Noradrenaline modulates the spontaneous firing activities of Purkinje cells via α2-adrenergic receptor in mouse cerebellar cortex / 生理学报

Cerebellar Purkinje cells (PCs) exhibit two types of discharge activities: simple spike (SS) and complex spike (CS). Previous studies found that noradrenaline (NA) can inhibit CS and bidirectionally regulate SS, but the enhancement of NA on SS is overwhelmed by the strong inhibition of excitatory molecular layer interneurons. However, the mechanism underlying the effect of NA on SS discharge frequency is not clear. Therefore, in the present study, we examined the mechanism underlying the increasing effect of NA on SS firing of PC in mouse cerebellar cortex in vivo and in cerebellar slice by cell-attached and whole-cell recording technique and pharmacological methods. GABAA receptor was blocked by 100 µmol/L picrotoxin in the whole process. In vivo results showed that NA significantly reduced the number of spikelets of spontaneous CS and enhanced the discharge frequency of SS, but did not affect the discharge frequency of CS. In vitro experiments showed that NA reduced the number of CS spikelets and after hyperpolarization potential (AHP) induced by electrical stimulation, and increased the discharge frequency of SS. NA also reduced the amplitude of excitatory postsynaptic current (EPSC) of parallel fiber (PF)-PC and significantly increased the paired-pulse ratio (PPR). Application of yohimbine, an antagonist of α2-adrenergic receptor (AR), completely eliminated the enhancing effect of NA on SS. The α2-AR agonist, UK14304, also increased the frequency of SS. The β-AR blocker, propranolol, did not affect the effects of NA on PC. These results suggest that in the absence of GABAA receptors, NA could attenuate the synaptic transmission of climbing fiber (CF)-PC via activating α2-AR, inhibit CS activity and reduce AHP, thus enhancing the SS discharge frequency of PC. This result suggests that NA neurons of locus coeruleus can finely regulate PC signal output by regulating CF-PC synaptic transmission.

Trends of vasopressor use in intensive care units in Colombia / Tendencias de consumo de vasopresores en unidades de cuidados intensivos de Colombia

Abstract Introduction Vasopressors are essential in the management of various types of shock. Objective To establish the trend of vasopressors use in the intensive care units (ICU) in a population of patients affiliated with the Colombian Health System, 2010-2017. Methods Observational trial using a population database of patients hospitalized in eleven ICUs in various cities in Colombia. The drugs dispensed to hospitalized patients over 18 years old, from January 2010 until December 2017 were considered. A review and analysis of the vasopressors dispensed per month was conducted, taking into account sociodemographic and pharmacological variables (vasopressor used and daily doses defined per 100/beds/day (DBD). Results 81,348 dispensations of vasopressors, equivalent to 26,414 treatments in 19,186 patients receiving care in 11 hospitals from 7 cities were reviewed. The mean age of patients was 66.3±18.1 years and 52.6 % were males. Of the total number of treatments recorded, 17,658 (66.8 %) were with just one vasopressor. Norepinephrine was the most frequently prescribed drug (75.9 % of the prescriptions dispensed; 60.5 DBD), followed by adrenaline (26.6 %; 41.6 DBD), dopamine (19.4%), dobutamine (16.0 %), vasopressin (8.5 %) and phenylephrine (0.9 %). The use of norepinephrine increased from 2010 to 2017 (+6.19 DBD), whilst the use of other drugs decreased, particularly the use of adrenaline (-60.6 DBD) and dopamine (-10.8 DBD). Conclusions Norepinephrine is the most widely used vasopressor showing a growing trend in terms of its use during the study period, which is supported by evidence in favor of its effectiveness and safety in patients with shock.

Resumen Introducción Los fármacos vasopresores son fundamentales en el manejo de los diferentes tipos de choque. Objetivo Determinar la tendencia de utilización de fármacos vasopresores en unidades de cuidados intensivos (UCI) en una población de pacientes afiliados al Sistema de Salud de Colombia, 2010-2017. Métodos Estudio observacional, a partir de una base de datos poblacional con pacientes hospitalizados en once UCI de diferentes ciudades de Colombia. Se obtuvieron las dispensaciones de pacientes mayores de 18 años hospitalizados desde enero de 2010 hasta diciembre de 2017. Se hizo revisión y análisis de la dispensación mensual de vasopresores. Se consideraron variables sociodemográficas y farmacológicas (medicamento vasopresor usado y dosis diarias definidas por 100 camas/día [DCD]). Resultados Se revisaron 81.348 dispensaciones de vasopresores, equivalentes a 26.414 terapias en 19.186 pacientes atendidos en 11 hospitales de 7 ciudades, cuya edad promedio fue 66,3±18,1 años y el 52,6 % eran hombres. Del total de terapias registradas, 17.658 (66,8 %) fueron con un solo vasopresor. La norepinefrina fue el más comúnmente prescrito (75,9 % de las dispensaciones; 60,5 DCD), seguido por adrenalina (26,6 %; 41,6 DCD), dopamina (19,4 %), dobutamina (16,0 %), vasopresina (8,5 %) y fenilefrina (0,9 %). El uso de norepinefrina se incrementó de 2010 a 2017 (+6,19 DCD), mientras que el de otros fármacos disminuyó, especialmente adrenalina (-60,6 DCD) y dopamina (-10,8 DCD). Conclusiones La norepinefrina es el fármaco vasopresor más utilizado y el que ha demostrado una tendencia de uso incremental durante el periodo de estudio, lo cual está respaldado por evidencia a favor de su efectividad y seguridad en pacientes con choque.

The effect of epinephrine for the treatment of spinal-hypotension: comparison with norepinephrine and phenylephrine, clinical trial / O efeito de epinefrina, norepinefrina e fenilefrina no tratamento da hipotensão pós-raquianestesia: estudo clínico comparativo

Abstract Background and objectives: Limited data are present on safety and efficiency of epinephrine for the prophylaxis and treatment of spinal-hypotension. This study was conducted to compare the effect of epinephrine with norepinephrine and phenylephrine on the treatment of spinal-hypotension and ephedrine requirement during cesarean delivery. Methods: One hundred and sixty parturients with uncomplicated pregnancies undergoing elective cesarean delivery under spinal anesthesia were recruited. They were allocated randomly to receive norepinephrine 5 µg.mL−1 (n = 40), epinephrine 5 µg.mL−1 (n = 40), phenylephrine 100 µg.mL−1 (n = 40) or 0.9% saline infusions (n = 40) immediately after induction of spinal anesthesia. Whenever systolic blood pressure drops to less than 80% of baseline, 5 mg of intravenous ephedrine was administered as rescue vasopressor. The incidence of hypotension, total number of hypotension episodes, the number of patients requiring ephedrine, the mean amount of ephedrine consumption and side effects were recorded. Results: There was no statistically significant difference in incidence of maternal hypotension between groups. The number of patients requiring ephedrine was significantly greater in group saline than in group phenylephrine (p< 0.001). However, it was similar between phenylephrine, norepinephrine, and epinephrine groups. The mean ephedrine consumption was significantly higher in group saline than in norepinephrine, epinephrine, phenylephrine groups (p= 0.001). Conclusion: There is no statistically significant difference in incidence of hypotension and ephedrine consumption during spinal anesthesia for cesarean delivery with the use of epinephrine when compared to norepinephrine or phenylephrine. Epinephrine can be considered an alternative agent for management of spinal hypotension.

Resumo Justificativa e objetivos: Existem dados limitados sobre segurança e eficiência da epinefrina na profilaxia e tratamento da hipotensão arterial associada à raquianestesia. O presente estudo foi realizado para comparar o efeito da epinefrina com norepinefrina e fenilefrina no tratamento da hipotensão após raquianestesia e necessidade de efedrina durante o parto cesáreo. Método: Foram recrutadas 160 parturientes com gestações não complicadas, submetidas a cesariana eletiva sob raquianestesia. Elas foram alocadas aleatoriamente para receber norepinefrina 5 µg.mL-1 (n = 40), epinefrina 5 µg.mL-1 (n = 40), fenilefrina 100 µg.mL-1 (n = 40) ou infusão de solução fisiológica NaCl a 0,9% (n = 40) imediatamente após a indução da raquianestesia. Sempre que houvesse redução da pressão arterial sistólica para valor inferior a 80% da linha de base, 5 mg de efedrina iv eram administrados como vasopressor de resgate. A incidência de hipotensão, o número total de episódios de hipotensão, o número de pacientes que necessitaram de efedrina, o consumo médio de efedrina e os efeitos colaterais foram registrados. Resultados: Não houve diferença estatisticamente significante na incidência de hipotensão materna entre os grupos. O número de pacientes que necessitaram de efedrina foi significantemente maior no grupo solução fisiológica do que no grupo fenilefrina (p< 0,001). No entanto, foi semelhante entre os grupos fenilefrina, norepinefrina e epinefrina. O consumo médio de efedrina foi significantemente maior no grupo solução fisiológica do que nos grupos norepinefrina, epinefrina e fenilefrina (p = 0,001). Conclusão: Não houve diferença estatisticamente significante na incidência de hipotensão e consumo de efedrina durante raquianestesia para parto cesáreo com uso de epinefrina quando comparada à norepinefrina ou fenilefrina. A epinefrina pode ser considerada como agente alternativo para o tratamento da hipotensão após raquianestesia.

Zigomicosis y síndrome hemofagocítico en un paciente inmunocompetente: informe de caso / Zygomycosis and hemophagocytic lymphohistiocytosis in an immunocompetent patient: a case report

Introducción: la zigomicosis es una infección fúngica poco frecuente, con alta tasa de mortalidad y de mal pronóstico. Afecta principalmente a pacientes inmunocomprometidos. La asociación con el síndrome hemofagocítico es extremadamente inusual, más aún en pacientes inmunocompetentes, con pocos ejemplos registrados en la literatura. Caso clínico: se presenta el caso de un paciente masculino inmunocompetente de 40 años con diagnóstico de mucormicosis y síndrome hemofagocítico que evoluciona desfavorablemente, con fallo multiorgánico, a pesar de los esfuerzos médicos. Conclusión: la asociación de mucormicosis con síndrome hemofagocítico en un paciente inmunocompetente es extremadamente rara; existen pocos casos informados en Latinoamérica. Debemos tener presente esta asociación, ya que requiere un tratamiento agresivo y soporte vital avanzado. (AU)

Introduction: zygomycosis is a rare fungal infection that carries with high mortality rates. This poor prognosis, rapidly progressive infection mainly affects immunocompromised patients. The association with hemophagocytic lymphohistiocytosis is extremely unusual, even more in immunocompetent patients, with few cases reported. Case: we present the case of an immunocompetent male patient who was diagnosed with zygomycosis and hemophagocytic lymphohistiocytosis. Despite medical efforts he developed multiorganic failure. Conclusion: the association of mucormycosis with hemophagocytic lymphohistiocytosis in an immunocompetent patient is exceptional with few cases reported in Latin America. We must always suspect this association considering they require aggressive treatment and advanced life support. (AU)

Effects of Beta; 1-adrenoceptors in the Basolateral Amygdala on Spatial Memory, Passive Avoidance, Long-term Potentiation and Neuronal Arborization in the Hippocampal CA1 Region in Response to Unavoidable Stress

Abstract Norepinephrine in the basolateral amygdala (BLA) plays a pivotal role in mediating the effects of stress on memory functions in the hippocampus, however, the functional contribution of β1-adrenergic receptors on the BLA inputs to the CA1 region of hippocampus and memory function are not well understood. In the present study the role of β1-adrenoreceptor in the BLA on memory, neuronal arborization and long-term potentiation (LTP) in the CA1 region of hippocampus was examined by infusion the β1-adrenoreceptor agonist (Dobutamine; 0.5µl/side) or antagonist (Atenolol; 0.25µL/side) bilaterally into the BLA before foot-shock stress. Passive avoidance test results showed that Step-through latency time was significantly decreased in the stress group rats one, four and seven days after the stress, which intra-BLA injection of Atenolol or Dobutamine before stress couldn't attenuate this reduction. Barnes-maze results revealed that infusion of Dobutamine and Atenolol significantly reduced spatial memory indicators such as increased latency time, the number of errors and the distance traveling to achieve the target hole in the stress group. These learning impairments in stress rats correlated with a reduction of LTP in hippocampal CA1 synapses in-vivo, which infusion of Dobutamine and Atenolol couldn't attenuate the population spike amplitude and mean-field excitatory postsynaptic potentials (fEPSP) slope reduction induced by stress. Also, the Golgi-Cox staining demonstrated that infusion of Atenolol attenuated stress decreased CA1 region dendritic and axonal arborization. These results suggest that β1-adrenergic receptors activation or block seem to exacerbate stress-induced hippocampal memory deficits and this effect is independent of CA1 LTP modulation.

Vasopressor Discontinuation Order in the Recovery Phase of Septic Shock: A Systematic Review and Meta-Analysis

@#BACKGROUND: Septic shock causes life threatening organ dysfunction needing vasopressor despite adequate fluid resuscitation. Numerous studies and meta-analysis have proven norepinephrine as the initial vasopressor of choice in septic shock with vasopressin as add-on. Although guidelines have established the goal monitoring response in septic shock, optimal approach in discontinuation of the vasopressors in the recovery phase of septic shock remains limited. METHODS: A systematic review and meta-analysis was performed on randomized controlled trials (RCTs) and nonrandomized studies comparing incidence of hypotension within 24 hours of discontinuing norepinephrine first versus vasopressin. Three reviewers independently selected studies, assessed their quality, and extracted the following data: the number and characteristics of patients enrolled, inclusion and exclusion criteria for each study, the description of interventions (discontinuing norepinephrine first versus discontinuing vasopressin first) and outcomes (incidence of hypotension within 24 hours). RESULTS: Seven retrospective cohort studies and one prospective randomized control trial were included. Compared with norepinephrine, risk of hypotension is higher when vasopressin is discontinued first among patients in the recovery phase of septic shock (RR 2.06; 95% CI [1.11,3.82]; I 2 91%). Results were consistent in the subgroup analysis after excluding abstract-only and poor-quality studies (RR 1.73; 95% CI [0.74, 4.03]; I 2 93%). There is no difference in ICU (RR 0.97; 95% CI [0.71, 1.32]; I 2 38%) and in-hospital mortality (RR 0.88; 95% CI [0.66, 1.16]; I 2 41%) between the two vasopressor weaning strategies. Finally ICU length of stay was reported on 5 studies with no significant difference between the two strategies. CONCLUSION: Based on the results, there is increased risk of hypotension when vasopressin is discontinued first versus norepinephrine.

Incidence of Hypotension after Discontinuation of Norepinephrine or Arginine Vasopressin in Patients with Septic Shock: a Systematic Review and Meta-Analysis

Quantification of Fat Concentration and Vascular Response in Brown and White Adipose Tissue of Rats by Spectral CT Imaging

Trombo serpiginoso em átrio direito: apresentação atípica de tromboembolismo pulmonar. Relato de caso / Serpiginous thrombus in right atrium: atypical presentation of pulmonary thromboembolism. Case report

O tromboembolismo pulmonar é um grave problema de saúde pública devido ao subdiagnóstico e às elevadas morbidade e mortalidade. Quando a embolia pulmonar é maciça com repercussão hemodinâmica importante e a terapia adequada não ocorre nas primeiras horas, a mortalidade é superior a 85%. Na suspeita clínica de tromboembolismo pulmonar, a avaliação ecocardiográfica pode ter papel fundamental na avaliação da mobilidade e da estrutura do ventrículo direito, presença de hipertensão pulmonar e documentação da presença de trombo. A detecção ecocardiográfica de trombo móvel nas câmaras cardíacas direitas permite identificar um grupo de pacientes de alto risco, com mortalidade muito elevada, quando comparada ao tromboembolismo pulmonar em geral. Além da terapia clínica clássica, com heparinas e trombolíticos, as terapêuticas endovascular e cirúrgica devem ser consideradas e podem contribuir para o prognóstico desses pacientes. Relata-se um caso de uma paciente de 33 anos de idade admitida em uma unidade de emergência da no 8o dia de pós-operatório de apendicectomia, com queixas de dor torácica e dispneia de início súbito. Ecocardiograma transtorácico evidenciou presença de trombo serpiginoso solto em átrio direito, que ocluía intermitentemente a valva tricúspide durante o ciclo cardíaco. Diante das características ecocardiográficas atípicas do trombo e da significativa chance de embolização maciça, optou-se por intervenção cirúrgica de emergência.

Pulmonary thromboembolism is a serious public health problem due to misdiagnosis and high morbidity and mortality. When pulmonary embolism is massive with important hemodynamic repercussion, and the appropriate therapy does not take place in the early hours, mortality is higher than 85%. If there is clinical suspicion of pulmonary thromboembolism, an echocardiographic evaluation may have a key role in the evaluation of mobility and structure of the right ventricle, presence of pulmonary hypertension, and documentation of the presence of thrombus. Echocardiographic detection of mobile thrombus in right cardiac chambers allows the identification of a group of high-risk patients with very high mortality when compared to pulmonary thromboembolism in general . In addition to the classical clinical therapy with heparins and thrombolytics, endovascular and surgical therapy should be considered and may contribute to these patients' prognosis. A case is reported of a 33-year-old female patient admitted to an Emergency Unit at 8th postoperative day (POD) of appendectomy, with complaints of chest pain and dyspnea of sudden onset. Transthoracic echocardiography showed the presence of a floating serpiginous thrombus in the right atrium, which intermittently occluded the tricuspid valve during the cardiac cycle. Due to the atypical echocardiographic features of the thrombus, and significant chance of massive embolization, an emergency surgery was chosen.

Hemodiafiltración intermitente en línea como terapia de reemplazo renal en paciente crítico: Experiencia en un centro de diálisis de agudo / Experience with inline intermittent hemodiafiltration as renal replacement therapy in critically ill patients

Background: In critical patients with acute renal failure, intermittent diffusive renal replacement techniques cause hemodynamic problems due to their high depurative efficiency. This situation is avoided using continuous low efficiency therapies, which are expensive, prevent patient mobilization and add hemorrhagic risk due to systemic anticoagulation. Intermittent and prolonged hemodiafiltration (HDF) has the depurative benefits of diffusion, plus the positive attributes of convection in a less expensive therapy. Aim: To report our experience with intermittent and prolonged on-line HDF in critically ill patients. Patients and Methods: During 2016, HDF therapies performed on critical patients with indication of renal replacement therapy were characterized. The hemodynamic profile was evaluated (doses of noradrenaline, blood pressure, heart rate and perfusion parameters). Results: Fifty-one therapies were performed in 25 critical patients, aged 58 ± 11 years (28% women), with an APACHE II score of 22.1 ±10. The average time of the therapies was 4.15 hours (range 3-8 hours), the replacement volume was 75 ± 18 mL/kg/h and ultrafiltration rate was 226 ± 207 mL/h. The mean initial, maximum and final noradrenaline doses were 0.07 ± 0.1, 0.13 ±0.18 and 0.09 ±0.16 μg/kg/min respectively. No differences between patients with low, medium and high doses of noradrenaline or dose increases during therapy, were observed. The greatest decrease in mean arterial pressure was 15.3% and the maximum increase in heart rate was 12.8%. Anticoagulation was not required in 88% of therapies. Conclusions: High-volume intermittent or prolonged HDF is an effective therapy in critical patients, with good hemodynamic tolerability, lower costs and avoidance of systemic anticoagulation risks.

Eventos adversos durante transporte intra-hospitalar de pacientes críticos em hospital de grande porte / Adverse events during intrahospital transport of critically ill patients in a large hospital

RESUMO Objetivo: Descrever a incidência de eventos clínicos e não clínicos durante o transporte intra-hospitalar de pacientes críticos e analisar os fatores de risco associados. Métodos: Estudo de coorte, com coleta retrospectiva, no período de outubro de 2016 a outubro de 2017, tendo sido analisados todos os transportes intra-hospitalares para fins diagnósticos e terapêuticos em hospital de grande porte, que contava com seis unidades de terapia intensiva adulto, sendo avaliados os eventos adversos e os fatores de risco relacionados. Resultados: No período, foram realizados 1.559 transportes intra-hospitalares, em 1.348 pacientes, com média de idade de 66 ± 17 anos, tempo médio de transporte de 43 ± 34 minutos. Durante o transporte, 19,8% dos pacientes estavam em uso de drogas vasoativas; 13,7% em uso de sedativos e 10,6% estavam sob ventilação mecânica. Eventos clínicos ocorreram em 117 transportes (7,5%) e não clínicos em 125 transportes (8,0%). Falhas de comunicação foram prevalentes, no entanto, aplicando-se análise multivariada, uso de sedativos, noradrenalina e nitroprussiato, e o tempo de transporte maior que 36,5 minutos estiveram associados a eventos adversos clínicos. Uso de dobutamina e tempo de transporte superior a 36,5 minutos estiveram associados a eventos não clínicos. Ao final do transporte, 98,1% dos pacientes apresentaram condições clínicas inalteradas em relação ao seu estado basal. Conclusão: Transportes intra-hospitalares estão relacionados à alta incidência de eventos adversos; o tempo de transporte e a utilização de sedativos e drogas vasoativas estiveram relacionados a esses eventos.

ABSTRACT Objective: To describe the incidence of clinical and non-clinical events during intrahospital transport of critically ill patients and to analyze the associated risk factors. Methods: Cohort study with retrospective data collected from October 2016 to October 2017. All cases of intrahospital transport for diagnostic and therapeutic purposes in a large hospital with six adult intensive care units were analyzed, and the adverse events and related risk factors were evaluated. Results: During the study period, 1,559 intrahospital transports were performed with 1,348 patients, with a mean age of 66 ± 17 years and a mean transport time of 43 ± 34 minutes. During transport, 19.8% of the patients were using vasoactive drugs; 13.7% were under sedation; and 10.6% were under mechanical ventilation. Clinical events occurred in 117 transports (7.5%), and non-clinical events occurred in 125 (8.0%) transports. Communication failures were prevalent; however, the multivariate analysis showed that the use of sedatives, noradrenaline and nitroprusside and a transport time greater than 36.5 minutes were associated with adverse clinical events. The use of dobutamine and a transport time greater than 36.5 minutes were associated with non-clinical events. At the end of transport, 98.1% of the patients presented unchanged clinical conditions compared with baseline. Conclusion: Intrahospital transport is related to a high incidence of adverse events, and transport time and the use of sedatives and vasoactive drugs were related to these events.

Factors associated to potential drug interactions in one Intensive Care Unit: a cross-sectional study / Factores asociados a interacciones medicamentosas potenciales en un Centro de Terapia Intensiva: estudio transversal / Fatores associados a interações medicamentosas potenciais em um Centro de Terapia Intensiva: estudo transversal

ABSTRACT Objective: to identify the factors associated to Potential Drug Interactions with High Alert Medications in the Intensive Care Unit of a Sentinel Hospital. Methods: a cross-sectional, retrospective study using a quantitative approach carried out at a Sentinel Hospital in Rio de Janeiro. The research was based on the analysis of the prescriptions of patients hospitalized in the Intensive Care Unit of the Hospital, in a period of one year, in order to identify the drug interactions related to high alert medications in these prescriptions. Results: Of the 60 prescriptions analyzed, 244 were selected. In these prescriptions, 846 potential drug interactions related to high alert medications and 33 high alert medications were identified. Of the 112 types of potential drug interactions identified, some were more recurrent: tramadol e ondansetron, midazolam and omeprazole, regular insulin and hydrocortisone, fentanyl and midazolam, and regular insulin and noradrenaline. The variables polypharmacy, length of hospital stay, and some specific medications were associated with drug interactions with high alert medications. Conclusion and Implications for practice: It is important to strengthen strategies to reduce adverse drug events. Therefore, the relevance of studies that investigate the origin of these events is highlighted. Drug interactions can represent medication errors. It's indispensable to work with strategies to better manage the medication system.

RESUMEN Objetivo: identificar los puntos asociados a las Interacciones Medicamentos Potenciales con Medicamentos de alta vigilancia en un Centro de Cuidados Intensivos de un Hospital de Guardia. Métodos: estudio transversal, retrospectivo, de abordaje cuantitativo, realizado en un hospital de guardia en Rio de Janeiro. Esta investigación se basó en el análisis de las prescripciones medicamentosas de pacientes internados en un Centro de Cuidados Intensivos de un hospital, en un período de 1 año, con el objetivo de identificar las interacciones medicamentosas relacionadas con Medicamentos de alta Vigilancia recurrentes en las mismas. Resultados: de los informes analizados, se seleccionaron 244 prescripciones medicamentosas. En las 244 prescripciones de medicamentos, se pudieron identificar 846 Interacciones de Medicamentos Potenciales (IMP) relacionados a Medicamentos de Alta Vigilancia y 33 Medicamentos de Alta Vigilancia. De los 112 tipos de interacciones de medicamentos potenciales identificados, algunos han sido más recurrentes; a saber: tramadol y ondansetrón, midazolam y omeprazol, insulina regular e hidrocortisona, fentanilo y midazolam, insulina regular y noradrenalina. Las variables polifarmacia, tiempo de internación y algunos medicamentos específicos se asociaron a las interacciones medicamentosas potenciales con Medicamentos de Alta Vigilancia. Conclusión e Implicaciones para la práctica: es importante fortalecer las estrategias para reducir los eventos adversos relacionados con medicamentos. Por lo tanto, se destaca la relevancia de los estudios que plantean la naturaleza de estos eventos. Las interacciones medicamentosas pueden provocar errores de medicación. Es imprescindible trabajar con estrategias para administrar mejor el sistema de medicación.

RESUMO Objetivo: Identificar os fatores associados às Interações Medicamentosas Potenciais com Medicamentos de alta vigilância em Centro de Terapia Intensiva de um Hospital Sentinela. Métodos: Estudo transversal, retrospectivo, de abordagem quantitativa, realizado em um hospital sentinela no Rio de Janeiro. A pesquisa apoiou-se na análise das prescrições de pacientes internados no setor, com recorte temporal de 1 ano, a fim de identificar as interações medicamentosas relacionadas a medicamentos de alta vigilância recorrentes nas mesmas. Resultados: Dos 60 prontuários analisados, selecionaram-se 244 prescrições. Nelas identificaram-se 846 interações medicamentosas potenciais, relacionadas aos medicamentos de alta vigilância e 33 medicamentos de alta vigilância. Dos 112 pares de interações identificadas, foram mais recorrentes: tramadol e ondansetrona, midazolam e omeprazol, insulina regular e hidrocortisona, fentanil e midazolam, e insulina regular e noradrenalina. As variáveis polifarmácia, tempo de internação e alguns medicamentos específicos foram associadas às interações com medicamentos de alta vigilância. Conclusão e Implicações para a prática: É importante fortalecer as estratégias para reduzir os eventos adversos relacionados a medicamentos. Portanto, destaca-se a relevância de estudos que levantem a natureza desses eventos. As interações medicamentosas podem configurar erros de medicação. Portanto, é indispensável que se trabalhe com estratégias para melhor manejar o sistema de medicação.

Methylphenidate and Central Precocious Puberty: A Probable Side Effect among Seven Children with the Attention Deficit Hyperactivity Disorder

Methylphenidate (MPH) is the most preferred drug for treatment of the attention deficit hyperactivity disorder (ADHD). Here, we aimed to discuss the possible effects and mechanisms of MPH on precocious puberty (PP) via a case series with seven children who had normal body mass index. In this case series we evaluated seven children with ADHD, who had received MPH for at least 6 months (0.5 mg/kg/dose three times a day, maximum 60 mg) and admitted to Department of Pediatric Endocrinology with PP symptoms. The mean age was 8.16 years. Basal hormonal levels (luteinizing hormone [LH], follicle stimulating hormone, and estrogen/testosterone) were within normal range. Results of LH-releasing hormone stimulation tests demonstrated central pubertal responses. Glutamine, dopamine and noradrenaline are most important excitatory neurotransmitters that have a role at the beginning of puberty. The effect of MPH, cumulating dopamine and noradrenaline in the synaptic gap could be associated with the acceleration of puberty with the excitatory effect of dopamine’s gonadotropin-releasing hormone (GnRH) release, excitatory effect of noradrenaline’s GnRH release and the disappearance of GnRH receptor expression suppressor effect on prolactin disinhibitory effect.

Neuroimmune interactions and kidney disease

The autonomic nervous system plays critical roles in maintaining homeostasis in humans, directly regulating inflammation by altering the activity of the immune system. The cholinergic anti-inflammatory pathway is a well-studied neuroimmune interaction involving the vagus nerve. CD4-positive T cells expressing β2 adrenergic receptors and macrophages expressing the alpha 7 subunit of the nicotinic acetylcholine receptor in the spleen receive neurotransmitters such as norepinephrine and acetylcholine and are key mediators of the cholinergic anti-inflammatory pathway. Recent studies have demonstrated that vagus nerve stimulation, ultrasound, and restraint stress elicit protective effects against renal ischemia-reperfusion injury. These protective effects are induced primarily via activation of the cholinergic anti-inflammatory pathway. In addition to these immunological roles, nervous systems are directly related to homeostasis of renal physiology. Whole-kidney three-dimensional visualization using the tissue clearing technique CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) has illustrated that renal sympathetic nerves are primarily distributed around arteries in the kidneys and denervated after ischemia-reperfusion injury. In contrast, artificial renal sympathetic denervation has a protective effect against kidney disease progression in murine models. Further studies are needed to elucidate how neural networks are involved in progression of kidney disease.

Renal sympathetic nerve activation via α₂-adrenergic receptors in chronic kidney disease progression

Chronic kidney disease (CKD) is increasing worldwide without an effective therapeutic strategy. Sympathetic nerve activation is implicated in CKD progression, as well as cardiovascular dysfunction. Renal denervation is beneficial for controlling blood pressure (BP) and improving renal function through reduction of sympathetic nerve activity in patients with resistant hypertension and CKD. Sympathetic neurotransmitter norepinephrine (NE) via adrenergic receptor (AR) signaling has been implicated in tissue homeostasis and various disease progressions, including CKD. Increased plasma NE level is a predictor of survival and the incidence of cardiovascular events in patients with end-stage renal disease, as well as future renal injury in subjects with normal BP and renal function. Our recent data demonstrate that NE derived from renal nerves causes renal inflammation and fibrosis progression through alpha-2 adrenergic receptors (α₂-AR) in renal fibrosis models independent of BP. Sympathetic nerve activation-associated molecular mechanisms and signals seem to be critical for the development and progression of CKD, but the exact role of sympathetic nerve activation in CKD progression remains undefined. This review explores the current knowledge of NE-α₂-AR signaling in renal diseases and offers prospective views on developing therapeutic strategies targeting NE-AR signaling in CKD progression.

Mechanisms of action and clinical applications of anti-obesity drugs currently available in Korea

Over the last 5 years, the Korean Ministry of Food and Drug Safety has approved four anti-obesity drugs for long-term weight management. In this review, the mechanisms of action and clinical applications of lorcaserin, naltrexone/bupropion, liraglutide, and phentermine/topiramate have been clarified. Lorcaserin stimulates proopiomelanocortin/cocaine- and amphetamine-regulated transcript neurons in the arcuate nucleus. Naltrexone/bupropion reduces body weight by controlling the hedonic reward system of food intake. The hypophagic effect of liraglutide depends on the direct activation of the proopiomelanocortin/cocaine- and amphetamine-regulated transcript neurons and indirect suppression of neuropeptide Y/agouti-related peptide neurons through gammaaminobutyric acid-dependent signaling, with an additional thermogenic effect. Phentermine/topiramate induces weight loss by elevating the norepinephrine levels in the hypothalamus, reducing energy deposition in the adipose tissue and skeletal muscle, and elevating the corticotropin-releasing hormone in the hypothalamus. In patients with high cardiovascular risks or type 2 diabetes mellitus, lorcaserin and liraglutide are appropriate. In patients with mood disorders, naltrexone/bupropion could be considered as the first choice of therapy. Notably, lorcaserin and liraglutide are neutral in the aspect of sleep disorder. In case of obese individuals with obstructive sleep apnea, liraglutide or phentermine/topiramate would be selected as the treatment option. These four drugs should be used after considering the patients' co-morbidities of obesity.

Pharmacotherapy for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder defined by impairing levels of inattention, disorganization, and/or hyperactivity-impulsivity. ADHD often persists into adulthood, with resultant impairments of social, academic and occupational functioning. ADHD is a very common disease during childhood and, the pooled overall prevalence of ADHD was found to be 5.29%. When screening for ADHD, clinicians should try to develop rapport with patients and their caregivers to increase the likelihood that they will follow the diagnostic process and treatment. The current drugs that have received Food and Drug Administration-approval for ADHD include stimulants (methylphenidate and dextroamphetamine) and non-stimulants (atomoxetine, guanfacine, and clonidine). Stimulants improve inattention, hyperactivity, and impulsivity in addition to decreasing disruptive behaviors and promoting academic achievement and the maintenance of appropriate friendships. In order to enhance drug compliance, the use of long-acting stimulants is increasing. Atomoxetine is a selective norepinephrine reuptake blocker, the effects of which may take 2 to 6 weeks to be noticeable. Furthermore, α2 agonists may help to improve behavioral side effects, tics, and sleep problems during stimulant or atomoxetine use. Common side effects of stimulants and atomoxetine include headache, stomachache, and loss of appetite. Routine electorcardiography before medication is not recommended unless there is a specific indication. Methylphenidate and atomoxetine are safe as first line therapies, and their side effects are well tolerated.

Postpartum depression: association with genetic polymorphisms of noradrenaline metabolic enzymes and the risk factors / 南方医科大学学报

OBJECTIVE@#To investigate the association of genetic polymorphisms of norepinephrine metabolizing enzymes with postpartum depression and analyze the risk factors for postpartum depression in women following cesarean section.@*METHODS@#A total of 591 Chinese woman of Han Nationality undergoing caesarean section were enrolled in this study. The diagnosis of postpartum depression was established for an Edinburgh Postnatal Depression Scale (EPDS) score ≥9. For all the women without antepartum depression, the genotypes of catechol-O-methyltransferase (COMT; at 5 sites including rs2020917 and rs737865) and monoamine oxidase A (rs6323) were determined using Sequenom Mass Array single nucleotide polymorphism (SNP) analysis. We analyzed the contribution of the genetic factors (SNPs, linkage disequilibrium and haplotype) to postpartum depression and performed logistic regression analysis to identify all the potential risk factors for postpartum depression and define the interactions between the genetic and environmental factors.@*RESULTS@#The incidence of postpartum depression was 18.1% in this cohort. Univariate analysis suggested that COMT polymorphism at rs2020917 (TT genotype) and rs737865 (GG genotype) were significantly correlated with the occurrence of postpartum depression ( < 0.05). Logistic regression analysis showed that COMT polymorphism at rs2020917 (TT genotype) and rs737865 (GG genotype), severe stress during pregnancy, and domestic violence were the risk factors for postpartum depression ( < 0.05); no obvious interaction was found between the genetic polymorphisms and the environmental factors in the occurrence of postpartum depression.@*CONCLUSIONS@#The rs2020917TT and rs737865GG genotypes of COMT, stress in pregnancy, and domestic violence are the risk factors for postpartum depression.

Gender Differences in the Clinical Manifestation of Depression and Related Neurotransmitters / 생물치료정신의학

Depression is almost twice as prevalent in women than men. Atypical symptoms, somatic complaints, and comorbid anxiety disorders are more common in women, whereas suicide and comorbid substance use disorders are more common in men. Previous studies have also reported gender differences in the efficacy of and tolerability to specific classes of antidepressants. Various psychosocial and biological factors have been proposed to explain the gender differences in clinical characteristics of depression. The predominant theory of depression pathogenesis is the monoamine hypothesis, and consequently, monoamine neurotransmitters have been the primary target of antidepressants. In the first section of this review, study findings of clinical differences in depression by gender are summarized. Then, we provide an overview of the findings from human and rodent studies of gender differences in serotonin, norepinephrine, dopamine, and glutamate neurotransmitter systems. Total level, rate of synthesis, and receptor profiles of neurotransmitters seem to differ by gender in the euthymic state, depressed state, and in responses to stress or antidepressants. Furthermore, these neurotransmitters interact with gonadal hormones and the hypothalamic-pituitary-adrenal axis, systems that innately exhibit gender differences. Although most of the studies conducted so far are limited to animal models and results of the studies are heterogeneous, growing evidence suggests that gender differences exist in neurotransmitter systems, which possibly leads to gender differences in depression. More intensive studies in this field are needed to build gender-specific treatment strategies.