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The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.

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El nitroprusiato de sodio fue aprobado desde 1974 como medicamento para las crisis hipertensivas. Desde entonces existe controversia sobre el potencial tóxico del mismo. La toxicidad por cianuro es una complicación poco común del nitroprusiato de sodio, que puede ser difícil de diagnosticar en pacientes críticamente enfermos. Dentro de los factores de riesgo está la utilización de infusiones prolongadas y dosis altas, por lo que se sugiere que la dosis no exceda 2 µg/kg/min. A continuación, se reporta el caso de un paciente de 49 años que ingresa a un servicio de urgencias después de un síndrome cerebrovascular y una emergencia hipertensiva que requirió infusión de nitroprusiato de sodio, seguida de signos y síntomas, los cuales sugirieron toxicidad. Entre dichos síntomas predominaban los cambios neurológicos, por lo cual fue manejado con hiposulfito de sodio y hubo una buena respuesta. El objetivo de este reporte de caso es sensibilizar al personal de salud sobre la necesidad de un uso adecuado del nitroprusiato y sobre la importancia de sospechar toxicidad en paciente con factores de riesgo.

Sodium Nitroprusside has been approved since 1974 as a medication for hypertensive crises. However, there has been ongoing controversy regarding its potential toxicity. Cyanide toxicity is a rare complication of Sodium Nitroprusside, which can be challenging to diagnose in critically ill patients. Risk factors include prolonged infusions and high doses; hence it is suggested that the dose should not exceed 2 µg/kg/min. Here, we present the case of a 49-year-old patient who entered the emergency department after a cerebrovascular event and a hypertensive emergency that required Sodium Nitroprusside infusion, followed by signs and symptoms suggestive of toxicity. Neurological changes were predominant among these symptoms, and the patient was managed with sodium thiosulfate, resulting in a good response. The objective of this case report is to raise awareness among healthcare professionals about the need for appropriate use of Sodium Nitroprusside and the importance of suspecting toxicity in patients with risk factors.

O nitroprussiato de sódio foi aprovado desde 1974 como medicamento para crises hipertensivas. Desde então tem havido controvérsia sobre o seu potencial tóxico. A toxicidade por cianeto é uma complicação rara do nitroprussiato de sódio, que pode ser difícil de diagnosticar em pacientes gravemente enfermos. Entre os fatores de risco está o uso de infusões prolongadas e altas doses, por isso sugere-se que a dose não ultrapasse 2 µg/kg/min. Relata-se a seguir o caso de uma paciente de 49 anos admitida em pronto-socorro após síndrome cerebrovascular e emergência hipertensiva com necessidade de infusão de nitroprussiato de sódio acompanhada de sinais e sintomas sugestivos de toxicidade. Dentre esses sintomas, predominaram as alterações neurológicas, para as quais foi tratado com hipossulfito de sódio e apresentou boa resposta. O objetivo deste relato de caso é sensibilizar os profissionais de saúde sobre a necessidade do uso adequado do nitroprussiato e sobre a importância de suspeitar de toxicidade em pacientes com fatores de risco.

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This work aimed to identify variables associated with increased risk of outcome severity as well as to describe clinical manifestations/symptoms and management of pesticide-related cases reported to a poison center in Brazil. An increased risk of more severe outcomes was observed when exposures occurred in rural areas, involved suicide attempts and moderately to extremely hazardous pesticides. Clinical manifestations with higher frequencies included vomiting, nausea, sialorrhea, headache, miosis and sweating. From the treatment initially applied to the patient, 51.91% encompassed gastric lavage, but this procedure was only recommended in 20.01% of cases by the CIATox. Identifying risk factors associated with poor outcome, describing clinical manifestations, and contrasting initial treatment measures adopted against those recommended by the Poison Center can help determine diagnosis, prognosis and ensure appropriate clinical interventions are used in cases of pesticide poisoning.

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Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.

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OBJECTIVE: To determine the effect and safety of IV lipid emulsion in rabbits with acute ivermectin toxicosis. DESIGN: Randomized controlled trial. SETTING: University research facility. ANIMALS: Twenty-four healthy male adult New Zealand rabbits. INTERVENTIONS: Three groups of rabbits (IV, IV_RL, and IV_LE) received 80 mg/kg of ivermectin (8 mL/kg) through a nasogastric tube, and 1 group (LE) received an equivalent volume (8 mL/kg) of 0.9% sodium chloride. Group IV_RL was treated with Ringer's lactate (2 mL/kg bolus, followed by 0.25 mL/kg/min for 60 minutes), whereas groups IV_LE and LE received 20% lipid emulsion. The rabbits were submitted to clinical and neurological evaluation, and blood samples were collected for biochemical analysis. All animals were euthanized, and tissue samples were collected and processed for histopathological evaluation and ivermectin quantification. MEASUREMENTS AND MAIN RESULTS: All animals exposed to ivermectin manifested clinical changes consistent with toxicosis, but the ones that received IV lipid emulsion infusion showed no significant clinical improvement. Intense increase in serum glucose and triglyceride concentrations was seen after ivermectin exposure, along with increased urea and creatinine concentrations, but the last 2 remained within the reference range. Lipid emulsion caused an intense increase in triglycerides and cholesterol concentrations. No pathological abnormalities were seen in the organs sampled. Toxicological analysis showed greater ivermectin concentration in adipose tissue and liver, followed by kidney and, finally, brain. The treatments did not change ivermectin tissue concentration. CONCLUSIONS: When given to rabbits intoxicated with ivermectin, IV lipid emulsion was biochemically and histologically safe but was not effective in treating, delaying, or reversing clinical signs and progression, nor did it alter ivermectin tissue concentration.

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Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care.

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Aunque poco común, la intoxicación por cianuro acarrea una mortalidad alta, sobre todo, cuando no se administra el tratamiento oportuno. La exposición a este tóxico puede darse por inhalación o por ingestión oral. Lo que se ha descrito sobre el manejo de esta intoxicación está basado en reportes de casos y pequeñas series, dado que en la literatura no se encuentran estudios que den un sustento claro. Dentro de estos reportes, y según los aspectos fisiopatológicos, son especialmente relevantes: el nitrito de sodio, el nitrito de amilo, el tiosulfito de sodio y la hidroxicobalamina, como arsenal terapéutico de esta intoxicación.

Cyanide intoxication is a rare condition. Yet, it leads to a high mortality, especially when proper treatment is not available. The exposure to this substance may occur via inhalation or oral ingestion. The basis of this intoxication´s treatment is on little case series and reports; this is due to the fact that the literature to support it remains scant and unclear. Based on physiopathological aspects, within this evidence the following are particularly relevant: sodium nitrile, amile nitrile, sodium tiosulphite, and hidroxicobalamin, as part of this intoxication´s treatment.

Embora pouco comum, a intoxicação por cianeto provoca uma mortalidade alta, sobre tudo, quando não se administra o tratamento oportuno. A exposição a este tóxico pode dar-se por inalação ou por ingestão oral. O que se há descrito sobre o manejo desta intoxicação está baseado em reportes de casos e pequenas séries, dado que na literatura não se encontram estudos que deem um sustento claro. Dentro destes relatos, e segundo os aspectos fisiopatológicos, são especialmente relevantes: o nitrito de sódio, o nitrito de amilo, o tiossulfato de sódio e a hidroxicobalamina, como arsenal terapêutico desta intoxicação.

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Intoxications caused by organophosphorus compounds (OPs) are associated with the reversible, and sometimes irreversible interaction with acetylcholinesterase (AChE). OPs are commonly used as pesticides mainly in developing countries, where the associated poisoning is a major health problem related to suicidal attempts, careless manipulation, and chemical warfare. The current antidotes are oxime-based drugs that can regenerate the AChE catalytic activity. Nevertheless, challenges associated with lack of efficiency and difficulties for crossing blood-brain barrier have motivated the design of novel alternatives. We used a validated molecular docking approach for the virtual screening of 579,890 synthetic ligands and 478 drugs against a human AChE in its apo conformation, and a murine AChE conjugated with the OP tabun. After filtering, 7 hits were selected as potential competitors due to the formation of key interactions within the active site gorge of the AChE structure, and potential reactivators based on interactions with amino acids of the catalytic triad in the presence of organophosphorus compounds. The selected candidates will be further evaluated through in vitro and in vivo assays.

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ABSTRACT CONTEXT AND OBJECTIVE: The lack of availability of antidotes in emergency services is a worldwide concern. The aim of the present study was to evaluate the availability of antidotes used for treating poisoning in Campinas (SP). DESIGN AND SETTING: This was a cross-sectional study of emergency services in Campinas, conducted in 2010-2012. METHODS: The availability, amount in stock, place of storage and access time for 26 antidotal treatments was investigated. In the hospitals, the availability of at least one complete treatment for a 70 kg adult over the first 24 hours of admission was evaluated based on stock and access recommendations contained in two international guidelines. RESULTS: 14 out of 17 functioning emergency services participated in the study, comprising pre-hospital services such as the public emergency ambulance service (SAMU; n = 1) and public emergency rooms for admissions lasting ≤ 24 hours (UPAs; n = 3), and 10 hospitals with emergency services. Six antidotes (atropine, sodium bicarbonate, diazepam, Phytomenadione, flumazenil and calcium gluconate) were stocked in all the services, followed by 13 units that also stocked activated charcoal, naloxone and diphenhydramine or biperiden. No service stocked all of the recommended antidotes; only the regional Poison Control Center had stocks close to recommended (22/26 antidotal treatments). The 10 hospitals had almost half of the antidotes for starting treatments, but only one quarter of the antidotes was present with stocks sufficient for providing treatment for 24 hours. CONCLUSION: The stock of antidotes for attending poisoning emergencies in the municipality of Campinas is incomplete and needs to be improved.

RESUMO CONTEXTO E OBJETIVO: A carência de disponibilidade de antídotos nas salas de emergência é uma preocupação mundial. O objetivo foi avaliar a disponibilidade de antídotos usados no tratamento de pacientes intoxicados no município de Campinas (SP). TIPO DE ESTUDO E LOCAL: Trata-se de estudo transversal de serviços de emergência de Campinas, realizado de 2010-2012. MÉTODOS: A disponibilidade, quantidade estocada, local de armazenamento e tempo de acesso a 26 tratamentos antidotais foi investigada. Nos hospitais, foi avaliada também a disponibilidade de pelo menos um tratamento complete para um adulto de 70 kg nas primeiras 24 horas da admissão, com base em recomendações de estoques e acesso contidas em duas diretrizes internacionais. RESULTADOS: 14 dentre 17 serviços de emergência em funcionamento participaram do estudo, que incluiu serviços pré-hospitalares, como o Serviço de Atendimento Móvel de Urgência (SAMU, n = 1) e três Unidades de Pronto Atendimento (UPAs, internação limitada até 24 horas), além de 10 hospitais com emergência. Seis antídotos (atropina, bicarbonate de sódio, diazepam, fitomenadiona, flumazenil e gluconate de cálcio) estavam estocados em todos os serviços, seguidos de 13 que também estocavam carvão ativado, naloxona, difenidramina ou biperideno. Nenhum serviço tinha estoque de todos os antídotos recomendados; somente o Centro de Controle de Intoxicações regional tinha estoque próximo ao perfil recomendado (22/26 opções terapêuticas). Os 10 hospitais tinham quase metade dos antídotos necessários para iniciar tratamento, mas somente um quarto dos antídotos estava em estoques suficientes para oferecer tratamento por 24 horas. CONCLUSÃO: O estoque de antídotos para atendimento de emergências toxicológicas no município de Campinas é incompleto e deve ser melhorado.

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Historical clinical case that presented back in 1968 at a time when respiratory support and intensive care techniques were just emerging, with many shortcomings in hospital care areas and monitoring devices. The case is of a 58 year-old patient, outstanding citizen, recent winner in a television contest on snakes, who was bitten accidentally by a coral snake Micrurus mipartitus. The poison of this snake is a macromolecule that induces complete depolarizing muscle blockade which, if not reverted, leads to death from respiratory failure. A group of social leaders in the region managed to obtain the specific anti-venom that was not produced in the country, as well as the mechanical ventilation equipment, a negative pressure "iron lung" and a Bird Mark 7 positive pressure device. Manual ventilation was initiated by the anaesthesia team with the support of the medical students. Then, with the Bird Mark 7, the patient survived under empirical "intensive" care after 17 days of respiratory depression and 33 days in the hospital. Voluntary contributions of the community in an effort to solve the clinical problem are narrated.

Se presenta un caso clínico de carácter histórico, sucedido en el año de 1968, época de un desarrollo incipiente de las técnicas de soporte respiratorio y cuidado intensivo, con deficiencias de los sitios de atención en el hospital y en equipos de monitoreo. Paciente de 58 años, líder cívico, ganador de un concurso de televisión sobre ofídicos, es mordido accidentalmente por una culebra "Rabo de Ají" Micrurus mApartitus cuyo veneno es una macro molécula que produce un bloqueo muscular completo tipo despolarizante que de no ser resuelto, el paciente muere por insuficiencia respiratoria. Un movimiento cívico de la región logra conseguir el antídoto específico que no se producía en el país y los equipos de ventilación mecánica, uno de presión negativa un "pulmón de acero" y otro de presión positiva un Bird Mark 7. Se inició ventilación manual con el equipo de anestesia y estudiantes de medicina, y luego con el Bird Mark 7 el paciente sobrevive a un cuidado empírico "intensivo" después de 17 días de depresión respiratoria y 33 días de hospitalización. Se narran aportes voluntarios de la comunidad en apoyo a la resolución del problema clínico.

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Antídotos e determinados medicamentos são essenciais ao tratamento de algumas intoxicações e não podem sofrer falhas no abastecimento, sob o risco de prejudicar a saúde e a segurança da população. O objetivo deste trabalho foi avaliar a disponibilidade de antídotos e medicamentos recomendados para o tratamento de intoxicações no Brasil. A partir de consensos internacionais, foram selecionados 41 antídotos para análise, todos sem patente em vigência. Desses, 27 são registrados, porém 11 estão disponíveis em formas inadequadas ao tratamento de intoxicações, restando 16 medicamentos comercialmente disponíveis. Somente um terço dos medicamentos necessários para o tratamento de intoxicações está incluído na relação de medicamentos essenciais do país. Em adição, é apresentada proposta de suprimento das demandas a um dos antídotos, anticorpo antidigoxina, considerando a capacidade de produção nacional de imunobiológicos. Os resultados demonstram limitação da assistência adequada aos pacientes intoxicados no país e reforçam a necessidade urgente de políticas públicas na área.

Antidotes and certain other drugs are essential for treating some types of poisoning. Failures in their supply can jeopardize the population's health and safety. The current study aimed to assess the availability of antidotes and other drugs used in the treatment of poisonings in Brazil. International guidelines were used as the basis for selecting 41 antidotes for analysis, none of which currently protected by patents. Of these, 27 are registered in Brazil, but 11 of these are available in inadequate forms for treating poisoning, leaving 16 commercially available antidotes. Only one-third of the drugs needed for treating poisoning are included in the country's list of essential drugs. The article also presents a proposal for supplying the demand for one of the antidotes, anti-digoxin antibody, considering Brazil's domestic capacity for manufacturing immunobiologicals. The study's results show the limitations to adequate treatment for poison victims in Brazil and reinforce the urgent need to strengthen public policies in this area.

Los antídotos y determinados medicamentos son esenciales para el tratamiento de algunas intoxicaciones, y su disponibilidad no puede fallar, o la salud y la seguridad de la población se ponen en peligro. Este estudio tuvo como objetivo evaluar la disponibilidad de antídotos y fármacos recomendados para el tratamiento por intoxicaciones en Brasil. Se seleccionaron para el análisis 41 antídotos de reconocido consenso internacional, todos ellos sin patentes en vigor. Veintisiete estaban registrados en Brasil, pero 11 se venden en preparados farmacéuticos, no apropiados para el tratamiento de intoxicaciones, lo que da como resultado 16 medicamentos disponibles en el mercado. Sólo se incluyen en la lista brasileña de medicamentos esenciales un tercio de los medicamentos necesarios para tratar intoxicaciones. Además, se presenta una propuesta para suplir uno de los antídotos, anticuerpo antidigoxina, considerando la capacidad de producción nacional. Los resultados muestran limitaciones en una atención adecuada a los pacientes intoxicados en Brasil y refuerzan la necesidad urgente de fortalecer las políticas públicas en este ámbito.

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Objetivos: Descrever um episódio de exposição coletiva a raticida do grupo superwarfarin e revisar a literatura a respeito do tema.Descrição dos casos: Cerca de 40 pessoas, incluindo crianças, ingeriram alimento contaminado por raticida em escola pública de ensino fundamental de Porto Alegre, Rio Grande do Sul. Foram registrados 34 casos individuais de ingestão acidental no Centro de Informação Toxicológica do Rio Grande do Sul. O caso foi amplamente divulgado na imprensa local. Após avaliação médica inicial, 19 pacientes apresentaram sintomas inespecíficos (como náuseas, dor abdominal e xerostomia), enquanto os outros permaneceram assintomáticos. Todos os pacientes foram acompanhados laboratorialmente, mediante controle do tempo de protrombina. Três deles apresentaram prolongamento do tempo de protrombina, tendo recebido vitamina K para reverter a coagulopatia. Dados locais e a revisão da literatura indicam que as exposições a raticidas da família dos superwarfarins são bastante frequentes. A ação desses agentes tóxicos ocorre principalmente sobre os fatores de coagulação produzidos pelo fígado e dependentes de vitamina K.Conclusões: Os pacientes expostos ao superwarfarin evoluíram bem, concordando com a literatura publicada, que indica que casos graves são incomuns. O seu acompanhamento e tratamento seguiu a indicação de utilizar a vitamina K como antídoto apenas nos casos em que se detecta efeito clínico ou laboratorial do agente tóxico.

Aims: To describe an episode of collective exposure to rodenticide of the superwarfarin group and to review the literatureon the subject.Cases description: About 40 people, including children, ate food contaminated with rodenticide in a public elementary school in Porto Alegre, Rio Grande do Sul. Thirty-four individual cases of accidental ingestion were reported to theToxicology Information Center of Rio Grande do Sul. The case was widely publicized in the local press. After initial medical evaluation, 19 patients had nonspecific symptoms (like nausea, abdominal pain and dry mouth), while the other remained asymptomatic. All patients were monitored by controlling the prothrombin time. Three of them showed prolongation ofprothrombin time and received vitamin K to reverse the coagulopathy. Local data and the literature review indicate thatexposures to rodenticides of the family of superwarfarins are frequent. The toxic action of these agents occurs mainly onclotting factors produced by the liver and vitamin K-dependent.Conclusions: The patients exposed to superwarfarin had a good outcome, in accordance with published literature, which indicates that severe cases are rare. The monitoring and treatment followed the indication of vitamin K as antidote onlyin cases where clinical or laboratorial effect of the toxic agent is detected.

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OBJETIVO: Descrever dois casos de distonia aguda após uso de bromoprida em crianças e realizar revisão da literatura em relação aos mecanismos fisiopatológicos de indução de liberação extrapiramidal, sua sintomatologia e tratamento. DESCRIÇÃO DO CASO: Caso 1: adolescente de 13 anos com quadro de dor e hipertonia cervical associados a febre, náuseas e vômitos, com hipótese inicial de meningite. A investigação subsequente revelou que o quadro iniciou-se após ingestão de uma única dose de bromoprida. O paciente apresentou boa resposta ao tratamento com difenidramina, sem necessidade de coleta de líquor. Caso 2: Lactente de seis meses que desenvolveu sintomas graves de liberação extrapiramidal relacionados à superdosagem de bromoprida, com reversão rápida dos sintomas após administração de biperideno. COMETÁRIOS: Este é o primeiro relato de distonia aguda após uso de bromoprida em crianças. Embora muito utilizada no Brasil como agente pró-cinético e antiemético, nenhum estudo clínico até o momento demonstrou melhor perfil de segurança da bromoprida em relação aos demais antieméticos antagonistas da dopamina. Até que tais estudos sejam realizados, sugere-se cautela na prescrição de bromoprida. Medidas não-farmacológicas devem ser recomendadas no tratamento de vômitos e da doença do refluxo gastresofágico. Quando o tratamento farmacológico for indispensável, deve-se dar preferência a drogas com perfil de segurança mais bem estabelecido.

OBJECTIVE: To report the case of two patients with acute dystonia induced by bromopride in children, followed by a review of the mechanisms of induction of movement disorders by antidopaminergic anti-emetic drugs, its clinical symptoms and treatment. CASE DESCRIPTION: Case 1: a 13 years old teenager who developed acute hypertonia and neck pain associated to fever and vomiting, suggestive of meningitis. Further investigation revealed that symptoms were associated with the ingestion of a single dose of bromopride. The symptoms stopped after administration of diphenidramine, preventing a spinal tap. Case 2: six months old infant who developed extrapyramidal movement disorder related to bromopride overdose, with prompt resolution of symptoms after treatment with biperiden. COMMENTS: This seems to be the first report of acute dystonia after the use of bromopride in children. Although frequently used in Brazil as an anti-emetic and prokynetic agent, no clinical study has showed that bromopride has a better safety profile than other antidopaminergic anti-emetic drugs. While such studies are not available, caution is needed in the context of pediatric prescription of bromopride. Non pharmacological measures should be adopted in the management of vomiting and gastroesophageal reflux. If medical treatment cannot be avoided, one would rather use medications with a better established safety profile.

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