Strategies of neutralization of the direct oral anticoagulants effect: review of the literature.

Many neutralizing agents of anticoagulant effect of factor Xa or thrombin inhibitors (xabans and dabigatran, respectively) have been developed since the commercialization of direct oral anticoagulants (DOAC) in 2008. Idarucizumab is a specific antidote of dabigatran commercialised since 2016. An antidote of xabans, andexanet-α, was very recently approved by the Food and Drug Administration (FDA). Other antidotes of DOAC are under pre-clinical or clinical development; the most advanced being the aripazine in addition to γ-thrombine S195A and GDFXa-α2M complex. Prothrombin complex concentrates activated or not, are part of the pro-hemostatic agents suggested for DOAC handling in case of haemorrhage or preceeding urgent surgery or invasive procedures. Other pro-hemostatic agents (FXaI16L, FX (a)-C, superFVa) are in pre-clinical stage. The efficacy of these different agents in DOAC reversal and mortality reduction is still controversal in the light of the sparse results of in vitro, ex vivo, pre-clinical and clinical studies.

Antidote availability in the municipality of Campinas, São Paulo, Brazil.

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.

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.

Antídotos: guía de utilización y stock mínimo en el servicio de urgencias / Antidotes: use guidelines and minimun stock in an Emergency department

Objetivo: Elaborar una guía de antídotos y otros medicamentos para intoxicaciones y definir el stock en el servicio de Urgencias, como cometido de seguridad prioritario para el farmacéutico adscrito a la unidad, tras su incorporación a tiempo parcial. Método Búsqueda en bases de datos y portales especializados de la Asociación Española de Toxicología y el National Poisons Information Service británico, entre otros; bases de datos de toxicología, TOXICONET; información de otros hospitales; fuentes terciarias; Micromedex y Medline. Resultados La guía, accesible para Farmacia y para Urgencias en formato electrónico, incluye 42 principios activos. Se acordó un stock mínimo en urgencias basado en el tratamiento de un día para un paciente de 100kg. Esta información, con fechas de caducidad actualizadas, se encuentra en los puntos de localización del stock de antídotos en urgencias, y en formato electrónico. El farmacéutico revisa mensualmente la necesidad de reposición por caducidad o por falta de solicitud. Discusión La reducida evidencia basada en estudios de calidad sobre antídotos, la variabilidad debida a las dificultades de actualización de las fuentes y algunas discordancias relacionadas con la utilización según áreas geográficas dificulta la toma de decisiones. Sería útil disponer de recomendaciones de cantidades mínimas por parte de sociedades de toxicología, agencias reguladoras u organizaciones como la Joint Commission on Accreditation of Healthcare Organizations. Es deseable una evaluación de riesgos a nivel suprahospitalario que optimice la gestión y asegure la disponibilidad de antídotos de costes elevados, caducidad reducida y difícil previsión de necesidades, en muchos casos (AU)

Objective: To develop a guide for antidotes and other medications used to counteract poisoning, and define the stock in an emergency department, as a safety priority for the part-timepharmacist assigned to the unit. Method: A search of specialist databases and web portals of the Spanish Society of Toxicology and the British National Poisons Information Service, as well as toxicology databases, TOXICONET, information from other hospitals, tertiary sources, Micromedex and Medline. Results: The Guide contains 42 active ingredients and is accessible to the Pharmacy and Emergency departments in electronic format. A minimum emergency stock was agreed based on the daily treatment of a 100 kg patient. This information, including updated expiry dates, is available at the emergency department antidote stock facilities and in electronic format. On amonthly basis, the pharmacist reviews the need to replace any drugs, due to their expiry dateor lack of use. Discussion: The lack of evidence from high quality antidote studies, the variability due to the difficulties of updating sources and some geographical differences in their use means that decision-making can be difficult. It would be useful to have minimum quantity recommendations from societies of toxicology, regulatory agencies and organisations such as the Joint Commission on the Accreditation ofHealthcare Organisations. It would also be useful to have a suprahospital risk assessment tooptimise management and ensure the availability of antidotes which are expensive, have alimited shelf life, or of which demand is difficult to forecast (AU)

Diversity of Micrurus snake species related to their venom toxic effects and the prospective of antivenom neutralization

Micrurus snake bites can cause death by muscle paralysis and respiratory arrest, few hours after envenomation.The specific treatment for coral snake envenomation is the intravenous application of heterologous antivenom and, inBrazil, it is produced by horse immunization with a mixture of M. corallinus and M. frontalis venoms, snakes that inhabit theSouth and Southeastern regions of the country. However, this antivenom might be inefficient, considering the existence ofintra- and inter-specific variations in the composition of the venoms. Therefore, the aim of the present study was toinvestigate the toxic properties of venoms from nine species of Micrurus: eight present in different geographic regions ofBrazil (M. frontalis, M. corallinus, M. hemprichii, M. spixii, M. altirostris, M. surinamensis, M. ibiboboca, M. lemniscatus) and one(M. fulvius) with large distribution in Southeastern United States and Mexico. This study also analyzed the antigenic crossreactivityand the neutralizing potential of the Brazilian coral snake antivenom against these Micrurus venoms

Current views on antidotal therapy in managing cases of poisoning and overdose.

While it is an acknowledged dictum that in poisoning or overdose cases, the emphasis must be on general management comprising supportive measures than the use of specific antidotes in the vast majority of cases, it is nevertheless true that there are some instances where the timely use of a specific antidote or antagonist will dramatically reverse or at least halt the progression of toxicity. For this reason, and also because the indications and the exact manner in which antidotes must be used could be controversial or unfamiliar to the physician, an attempt has been made to review the current concepts on antidotal therapy of poisoning. There is enough evidence that the proper use of specific antidotes when combined with general supportive care does reduce the morbidity and mortality associated with severe poisonings. Common antidotes used in a hospital setting have been discussed in some detail.

The approach to the patient with an unknown overdose.

Toxic overdose can present with various clinical signs and symptoms. These may be the only clues to diagnosis when the cause of toxicity is unknown at the time of initial assessment. The prognosis and clinical course of recovery of a patient poisoned by a specific agent depends largely on the quality of care delivered within the first few hours in the emergency setting. Usually the drug or toxin can be quickly identified by a careful history, a directed physical examination, and commonly available laboratory tests. Once the patient has been stabilized, the physician must consider how to minimize the bioavailability of toxin not yet absorbed, which antidotes (if any) to administer, and if other measures to enhance elimination are necessary.

The dilemma of approving antidotes.

Clinical trials with antidotes are difficult to perform for a variety of practical, ethical, and financial reasons. As acute poisoning is a rare event, the commercial interest in basic and clinical research is low. Poisoned patients are usually not available for normal clinical trial procedures and, if they are, they cannot give informed consent. This situation results in a dilemma: antidotes are essential drugs. A resolution of the Council of Europe requests to guarantee the optimal availability of antidotes and the improvement of their use. As comprehensive data on the efficacy of antidotes are often missing, a marketing authorisation under exceptional circumstances according to Article 14(8) of Regulation (EC) No. 276/2004, will often be the only way to get an approval, as: (1) the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence ("orphan drug"), (2) in the present state of scientific knowledge, comprehensive information cannot be provided, or (3) it would be contrary to generally accepted principles of medical ethics to collect such data. Typically, data on antidotes are obtained from a patchwork of studies with animals, human tissue and a few observations from human poisoning corroborated with data from clinical observations and biochemistry. Generalisations from chemical and mechanistic similarities between groups of poisons are usual, but often lack scientific evidence. Current standards of good clinical practice can rarely be observed. Therefore, public funding and other financial support are necessary incentives to initiate trials in this important area.

Diagnosis and management of the poisoned child.

Pediatric toxic ingestions are treated commonly by pediatricians and emergency physicians. Significant injury after these ingestions is infrequent, but identifying the dangerous ingestion is sometimes a difficult task. By performing a detailed history, focused physical examination, and directed laboratory evaluation, an estimation of risk can be developed. This article introduced the term "toxic triage" to describe this process. The toxic triage estimation allows the clinician to make thoughtful decontamination and treatment decisions. Familiarity with the literature supporting or refuting each decontamination method allows educated decisions to be made. Supportive care is an integral part of treatment for all poisonings, from asymptomatic to life-threatening. Most antidotes are used rarely in clinical practice, but familiarity with common antidotes benefits those patients with specific hazardous ingestions. Prevention efforts have the potential to decrease the incidence of pediatric poisonings. The universal poison control center number provided should be distributed and posted in homes, clinics, and emergency departments.

[Prophylactic efficiency of tietasol and oxymethyluracyl against chlorphenols exposure in experimental and real conditions]. / Profilakticheskaia éffektivnost' tietazola i oksimetiluratsila pri vozdeistvii khrorfenolov.

The authors studied protective efficiency of tietasol and oxymethyluracyl in experiments with animals exposed to 2,4-dichlorphenol and in real chlorphenol production. According to the results, oxymethyluracyl could be recommended to increase resistance against chemicals in occupational conditions.

Consideraciones acerca del tratamiento de las intoxicaciones agudas en Atención Primaria / Aspects about poisoning treatment in Primary Health Care

En muchas ocasiones la posibilidad de que una intoxicación aguda tenga una buena evolución viene condicionada por las medidas terapéuticas que se realicen en los primeros minutos. Dichas medidas son básicamente de tres tipos: soporte vital, técnicas encaminadas a impedir la absorción del tóxico y favorecer la eliminación del ya absorbido, y la administración de antídotos. En los últimos años se ha puesto en duda la eficacia de las técnicas de descontaminación gástrica cuando el tiempo transcurrido tras la ingestión del tóxico es mayor de una hora. Esto hace que en un gran número de pacientes intoxicados sólo sea posible su realización en el contexto de Atención Primaria ya que es únicamente en este nivel asistencial donde es posible atenderlos con un margen de tiempo menor del referido. Por otra parte, también es necesario plantearse cuál es el arsenal de antídotos del que se debe disponer en el ámbito de la asistencia primaria (AU)

Clinical and institutional aspects of antidote therapy in Russia.

The problem of antidote application for treatment of acute poisoning is related to epidemiology and characterization of poisoning cases, and possibilities for supplying antidotes to health care institutions. To investigate the situation in Russia we have analyzed reports by poisoning treatment centers for 1997-1999, comparison of medical aid standards for poisoning treatment in Russia with WHO recommendations. Acute poisoning pattern varies in different regions. Particularly, poisoning pattern in large cities in European Russia and the Urals is dominated by pharmaceuticals (up to 63.1%). Pesticide and insecticide poisoning cases do not exceed 1 to 2%, metal compounds and methemoglobin forming poisons (below 1% in each group). Antidotes are used in Russia in line with the recommendations adopted in international toxicological practice. The most actual are antagonists of opiates and benzodiazepines, physostigmine, atropine, pyridoxine, antagonists of beta-adrenergic blockers, activated charcoal. Such antidotes as DMPS (Unithiol), N-acetylcysteine, methylene blue, amyl nitrite (or sodium nitrite), complex formers of EDTA group are also included in the list of specific agents. The main problem is that some important antidotes are currently not produced in Russia. The Ministry of Health of the Russian Federation is taking efforts to launch production of some previously known and also newly developed important antidotes.

[Specific drug therapy of acute poisoning]. / Spetsificheskaia farmakoterapiia ostrykh otravlenii.

Antidote therapy is an important component of urgent treatment of acute poisonings. However, due to high specificity of the antidote action they can be effectively and safely used only under certain conditions. According to Ye. A. Luzhnikov's classification, 4 main groups of antidotes are distinguished: toxicotropic, toxicokinetic, symptomatic, and antitoxic immunopreparations. The use of individual antidotes, mainly symptomatic and some toxicotropic and toxicokinetic, is determined by the presence of typical clinical signs of poisoning and the anamnesis. In the rest cases the diagnosis is to be confirmed by laboratory findings, which is particularly important in poisoning with alcohol substitutes and metal compounds. Antidotes can cause side effects and complications, and therefore cannot be used in some cases.

Evaluation of antidotes: activities of the International Programme on Chemical Safety.

Important developments concerning the role of antidotes in managing poisoning cases have taken place in recent decades due to new toxicodynamic and toxicokinetic studies and to growing international concern regarding the effectiveness of antidotes. A number of activities are carried out by the International Programme on Chemical Safety which aim to: (1) evaluate their effectiveness in clinical practice, (2) disseminate evaluated information, and (3) promote the availability of useful antidotes. The International Programme on Chemical Safety has undertaken the preparation of Antidote Monographs that summarize and assess the clinical use, mode of action, effectiveness, and other evaluated information, and a consolidated International Programme on Chemical Safety List of Antidotes that classifies antidotes and related drugs by their clinical effectiveness and urgency of need. A chart of Antidote Dosages, with information concerning the recommended antidotes and their indications, is being prepared, and the Availability of Antidotes in different countries is being surveyed. Further International Programme on Chemical Safety initiatives are also being undertaken in the area of antidotes and clinical toxicology in order to examine particular issues. The International Programme on Chemical Safety INTOX Project and related activities provide powerful tools for multicenter studies, but such research faces continuing financial and regulatory difficulties. Twinning arrangements between scientists from different parts of the world are being promoted to enhance the capabilities of evaluating treatment procedures and to compare clinical data. International organizations have important aims: to promote adequate and appropriate regulations and increase antidote availability, to establish international consensus and to increase interest in co-operative research. Cooperation with scientific bodies is essential in supporting these aims.

The relative efficacy of antidotes: the IPCS evaluation series. International Programme on Chemical Safety.

Antidotes may play an important role in the treatment of poisoning. For many physicians and toxicologists an antidote is an antidote. According to the IPCS definition, an antidote is a therapeutic substance used to counteract the toxic action(s) of a specified xenobiotic. Given this wide definition, the efficacy of an antidote may vary considerably depending on which toxic action(s) is/are being counteracted and on the level of counteracting power: An almost 100% efficacy is seen using specific antagonists, such as naloxone in opiate poisoning or flumazenil in benzodiazepine poisoning, e.g. resulting in complete reversal of opiate toxicity unless complications, such as anoxic brain damage, have developed. At the other end of the efficacy scale, we may place chelating agents for heavy metal poisoning and diazepam for organophosphorus insecticide poisoning. Therefore, in the IPCS/EC evaluation series of antidotes, some chelating agents are considered only to be an adjunct to supportive care which is the cornerstone of treatment. When teaching clinical toxicology or recommending the use of antidotes in poisoned patients, the expected efficacy level of the antidote in question should be stressed. This may be particularly important in severe poisonings when the antidote may only be considered as an adjunct to supportive care, e.g. deferoxamine in acute iron poisoning. Unless this is stressed, the unexperienced physician may rely too much on the antidote and may not pay sufficient attention to the supportive care. In this presentation, the varying efficacy levels of antidotes are discussed as based on the presently ongoing IPCS/EC evaluation programme on antidotes.