Landscape of research, production, and regulation in venoms and antivenoms: a bibliometric analysis / Panorama de la investigación, la producción y la regulación de venenos y antivenenos: un análisis bibliométrico / Panorama de pesquisa, produção e regulação de venenos e antivenenos: análise bibliométrica

ABSTRACT Objectives. To assess the productivity and visibility in research, clinical studies, treatment, use and production of antivenoms against poisonous snakes, scorpions and spiders. Methods. Bibliometric analysis of research and other activities. Articles on venoms and antivenoms published between 2000 and 2020 were retrieved from the Scopus database. The records were analyzed by bibliometric indicators including number of documents per year, journals, authors, and citation frequency. VOSviewer® v.1.6.13 was used to construct bibliometric networks for country co-authorships and co-occurrence of terms. Results. Australia, Brazil, Costa Rica and India were among the six top countries with most documents and were selected for more detailed analysis. Costa Rica was the country with the largest percentage of its publications dedicated to antivenom production and venomics. Only a few papers dealt with the issues of quality, safety, and efficacy of antivenoms or the role of the national regulatory authorities. The use of VOSviewer® allowed visualization through joint publications of networking between countries. Visualization by co-occurrence of terms showed differences in the research carried out. Conclusions. Working in a collaborative and coordinated manner these four countries could have a major impact on envenoming globally. Attention should be given not only to antivenom production but also to strengthening regulatory oversight of antivenom products.

RESUMEN Objetivos. Evaluar la productividad y la visibilidad en la investigación, los estudios clínicos, el tratamiento, el uso y la producción de antivenenos contra las picaduras de serpientes, arañas y escorpiones venenosos. Métodos. Análisis bibliométrico de la investigación y de las otras actividades. Se tomaron los artículos sobre venenos y antivenenos publicados entre el 2000 y el 2020 en la base de datos de Scopus. Estos documentos se analizaron mediante indicadores bibliométricos como el número de documentos por año, revistas, autores o frecuencia en las citas. Se utilizó VOSviewer® v.1.6.13 para crear una red bibliométrica para coautorías de países y coapariciones de términos. Resultados. Australia, Brasil, Costa Rica e India estaban entre los seis primeros países con más documentos y se seleccionaron para un análisis más detallado. Costa Rica fue el país con el mayor porcentaje de sus publicaciones dedicadas a la producción de antivenenos y la venómica. Solo unos pocos artículos trataban los temas de la calidad, la seguridad y la eficacia de los antivenenos, o la función de las autoridades regulatorias nacionales. Gracias a VOSviewer® pudimos visualizar las publicaciones conjuntas de las colaboraciones entre países. La visualización por la coaparición de términos arrojó diferencias en la investigación realizada. Conclusiones. Si estos cuatro países trabajasen de forma colaborativa y coordinada, podrían tener una repercusión mayor en los envenenamientos por picaduras en el mundo. El foco no debe ponerse solo en la producción de antivenenos, sino también en fortalecer la supervisión regulatoria de estos productos.

RESUMO Objetivos. Avaliar a produtividade e visibilidade em pesquisa, estudos clínicos, tratamento, uso e produção de antivenenos contra peçonhas de serpentes, escorpiões e aranhas. Métodos. Análise bibliométrica de pesquisas e outras atividades. Artigos sobre venenos e antivenenos publicados entre 2000 e 2020 foram obtidos da base de dados Scopus. O conteúdo foi analisado segundo indicadores bibliométricos, como número de artigos por ano, periódicos, autores e frequência de citação. Utilizou-se o software VOSviewer® v.1.6.13 para construir redes bibliométricas de coautoria de países e co-ocorrência de termos. Resultados. Austrália, Brasil, Costa Rica e Índia figuraram entre os seis principais países com o maior número de artigos e, assim, foram selecionados para uma análise mais aprofundada. A Costa Rica teve a maior porcentagem de publicações dedicadas à produção de antivenenos e pesquisa em venômica. Apenas um pequeno número de artigos tratou de questões relacionadas à qualidade, segurança e eficácia dos antivenenos ou ao papel das autoridades nacionais reguladoras. O software VOSviewer® permitiu visualizar, através das publicações conjuntas, as redes formadas entre diferentes países. A visualização por co-ocorrência de termos revelou diferenças nas pesquisas realizadas. Conclusões. Trabalhando de forma colaborativa e coordenada, esses quatro países tiveram uma influência importante em nível mundial no campo de acidentes por animais peçonhentos. Deve-se atentar não apenas à produção de antivenenos, mas também ao fortalecimento da fiscalização regulatória destes.

Intoxicación por cianuro, perspectiva desde urgencias: reporte de dos casos y revisión de la literatura / Cyanide poisoning, perspective from the emergency room: report of two cases and literature review / Intoxicação por cianeto, perspectiva desde urgências: relato de dois casos e revisão da literatura

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.

Manejo de hemorragia asociada a anticoagulantes orales directos: estado actual de las estrategias de reversión / Management of bleeding associated with direct oral anticoagulants: update on reversal strategies

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.

Extracorporeal Life Support in Acute Poisoning

PURPOSE: Cardiovascular or respiratory complications of acute intoxication are the most common causes of mortality. Advanced cardiac life support (ACLS) or specific antidotes help manage these cardiac or respiratory complications in acute intoxication. On the other hand, some cases do not respond to ACLS or antidotes and they require some special treatment, such as extracorporeal life support (ECLS). ECLS will provide the chance of recovery from acute intoxication. This study examined the optimal timing of ECLS in acute intoxication cases. METHODS: This paper is a brief report of a case series about ECLS in acute poisoning. The cases of ECLS were reviewed and the effects of ECLS on the blood pressure and serum lactate level of the patients were analyzed. RESULTS: A total of four cases were reviewed; three of them were antihypertensive agent-induced shock, and one was respiratory failure after the inhalation of acid. The time range of ECLS application was 4.8-23.5 hours after toxic exposure. The causes of ECLS implementation were one for recurrent cardiac arrest, two for shock that did not respond to ACLS, and one for respiratory failure that did not respond to mechanical ventilator support. Three patients showed an improvement in blood pressure and serum lactate level and were discharged alive. In case 1, ECLS was stared at 23.5 hours post toxic exposure; the patient died due to refractory shock and multiple organ failure. CONCLUSION: The specific management of ECLS should be considered when a patient with acute intoxication does not recovery from shock or respiratory failure despite ACLS, antidote therapies, or mechanical ventilator support. ECLS improved the hemodynamic and ventilator condition in complicated poisoned patients. The early application of ECLS may improve the tissue perfusion state and outcomes of these patients before the toxic damage becomes irreversible.

The Effect of Glehnia Littoralis on Alpha-amanitin Induced Hepatotoxicity in a Murine Model

PURPOSE: Glehnia littoralis has been reported to have several pharmacological properties but no in vivo reports describing the protective effects of this plant on α-amanitin-induced hepatotoxicity have been published. α-Amanitin is a peptide found in several mushroom species that accounts for the majority of severe mushroom poisonings leading to severe hepatonecrosis. In our previous in vitro study, we found that α-amanitin induced oxidative stress, which may contribute to its severe hepatotoxicity. The aim of this study was to investigate whether Glehnia littoralis acetate extract (GLEA) has protective antioxidant effects on α-amanitin-induced hepatotoxicity in a murine model. METHODS: Swiss mice (n=40 in all groups) were divided into four groups (n=10/group). Three hours after giving α-amanitin (0.6 mg/kg, i.p.) to the mice, they were administered silibinin (50 mg/kg/d, i.p.) or Glehnia littoralis ethyl acetate extract (100 mg/kg/d, oral) therapies once a day for 3 days. After 72 hours of treatment, each subject was killed, cardiac blood was aspirated for hepatic aminotransferase measurement, and liver specimens were harvested to evaluate the extent of hepatonecrosis. The degree of hepatonecrosis was assessed by a pathologist blinded to the treatment group and divided into 4 categories according to the grade of hepatonecrosis. RESULTS: GLEA significantly improved the beneficial functional parameters in α-amanitin-induced hepatotoxicity. In the histopathological evaluation, the toxicity that was generated with α-amanitin was significantly reduced by GLEA, showing a possible hepatoprotective effect. CONCLUSION: In this murine model, Glehnia littoralis was effective in limiting hepatic injury after α-amanitin poisoning. Increases of aminotransferases and degrees of hepatonecrosis were attenuated by this antidotal therapy.

Consensus Guides on Stroke Thrombolysis for Anticoagulated Patients from Japan: Application to Other Populations / 대한뇌졸중학회지

Development of direct oral anticoagulants and their antidotes has led to the need to reconsider the eligibility of acute stroke patients who have been taking oral anticoagulants for intravenous thrombolysis. Officially authorized Japanese guidelines on this issue were revised twice at the time of approval for clinical use of direct oral anticoagulants and idarucizumab, a specific reversal agent for dabigatran. A unique recommendation in the latest Japanese clinical guides was that thrombolysis can be recommended if the time of the last dose of direct oral anticoagulants exceeds 4 hours and if commonly available anticoagulation markers are normal or subnormal, i.e., international normalized ratio of prothrombin time < 1.7 and activated partial thromboplastin time < 1.5 times the baseline value (≤40 seconds only as a guide). These criteria are partly supported by the findings of domestic multicenter and single-center surveys that symptomatic or asymptomatic intracranial hemorrhage following thrombolysis was rare under the conditions of the criteria. Even for dabigatran users, stroke thrombolysis can be considered without pretreatment by idarucizumab if patients meet the above criteria. If not, direct mechanical thrombectomy can be considered without pretreatment by idarucizumab or thrombolysis, and use of idarucizumab, followed immediately by thrombolysis, can be considered only when thrombectomy cannot be quickly performed. These clinical guides are practical and to some extent economical, but they have some limitations, including lack of corroborating information from sufficient numbers of relevant cases. The guides will be further modified based on the results of future research.

Non-Vitamin K Oral Anticoagulants Associated Bleeding and Its Antidotes / 대한뇌졸중학회지

Oral anticoagulant-associated intracerebral hemorrhage (OAC-ICH) accounts for nearly 20% of all ICH. The number of patients with an indication for oral anticoagulant therapy (OAT) increases with increasing age. OAT became less complicate with the introduction of non-vitamin K oral anticoagulants (NOAC) OAT because of easier handling, favorable risk-benefit profile, reduced rates of ICH compared to vitamin K antagonists and no need for routine coagulation testing. Consequently, despite a better safety profile of NOAC the number of patients with OAC-ICH will increase. The mortality and complication rates of OAC-ICH are high and therefore they are the most feared complication of OAT. Immediate normalization of coagulation is the main goal and therefore knowledge of pharmacodynamics and coagulation status is essential. Laboratory measurements of anticoagulant activity in NOAC patients is challenging as specific tests are not widely available. More accessible tests such as the prothrombin time and activated partial thromboplastin time have important limitations. In dabigatran-associated ICH 5 g Idarucizumab should be administered. In rivaroxaban and apixaban-associated ICHs administration of andexanet alpha should be considered. Prothrombin complex concentrate may be considered if andexanet alpha is not available or in case of an ICH associated with edoxaban.

Antidotes Stocking and Delivery for Acute Poisoning Patients at 20 Emergency Departments in Korea 2015–2017

PURPOSE: The National Emergency Medical Center has been running a project for the storage and delivery of antidotes for acute poisoning patients of the Department of Health and Welfare, Korea. This study analyzed the results of this project over the past two years. METHODS: The requests received by the National Emergency Medical Center and the data on the delivery process were analyzed. RESULTS: This study analyzed a total of 121 patients with acute poisoning, who were requested to receive an antidote reserved at 20 key hospitals in 2015–2017, and whose age was 52.3±23.5 years; old; 54 were women. Intentional poisoning were 58.7%, and the home was the most common place of exposure (66.9%). The toxic substances were chemicals (32.2%), pesticides (27.3%), medicines (24.8%), and snake venom (4.1%). The patient's poison severity score was 2.4±0.7 (median 3) indicating moderate-to-severe toxicity. Antidote administration was the cases treated in key hospitals 67.8% (82/121), in which transferred patients accounted for 57.3% (47/82). After receiving an antidote request from a hospital other than the key hospitals, the median was 75.5 minutes (range 10 to 242 minutes) until the antidote reached the patient, and an average of 81.5 minutes was required. The results of emergency care were intensive care unit (70.3%), general wards (13.2%), death (10.7%), and discharge from emergency department (5.0%). CONCLUSION: This study showed that the characteristics of acute poisoning patients treated with an antidote were different from previous reports of poisoned patients in the emergency department, and basic data on the time required for delivery from key hospitals was different.

Antivenom therapy: efficacy of premedication for the prevention of adverse reactions

Antivenoms or antitoxins have been effectively used for more than a century. During this time, these products have always proven to be highly effective in the treatment of infections and envenomations. However, antivenoms did not exhibit good safety results in their initial applications. After many improvements, antivenoms have substantially better safety profiles but still have some side effects. Due to the occurrence of adverse reactions, the practice of using premedication with the intent to decrease side effects has become accepted or mandatory in many countries. The drugs used for premedication belong to the histamine H1 antagonist, glucocorticoid and catecholamine groups. Currently, this practice is being questioned due to low or controversial efficacies in clinical assays. In this article, we discuss the causes of adverse reactions, the mechanisms of drugs that block the undesired effects and the results obtained in clinical trials. Although these three families of drugs could have positive effects on reducing adverse reactions, only adrenaline has demonstrated positive results in clinical assays.

Metahemoglobinemia relacionada con ingesta de puré de acelgas / Methemoglobinemia due to ingestion of chard puree

La metahemoglobinemia es un síndrome clínico dado por la presencia de una forma aberrante de hemoglobina, ocasionada por diversos agentes oxidantes. Se describe un caso clínico de metahemoglobinemia severa asociada a la ingesta de puré de acelgas con alto contenido en nitratos y nitritos. Paciente de un año, con antecedentes de comunicación interauricular (CIA), que presentó un cambio en coloración de la piel 7 h antes, en forma progresiva, acompañado de vómitos. Ingresó al Departamento de Emergencia con cianosis generalizada que no mejoró con oxigenoterapia, taquicardia y tendencia a hipotensión arterial. En cuidados intensivos se realizó ecocardiograma que evidenció CIA sin repercusión hemodinámica. Metahemoglobinemia 37%. Se realizó dosis de azul de metileno al 1% por vía intravenosa, con franca mejoría clínica a la hora de la administración del antídoto y descenso de niveles de metahemoglobina. Alta médica a las 36 horas del ingreso. Existía una relación cronológica entre la exposición a nitratos por ingesta de un puré de acelgas y la aparición del cuadro. Los niveles de nitratos hallados en dicho alimento fueron muy elevados considerando estándares internacionales, lo que sumado a una inadecuada conservación del alimento cocido los días previos, permitió confirmar el planteo etiológico realizado. Resulta importante sospechar esta entidad patológica poco frecuente frente a cianosis que no mejora con oxígeno, y prevenir cuadros similares al descrito mediante una adecuada manipulación y conservación de las verduras con alto contenido en nitratos.

Methemoglobinemia is a clinical syndrome due to the presence of an aberrant form of hemoglobin, caused by various oxidizing agents. The study reports a case of severe methemoglobinemia associated with the ingestion of chard puree with high levels of nitrates and nitrites. A 1-year-old patient with a history of atrial septal defect (ASD), who progressively showed change of skin color 7 hours earlier, accompanied by vomiting. She was admitted to the Emergency Department with generalized cyanosis not improving with oxygen therapy, tachycardia and tendency to hypotension. In the intensive care unit, an echocardiogram showed ASD without hemodynamic complications. Methemoglobinemia 37%. A 1% methylene blue dose was administered intravenously, with clinical improvement one hour after antidote administration and decrease in methemoglobin levels. Medical discharge at 36 hours of admission. There was a chronological relationship between nitrates exposure by ingestion of chard puree and the clinical onset of methemoglobinemia. The toxic cause was confirmed after high nitrates levels were found in this vegetable considering international standards, and an inadequate preservation of the cooked chard on previous days. It is important to suspect this rare pathological entity when cyanosis fails to improve with oxygen, and to prevent poisonings similar to those described by an adequate manipulation and preservation of vegetables with high nitrate levels.

Caracterización clínico-epidemiógica de mordedura de serpiente en el Hospital Regional Santa Teresa de Comayagua, 2014-2015 / Clinical-epidemiological characterization of snakebite at the Hospital Regional Santa Teresa de Comayagua, 2014-2015

Antecedente. La mordedura por serpiente o accidente ofídico consiste en una lesión cutánea, seguida de la inoculación de sustancias tóxicas con daño a los tejidos y condicionante de alteraciones fisiopatológicas locales y sistémicas de gravedad variable. Objetivo. Describir las características clínicas y epidemiológicas de las mordeduras de serpiente en el Hospital Regional Santa Teresa, Comayagua, enero 2014 ­ diciembre 2015. Metodología. Estudio descriptivo transversal. De 58 casos hospitalizados, solo se obtu - vieron expedientes clínicos de 36 (62.1%). Las variables incluyeron datos clínico-epidemiológicos, características del ofídeo, atención pre-hospitalaria e intrahospitalaria, y antecedentes personales patológicos. La información recolectada fue ingresada en base de datos Epiinfo versión 7.1.5 (CDC, Atlanta). Los resultados se presentan como frecuencias, porcentajes, rangos y promedios. La información personal de los casos se manejó confidencialmente. Resultados. De 36 pacientes, 33.3%(12) eran adolescentes entre 11-19 años, la afectación por sexo fue de 50% (18), obteniendo una relación de 1:1. 22.2%(8) se identificó al cascabel como el ofideo que produjo mayores afectaciones, la localización anatómica más afectada fue el miembro inferior izquierdo en un 33.3%(12), el 66.7%(24) pre - sentó Lesión grado I - leve según la clasificación de Christopher Rodning y Audebert. 77.8%(28) recibió administración de antiofídico. 97.2%(35) obtuvo mejoría al egreso. No se reportaron casos de mortalidad. Discusión: La mordedura de serpiente es un motivo de consulta poco habitual en los servicios de urgencias. Esto puede comportar dudas sobre su tratamiento, especialmente sobre el uso de un antídoto muy específico, caro, con escasa distribución y potenciales efectos adversos...(AU)

Antidote availability in the municipality of Campinas, São Paulo, Brazil / Disponibilidade de antídotos no município de Campinas, São Paulo

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.

Inhibición de los efectos coagulante, fosfolipasa A2 y proteolítico del veneno de Bothrops asper por plantas usadas tradicionalmente en Centroamérica / Inhibition of the coagulant, phospholipase A2 and proteolytic effects of Bothrops asper venom by plants traditionally used in Central America

Existen pocos estudios científicos que demuestren el valor terapéutico de las plantas usadas en la medicina tradicional centroamericana para tratar el envenenamiento ofídico. En este estudio se evaluó la capacidad de los extractos etanólicos de nueve plantas de uso etnomédico en Centroamérica (Acacia hindsii, Aristolochia maxima, Bursera simaruba, Cissampelos pareira, Eryngium foetidum, Hamelia patens, Pimenta dioica, Piper peltatum y Sansevieria hyacinthoides) para inhibir el efecto coagulante del veneno de Bothrops asper. Tres de ellas (B. simaruba, E. foetidum y P. dioica) también fueron evaluadas en cuanto a su capacidad inhibitoria de los efectos fosfolipasa A2 (PLA2) y proteolítico del veneno. Las plantas fueron colectadas en Guatemala, secadas, extraídas con etanol y los efectos inhibitorios evaluados in vitro después de preincubar concentraciones variables de extracto con concentraciones fijas de veneno. Los resultados demostraron que ninguno de los extractos logró inhibir los efectos coagulante y PLA2, pero los extractos clorofilados de P. dioica y E. foetidum inhibieron efectivamente la actividad proteolítica del veneno. El tamizaje fitoquímico, mediante ensayos macro y semimicrométricos de cromatografía en capa fina, demostró la presencia de metabolitos secundarios reportados con actividad antiproteolítica (flavonoides, antocianinas, catequinas y taninos) en la composición química de los extractos de E. foetidum y P. dioica. Su efecto sobre el veneno se evaluó mediante electroforesis SDS-PAGE, demostrándose que no está mediado por degradación proteolítica de los componentes del veneno. El aislamiento y caracterización específica de sus metabolitos secundarios en futuros estudios, permitirá determinar el mecanismo de acción inhibitoria ejercido por estos extractos.

Medicinal plants have been traditionally used in Central America to treat snakebite envenomations, however, very few scientific studies aimed to demonstrate their efficacy and safety have been performed. In this study, ethanolic extracts of nine plants used in the region by traditional healers in snakebite cases (Acacia hindsii, Aristolochia maxima, Bursera simaruba, Cissampelos pareira, Eryngium foetidum, Hamelia patens, Pimenta dioica, Piper peltatum and Sansevieria hyacinthoides) were evaluated for their ability to inhibit the coagulant effect induced by the venom of the snake Bothrops asper. Three of these extracts (B. simaruba, E. foetidum and P. dioica) were also evaluated for their inhibitory effect on the phospholipase A2 (PLA2) and proteolytic activities of the venom. Plants were collected in Guatemala, dried, extracted with ethanol, and their inhibitory effects were evaluated in vitro after pre-incubation of several amounts of each extract with a challenge concentration of venom. Results showed that none of the extracts inhibited the coagulant and PLA2 effects; however, chlorophyllated extracts of E. foetidum and P. dioica effectively inhibited the proteolytic activity of the venom. Phytochemical analysis of these extracts, conducted by macrometric assays and semimicroanalysis by thin layer chromatography, identified secondary metabolites (flavones, anthocyanins, catequines and tannins) whose anti-proteolytic activities have been widely reported. SDS-PAGE analysis demonstrated that the mechanism of inhibition is not related to proteolytic degradation of the venom proteins by the plant extracts. Further studies are needed to isolate and identify the active venom inhibitory compounds of these plants, aimed to understand their mechanism of action.

Pneumatosis Cystoides Intestinales and Portomesenteric Venous Gas following Anticholinesterase Pesticide Poisoning

Pneumatosis cystoides intestinalis and portomesenteric venous gas are uncommon radiological findings, but are found commonly in cases of bowel ischemia, or as a result of various non-ischemic conditions. A 72-year-old man visited an emergency center with altered mental status 2 hours after ingestion of an unknown pesticide. On physical examination, he showed the characteristic hydrocarbon or garlic-like odor, miotic pupils with no response to light, rhinorrhea, shallow respiration, bronchorrhea, and sweating over his face, chest and abdomen. Laboratory results revealed decreased serum cholinesterase, as well as elevated amylase and lipase level. We made the clinical diagnosis of organophosphate poisoning in this patient based on the clinical features, duration of symptoms and signs, and level of serum cholinesterase. Activated charcoal, fluid, and antidotes were administered after gastric lavage. A computerized tomography scan of the abdomen with intravenous contrast showed acute pancreatitis, poor enhancement of the small bowel, pneumatosis cystoides intestinalis, portomesenteric venous gas and ascites. Emergent laparotomy could not be performed because of his poor physical condition and refusal of treatment by his family. The possible mechanisms were believed to be direct intestinal mucosal damage by pancreatic enzymes and secondary mucosal disruption due to bowel ischemia caused by shock and the use of inotropics. Physicians should be warned about the possibility of pneumatosis cystoides intestinalis and portomesenteric venous gas as a complication of pancreatitis following anticholinesterase poisoning.

Hemorrhagic pericarditis associated with rivaroxaban in an atrial fibrillation patient with pacemaker

Rivaroxaban is a new oral anticoagulant used for the prevention of stroke in patients with atrial fibrillation. Hemorrhagic pericarditis is known to occur with rivaroxaban; however, only a few case reports in the literature describe such events. Recently, we experienced hemorrhagic pericarditis that treated with rivaroxaban for anticoagulation of newly diagnosed, non valvular AF patients with pacemaker. An 83 year old male with permanent pacemaker receiving rivaroxaban 20 mg daily once for 3 months presented at our emergency department complaining of exertional dyspnea. ECG showed intermittent atrial pacing failure and echocardiography showed large amount of pericardial effusion. After urgent pericardiocentesis, which resulted in removal of 500cc bloody fluid, there was an immediate and dramatic improvement in the patient's clinical state. He was discharged without anticoagulation therapy due to concern for further bleeding. This case highlight the potential for bleeding complications associated with novel anticoagulants. Rivaroxaban is being used with increasing frequently in outpatient care. However, no available laboratory test specifically measures the anticoagulant effect of rivaroxaban. Also, in the events of serious bleeding, no specific antidotes, reversal agents were available. Clinicians should be aware of the possibility of hemopericardium in patients treated with anticoagulants, including rivaroxaban who presented with cardiomegaly.

Availability of antidotes and key emergency drugs in tertiary care hospitals of Punjab and assessment of the knowledge of health care professionals in the management of poisoning cases

This study was conducted to evaluate the availability of antidotes / key emergency drugs in tertiary care hospitals of the Punjab province, and to assess the knowledge of health care professionals in the stocking and administration of antidotes in the proper management of poisoning cases. Seventeen [n=17] tertiary care hospitals of Punjab Pakistan were selected. Two performas [A and B] were designed for 26 antidotes / key emergency drugs and given to the hospital pharmacists and physicians respectively. It was observed that Activated Charcoal, being the universal antidote was found only in 6 hospitals [41%]. Digoxin Immune Fab, Edentate Calcium disodium and Glucagon were not available in emergency department of any hospital and even not included in the formulary of any hospital. About 80% pharmacists were aware of the method of preparation of Activated Charcoal and 85% physicians were familiar with its route of administration. Data showed that tertiary care hospitals of Punjab do not stock antidotes according to national drug policy. Moreover the study strongly suggests the development of health care centers and professional by organizing antidote awareness programs, continuous education and record keeping of poisonous cases and availability of emergency drugs around the clock

Venous Thromboembolism Following Dantrolene Treatment for Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is one of the most severe iatrogenic emergencies in clinical service. The symptoms including sudden consciousness change, critical temperature elevation and electrolytes imbalance followed by mutli-organ system failure were common in NMS. In addition to aggressive interventions with intravenous fluid resuscitation and antipyretics, several antidotes have been suggested to prevent further progression of the muscle damage. Dantrolene has been reported to be one of the most effective treatments for NMS. However, the adverse effects of dantrolene treatment for NMS have not yet been evaluated thoroughly. Here we report a young male patient with bipolar I disorder who developed NMS after rapid tranquilization with haloperidol. Dantrolene was given intravenously for the treatment of NMS. However, fever accompanied with local tenderness, hardness with clear border and swelling with heat over the patient's left forearm occurred on the sixth day of dantrolene treatment. Venous thromboembolism (VTE) over intravenous indwelling site at the patient's forearm was noted and confirmed by Doppler ultrasound. The patient's VTE recovered after heparin and warfarin thrombolytic therapy. To our knowledge, this is the first case report demonstrating the possible relationship between dantrolene use and VTE in a patient with antipsychotic treatment. Although the causal relationship and the underlying pathogenesis require further studies, dantrolene should be used with caution for patients with NMS.

A Case of Aconite Poisoning Successfully Recovered after Intravenous Fat Emulsion Therapy

Aconitum is a genus of various species of flowering plants that belongs to the Family Ranunculaceae. Most Aconitum sp. have extremely toxic alkaloid substances such as aconitine, mesaconitine and hypaconitine. Among these substances, aconitine can cause fatal cardiotoxicity by activating sodium channels followed by calcium channels in myocardial cells. Even though there have been various therapeutic plans suggested comprising antidotes based on diverse case reports and studies, there is no confirmatory treatment protocol for aconite poisoning. Here, we report an aconite poisoning patient who had refractory ventricular tachyarrhythmia that did not respond to intravenous amiodarone therapies even though they were sustained for over 2 hours, but showed successful recovery following intravenous fat emulsions (IFE) therapy.

A Case of Aconite Poisoning Successfully Recovered after Intravenous Fat Emulsion Therapy

Aconitum is a genus of various species of flowering plants that belongs to the Family Ranunculaceae. Most Aconitum sp. have extremely toxic alkaloid substances such as aconitine, mesaconitine and hypaconitine. Among these substances, aconitine can cause fatal cardiotoxicity by activating sodium channels followed by calcium channels in myocardial cells. Even though there have been various therapeutic plans suggested comprising antidotes based on diverse case reports and studies, there is no confirmatory treatment protocol for aconite poisoning. Here, we report an aconite poisoning patient who had refractory ventricular tachyarrhythmia that did not respond to intravenous amiodarone therapies even though they were sustained for over 2 hours, but showed successful recovery following intravenous fat emulsions (IFE) therapy.