Atividade de alcaloides inibidores da acetilcolinesterase no tratamento da doença de Alzheimer: uma revisão sistemática / Activity of Acetylcholinesterase inhibitor Alkaloids in the treatment of Alzheimer's Disease: a systematic review

Objetivo: descrever a atividade de inibição da enzima acetilcolinesterase (AChE), por meio de ativos extraídos de alcaloides naturais. Metodologia: este estudo se configura como uma revisão sistemática da literatura, no período de janeiro de 2015 a setembro de 2021, nas bases de dados PUBMED, LILACS e SCIENCE DIRECT, com os descritores Acetylcholinesterase; Alzheimer; Alkaloids. As informações obtidas foram tabuladas para avaliação dos alcaloides inibidores da acetilcolinesterase. Resultados: de 563 artigos encontrados, 17 foram utilizados. Dois deles relataram a atividade de alcaloides inibidores da AChE por meio de ensaios clínicos, enquanto os demais a realizaram por testes in vitro. De 160 substâncias estudadas, 48 apresentaram atividade anticolinesterásica, as quais foram avaliadas de acordo com a sua concentração inibitória média (IC50). Discussão: a eficiência dos alcaloides como inibidores da AChE, provavelmente está relacionada com sua carga positiva no pH do organismo e sua boa biodisponibilidade, tendo como consequência uma atividade duradoura in vivo, em comparação com os medicamentos sintéticos. Conclusão: no presente estudo, foi possível observar uma grande diversidade de substâncias alcalóidicas antiAChE. Contudo, torna-se necessária a realização de mais ensaios in vivo e in vitro para a constatação efetiva da atividade dessas moléculas.

Objective: describe the activity of the enzyme Acetylcholinesterase (AChE) through natural actives extracted from alkaloids. Methodology: this study is a systematic literature review, from January 2015 to September 2021, in the PUBMED, LILACS, and SCIENCE DIRECT databases, with the descriptors Acetylcholinesterase; Alzheimer's; Alkaloids. The information obtained was tabulated for the evaluation of Acetylcholinesterase inhibitor alkaloids. Results: of 563 articles found, 17 were used. Two of them reported the activity of AChE-inhibiting Alkaloids through clinical trials, while the others performed it through in vitro tests. Of 160 substances studied, 48 showed anticholinesterase activity, which was evaluated according to their mean inhibitory concentration (IC50). Discussion: the efficiency of Alkaloids as AChE inhibitors is probably related to their positive charge on the body's pH and their good bioavailability, resulting in a long-lasting activity in vivo compared to synthetic drugs. Conclusion: in the present study, it was possible to observe a great diversity of antiAChE alkaloid substances. However, it is necessary to carry out more in vivo and in vitro tests to verify the effective activity of these molecules.

Síndrome neuroléptico maligno asociado con intoxicación aguda por un organofosforado: reporte de caso / Neuroleptic malignant syndrome associated with acute organophosphate poisoning: Case report

El síndrome neuroléptico maligno es una condición clínica rara y potencialmente letal que frecuentemente se asocia con el uso de antipsicóticos. En la literatura especializada se encontró únicamente un reporte de caso relacionado con la ingestión de organofosforados. Se presenta un paciente con un cuadro clínico correspondiente al síndrome neuroléptico maligno posterior a la ingestión de clorpirifós. Como resultado de un intento de suicidio con el mencionado organofosforado, el hombre de 57 años presentó deterioro agudo del estado de consciencia, evolución neurológica tórpida e inestabilidad autonómica asociada a rigidez e hipertermia persistentes, así como incremento de la creatina-fosfocinasa (creatine phosphokinase, CPK). Se le administró tratamiento con bromocriptina, con lo cual el cuadro clínico remitió, y fue dado de alta sin secuelas. El diagnóstico del síndrome neuroléptico maligno es clínico y debe contemplarse en cualquier caso de exposición a sustancias que puedan resultar en una desregulación de la neurotransmisión dopaminérgica, con el fin de iniciar el tratamiento oportuno y contrarrestar efectivamente los efectos.

Neuroleptic malignant syndrome is a rare and potentially fatal clinical condition frequently associated with the use of antipsychotics. In the literature, there is only one case report associated with the intake of organophosphates. We present the case of a patient who presented with a clinical picture compatible with neuroleptic malignant syndrome, after the ingestion of an organophosphate (chlorpyrifos). A 57-year-old man who consulted for attempted suicide, acute deterioration of consciousness, torpid neurological evolution, and associated autonomic instability associated with rigidity, persistent hyperthermia, and elevated CPK. Bromocriptine treatment was offered, which resolved the clinical picture. The association with the ingestion of an organophosphate was established, and he was discharged without sequelae. The diagnosis of neuroleptic malignant syndrome is clinical and should be considered in any case of exposure to substances that may lead to dysregulation of dopaminergic neurotransmission in order to initiate timely therapy and impact outcomes.

Casuística das intoxicações por inibidores das colinesterases pelo Centro de Informação e Assistência Toxicológica do Paraná (CIATox/PR) entre 2015 e 2019 / Casuistics of poisonings by cholinesterases inhibitors by the Information and Toxicological Assistance Center of Paraná (CIATox/PR) between 2015 and 2019

Esta pesquisa buscou analisar os casos de intoxicações por organofosforados e carbamatos, presentes em agrotóxicos e pesticidas, registrados na base de dados do Centro de Informação e Assistência Toxicológica do Paraná (CIATox/PR). Trata-se de estudo retrospectivo em que foram avaliadas variáveis sociodemográficas e clínicas relacionadas à intoxicação, à forma de exposição, à causa e ao desfecho. Para a análise estatística foram utilizados testes de Kolmogorov-Smirnov, Shapiro-Wilk, Qui-Quadrado e Teste Exato de Fisher, considerando p<0,05. A amostra foi composta por 426 casos, sendo 218 (51,2%) mulheres. O principal agente foi raticida clandestino em 278 (65,2%) pacientes. A principal circunstância das intoxicações foi tentativa de suicídio com 293 (68,8%) casos. Houve predominância de exposição via oral (89,9%) e zona urbana em 349 (81,9%) casos, a maioria considerados leves (52,6%) e assistidos em serviços médicos (66,4%). Cerca de 327 (76,8%) indivíduos apresentavam manifestações clínicas. O tempo decorrido entre a exposição e o contato com o CIATox/PR foi maior nos casos considerados graves (p= 0,041). A atropina foi utilizada em 94 (49%) pacientes intoxicados por carbamatos, em 31 (33,3%) por organofosforados e em 84 (59,6%) por outros inibidores da colinesterase não especificados. Duas mulheres e um adolescente apresentaram desfecho fatal, tendo em comum a ingesta intencional de "chumbinho". A casuística predominante nesta série histórica foi paciente do sexo feminino, faixa etária adulta, residente na região metropolitana, exposta a agrotóxico por via oral, sintomática, classificada como gravidade leve, sem necessidade de atropina, contudo ocorreram três casos com desfecho para o óbito.

This research aimed to analyze the cases of poisoning by organophosphates and carbamates, present in agrochemicals and pesticides, registered in the database of the Information and Toxicological Assistance Center of Paraná (CIATox/PR). This is a retrospective study in which sociodemographic and clinical variables related to intoxication, form of exposure, cause and outcome were evaluated. For the statistical analysis, the Kolmogorov-Smirnov, Shapiro-Wilk, Chi-Square and Fisher's Exact Test were used, considering p<0.05. The sample consisted of 426 cases, 218 (51.2%) of which were women. The main agent was clandestine rodenticide in 278 (65.2%) patients. The main circumstance of intoxication was a suicide attempt with 293 (68.8%) cases. There was a predominance of oral exposure (89.9%) and urban areas in 349 (81.9%) cases, most considered mild (52.6%) and assisted in medical services (66.4%). About 327 (76.8%) individuals had clinical manifestations. The time elapsed between exposure and contact with CIATox/PR was longer in cases considered severe (p=0.041). Atropine was used in 94 (49%) patients intoxicated by carbamates, in 31 (33.3%) by organophosphates and in 84 (59.6%) by other unspecified cholinesterase inhibitors. Two women and one teenager had a fatal outcome, having in common the intentional ingestion of "chumbinho". The predominant casuistry in this historical series was a female patient, adult age, living in the metropolitan region, exposed to pesticides orally, symptomatic, classified as mild severity, without the need for atropine, however, there were three cases with an outcome of death.

Efeitos dos agrotóxicos na saúde do agricultor familiar dos municípios de Capitólio e Pimenta - Minas Gerais: avaliação de biomarcadores colinesterase eritrocitárias e plasmática / Effects of pesticides on the health of family farmers in the cities of Capitólio and Pimenta - Minas Gerais: evaluation of erythrocyte and plasma cholinesterase biomarkers

portuguêsO Brasil é o maior consumidor global de agrotóxico tendo como consequência intoxicações de um grande número de trabalhadores, com altos gastos com a saúde e prejuízos ambientais. Objetivo geral: avaliar os efeitos do uso de agrotóxicos sobre a saúde de trabalhadores atuantes na agricultura familiar. Método: estudo transversal, analítico e comparativo entre o Grupo (1) composto por 80 trabalhadores rurais atuantes na agricultura familiar, expostos diretamente a agrotóxicos e o Grupo (2) composto por 60 usuários dos Programas de Saúde da Família (PSF) dos municípios de Capitólio e Pimenta - Minas Gerais - não diretamente expostos a agrotóxicos sendo o grupo controle por meio da análise de biomarcadores colinesterase eritrocitária e plasmática. Resultados: dos 140 participantes deste estudo, a maioria (51,2%) não referiu problemas de saúde e tratamento medicamentoso, 6,3% deles, expostos a agrotóxicos, referiram intoxicações e 42,5% relataram terem algum sinal e/ou sintoma de intoxicação com predominância (33,8%) para a dor de cabeça. O biomarcador colinesterase eritrocitária apresentou normalidade em 63,8% dos trabalhadores rurais e 36,2% com alteração na butirilcolinesterase. Conclusão: a butirilcolinesterase encontrada em 1/3 dos participantes expostos a agrotóxicos correlacionam-se à presença dos sintomas dor de cabeça e irritabilidade/nervosismo. Existe, portanto, a necessidade da educação e capacitação dos agricultores no uso de agrotóxicos para limitar níveis de exposição e efeitos nocivos à saúde para prevenir, diagnosticar e tratar possíveis disfunções causadas por esses produtos químicos

Brazil is the largest global consumer of pesticides, resulting in the intoxication of a large number of workers, with high expenditures on health and environmental damage. General objective: to evaluate the effects of the use of pesticides on the health of rural workers working in family farming in terms of intoxication through the evaluation of the erythrocyte and plasma cholinesterase biomarkers. Method: cross-sectional, analytical and comparative study between Group (1) of rural workers working in family farming, directly exposed to pesticides and Group (2) of users of Family Health Programs (PSF), in the municipalities of Capitólio and Pimenta - Minas Gerais State (Brazil) - not directly exposed to pesticides, being a control group through the analysis of biomarkers. Results: in this study of 140 participants, the most of them did not report health problems and drug treatment, 6.3% of participants, exposed to pesticides, reported poisoning and 42.5% reported having any signs and/or symptoms of intoxication with predominance for headache. The erythrocyte cholinesterase biomarker showed normality in 63.8% rural workers and 36.2% with alteration in butyrylcholinesterase. Conclusion: butyrylcholinesterase alteration was proven in 36.2% of participants exposed to pesticides and these results correlate with the presence of headache and irritability/nervousness symptoms. There is, therefore, a need for education and training of farmers to limit levels of exposure and harmful health effects to prevent, diagnose and treat possible dysfunctions caused by these chemicals applied to agriculture

Valores normais da atividade da colinesterase plasmática em anseriformes, com destaque para Alopochen aegyptiacus / Normal values of plasma cholinesterase activity in anseriformes, with emphasis on Alopochen aegyptiacus

A inibição da enzima colinesterase plasmática (BChE) pode ser utilizada como biomarcador para os efeitos da intoxicação por organofosforados e carbamatos. Nas aves, esta inibição ocorre de forma mais acentuada que nos mamíferos, porém poucos são os trabalhos publicados nestas espécies. O objetivo do estudo fo a dosagem da BChE em gansos-egípcios (Alopochen aegyptiacus) e nos anseriformes domésticos: gansos-domésticos (Anser anser domesticus) e marrecos (Anas platyrhynchos domesticus), para o estabelecimento de valores de referência normais. O trabalho possui ineditismo com relação à determinação desta enzima nos gansos-egípcios e domésticos. Os gansos e marrecos são mantidos em confinamento com fornecimento de alimentos e água ad libitum e em espaço adequado à sua manutenção no Instituto Adolfo Lutz (IAL), com a finalidade de fornecimento de sangue para a alimentação de triatomídeos do insetário de criação no Núcleo de Parasitoses Sistêmicas. Nos Alopochen aegyptiacus a média e o desvio padrão da BChE foram de 1.868 + 263,6 U/L, nos Anser anser domesticus 2.311 + 673,2 U/L e nos Anas platyrhynchos domesticus 4.290 + 86,11 U/L. (AU)

The inhibition of the plasma cholinesterase enzyme (BChE) can be used as a biomarker for the effects of intoxication by organophosphates and carbamates. In birds, this inhibition is more pronounced than in mammals, however there are few specific studies were conducted in this field. The aim of this study was to measure BChE in Egyptian geese (Alopochen aegyptiacus) and domestic anseriforms: domestic geese (Anser anser domesticus) and mallards (Anas platyrhynchos domesticus), not exposed to pesticides, for the establishment of normal values. The work is unprecedented regarding the determination of this enzyme in egyptian geese and domestic geese. Geese and mallards are kept in confinement with ad liditum food and water supply and in adequate space for their maintenance at the Adolfo Lutz Institute (IAL), for the purpose of supplying blood for the feeding of triatomines from the insectary of the Nucleus of Systemic Parasitoses. In Alopochen aegyptiacus the mean and standard deviation of BChE were 1,868 + 263,6 U/L, in Anser anser domesticus 2,311 + 673,2 U/L and in Anas platyrhynchos domesticus 4,290 + 86.11 U/L. (AU)

Plasma cholinesterase activity as an environmental impact biomarker in juvenile green turtles (Chelonia mydas) / Atividade da colinesterase plasmática como biomarcador de impacto ambiental em tartarugas verdes juvenis (Chelonia mydas)

The objective of this study was to evaluate the enzymatic activity of plasma cholinesterase in Chelonia mydas marine turtles belonging to two populations, according to their capture sites, under the absence and probable influence of anthropic effects. A total of 74 animals were used and later divided into two groups, based on the capture site. Blood samples were collected from all captured animals, which were then released into the sea at the site of capture. A descriptive statistical analysis of the plasma cholinesterase activity values and an analysis comparing these values based on the capture site were performed. Samples of heparinized plasma from animals captured at the two different sites were analyzed. Plasma cholinesterase activity ranged from 121 to 248U/L, with a mean and standard deviation of 186.1±30.68U/L. When comparing plasma cholinesterase activity values in individuals based on the capture site, a significant difference was observed. Establishing reference values for different sea turtle populations is necessary to interpret future sampling results and to allow sea turtles to be used as sentinels of ecosystem health. Future studies are needed to evaluate other populations and the activity of plasma cholinesterase in juvenile marine turtles, in relation to environmental contamination.(AU)

O objetivo desse estudo foi avaliar a atividade enzimática da colinesterase plasmática em tartarugas marinhas da espécie Chelonia mydas em duas populações de acordo com o local de captura, sob ausência e provável influência de efeito antrópico. Foi utilizado um total de 74 animais e posteriormente divididos em dois grupos de acordo com o local de captura. Foram coletadas amostras de sangue de todos os animais capturados e em seguida liberados ao mar no mesmo local. Foi realizada uma análise estatística descritiva dos valores da atividade plasmática de colinesterase do total de animais e análise comparando os valores de acordo com o local de captura. Foram analisadas amostras de plasma heparinizado de animais capturados em dois locais distintos. Os valores da atividade plasmática de colinesterase variaram de 121 a 248U/L, com média e desvio padrão de 186.1±30.7U/L. Quando comparados os valores de atividade plasmática da colinesterase nos indivíduos de acordo com o local de captura, foi observada diferença significativa. O estabelecimento de valores de referência para diferentes populações de tartarugas marinhas são necessários para interpretar os futuros resultados amostrais e permitir que as tartarugas marinhas sejam usadas como sentinelas da saúde do ecossistema. Estudos futuros são necessários para avaliar outras populações e a atividade da colinesterase plasmática de tartarugas marinhas juvenis em relação à contaminação ambiental.(AU)

Efeitos à saúde por exposição ambiental e ocupacional aos pesticidas de uso agrícola / Health effects of environmental and occupational exposure to agricultural pesticides

Introdução: O uso excessivo e descuidado de pesticidas tem se tornado um problema global de saúde pública, especialmente nos países de baixa e média renda. O Brasil é o maior consumidor mundial de pesticidas desde 2018, mas poucos estudos epidemiológicos exploram os seus efeitos à saúde. Objetivos: Avaliar os efeitos da exposição aos pesticidas à saúde de agricultores familiares em São José de Ubá (SJU), Estado do Rio de Janeiro, e analisar os efeitos respiratórios em crianças por exposição aos pesticidas, a partir de revisão da literatura. Métodos: Na safra de 2014, 82 agricultores familiares convenientemente selecionados foram entrevistados sobre a exposição aos pesticidas e submetidos à avaliação clínica com anamnese, avaliação respiratória (questionário e espirometria) e rastreamento de saúde mental (SRQ-20). Analisou-se as enzimas colinesterase (AChE e BChE) como biomarcadores de efeito. A avaliação respiratória foi repetida na entressafra de 2015 para comparação entre os períodos de maior e menor uso de pesticidas. Os participantes foram comparados com valores de referência e entre os grupos ocupacionais (aplicadores ou ajudantes) e os efeitos respiratórios foram analisados por regressão múltipla. Para ampliar o olhar aos riscos da exposição ambiental, realizou-se uma revisão sistemática sobre os efeitos dos pesticidas à saúde respiratória de crianças. Resultados: Os agricultores familiares avaliados em SJU estavam ocupacionalmente e ambientalmente expostos aos pesticidas desde tenra idade, trabalhavam sem apoio técnico e uso de equipamentos de proteção individual (EPI) completo, estavam expostos a complexas misturas de pesticidas frequentemente e apresentaram diversos sintomas de intoxicação aguda, mentais, respiratórios e alterações na espirometria. No geral, observou-se uma maior prevalência de efeitos respiratórios na safra do que na entressafra e associações significativas entre alterações espirométricas e os indicadores de exposição tanto na safra quanto na entressafra. Enquanto os aplicadores eram principalmente homens e apresentaram mais alterações de BChE, os ajudantes eram majoritariamente mulheres, tiveram ainda menos treinamento, usavam menos EPI e relataram maior prevalência de sintomas de intoxicação, saúde mental e o dobro apresentou um possível transtorno mental comum (depressão e ansiedade). A revisão da literatura sobre efeitos da exposição aos pesticidas agrícolas à saúde infantil apresentou vasta evidência sobre efeitos respiratórios e alérgicos. Conclusões: É fundamental melhorar o apoio técnico e treinamento ocupacional dos agricultores familiares brasileiros e promover práticas laborais e alternativas de cultivo mais sustentáveis. São necessários mais estudos sobre os efeitos dos pesticidas à saúde dos agricultores familiares e à saúde respiratória de crianças no Brasil e em outros países de menor renda, que usam métodos mais convencionais de cultivo e possuem maior população infantil no campo. Recomenda-se o fortalecimento de políticas públicas e a implementação de ações integrais e transversais a todos os níveis de atenção à saúde e áreas de governo, além da promoção de estratégias mais abrangentes de mitigação de riscos e intervenções comportamentais para reduzir o uso de pesticidas, a exposição e os riscos à saúde.

Introduction: Excessive and careless use of pesticides has become a global public health problem, especially in low- and middle-income countries. Brazil is the world's largest consumer of pesticides since 2018, but few epidemiological studies explore its health effects. Objectives: To evaluate the health effects of pesticide exposure on family farmers in São José de Ubá (SJU), State of Rio de Janeiro, and to analyze the respiratory effects of pesticide exposure among children, based on a literature review. Methods: In the crop season of 2014, 82 family farmers conveniently selected were interviewed about pesticide exposure and subjected to clinical evaluation with anamnesis, respiratory assessment (questionnaire and spirometry), and mental health screening (SRQ-20). Cholinesterase enzymes (AChE and BChE) were analyzed as effect biomarkers. The respiratory assessment was repeated in the off-season period (2015) to compare periods of higher and lower pesticide use. Participants were compared with reference values and between occupational groups (applicators or helpers), and respiratory effects were analyzed by multiple regression. A systematic review of the pesticide effects of children's respiratory health was conducted to broaden the understanding of the pesticide risks of environmental exposure. Results: Family farmers evaluated in SJU were occupationally and environmentally exposed to pesticides from an early age, worked without technical support and use of full personal protection equipment (PPE), were frequently exposed to complex mixtures of pesticides and presented several symptoms of acute intoxication, mental, respiratory, and changes in spirometry. Overall, there was a higher prevalence of respiratory effects in the crop season than in the off-season and significant associations between spirometric changes and exposure indicators in both the crop season and off-season. While the applicators were mostly men and had more BChE depletion, the helpers were mostly women, had even less occupational training, used less PPE, and reported a higher prevalence of pesticide poisoning symptoms, mental health, and twice as much as a probable common mental disorder (depression and anxiety). The literature review on the effects of agricultural pesticide exposure on children's health has provided ample evidence on respiratory and allergic effects. Conclusions: It is essential to improve the technical support and occupational training of Brazilian family farmers and to promote more sustainable labor practices and farming alternatives. Further studies are needed on the effects of pesticides on family farmer's health and children's respiratory health in Brazil and other lower-income countries that use more conventional cultivation methods and have a larger child population in the countryside. Strengthening public policies and implementing comprehensive and crosscutting actions at all levels of health care and areas of government is recommended, along with the promotion of broader risk mitigation strategies and behavioral interventions to reduce pesticide use, exposure, and health risks.

Anti-tick effect and cholinesterase inhibition caused by Prosopis juliflora alkaloids: in vitro and in silico studies / Efeito carrapaticida e inibição da acetilcolinesterase por alcaloides de Prosopis juliflora: estudos in vitro e in silico

Abstract We investigated the in vitro acaricide activity of the methanolic extract (ME) and alkaloid-rich fraction (AF) of Prosopis juliflora on Rhipicephalus microplus and correlated this effect with acetylcholinesterase (AChE) inhibition. The acaricide activity was evaluated using adult and larval immersion tests. Also, we studied the possible interaction mechanism of the major alkaloids present in this fraction via molecular docking at the active site of R. microplus AChE1 (RmAChE1). Higher reproductive inhibitory activity of the AF was recorded, with effective concentration (EC50) four times lower than that of the ME (31.6 versus 121 mg/mL). The AF caused mortality of tick larvae, with lethal concentration 50% (LC50) of 13.8 mg/mL. Both ME and AF were seen to have anticholinesterase activity on AChE of R. microplus larvae, while AF was more active with half-maximal inhibitory concentration (IC50) of 0.041 mg/mL. The LC-MS/MS analyses on the AF led to identification of three alkaloids: prosopine (1), juliprosinine (2) and juliprosopine (3). The molecular docking studies revealed that these alkaloids had interactions at the active site of the RmAChE1, mainly relating to hydrogen bonds and cation-pi interactions. We concluded that the alkaloids of P. juliflora showed acaricide activity on R. microplus and acted through an anticholinesterase mechanism.

Resumo A atividade carrapaticida in vitro do extrato metanólico (EM) e da fração de alcaloides (FA) de Prosopis juliflora foi investigada, frente ao Rhipicephalus microplus, e relacionada com a inibição da enzima acetilcolinesterase (AChE). A predição in silico das interações de alcaloides dessa fração com a AChE1 de R. microplus (RmAChE1) foi realizada por acoplamento molecular. A atividade carrapaticida foi avaliada, utilizando-se os ensaios de imersão de adultos e larvas. Maior efeito sobre parâmetros reprodutivos de teleóginas foi verificado para a FA, com valor de Concentração Efetiva 50% (CE50) (31.6 mg/mL), quatro vezes menor do que o valor do EM (121 mg/mL). A FA induziu mortalidade de larvas (Concentração Letal de 50% - CL50 = 13,8 mg/mL). A inibição da atividade da AChE de larvas do carrapato foi observada para EM e FA, sendo a FA mais ativa (Concentração Inibitória 50%- CI50 de 0,041mg/mL). As análises químicas da FA permitiram a identificação dos alcaloides prosopina (1), juliprosinina (2) e juliprosopina (3). No ensaio in silico, observou-se que esses alcaloides podem interagir com o sítio ativo da RmAChE1, principalmente por ligações de hidrogênio e interações cátion-pi. Os alcaloides de P. juliflora têm atividade carrapaticida contra R. microplus, atuando através do mecanismo anticolinesterásico.

Condición clínica y niveles de colinesterasa de trabajadores informales dedicados a la fumigación con plaguicidas / Clinical condition and colinesterase levels of informal workers dedicated to fumigation with pesticides

Resumen Introducción. Las prolongadas exposiciones a diversos plaguicidas pueden alterar la salud de los individuos mediante alteración de la funcionalidad de la enzima colinestera. Objetivo. Determinar los síntomas clínicos por efectos probables de inhibición de las enzimas colinesterasas en un grupo de fumigadores del sector informal de la economía. Materiales y métodos. Diseño analítico, prospectivo. A cada uno de los 256 fumigadores sin otras condiciones susceptibles de afectar la enzima, se le tomó semestralmente muestra de 10 mL de sangre venosa periférica; hasta completar 4 mediciones. Cada muestra de sangre fue repartida en dos tubos heparinizados, preservados en frío (2-8°C) hasta 10 horas máximo. El rango de normalidad utilizado como referencia fueron las cifras encontradas para Colombia por Carmona-Fonseca en adultos no expuestos utilizando la técnica EQM®, la misma que ha sido utilizada en este estudio. Resultados. La edad de inicio en la tarea de fumigación fue de 14 a 16 años (73%), 100% se mantuvo laboralmente activos, en contacto laboral con insecticidas órgano-fosforados y diversos compuestos activos herbicidas durante tiempo de exposición entre 8 y 28 años (67%). El promedio de las cuatro mediciones de colinesterasa eritrocitaria en fumigadores osciló entre 33.8 y 27.6, con descensos progresivos del valor inicial (67%) en las mediciones sucesivas, existe 37.2% de sintomáticos para intoxicación crónica. Conclusiones. La exposición continuada a plaguicidas refleja alteraciones de la colinesterasa eritrocitaria entre los fumigadores informales. Discusión. Hallazgos similares con Abou-Hatab en relación con resultados y la edad, entre expuestos sintomáticos se evidencia intoxicación crónica.

Abstract Introduction. Prolonged exposures to various pesticides can alter the health of individuals by altering the functionality of the cholinesterase enzyme. Objective. To determine the clinical symptoms by probable effects of inhibition of the cholinesterase enzymes in a group of fumigators of the informal sector of the economy. Materials and methods. Analytical, prospective design. To each of the 256 fumigators without other conditions susceptible to affect the enzyme, a 10mL sample of peripheral venous blood was taken every six months; until completing 4 measurements. Aach blood sample was divided into two heparinized tubes, preserved in cold (2-8°C) up to 10 hours-maximum. The normality range used as a reference was the figures found for Colombia by Carmona-Fonseca in adults not exposed using the EQM® technique, the same one that has been used in this study. Results. The age of initiation in the fumigation was 14 to 16 years (73%), 100% remained labor-active, in labor contact with organophosphorus insecticides and various herbicidal active compounds during exposure time between 8 and 28 years (67%). The average of the four measurements of erythrocyte cholinesterase in sprayers ranged between 33.8 and 27.6, with progressive decreases of the initial value (67%) in the successive measurements; there are 37.2% of symptomatic for chronic intoxication. Conclusions. The continuous exposure to pesticides reflects alterations in the erythrocyte cholinesterase among the informal fumigators. Discussion. Similar findings with Abou-Hatab in relation to results and age, among symptomatic exposed chronic poisoning are evidenced.

Chemical Constituents from Solenostemma argel and their Cholinesterase Inhibitory Activity

Alzheimer's disease is a chronic neurodegenerative disorder with no curative treatment. The commercially available drugs, which target acetylcholinesterase, are not satisfactory. The aim of this study was to investigate the cholinesterase inhibitory activity of Solenostemma argel aerial part. Eight compounds were isolated and identified by NMR: kaempferol-3-O-glucopyranoside (1), kaempferol (2), kaempferol-3-glucopyranosyl(1→6)rhamnopyranose (3) p-hydroxybenzoic acid (4), dehydrovomifoliol (5), 14,15-dihydroxypregn-4-ene-3,20-dione (6), 14,15-dihydroxy-pregn-4-ene-3,20-dione-15β-D-glucopyranoside (7) and solargin I (8). Two of them (compounds 2 and 3) could inhibit over 50 % of butyrylcholinesterase activity at 100 µM. Compound (2) displayed the highest inhibitory effect against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with a slight selectivity towards the latter. Molecular docking studies supported the in vitro results and revealed that (2) had made several hydrogen and π-π stacking interactions which could explain the compound potency to inhibit AChE and BChE.

A suspected sugammadex-induced anaphylactic shock: A case report

BACKGROUND: The reversal of a neuromuscular blockade has typically been achieved with a cholinesterase inhibitor and the concomitant use of an anticholinergic agent, and this remains a popular method. Since the introduction of sugammadex in the market, its use has been increasing because of the rapid recovery from a neuromuscular blockade achieved by rocuronium. The occurrence of anaphylaxis or an anaphylactic reaction resulting from sugammadex is rare and has been reported sparsely. Thus, one may not recognize the possibility of sugammadex-induced hypersensitivity when sudden life-threatening hypotension occurs, especially without skin manifestations during the emergence of anesthesia. This may delay treatment and increase morbidity. CASE: We report a case of a sugammadex-related hypersensitivity reaction which manifested as pure cardiovascular collapse during the emergence of anesthesia. CONCLUSIONS: We emphasize that vigilance should be paid for at least five minutes following sugammadex administration in daily clinical practice.

Serum cholinesterase level as a biomarker in detecting liver injury in Patients with chronic hepatitis c

Background: hepatitis C virus can cause both acute and chronic hepatitis. The acute process is self-limited, rarely causes hepatic failure and usually leads to chronic infection. Chronic HCV infection often follows a progressive course over many years and can ultimately result in cirrhosis, HCC and the need for liver transplantation. Objective: the aim of this study is to evaluate serum cholinesterase (CHE) level as a biomarker for detecting liver damage in patients with chronic hepatitis C. Patients and Methods: the current study was carried out on 50 subjects selected from the outpatient's clinic of Internal Medicine Department of Sayed Galal Hospital, Al-Azhar University and admitted to the internal department. The study was performed in the period between July-2014 to July -2019. Results: Sensitivity of cholinesterase is 100%, its specificity is 100% and its accuracy is 100%, in predicting liver injury in patients with chronic hepatitis C. Cholinesterase is positively correlated with Hb, platelets and albumin. Cholinesterase is negatively correlated with ALT, AST and ALP, total & direct bilirubin, PT, INR, urea, creatinine and AFP. There is significant increase of cholinesterase among compensated compared with decompensated cirrhotic patients. There is significant decrease of cholinesterase among compensated cirrhotic patients compared with controls. There is significant decrease of cholinesterase among decompensated cirrhotic patients compared with controls. Conclusion: cholinesterase is an excellent biomarker of cirrhosis with good sensitivity and specificity. Cholinesterase shows good correlation with albumin, PT, INR and Child-Puch score. Cholinesterase distinguishes decompensated cirrhosis from compensated cirrhosis well

Análise do impacto do uso de organofosforados e carbamatos em trabalhadores rurais de um município da região noroeste do estado do Rio Grande do Sul / Impact analysis of the use of organophosphates and carbamates rural workers of the municipality in a northwest region of Rio Grande do Sul

Anualmente milhões de agricultores são intoxicados no mundo, e destes, mais de 20 mil morrem em consequência da exposição a agrotóxicos. Intoxicações por organofosforados (OF) e carbamatos (CAR) representam as maiores ameaças à saúde dos trabalhadores rurais. Os OF e CAR atuam na inibição da enzima colinesterase, sendo assim a inibição desta mostra-se um excelente indicador da severidade da intoxicação. O objetivo deste estudo foi analisar o impacto do uso de OF e CAR em trabalhadores rurais na cidade de Mato Queimado/RS. Foi realizado um estudo transversal, prospectivo e experimental. Investigaramse 27 trabalhadores rurais expostos. Foram realizadas coletas sanguíneas e dados epidemiográficos nos meses de fevereiro e março de 2014. A atividade da colinesterase foi determinada através do método bioquímico cinético colorimétrico. A faixa etária média dos participantes foi 34,6 anos (± 8,5). A forma de contato mais prevalente foi a aplicação do produto (88,9%). O tempo médio de exposição foi de 10,7 anos. 70,4% relataram usar equipamentos de proteção individual (EPI), sendo mais frequente o uso de máscara (55,5%). A média dos valores de colinesterase para foi de 3244,45 U/I (± 345,8), níveis estes abaixo dos de referência. Através dos resultados obtidos nesta pesquisa torna-se imprescindível a utilização de meios de monitoramento biológico dos trabalhadores rurais na finalidade de prevenção e promoção da saúde.

Annually millions of rural workers are intoxicated in the world, and of these, more than 20,000 die as a result of exposure to pesticides. Intoxication by insecticides organophosphate (OF) and carbamates (CAR) represent the greatest threats to the health of rural workers. OF CAR and act on the inhibition of cholinesterase enzyme, thus inhibition of this proves to be an excellent indicator of the severity of the intoxication. The objective of this study was to analyze the impact of using OF CAR and in rural workers in the city of Mato Queimado/RS. A cross-sectional, prospective and experimental study was conducted. Twenty-three rural workers exposed were investigated. Sample collection and data demographic were conducted in February and March 2014. The cholinesterase activity was determined by biochemical kinetic colorimetric method. The average age of participants was 34.6 years (± 8.5). The most prevalent form of contact is via the application of the product (88.9%). The mean duration of exposure was 10.7 years. Still, 70.4% reported using personal protective equipment (PPE), more frequent use of mask (55.5%). The average values for cholinesterase was 3244.45 U/l (± 345.8) levels below those of the reference. The results obtained in this study are essential to use biological monitoring means of rural workers in purpose of prevention and health promotion.

Duración del bloqueo neuromuscular con succinilcolina y su relación con niveles de colinesterasa plasmática en pacientes sépticos: Hospital Central Universitario Dr. Antonio María Pineda / Neuromuscular blockade duration with succinylcholine and its correlation with levels of plasma cholinesterase in septic patients: Hospital Central Universitario Dr. Antonio María Pineda

La succinilcolina es un fármaco neuromuscular despolarizante generalmente utilizado en el contexto de protocolo de intubación de secuencia rápida indicada en pacientes en los cuales es necesario asegurar la vía aérea en menos de sesenta segundos. Se realizó un estudio descriptivo transversal con el objetivo de determinar la duración del bloqueo neuromuscular con succinilcolina y los niveles de colinesterasa plasmática en pacientes sépticos intervenidos en el Hospital Central Universitario Dr. Antonio María Pineda. Se incluyeron 30 pacientes con sepsis con un promedio de edad de 49,6 ± 17,4 años y predominio del sexo masculino (70%); la principal indicación de cirugía abdominal fue obstrucción intestinal (36,6%) y peritonitis secundaria (23,3%). Los valores de colinesterasa plasmática se registraron disminuidos en 42,8% de los hombres y 33,3% de las mujeres encontrándose valores promedios de 5554,1 ± 1220,5 U/L y 4770,1 ± 1627,4 U/L, respectivamente. La duración del bloqueo neuromuscular fue mayor de 14 minutos en 66,6% de las mujeres; el promedio de duración fue de 14,4 ± 5,1 min (mujeres) y 9,4 ± 4,3 min en hombres. Hubo una pobre correlación entre los niveles de colinesterasa plasmática y la duración así como el tiempo de recuperación del bloqueo neuromuscular. En conclusión, el bloqueo neuromuscular prolongado debido a la baja actividad de la colinesterasa después de la administración de succinilcolina se presenta en menos de la mitad de los pacientes sépticos estudiados(AU)

Succinylcholine is a depolarizing neuromuscular drug generally used in the context of rapid sequence intubation indicated in patients in whom it is necessary to secure the airway in less than sixty seconds. A descriptive cross-sectional study was conducted in order to determine the duration of neuromuscular blockade with succinylcholine and plasma cholinesterase levels in septic patients admitted at Hospital Central Universitario Dr. Antonio Maria Pineda. A sample of 30 patients with sepsis were studied, with a mean age of 49.6 ± 17.4 years, predominantly male (70%). The main indication for abdominal surgery was intestinal obstruction (36.6%) and secondary peritonitis (23.3%). Diminished values of plasma cholinesterase were recorded in 42.8% of men and 33.3% of women; mean plasma levels were 5554.1 ± 1220.5 U/L and 4770.1 ± 1627.4 U/L, respectively. Duration of neuromuscular blockade was longer in women (66.6%) with an average duration of 14.4 ± 5.1 min and 9.4 ± 4.3 min for men. A poor correlation between cholinesterase plasmatic levels and duration as well as time of recovery of neuromuscular blockage was found. Prolonged neuromuscular blockade is due to low cholinesterase activity after administration of succinylcholine and occurs in less than half of septic patients studied(AU)

Usefulness of serum lactate as a predictor of successful discontinuation of continuous atropine infusion in patients with severe acute organophosphate poisoning

OBJECTIVE: In severe organophosphate (OP) poisoning, administration of atropine via continuous intravenous infusion is typically considered. To date, there have been no studies on predicting successful atropine discontinuation through plasma cholinesterase (PChE) and serum lactate levels, which are monitored during critical care in severe acute OP poisoning. Therefore, we retrospectively evaluated the usefulness of serum lactate and PChE as predictors of successful discontinuation of atropine infusion. METHODS: This retrospective observational study was performed on consecutive adult patients treated for severe acute OP poisoning between March 2011 and December 2016. We sequentially evaluated serum lactate and PChE levels on emergency department arrival and before a discontinuation trial of atropine infusion. Discontinuation of atropine intravenous infusion was attempted in patients after clearance of respiratory secretions and cessation of bronchoconstriction. Discontinuation of atropine infusion attempts were divided into successful and failed trials. RESULTS: A total of 95 trials were conducted in 62 patients. Serum lactate levels before trials were significantly different between patients with successful and failed trials. The area under the curve for prediction of successful atropine discontinuation using serum lactate levels before trial discontinuation were 0.742 (95% confidence interval, 0.638 to 0.846). PChE level was not significantly different between two groups. CONCLUSION: Serum lactate levels before the discontinuation trial of atropine infusion served to predict successful discontinuation in severe acute OP poisoning.

Garcinexanthone G, a Selective Butyrylcholinesterase Inhibitor from the Stem Bark of Garcinia atroviridis

The present study was undertaken to investigate the isolated compounds from the stem bark of Garcinia atroviridis as potential cholinesterase inhibitors and the ligand-enzyme interactions of selected bioactive compounds in silico. The in vitro cholinesterase results showed that quercetin (3) was the most active AChE inhibitor (12.65 ± 1.57 µg/ml) while garcinexanthone G (6) was the most active BChE inhibitor (18.86 ± 2.41 µg/ml). It is noteworthy to note that compound 6 was a selective inhibitor with the selectivity index of 11.82. Molecular insight from docking interaction further substantiate that orientation of compound 6 in the catalytic site which enhanced its binding affinity as compared to other xanthones. The nature of protein-ligand interactions of compound 6 is mainly hydrogen bonding, and the hydroxyl group of compound 6 at C-10 is vital in BChE inhibition activity. Therefore, compound 6 is a notable lead for further drug design and development of BChE selective inhibitor.

Isolation of Flavonoid Glycosides with Cholinesterase Inhibition Activity and Quantification from Stachys japonica

The three flavone glycosides, 4′-O-methylisoscutellarein 7-O-(6‴-O-acetyl)-β-D-allopyranosyl(1→2)-β-D-glucopyranoside (1), isoscutellarein 7-O-(6‴-O-acetyl)-β-D-allopyranosyl(1→2)-β-D-glucopyranoside (3), and isoscutellarein 7-O-β-D-allopyranosyl(1→2)-β-D-glucopyranoside (4) in addition to a flavonol glycoside, kaempferol 3-O-β-D-glucopyranoside (astragalin, 2), were isolated from Stachys japonica (Lamiaceae). In cholinesterase inhibition assay, compound 1 significantly inhibited aceylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities (IC₅₀s, 39.94 µg/ml for AChE and 86.98 µg/ml for BChE). The content of isolated compounds were evaluated in this plant extract by HPLC analysis. Our experimental results suggest that the flavonoid glycosides of S. japonica could prevent the memory impairment of Alzheimer's disease.

Relative Risk and Clinical Severity Assessment in Patients with Non-Oral Route Organophosphate Poisoning Compared with Oral Route Poisoning

PURPOSE: Organophosphates, commonly used in agricultural pesticides, pose high risks and incidences of poisoning. In the present study, we investigated the relative risk and clinical severity, including laboratory results, of non-oral route poisoning (NORP) patients, compared to oral route poisoning (ORP) patients. MATERIALS AND METHODS: A single institutional toxicology database registry was utilized to gain information on clinical laboratory results on organophosphate poisoning patients who visited the emergency department (ED) between January 2000 and October 2016. Clinical outcomes, such as mortality and complication rates, were compared using 1:2 propensity score matching in the total cohort. RESULTS: Among a total of 273 patients in our study, 34 experienced NORP. After 1:2 propensity score matching, rates of respiratory complications and mortality were higher in the ORP group than in the NORP group. However, there was no difference in hospitalization time and time spent in the intensive care unit between the two groups. Compared with ORP patients after matching, the relative risk of mortality in NORP patients was 0.34, and the risk of respiratory distress was 0.47. The mean level of pseudocholinesterase was significantly higher in the NORP group than in the ORP group, while recovery rates were similar between the two groups. CONCLUSION: Although the majority of NORP patients were admitted to the ED with unintentional poisoning and the relative risk of NORP was lower than that for ORP, we concluded that NORP is as critical as ORP. Considerable medical observation and intensive therapeutic approaches are also needed for NORP patients.

Actividad de butirilcolinesterasa y micronúcleos en trabajadores agrícolas expuestos a mezclas de plaguicidas / Butyrylcholinesterase activity and micronuclei in agricultural workers exposed to pesticide mixtures

Los plaguicidas son xenobióticos de gran utilidad para el control de las plagas y su uso es una realidad para obtener mayor rendimiento en los cultivos. Sin embargo, tienen el riesgo de producir toxicidad, por lo que es necesario el monitoreo biológico de los trabajadores expuestos a estas sustancias. El objetivo de este estudio fue evaluar la actividad de la butirilcolinesterasa (BCh) y la presencia de micronúcleos (MN) en trabajadores expuestos a mezclas de plaguicidas en el municipio Urdaneta, estado Lara. Participaron 82 individuos de sexo masculino, 41 expuestos (GE) y 41 no expuestos (GNE), la determinación de la butirilcolinesterasa se realizó en muestras de sangre, y la de micronúcleos en muestras epiteliales de la mucosa bucal. Los resultados fueron presentados empleando estadísticos descriptivos, frecuencias absolutas y porcentajes, utilizando el paquete libre PAST v.2.04. Los valores de actividad de BCh en el GE (3528,75+/- 1162,45U/L) mostraron diferencias estadísticamente significativas (P<0,001) en relación al GNE (5764,41+/-1641,43U/L). La frecuencia de MN presentó mayor mediana en el GE respecto al GNE (3,09 vs 0,73) con una diferencia significativa (P<0,001). Al asociar el tiempo de exposición con la actividad de BCh y la frecuencia de MN, se presentó una correlación negativa con la actividad de BCh y una correlación positiva con los MN, estadísticamente significativas P<0,001 y P<0,05. Los hallazgos obtenidos reflejan que los plaguicidas fueron utilizados en forma de mezclas siendo los más usados: organofosforados, carbamatos y piretroides produciendo modificaciones en los valores de actividad de BCh y la frecuencia de MN en individuos expuestos a plaguicidas(AU)

Pesticides are xenobiotics, useful in controlling pests and their use ileads to greater crop yields. However, they carry a risk of toxicity so biological monitoring of exposed workers is necessary. The aim of this study was to evaluate the cholinesterase activity and the presence of micronuclei in workers exposed to pesticide mixtures in the town of Urdaneta, Lara. Eighty-two workers participated, 41 exposed (EG) and 41 nonexposed (NEG), all of whome were male. Blood samples were obtained for the determination of butyrylcholinesterase (BCh); buccal mucosal epithelial samples were obtained for micronuclei (MN) sampline. The results were presented as descriptive statistics, absolute frequencies and percentages, using the PAST v.2.04 a free online software package. The BCh activity values in the EG (3528.75+/-1162.45U/L) showed statistically significant differences (P<0.001) in relation to the UEG (5764.41 +/- 1641.43U/L). Median MN frequency was highest in the EG compared to UEG (3.09vs 0.73), a significant difference (P<0.001). By associating exposure time with BCh activity and MN frequency, a negative correlation was found with BCh activity and a positive correlation with MN, both statistically significant (P<0.001 and P<0.05, respectively). The results suggested pesticide mixtures were the most often used: organophosphates, carbamates and pyrethroids produced changes in the activity values of BCh and the frequency of MN in individuals exposed to pesticides(AU)

Factors that affect the onset of action of non-depolarizing neuromuscular blocking agents / 대한마취과학회지

Neuromuscular blockade plays an important role in the safe management of patient airways, surgical field improvement, and respiratory care. Rapid-sequence induction of anesthesia is indispensable to emergency surgery and obstetric anesthesia, and its purpose is to obtain a stable airway, adequate depth of anesthesia, and appropriate respiration within a short period of time without causing irritation or damage to the patient. There has been a continued search for new neuromuscular blocking drugs (NMBDs) with a rapid onset of action. Factors that affect the onset time include the potency of the NMBDs, the rate of NMBDs reaching the effect site, the onset time by dose control, metabolism and elimination of NMBDs, buffered diffusion to the effect site, nicotinic acetylcholine receptor subunit affinity, drugs that affect acetylcholine (ACh) production and release at the neuromuscular junction, drugs that inhibit plasma cholinesterase, presynaptic receptors responsible for ACh release at the neuromuscular junction, anesthetics or drugs that affect muscle contractility, site and methods for monitoring neuromuscular function, individual variability, and coexisting disease. NMBDs with rapid onset without major adverse events are expected in the next few years, and the development of lower potency NMBDs will continue. Anesthesiologists should be aware of the use of NMBDs in the management of anesthesia. The choice of NMBD and determination of the appropriate dosage to modulate neuromuscular blockade characteristics such as onset time and duration of neuromuscular blockade should be considered along with factors that affect the effects of the NMBDs. In this review, we discuss the factors that affect the onset time of NMBDs.