepínico de ação central (GABAA) e periférica (TSPO), é capaz de modular os efeitos inflamatórios induzidos pela incubação das células 3T3-L1 com TNF-α. Nossos resultados evidenciaram que, em nosso estudo, o tratamento de pré-adipócitos com diazepam não modulou a adipogênese. Entretanto, apesar de o diazepam per se não modular o acúmulo de triacilglicerol e a expressão gênica e protéica de PPAR-γ; em células estimuladas pelo TNF-α, o tratamento com diazepam foi capaz de reverter a diminuição da expressão gênica e protéica de PPAR-γ induzida pelo TNF-α. Ademais, o tratamento dos adipócitos com diazepam foi capaz de modular positivamente a expressão protéica de TSPO, efeito este que não observamos em células tratadas pelo clonazepam, um benzodiazepínico de ação exclusivamente central. Em resumo, os dados obtidos neste estudo, pela primeira vez, demonstram a possível relação entre as vias que controlam a sinalização de TSPO, TNF-α e PPAR-γ. Assim, nos é possível inferir que a ativação de TSPO pelo seu ligante diazepam foi capaz de modular a ativação de NF-kB induzida pelo TNF-α, promovendo, com a diminuição da lipólise e aumento da expressão gênica de TSPO e gênica e protéica de PPAR-γ, o reestabelecimento da homeostase celular, o que aumentaria a sobrevida das células, a atividade mitocondrial, e a atividade adipogênica dos adipócitos

Obesity is associated with a chronic low-grade inflammation and these represents one of the risk factors to development of other non-communicable diseases. TSPO 18 kDa is involved in several cellular functions, including biosynthesis and steroids transport, porphyrin transport, apoptosis, heme biosynthesis, oxidative metabolism and immunomodulation. Furthermore, the TSPO expression and function on adipose tissue and in the chronic low-grade inflammation have not been established. Thus, the aim of present study was to validate the TSPO expression and function on the 3T3-L1 differentiation process and to investigate whether diazepam treatment is able to modulate the TNF-α induced inflammatory effects on 3T3-L1 cells. Our results showed that diazepam treatment of preadipocytes was not able to modulate the adipogenesis. However, although diazepam treatment per se does not modulate the triacylglycerol accumulation and gene and protein expression of PPAR-γ; in TNF-α stimulated adipocytes, the treatment with diazepam was able to modulate the decreased of PPAR-γ gene and protein expression induced by TNF-α. In addition, the diazepam treatment of adipocytes was able to positively modulate the TSPO protein expression, an effect that we did not observe in cells treated with clonazepam, a central benzodiazepine ligand. In summary, the data obtained in this study, for the first time, demonstrate the possible relationship between the pathways that control the TSPO, TNF-α and PPAR-γ signaling. Thus, it is possible that the activation of TSPO by diazepam was able to modulate TNF-α-induced activation of NF-kB, promoting the reduction of lipolysis and increased of TSPO gene expression and PPAR-γ gene and protein expression, reestablishment of cellular homeostasis, which would increase cell survival, mitochondrial activity, and adipogenic activity of adipocytes

Pharmacotherapy of adolescents in the use of psychoactive substances

The use of Psychoactive Substances brings problems in several areas of the subject's life such as: health, psychological and social. It´s necessary evaluate the factors involved in drug use and potential drug interactions (PDI) in adolescents using psychoactive substances. It was a Cross-sectional, analytical and quantitative study. The research was carried out at the Center for Psychosocial Care and other drugs for children and adolescents 24h, with adolescents under 18 years of age, using medication. The data were obtained by reviewing the charts and the potential interactions were evaluated through the database Micromedex® and Medscape®. Of the 159 records used, there were 815 PDI. By gravity were 59.4% moderate, 23.8% secondary, 15.7% severe and 1.1% contraindicated. The drugs that presented the most PDI were Chlorpromazine (32.3%) and Diazepam (19.6%). The factors involved in polypharmacy were total PDI and those involved in the occurrence of total PDI were studying and the quantity diagnostic hypotheses. Due to the high PDI index, the relationship with polypharmacy and a high number of diagnostic hypotheses, it is necessary to increase the attention of health professionals regarding the topic and the development of protocols to support decision making.(AU)

A study on the knowledge and management practices on hypertension in pregnancy among midwives in the different public health centers of Cebu City / Philippine Journal of Obstetrics and Gynecology

ABSTRACT:BACKGROUND: The Millennium Development Goal (MDG) for 2015 has a target MMR of 52/100,000 live births but this goal been difficult to achieve. In the Philippines, 11 mothers die everyday from pregnancy related complications, a bulk contributed by Hypertension. Public health midwives sometimes attend to these obsterical emergencies often in the absence of a physician. this led to the BEmONC program, which addresses the rising morbidities from far-flung areas where resources are scarce, and helps train midwives in essential obsterical emergency care. The midwives are our allies in providing the best standard of care every mother and child rightfully deserves. Only thru periodic evaluation can we help strengthen BEmONC program, making it crucial to evaluate the midwives' knowledge and management practices in hypertension to help identify the setbacks that have impeded our progress in achieving the MDG.GENERAL OBJECTIVE: To access the knowledge and management practices of midwives in the management of hypertension in pregnancy in accourdance to the BEmONC protocol.STUDY DESIGN: Descriptive StudySTUDY SETTING: The 69 public health centers of Cebu CitySTUDY POPULATION: Public Health MidwivesMETHODOLOGY:This is descriptive study where a survey questionnaire was used and convenience sampling was done. Chi square and Fischer exact tests were employed to compare proportions. Descriptive statistics was used to summarize the data in proportion.RESULT: More than 70% of the midwives were knowledgeable regarding expected competencies, where BEmONC-trained midwives were 5-14x more likely to identity appropriate function. However, Only a dismal 22-36% will actually administer Magnesium Sulfate, which shows that knowledge is not translated into practice. Also, more than 70% were knowledgeable on the risk factors and danger signs of hypertension in pregnancy. It also showed that the midwives agreed to give antihypertensive medications- where Methyldopa was commonly given. Among those who agreed too give Methyldopa, majority were BEmONC-trained. A number also agreed to give hydralazine and diazepam in the setting of sever preeclampsia and eclampsia, where more non-BEmONC midwives agreed. Alarmlingly, only less than 50% will refer to a physician in the management og gestational hypertension and mild preeclampsia, and only 50%-60% agreed to facilitate hospital transport in the setting of severe preeclampsia and eclampsia.CONCLUSION: The BEmONC manual must be updated to keep up with current guidelines and ensure the conversation of knowledge into practice. The BEmONCcoverage of training must also be expanded so that all practicing midwives know the protocol. However, the DOH must further strengthen their role in the active surveillance of public health midwives and review the retention of their skills and regular practice of knowledge. Midwives must also be certified proficient, not merely trained. The must also be consulted to explore their problems in the implementation of current guidelines so we can better understand their situation as to why knowledge is not put into practice. By identifying deficiencies, we can improve and address setbacks that have impeded our progress towards achieving the Millennium Development Goal.

Monoterpenoids (thymol, carvacrol and S-(+)-linalool) with anesthetic activity in silver catfish (Rhamdia quelen): evaluation of acetylcholinesterase and GABAergic activity

This study evaluated the anesthetic potential of thymol and carvacrol, and their influence on acetylcholinesterase (AChE) activity in the muscle and brain of silver catfish (Rhamdia quelen). The AChE activity of S-(+)-linalool was also evaluated. We subsequently assessed the effects of thymol and S-(+)-linalool on the GABAergic system. Fish were exposed to thymol and carvacrol (25, 50, 75, and 100 mg/L) to evaluate time for anesthesia and recovery. Both compounds induced sedation at 25 mg/L and anesthesia with 50-100 mg/L. However, fish exposed to carvacrol presented strong muscle contractions and mortality. AChE activity was increased in the brain of fish at 50 mg/L carvacrol and 100 mg/L thymol, and decreased in the muscle at 100 mg/L carvacrol. S-(+)-linalool did not alter AChE activity. Anesthesia with thymol was reversed by exposure to picrotoxin (GABAA antagonist), similar to the positive control propofol, but was not reversed by flumazenil (antagonist of benzodiazepine binding site), as observed for the positive control diazepam. Picrotoxin did not reverse the effect of S-(+)-linalool. Thymol exposure at 50 mg/L is more suitable than carvacrol for anesthesia in silver catfish, because this concentration did not cause any mortality or interference with AChE activity. Thymol interacted with GABAA receptors, but not with the GABAA/benzodiazepine site. In contrast, S-(+)-linalool did not act in GABAA receptors in silver catfish.

Development of a simple and sensitive HPLC-MS/MS method for determination of diazepam in human plasma and its application to a bioequivalence study

We developed a simple, sensitive, and effective ultra-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method with an electrospray ionization (ESI) interface in multiple reaction monitoring (MRM) and positive ion modes to determine diazepam concentrations in human plasma using voriconazole as an internal standard (IS). Diazepam and IS were detected at transition 285.2→193.1 and 350.2→127.1, respectively. After liquid-liquid extraction (LLE) using 1.2 ml of ethyl acetate:n-hexane (80:20, v/v), diazepam and IS were eluted on a Phenomenex Cadenza CD-C18 column (150 × 3.0 mm, 3 µm) with an isocratic mobile phase (10 mM ammonium acetate in water:methanol [5:95, v/v]) at a flow rate of 0.4 mL/min. The peak retention time was 2.32 min for diazepam and 2.01 min for IS, respectively. The lower limit of quantitation (LLOQ) was 0.5 ng/mL (S/N > 10) using 50 µL of plasma, and no interferences were observed in chromatograms. Our analytical method was fully validated and successfully applied to a bioequivalence study of two formulations of diazepam in healthy Korean volunteers.

Botulinum Toxin Type A Injection for Neuropathic Pain in a Patient With a Brain Tumor: A Case Report

Neuropathic pain is usually managed pharmacologically, rather than with botulinum toxin type A (BTX-A). However, medications commonly fail to relieve pain effectively or have intolerable side effects. We present the case of a 62-year-old man diagnosed with an intracranial chondrosarcoma, which was removed surgically and treated with radiation therapy. He suffered from neuropathic pain despite combined pharmacological therapy with gabapentin, amitriptyline, tramadol, diazepam, and duloxetine because of adverse effects. BTX-A (100 units) was injected subcutaneously in the most painful area in the posterior left thigh. Immediately after the injection, his pain decreased significantly from 6/10 to 2/10 on a visual analogue scale. Pain relief lasted for 12 weeks. This case report describes intractable neuropathic pain caused by a brain tumor that was treated with subcutaneous BTX-A, which is a useful addition for the management of neuropathic pain related to a brain tumor.

Sinomenine, an Alkaloid Derived from Sinomenium acutum Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep in Rodents

Sinomenium acutum has been long used in the preparations of traditional medicine in Japan, China and Korea for the treatment of various disorders including rheumatism, fever, pulmonary diseases and mood disorders. Recently, it was reported that Sinomenium acutum, has sedative and anxiolytic effects mediated by GABA-ergic systems. These experiments were performed to investigate whether sinomenine (SIN), an alkaloid derived from Sinomenium acutum enhances pentobarbital-induced sleep via γ-aminobutyric acid (GABA)-ergic systems, and modulates sleep architecture in mice. Oral administration of SIN (40 mg/kg) markedly reduced spontaneous locomotor activity, similar to diazepam (a benzodiazepine agonist) in mice. SIN shortened sleep latency, and increased total sleep time in a dose-dependent manner when co-administrated with pentobarbital (42 mg/kg, i.p.). SIN also increased the number of sleeping mice and total sleep time by concomitant administration with the sub-hypnotic dosage of pentobarbital (28 mg/kg, i.p.). SIN reduced the number of sleep-wake cycles, and increased total sleep time and non-rapid eye movement (NREM) sleep. In addition, SIN also increased chloride influx in the primary cultured hypothalamic neuronal cells. Furthermore, protein overexpression of glutamic acid decarboxylase (GAD(65/67)) and GABA(A) receptor subunits by western blot were found, being activated by SIN. In conclusion, SIN augments pentobarbital-induced sleeping behaviors through GABA(A)-ergic systems, and increased NREM sleep. It could be a candidate for the treatment of insomnia.

El Diazepam altera la ultraestructura del atrio fetal de ratón / Diazepam alters the ultrastructure of fetal atrium in rat

El diazepam (DZ) es un tranquilizante menor sintético, utilizado en pacientes con trastornos psicológicos y psiquiátricos. Es sedante, miorrelajante, anticonvulsionante y antipsicótico. El DZ atraviesa la barrera placentaria humana y la del ratón. Mujeres jóvenes que son adictas al fármaco, si se embarazan y continúan utilizándolo, sobre todo durante el primer trimestre, exponen a sus hijos a presentar alteraciones psicomotoras. El propósito de este trabajo fue investigar si el DZ administrado durante la gestación,induce alteraciones ultraestructurales del miocardio fetal de ratón. El grupo (DZ) de hembras gestantes deratón de la cepa CD-1 fue tratado con dosis únicas diarias de 1,0 mg/kg/pc/sc del día 6 al 17 y un grupo (C)que recibió solución salina. El día 18 las hembras de ambos grupos se anestesiaron, los fetos se perfundieron por vía intracardiaca con paraformaldehído al 1 % y glutaraldehido al 2,5 %, se les extrajo el corazón, se disecó el atrio, se fijó en OsO4 al 1 % y se incluyó en resina epóxica. Los cortes finos se contrastaron conacetato de uranilo y citrato de plomo y se observaron en un microscopio electrónico de transmisión. En los miocitos de los fetos del grupo DZ las sarcómeras del miocardio compacto tenían menor longitud que las del grupo C. Se observaron zonas con miofibrillas desorganizadas. El retículo sarcoplásmico de algunos miocitos presentaba cisternas distendidas y fragmentadas, mitocondrias alteradas y se observaron abundantes polirribosomas. Los cambios podrían deberse al efecto del DZ sobre la síntesis de actina y miosina pesada y sobre los organelos citoplásmicos, mediados por receptores benzodiazepínicos periféricos presentes en la membrana externa de las mitocondrias y asociados a canales de calcio dependientes de voltaje. Las alteraciones ultraestructurales del miocardio atrial de fetos de ratones expuestos in utero a DZ podrían tener efectos posnatales.

Diazepam (DZ) is a syntheticminor tranquilizer, used in patients with psychologicaland psychiatric disorders. It is a relaxing sedative,anticonvulsant and antipsychotic. DZ crosses thehuman placental barrier in mouse. Young women who are addicted to the drug, if they become pregnantand continue to use it, particularly during the firsttrimester, expose their children to psychomotor disorders. The purpose of this study was to investigate whether DZ administered during pregnancy induces ultrastructural alterations of fetal mouse myocardium.The group (DZ) of pregnant female mice of the CD-1strain was treated with a single daily dose of 1.0 mg/ kg / pc / sc of day 6 to 17 and a group (C) that received saline solution. On day 18 females of bothgroups were anesthetized, the fetuses were perfusedby intracardiac route with 1 % paraformaldehyde and 2.5 % glutaraldehyde, the heart was removed, theatrium was dissected, fixed in 1 % OsO4, it wasimmersed in epoxy resin. The fine sections werecontrasted with uranyl acetate and lead citrate and observed in a transmission electron microscope. Inthe myocytes of the fetuses of the DZ group, the sarcomers of the compact myocardium were shorter than those of the C group. Areas with disorganized myofibrils were observed. The sarcoplasmic reticulumof some myocytes had distended and fragmented 996cisterns, altered mitochondria, and abundant polyribosomes were observed. The changes may bedue to the effect of DZ on the synthesis of actin and heavy myosin and on cytoplasmic organelles mediatedby peripheral benzodiazepine receptors present onthe outer membrane of the mitochondria and associated with voltage-dependent calcium channels.Ultrastructural alterations of the atrial myocardium of fetuses of mice exposed to DZ in utero may have postnatal effects.