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Introduction Acetaminophen (paracetamol, APAP) poisoning is a prominent global cause of drug-induced liver injury. While N-acetylcysteine (NAC) is an effective antidote, it has therapeutic limitations in massive overdose or delayed presentation. The objective is to comprehensively review the literature on fomepizole as a potential adjunct antidote for acetaminophen toxicity. Methods A scoping review was performed using standardized search terms from inception through July 2021. Results Reports on fomepizole as a therapeutic adjunct for APAP toxicity span heterogeneous types of evidence. Eleven preclinical studies (in vitro and animal), fourteen case reports/series, and one human volunteer study were included. Fomepizole's action is mediated by inhibition of CYP2E1 to prevent oxidant stress generation, and inhibition of c-Jun N-terminal kinase (JNK) to decrease amplification of oxidant stress signaling to mitochondria. Studies have shown a reduction in oxidative metabolites likely by shunting metabolism away from CYP2E1 and a resultant decrease in liver injury in animals, independent of CYP2E1 interactions. Fomepizole has been linked to few adverse effects. Conclusion Based on in vitro and animal studies, and bolstered by case reports, fomepizole likely offers benefit as an adjunct antidote for APAP toxicity, however this remains to be shown in a human trial. NAC remains the standard of care antidote, but given that fomepizole is approved and generally safe, it may be considered for APAP toxicity as off-label use by experienced clinicians, in rare circumstances associated with increased risk of hepatotoxicity despite standard NAC dosing. The marginal clinical benefit of fomepizole adjunct therapy beyond NAC monotherapy remains to be clearly defined, and routine use for APAP overdose is premature based on current evidence.

Opioid overdoses (ODs) are increasing in Mexico's northern border. Because naloxone is usually not available, witnesses inject common salt (NaCl) into a vein of OD victims in an attempt to help them regain consciousness. Despite this widespread practice, no preclinical studies have addressed the efficacy of NaCl as an opioid antidote. Here we tested saline solutions at different concentrations. Because the highest (31.6 %) caused tail necrosis, we selected 17.7 % as a hypertonic saline solution (HSS) to determine if it could prevent the lethal effect of morphine (Mor), fentanyl (Fen), or Mor + Fen in adult Wistar male rats. We also evaluated if NaCl could modify the opioid antagonist effect of naloxone. Our results show that HSS: a) sensitizes animals to thermal but not mechanical stimuli; b) does not prevent mortality caused by high morphine or fentanyl doses; c) decreases the latency to recovery from the sedative effects caused by low doses of morphine or fentanyl; and d) increases naloxone's efficacy to prevent the lethality produced by Mor or Fen, but not by Mor + Fen. These results suggest that HSS is marginally effective in shortening the recovery time from nonfatal opioid ODs and increases naloxone's efficacy to counteract opioid-induced ODs.

Cyanide induces acute lethal poisoning resulting from inhibition of cytochrome c oxidase located in the complex IV (Complex IV) of mitochondria. However, current therapies for cyanide poisoning using hydroxocobalamin and nitrous acid compounds remain a clinical issue. Here, we show that liposome-encapsulated methemoglobin (metHb@Lipo), nanosized biomimetic red blood cells, replicate the antidotal mechanism of nitrous acid compounds against cyanide poisoning, achieving superior efficacy and fast action with no adverse effects. The structure of metHb@Lipo, which consists of concentrated methemoglobin in its aqueous core and a lipid membrane resembling the red blood cell membrane, provides favorable characteristics as a cyanide antidote, such as binding properties and membrane permeability. Upon cyanide exposure, metHb@Lipo maintained the mitochondrial function in PC12 cells, resulting in a cell viability comparable to treatment with nitrous acid compounds. In a mouse model of cyanide poisoning, metHb@Lipo treatment dramatically improved mortality with a rapid recovery from the symptoms of cyanide poisoning compared to treatment with nitrous acid compounds. Furthermore, metHb@Lipo also possesses satisfactory pharmacokinetic properties without long-term bioaccumulation and toxicity. Our findings showed a novel concept to develop drugs for cyanide poisoning and provide a promising possibility for biomimetic red blood cell preparations for pharmaceutical applications.

Aluminum phosphide (AlP) is a popular fumigant used widely for the safe storage of food grain. Although A1P is free from toxic residues, it releases phosphine which acts on mitochondrial components of almost all types of pests. Unfortunately A1P is also a common suicidal agent in developing countries with no known antidote. In addition, accidental exposure to phosphine may also occur. AlP poisoning affects cardiac and vascular tissue directly and can result in multiorgan system failure leading to death in severe cases. There is no specific biomarker for diagnosing AlP poisoning and management depends on a high level of clinical suspicion. Although acetylcholinesterase has been suggested as a surrogate biomarker of AlP exposure, there are opposing views. In this review, we analyzed the relevant published material with emphasis on the need to recognize and explore the use of plasma mitochondrial enzyme activity as a potential biomarker for AlP exposure.

International audience; Alpha2-macroglobulin (α2M) is a physiological macromolecule that facilitates the clearance of many proteinases, cytokines and growth factors in human. Here, we explored the effect of induced forms of α2M on anticoagulant drugs. Gla-domainless factor Xa (GDFXa) and methylamine (MA)-induced α2M were prepared and characterized by electrophoresis, immunonephelometry, chromogenic, clot waveform and rotational thromboelastometry assays. Samples from healthy volunteers and anticoagulated patients were included. In vivo neutralization of anticoagulants was evaluated in C57Bl/6JRj mouse bleeding-model. Anticoagulant binding sites on induced α2M were depicted by computer-aided energy minimization modeling. GDFXa-induced α2M neutralized dabigatran and heparins in plasma and whole blood. In mice, a single IV dose of GDFXa-induced α2M following anticoagulant administration significantly reduced blood loss and bleeding time. Being far easier to prepare, we investigated the efficacy of MA-induced α2M. It neutralized rivaroxaban, apixaban, dabigatran and heparins in spiked samples in a concentration-dependent manner and in samples from treated patients. Molecular docking analysis evidenced the ability of MA-induced α2M to bind non-covalently these compounds via some deeply buried binding sites. Induced forms of α2M have the potential to neutralize direct oral anticoagulants and heparins, and might be developed as a universal antidote in case of major bleeding or urgent surgery. © 2021 Elsevier B.V.

Oxime reactivators of acetylcholinesterase (AChE) represent an integral part of standard antidote treatment of organophosphate poisoning. Oxime K869 is a novel bisquaternary non-symmetric pyridinium aldoxime with two pyridinium rings connected by a tetramethylene bridge where two chlorines modify the pyridinium ring bearing the oxime moiety. Based on in vitro assays, K869 is a potent AChE and butyrylcholinesterase (BChE) reactivator. For the investigation of the basic pharmacokinetic properties of K869 after its intramuscular application, new HPLC-UV and LC-MS/MS methods were developed and validated for its determination in rat body fluids and tissues. In this study, the SPE procedure for sample pretreatment was optimized as an alternative to routine protein precipitation widely used in oxime pharmacokinetics studies. K869 oxime is quickly absorbed into the central compartment reaching its maximum in plasma (39 ± 4 μg/mL) between 15 and 20 min. The majority of K869 was eliminated by kidneys via urine when compared with biliary excretion. However, only a limited amount of K869 (65 ± 4 ng/g of brain tissue) was found in the brain 30 min after oxime administration. Regarding the brain/plasma ratio calculated (less than 1%), the penetration of K869 into the brain did not exceed conventionally used oximes.

Summary Amitraz is an insecticide of the formamidine pesticides family, used in veterinary medicine for the treatment of ectoparasites of certain animals. It inhibits monoamine oxidase (MAO) activity, but above all has alpha-2-adrenergic properties in mammals. Very few cases in men have been reported whose circumstances may be accidental or voluntary. Evolution can be fatal if management is delayed. The toxicological screening using high performance liquid chromatography (HPLC) returned positive to amitraz in the biological matrices. The care in the intensive care unit has consisted in treatment disinfector skin, gastric, and symptomatic in the absence of a specific antidote treatment. Although rare, poisoning with amitraz can be serious. It must be diagnosed and treated early to ensure life-threatening conditions. We report two cases of amitraz poisoning. The main objective is to describe the clinical signs of acute poisoning caused by this uncommon pesticide and to prevent its abuse for the maintenance of hives instead of its usual use as veterinary antiparasitic drugs in vertebrate animals.

Purpose To determine the long-term prevalence and characteristics of acute hydrofluoric acid (HF) exposure in 2223 patients during the first 30 months after a mass-casualty exposure, and to confirm the antidotal effect of nebulized calcium on inhalation burns caused by HF. Methods This observational cohort study included patients after an HF spill in the Republic of Korea on September 27, 2012; registered patients were followed until April 2015. We assessed toxic effects, distance from spill, degree of acute poisoning, and the effect of nebulized calcium in HF-exposed individuals. Results Overall, 2223 patients received emergency management or antidote therapy for 20 days. Seventy-four of 134 patients with dermal toxicity received calcium–lidocaine gel, and 368 individuals with bronchial irritation signs received calcium gluconate via nebulizer nCG. A total 377 ampoules 786 g of calcium gluconate were used in the nCG formulation. Calcium administration did not cause adverse reactions during the observation period. Long-term cohort observation showed that 120 patients (120/2233, 5.4%) returned to medical facilities for management of HF-related symptoms within 1 month; 18 persons (18/1660, 1.1%) returned 1–3 months later with chronic cough and respiratory symptoms; and 3 patients (3/1660, 0.2%) underwent medical treatment due to upper-airway toxic symptoms more than 2 years after HF exposure. Conclusion Respiratory toxicity after mass exposure to an HF spill was successfully treated by calcium nebulizer. Based on our experience, detoxification processes and the amounts of antidote stocked are important when planning for future chemical disasters at the community level.

Sulfur mustard (SM) is a toxicant and chemical warfare agent with strong vesicant properties. The mechanisms behind SM-induced toxicity are not fully understood and no antidote or effective therapy against SM exists. Both, the risk of SM release in asymmetric conflicts or terrorist attacks and the usage of SM-derived nitrogen mustards as cancer chemotherapeutics, render the mechanisms of mustard-induced toxicity a highly relevant research subject. Herein, we review a central role of the abundant cellular molecule nicotinamide adenine dinucleotide (NAD+) in molecular mechanisms underlying SM toxicity. We also discuss the potential beneficial effects of NAD+ precursors in counteracting SM-induced damage.

Acetaminophen is a widely used analgesic and antipyretic, which can cause liver injury after an overdose. Although a controversial topic for some time, solid evidence for a critical role of oxidative and nitrosative stress has emerged during the last two decades. This review will discuss the cellular sources, amplification mechanisms and the consequences of the excessive formation of reactive oxygen and nitrogen species in the clinically relevant mouse model of acetaminophen hepatotoxicity. This new mechanistic insight contributes to the better understanding of the mechanism of action of N-acetylcysteine, the only clinically approved antidote. In addition, it provides the rationale for the development of new antidotes that target the formation or metabolism of mitochondrial superoxide.

Highlights • Azure B at 4 mg/kg is an extremely potent Cyanide antidote in unsedated rats. • Azure B was very effective in preventing apnea as well as gasping and cardiac arrest in lethal cyanide intoxication. • Azure B appears to be more effective than Methylene blue at low doses., We have determined the effects of azure B (AzB), the main demethylated metabolite of methylene blue (MB), on a model of lethal cyanide intoxication. Our rationale was the following: AzB 1- possesses redox properties very similar to those of MB, which is a potent cyanide antidote, 2- may present a higher intracellular diffusibility than MB, 3- is already present in commercially available solutions of MB, and 4- appears very quickly in the blood after MB administration. AzB could therefore be a member of the phenothiazium chromophore family of interest to treat cyanide intoxication. We found, in spontaneously breathing urethane sedated rats, that AzB mimicked the effects of MB by increasing metabolism, ventilation and cardiac contractility up to 30−40 mg/kg. AzB had a lethal toxicity when the dose of 60 mg/kg was reached. Doses of AzB were therefore chosen in keeping with these data and the doses of MB previously used against cyanide intoxication (4–20 mg/kg) in the rat – doses corresponding to those used in humans to treat methemoglobinemia. KCN, infused at the rate of 0.375 mg/kg/min iv for 13 min, was fatal within 15 min in 100 % of our un-anesthetized rats. AzB at the dose of 4 mg/kg (n = 5) or 10 mg/kg (n = 5) administered 3 min into cyanide infusion allowed 100 % of the animals to survive with no clinical sequelae. The onset of coma was also significantly delayed and no apnea or gasping occurred. At the dose of 20 mg/kg, AzB was much less effective. At 4 mg/kg, the antidotal effects of AzB were significantly better than those produced by MB at the same dose and were not different from the effects produced by 20 mg/kg MB. We conclude that AzB is a potent cyanide antidote at relatively low doses.

Lead can be absorbed after inhalation or ingestion and is toxic to most organ systems. Management involves avoidance of exposure and, in more severe cases, chelation therapy with either sodium calcium edetate or dimercaptosuccinic acid. Iron poisoning causes its metabolic effects in proportion to the concentrations of free iron, although individual responses vary. Toxicity is therefore related to the dose ingested. Iron concentrations can rise and fall, making plasma concentrations difficult to interpret in acute poisoning. Clinical features include severe gastrointestinal irritation, cardiovascular collapse and direct organ damage to the liver and kidneys. Unconsciousness occurs in severe cases. The chelating agent desferrioxamine is used as the antidote, although uncertainty remains over the optimal dose in individual patients. Chelating agents are also used in other metal poisonings.

With approximately 48,000 attributed deaths in 2017, the opioid overdose is now the leading cause of death amongst Americans under the age of 50. The overdose process can be interrupted by the administration of naloxone, a safe and effective opiate antagonist that can reverse the effects of overdose and minimizing the delay in administering the antidote is critical in preventing permanent damage to patients. A closed-loop implantable drug delivery system is an ideal solution to minimize the response time, however, they often feature complex designs that are expensive to fabricate and require a more invasive surgical implantation. Here we propose a simple, low-cost, minimally-invasive automatic antidote delivery device (A2D2) that can administer a large dose of naloxone upon detection of overdose-induced respiratory failure. The subcutaneously placed device can be activated using an externally applied time varying magnetic field from a wearable device. Using a custom magnetic field generator, we were able to release the drug within 10 s. Our bench-top evaluation showed that A2D2 can release 1.9 mg of powdered drug within 60 s and up to 8.8 mg in 600 s. We also performed in vivo evaluation to demonstrate rapid drug releasing capability in the subcutaneous space of mice. However, we saw a small amount of leakage (1.75% of payload) over the course of 1000 h of simulated implantation. Thus, additional research is needed to verify the long term stability of our device and to demonstrate the closed-loop release mechanism to revive overdosed animals. Nevertheless, our preliminary results show the potential of using a simple, low-cost, subcutaneous device for emergency drug delivery application.

Sulfur mustard (SM) is a chemical warfare agent that was applied in a series of military conflicts and still poses a severe threat to civilians and military personnel. Although the cellular and molecular mechanisms of SM toxicity are still not fully understood, oxidative stress has been considered as the initial vital process for damage. Polydatin, the product of resveratrol and glucose, is a promising candidate for the treatment of oxidative stress-related diseases. However, its effects on SM-induced hepatic injury remain unknown. Thus, we investigated the protective effects of polydatin against SM-induced hepatic injury and its possible mechanism. We found that treatment with polydatin remarkably improved the survival rate of mice bear subcutaneously injected with SM. Polydatin decreased the SM-induced increase of serum aminotransferase levels and ameliorated hepatic pathological damage. We also found that indexes of oxidative stress were improved in mouse liver samples and L02 cells. Meanwhile, changes in the Sirtuin family after treatment with SM were explored in mice and cells since polydatin is a potent activator of Sirt1 and Sirt3. Polydatin significantly increased the expression of Sirt1, HO-1, and NQO1; and the nuclear translocation of Nrf2 in mouse liver and L02 cells. Furthermore, we also observed that either Sirt1 or Nrf2 knockdown abolished the protective effect of polydatin. Our data indicated that polydatin could provide protection against SM-induced hepatic injury through the Sirt1/Nrf2 pathway, suggesting that polydatin is a novel potential antidote for sulfur mustard.

Dabigatran is a direct thrombin inhibitor, the sole agent of its class. It is an effective anticoagulant1 with a specific antidote, idarucizumab.2 It is, however, renally cleared such that should patients prescribed dabigatran develop an acute kidney injury (AKI), a coagulopathic state can be anticipated. We describe a multimodal approach involving the use of hemodialysis and 3 doses of idarucizumab to manage coagulopathy and major hemorrhage in a patient prescribed dabiagatran with severe AKI. We also illustrate that dabiagatran can be implicated as a cause of acute interstitial nephritis.

In recent years, Drosophila melanogaster has emerged as a model for studies on aluminum toxicity. The current study aimed to disclose the mechanisms of aluminum toxicity in D. melanogaster at larval and adult stages and examined the potential protective effects of dietary alpha-ketoglutarate (AKG). Flies were reared on food containing 10 mM AlCl3, 10 mM AKG or both additives. Rearing on an AlCl3-containing diet induced behavioral defects, and decreased fecundity and long-term survival of female flies. The addition of dietary AKG did not ameliorate locomotor and taste behavior defects or the higher sensitivity to oxidative stress, but improved heat stress resistance, egg-laying capability and survival of females treated with AlCl3. Metabolic effects of AlCl3 exposure on flies included an imbalance of metal content, decreased glucose levels, increased free iron and storage triacylglyceride (TAG) levels, mitochondria dysfunction, and the development of oxidative stress. Dietary AKG did not prevent AlCl3 effects on glucose and TAG, but improved metal homeostasis, inhibited the increase in free Fe and restored the functional activity of iron-containing enzymes such as aconitase. In addition, AKG decreased the intensity of oxidative stress seen in AlCl3-reared adult flies, probably due to inhibition of iron mobilization. The results show that AKG is not a full antidote against Al toxicity but is able to relieve multiple metabolic effects of high aluminum. Furthermore, the modulating ability of AKG can clearly be helpful in exploring the molecular mechanisms of Al toxicity.

Cadmium (Cd) is an environmental pollutant shown to induce multi organ dysfunction. In this study we present novel data about the effects of meso-2,3-dimercaptosuccinic acid (DMSA), monensin and salinomycin on the concentration of Cd in skeletal muscles of mice exposed to Cd (II) acetate treatment for 14 days. The impact of Cd and the chelating agents on the endogenous concentrations of calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), phosphorous (P), selenium (Se) and zinc (Zn) was also investigated. Subacute exposure of mice to Cd (II) acetate resulted in a significant accumulation of the toxic metal ion in the skeletal muscles compared to the untreated controls. Salinomycin most effectively mobilized Cd from the muscles compared to DMSA and monensin. The Cd exposure and the tested chelating agents did not significantly alter the endogenous concentrations of the selected essential elements in mouse muscles. The presented results confirmed that among the tested chelating agents salinomycin is superior as a potential antidote to Cd poisoning.

Developing an effective antidote for fentanyl-induced overdose (OD) is an unmet medical need that requires both lipophilicity comparable to fentanyl and fast onset of overdose reversal. We synthesized and evaluated a bioreversible derivative of naloxone (NX-90) in silico, in vitro and in vivo to yield a robust reversal of fentanyl-induced OD in rats. All monitored reflexes along with the heart rate (HR) and respiratory rate (RR) were fully restored faster in the NX-90 groups than in naloxone groups on equimolar bases when given intranasally. In NX-90 treated rats RR over the time of observation (RR AUC) was significantly higher at all respective doses with no re-narcotization observed. Apart from the enhanced pharmacodynamics profile, NX-90 was found to have lower circulating levels of naloxone, clean profile in in vitro selectivity panels, as well as Ames and CYP450 counter screens. Finally, we demonstrated a robust release of the parent naloxone in brain matrix, as well as lower peripheral naloxone levels after NX-90 iv administration. With the demonstrated pharmacological profile superior yet congruent to naloxone we nominated NX-90 for preclinical development as an effective intranasal fentanyl antidote.

Use of intravenous lipid emulsion (ILE) as an antidote for severe cardiotoxicity and neurotoxicity has expanded in the veterinary world in the past decade. Despite advances in understanding of potential mechanisms of action of antidotal ILE, knowledge gaps remain in efficacy, appropriate dosing rates for various toxicants, and potential adverse reactions. Use of ILE in management of toxicoses of veterinary patients should be considered investigational, and should not be first-line treatment of most toxicoses, especially where established treatment protocols have good likelihood of positive outcomes. Use of ILE in veterinary toxicology cases requires judicious assessment of individual cases and proper informed consent of clients.

Background Physostigmine and its analogues neostigmine, pyridostigmine and rivastigmine are carbamates nowadays used in many indications, including antidotal effects against antimuscarinic poisonings, reversal of competitive neuromuscular block, myasthenia gravis, Alzheimer’s disease and prophylaxis against nerve agent intoxications. Use of these medicinal carbamates, but also of carbamate insecticides, created need for research into the potential and mechanisms of action of several antidotes against carbamate poisonings, including anticholinergics and oximes. Aim The goal of this experimental study was to ascertain the life-preserving potential of anticholinergics atropine, hexamethonium and d- tubocurarine, oxime HI-6 and their combinations in rats poisoned with physostigmine or pyridostigmine. Materials and methods Experiments were performed in Wistar rats. Carbamates were injected subcutaneously (sc) and antidotes intramuscularly (im). Median lethal dose (LD50) in animals treated with antidotes were compared to the ones in saline-treated rats and protective ratios (PRs) were calculated. Atropine (5, 10 and 20 mg/kg), hexamethonium (5, 10 and 20 mg/kg), d -tubocurarine (0.005, 0.010 and 0.020 mg/kg) and oxime HI-6 (25, 50 and 100 mg/kg) were used as monotherapies and in dual combinations, where atropine was the obligatory antidote. Biochemical experiments consisted in measuring of the cholinesterase activities in brain, whole blood and diaphragm in rats 5, 15, 30, 60, 120 and 240 min after poisoning with 0.8 LD50 of physostigmine or pyridostigmine. Results All the tested antidotes assured some degree of protection against the two carbamates. Atropine and hexamethonium produced better protection in physostigmine-poisoned rats, while d -tubocurarine and HI-6 were more efficacious in pyridostigmine-intoxicated animals. Oxime HI-6 50 mg/kg reactivated acetylcholinesterase (AChE) in brain inhibited by physostigmine and in diaphragm inhibited by pyridostigmine. Conclusions Mechanism of physostigmine-induced lethal effect is predominantly central and it involves inhibition of brain AChE, while pyridostigmine produces the same effect exclusively outside the central nervous system, by inhibiting AChE in the respiratory muscles. As a consequence, increasing doses of atropine and their combination with hexamethonium assure excellent protection against physostigmine toxicity, while the best protection against pyridostigmine is provided by a strictly peripherally acting antinicotinic d -tubocurarine and bispyridinium oxime HI-6. The oxime acts as antidote against physostigmine and pyridostigmine poisoning by reactivating AChE in the brain and diaphragm, respectively.

Echis pyramidum is a highly poisonous viper snake. Previous studies have shown acute phase hepatic and renal toxicities of Echis pyramidum venom (EPV) in rats. This study reports the protective effects of a natural herbal compound quercetin (QRC) on EPV-induced hepatic and renal toxicities in rats. A singly injection of EPV (4.76 mg/kg) caused significant increase in serum biomarkers of liver and kidney function. Pre-treatment of QRC (10 mg/kg) significantly reduced the toxic effects of EPV on functional impairment in liver and kidneys of rats. Administration of QRC also reversed EPV-induced increase in lipid peroxidation and decrease in total thiols. The histopathology of liver showed fat accumulation, focal degeneration and cytoplasmic vacuolation of hepatocytes in EPV treated rats. EPV also caused renal tubular dilation and focal atrophy of glomerular tufts in rat kidneys. Administration of QRC prevented EPV-induced structural tissue damage in liver and kidneys of rats. In conclusion, QRC significantly inhibited the acute phase toxic effects of EPV on liver and kidneys of rats by preventing the oxidative stress in these organs. QRC is also known for its anti-inflammatory, anti-edema, anti-hemorrhagic and PLA2-inhibitory properties and therefore may be regarded as a multi-action antidote against snake venom toxicity.

Uridine triacetate has been shown to be an effective antidote against mortality and toxicity caused by either overdoses or exaggerated susceptibility to the widely used anticancer agents 5-fluorouracil (5-FU) and capecitabine. However, a direct assessment of efficacy based on when emergency treatment was initiated was not clinically feasible. In this study we used mouse models of 5-FU overdose and of dihydropyrimidine dehydrogenase (DPD) deficiency to compare the efficacy of uridine triacetate in reducing toxicity and mortality when treatment was initiated at time points from 4 to 144 h after administration of 5-FU. We found that uridine triacetate was effective both in the 5-FU overdose and DPD deficiency models. Starting treatment within 24 h was most effective at reducing toxicity and mortality in both models, while treatment starting more than 96 to 120 h after 5-FU was far less effective. Uridine triacetate also reduced mortality in the DPD deficiency model when mice were treated with the 5-FU prodrug capecitabine. The results of this study are supportive of clinical observations and practice, indicating that efficacy declined progressively with later and later treatment initiation. Prompt treatment with uridine triacetate, within 24 h, conferred the greatest protection against 5-FU overexposure.

Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in many developed countries. Mitochondrial oxidative stress is considered to be the predominant cellular event in APAP-induced liver injury. Accordingly, N-acetyl cysteine, a known scavenger of reactive oxygen species (ROS), is recommended as an effective clinical antidote against APAP-induced acute liver injury (AILI) when it is given at an early phase; however, the narrow therapeutic window limits its use. Hence, the development of novel therapeutic approaches that can offer broadly protective effects against AILI is clearly needed. To this end, it is necessary to better understand the mechanisms of APAP hepatotoxicity. Up to now, in addition to mitochondrial oxidative stress, many other cellular processes, including phase I/phase II metabolism, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction, and liver regeneration, have been identified to be involved in the pathogenesis of AILI, providing new targets for developing more effective therapeutic interventions against APAP-induced liver injury. In this review, we summarize intracellular and extracellular events involved in APAP hepatotoxicity, along with emphatic discussions on the possible therapeutic approaches targeting these different cellular events. Keywords: Acetaminophen, Mitochondrial oxidative stress, Endoplasmic reticulum stress, Autophagy, Sterile inflammation, Liver regeneration

The chelating thiols dimercaptosuccinate (DMSA) and dimercaptopropane sulfonate (DMPS) are effective in enhancing urinary excretion of mercury and lead. However, strategies for mobilization of toxic metals from aged brain deposits may require combined use of a water soluble agent, removing circulating metal into urine, as well as lipophilic chelator, being used to facilitate the brain-to-blood mobilization. Pb(II) and Hg(II) ions are coordinated with DMSA through one COOH and one SH group. However Pb(II) can bind with racemic DMSA through two SH groups in non-aqueous solvents (when COOH groups are esterified). Generally, such Pb(II) and Hg(II) complexes have a composition of 1:1 and 1:2. However, binuclear and polynuclear species with DMSA like 2:1, 2:2, 2:3, 3:3 have been identified for Hg(II) ions. Both Pb(II) and Hg(II) ions are formed with BAL 1:1 and 1:2 complexes with coordination through two mercapto groups. Early experiments showed promising results with the SH–dextran–British anti-lewisite (BAL) combination. Later insight indicates that the DMPS–BAL could be preferred in cases of long-term Hg exposure. In cases of lead poisoning DMSA has been the recommended antidote due to its low toxicity. However, DMSA is distributed extracellularly, and its efficacy might be improved when combined with a brain-to-blood shuttling agent. Thus it has been found that the ionophore Monensin can improve its effect by increasing the egress of intracellularly deposited Pb. Previously, BAL was combined with ethylenediaminetetraacetic acid (EDTA) in severe cases. Today, it is reasonable that low-dosed BAL can facilitate mobilization of Pb from brain to blood during DMSA-treatment.

Venomous reptiles especially serpents are well known for their adverse effects after accidental conflicts with humans. Upon biting humans these serpents transmit arrays of detrimental toxins with diverse physiological activities that may either lead to minor symptoms such as dermatitis and allergic response or highly severe symptoms such as blood coagulation, disseminated intravascular coagulation, tissue injury, and hemorrhage. Other complications like respiratory arrest and necrosis may also occur. Bungarotoxins are a group of closely related neurotoxic proteins derived from the venom of kraits (Bungarus caeruleus) one of the six most poisonous snakes in India whose bite causes respiratory paralysis and mortality without showing any local symptoms. In the current study, by employing various pharmacoinformatic approaches, we have explored the antidote properties of 849 bioactive phytochemicals from 82 medicinal plants which have already shown antidote properties against various venomous toxins. These herbal compounds were taken and pharmacoinformatic approaches such as ADMET, docking and molecular dynamics were employed. The three-dimensional modelling approach provides structural insights on the interaction between bungarotoxin and phytochemicals. In silico simulations proved to be an effective analytical tools to investigate the toxin–ligand interaction, correlating with the affinity of binding. By analyzing the results from the present study, we proposed nine bioactive phytochemical compounds which are, 2-dodecanol, 7-hydroxycadalene, indole-3-(4'-oxo)butyric acid, nerolidol-2, trans-nerolidol, eugenol, benzene propanoic acid, 2-methyl-1-undecanol, germacren-4-ol can be used as antidotes for bungarotoxin., Graphical abstract Unlabelled Image

Background Chronic subdural hematoma (CSDH) is a common intracranial hematoma. The number of patients who undergo anticoagulant therapy including a direct oral anticoagulant (DOAC) is expected to increase. Recently, idarucizumab, the antidote for dabigatran, which is a DOAC, has been developed. We successfully treated CSDH with dabigatran using emergency burr hole surgery and idarucizumab. Case Description A 79-year-old Japanese man severely hit his head and visited the emergency department. Computed tomography (CT) showed tiny traumatic acute subdural hematoma, for which he was admitted. At that time, atrial fibrillation was newly detected, for which dabigatran, having a specific antidote (idarucizumab), was chosen and started 2 weeks after the discharge. Two months after the trauma episode, he revisited the emergency department because of acute left upper and lower limb motor weakness. CT revealed a midline shifted CSDH. Considering rush course of motor weakness and shifted brain, we performed emergency surgery using an antidote for dabigatran, idarucizumab. He was discharged 5 days after surgery without any complications or excessive perioperative hemorrhage. Conclusion Dabigatran should be used for atrial fibrillation detected after head trauma. Emergency surgery can be safely performed for CSDH with dabigatran using idarucizumab.

Introduction Naloxone is a safe and effective antidote for reversing opioid overdose. Layperson administration of naloxone is increasingly common, yet little is known about demographic and clinical factors associated with opioid users' likelihood of having administered naloxone to another opioid user who had overdosed. We examined predictors of reported naloxone administration in the past year. Methods Four hundred and sixty-eight patients were interviewed upon admission to brief, inpatient opioid detoxification between May and December of 2015. Between group differences were tested using t-tests for differences in means and χ2-tests for differences in counts. Results Participants averaged 32 years of age, 28.9% were female, and 86.8% were White. Most (86.8%) reported detoxifying from heroin, 69.0% had injected drugs in the last 30 days. One sixth (n = 68) of those detoxifying from heroin, but none of those detoxifying from other opioids (n = 62) had administered naloxone in the past year. Among the small number of Black/African American participants (n = 20), none had administered naloxone, although 90% were heroin users. Respondents were more likely to have administered naloxone if they reported recent injection drug use (IDU), had a history of overdose, or witnessed an overdose in the past year (ps Conclusions Higher opioid-related mortality risk (heroin use, IDU, past overdose) was associated with greater likelihood of reported naloxone administration in the past year. The non-use of naloxone among certain groups—prescription pill users and Blacks—was unexpected.

Background and objective Antidotes may have a relevant role in acute intoxication management and the time until its administration can influence patient survival. Patients and method Study conducted by a questionnaire sent in early 2015 to 70 hospitals in Catalonia providing emergency services. Qualitative availability on each antidote was considered adequate when present in at least 80% of hospitals. The quantitative availability was considered adequate when at least 80% of hospitals had the number of units of antidote recommended. Results Lower complexity hospitals (level A) showed a percentage of adequate qualitative and quantitative availability of 66.7 and 42.9% respectively. In higher complexity hospitals (level B) qualitative and quantitative availability was adequate in 64.5 and 38.7% of the antidotes respectively. Data showed no differences between the different health regions as well as a positive correlation (p Conclusions The availability of antidotes in Catalonia hospitals is generally low and shows differences across health regions and depending on level of complexity.

Liposome-encapsulated methemoglobin (metHb@Lipo) has been developed as a novel antidote for cyanide poisoning. Antidotes for lethal acute poisoning should be capable of being easily stored as ready-to-use formulations without temperature restrictions. Here, we investigated the pharmaceutical stability of the metHb@Lipo suspension after one-year storage as a ready-to-use formulation at 4 °C, room temperature (23–28 °C) and 37 °C. The liposomal integrity of metHb@Lipo was observed after one year of storage at all storage temperatures with no physicochemical change or methemoglobin leakage outside the liposome. Furthermore, the encapsulated methemoglobin remained intact without aggregation, fragmentation, denaturation, or dissociation of heme. Fresh and stored metHb@Lipo were equivalent in their binding affinity against cyanide. Moreover, all one-year stored metHb@Lipo suspensions improved the mortality rates of lethal cyanide poisoning mice comparable to fresh metHb@Lipo suspension. Additionally, all stored metHb@Lipo suspensions preserved high biocompatibility, including blood compatibility and the lack of organ toxicity. In conclusion, the metHb@Lipo suspension was a pharmaceutically stable antidote for cyanide poisoning for at least one year without any temperature restrictions.

Many of macromolecular toxins induce cell death by directly interacting with cells or induction of inflammatory cytokines. Abiotic polymer ligands (PLs) composed of functional monomers are able to bind and neutralize toxins in vivo and are of great interest for efficient antidotes. However, little has been reported about recognition and neutralization of target molecules in the bloodstream because of readily elimination from the bloodstream. Here, we report a rational design of PLs-decorated lipid nanoparticles (PL-NPs) for neutralizing a target toxin in vivo. PL that decorated on the NPs would cooperatively interacts with target biomacromolecules since the lipid molecules in NPs have a high degree of freedom. In the present study, N-isopropylacrylamide based PLs interacting with histones, major mediators of sepsis, were synthesized. Affinity between PL-NPs and histones depends on monomer composition and polymer length. The optimized PL-NP showed little affinity for plasma proteins. The PL-NPs inhibited the toxicity of histones both in vitro and in vivo, suggesting that PLs on the NPs cooperatively bound to histones and neutralized their toxicity. In addition, circulation time of optimized PL was significantly prolonged by the modification onto NPs. These results provide a platform for designing antidote nanoparticles neutralizing toxic biomacromolecules.

Graphical abstract, Explicit hindrance and blockade of the viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is considered one of the most promising and efficient approaches for developing highly potent remedies for COVID-19. However, almost all of the reported viral RdRp inhibitors (either repurposed or new antiviral drugs) lack specific selectivity against the novel coronaviral RdRp and still at a beginning phase of advancement. Herein, I discovered and introduce a new pyrazine derivative, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 RdRp inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). This promising selective specific anti-COVID-19 compound is also deemed to be the first distinctive derivative of favipiravir. Cyanorona-20, the unprecedented nucleoside/nucleotide analog, was designed, synthesized, characterized, computationally studied, and biologically evaluated for its anti-COVID-19 actions (through a precise in vitro anti-COVID-19 assays). The results of the biological assay displayed that cyanorona-20 surprisingly exhibited very high and largely significant anti-COVID-19 activities (anti-SARS-CoV-2 EC50 = 0.45 μM), and, in addition, it could be also a very promising guide and lead compound for the design and synthesis of new anti-SARS-CoV-2 and anti-COVID-19 agents through structural modifications and further computational studies. Further appraisal for the improvement of cyanorona-20 medication is a prerequisite requirement in the coming days. In a word, the ascent of the second member (cyanorona-20 “Corona Antidote”) of the novel and promising class of anti-COVID-19 pyrazine derivatives would drastically make a medical uprising in the pharmacotherapeutic treatment regimens and protocols of the recently-emerged SARS-CoV-2 infection and its accompanying COVID-19.

Atropine sulfate (AS) auto-injectors are the only approved antidote for out-of-hospital emergency treatment of organophosphates (OP) toxicity. However, they are only available for military use and require the administration of multiple auto-injectors. Therefore, an alternative, patient-friendly and more affordable fast-disintegrating sublingual tablets (FDSTs) of AS were previously developed. In this article, the effect of modifying the microenvironment’s pH and/or using penetration enhancers on AS sublingual transport pathways were evaluated in an attempt to further enhance AS sublingual permeability. Ten different AS FDST formulations with or without the incorporation of alkalizer and various penetration enhancers were manufactured and characterized. AS permeability was investigated through excised porcine sublingual membrane using Franz cells. Results showed that the incorporation of either a transcellular enhancer or alkalizer achieved a significantly higher AS permeability enhancement (twofold). Combining sodium bicarbonate (Na Bicarb) 2% as alkalizer with sodium dodecyl sulfate (SDS) 1% as a transcellular enhancer resulted in the greatest synergistic enhancement in AS sublingual permeability (up to twelvefold). In conclusion, the modified AS FDST developed in this work has the potential to improve the pharmacokinetic parameters of AS following sublingual administration for the first-aid treatment of OP toxicity in future animal bioequivalency studies.

Mercury (Hg) is a prevalent environmental toxicant to which older individuals are particularly susceptible. Selenium (Se) has been used as an antidote following exposure to Hg. However, little is known about the effect of prophylactic supplementation with Se on the handling of Hg. The current study was designed to test the hypothesis that oral pre-treatment with Se alters the corporal disposition of Hg and reduces the risk of Hg-induced toxicity. Young and aged rats were gavaged for 10 days with sodium selenite or saline. On day 11, rats were injected intravenously with 0.5 μmol HgCl2·kg−1·2 mL−1 normal saline. After 24 h, rats were euthanized and organs and tissues were harvested for determination of Hg content. Accumulation of Hg in the kidney was reduced significantly by pre-treatment with Se in both young and aged rats. In the renal cortex, the magnitude of the reduction was greater in aged rats than in young rats but in the outer stripe of the outer medulla, the magnitude of the reduction was similar between groups of rats. Urinary excretion of Hg was also reduced in rats pre-treated with Se. In contrast, the hepatic and hematologic burden of Hg increased in rats pre-treated with Se. Fecal excretion of Hg was decreased significantly by pre-treatment with Se in young rats but not in aged rats. These data suggest that prophylactic supplementation with Se alters the corporal disposition of Hg in a way that may reduce Hg-induced toxicity in target organs.

Endosulfan, an organochlorine (OC) insecticide, is a widely used agricultural pesticide, despite its life threatening toxic effects. In this review, the pharmacokinetics of endosulfan, mechanism of endosulfan toxicity, clinical presentations and management, histopathological findings, and toxicological analysis are described, in addition to its environmental toxicity. The toxic effects of endosulfan can affect many organs and systems presenting in a wide array of signs and symptoms. Although termed a restricted OC-classed pesticide, it continues to be used, especially in the developing world, owing to its beneficial effects on agriculture. Several cases of endosulfan poisoning have been reported from different regions of the world. Whether accidental or intentional, endosulfan ingestion proves to be fatal unless immediate, aggressive treatment is initiated. Management is mainly supportive as no antidote exists for endosulfan poisoning as yet. The use of endosulfan needs to be strictly regulated and eventually banned worldwide altogether to lower the current morbidity and mortality resulting from this pesticide. Additionally, monitoring biological samples, using non-invasive techniques such as breast milk sampling, can provide an effective method of observing the elimination of this environmentally persistent organic pollutant from the general population.

Clinical evaluation of a colchicine specific antigen-binding fragment (Fab) in order to treat colchicine poisoning required the development of an accurate method allowing quantification of free and Fab-bound colchicine in plasma and urine, and free colchicine in tissues, to measure colchicine redistribution after Fab administration. Three methods have been developed for this purpose, and validated in plasma, urine and liver: total colchicine was determined after denaturation of Fab by dilution in water and heating; free colchicine was separated from Fab-bound colchicine by filtration with 30KDa micro-filters; tissues were homogenized in a tissue mixer. Deuterated colchicine was used as internal standard. Samples were extracted by liquid-liquid extraction and analyzed with a LC-MS/MS. LOQ were 0.5ng/mL in plasma and urine for free and total colchicine and 5pg/mg in tissues. The methods were linear in the 0.5-100ng/mL range in plasma and urine, and 5-300pg/mg in tissues with determination coefficients>0.99. Precision and accuracy of QC samples presented a CV

Essentials An antidote for apixaban is not yet available.We tested the effect of different haemostatic agents to reverse the apixaban effect in vitro.Activated prothrombin complex concentrate (aPCC) was superior to prothrombin complex concentrate and recombinant activated factor VII.Even low doses of aPCC reversed the apixaban effect completely in vitro. Background The number of patients under treatment with FXa inhibitors is increasing, but there is no concensus on how to reverse their anticoagulant effect in case of a life‐threatening bleeding. A specific antidote is not yet commercially available. Prothrombin complex concentrate (PCC), activated PCC (aPCC) and recombinant factor VIIa (rFVIIa) are suggested available reversal agents. Objectives To find the most effective reversal agent to apixaban and to determine the optimal dose. Patients/Methods PCC, aPCC, and rFVIIa at concentrations imitating 80%, 100%, and 125% of suggested therapeutic doses were added to blood drawn from apixaban‐treated patients (n=30). aPCC was also tested in a 50% dose. Samples from healthy subjects (n=40) were used as controls. Thromboelastometry in whole blood (WB) and thrombin generation in platelet‐poor plasma (PPP) were measured to assess the reversal effect. Results aPCC shortened clotting time (CT) in WB, and increased the peak thrombin concentration and velocity index in PPP to a greater extent than PCC and rFVIIa. No significant differences were seen between rFVIIa and aPCC on thrombin generation lag time, or between PCC and aPCC on endogenous thrombin potential (ETP). The 50% dose of aPCC had a slightly inferior effect, but was comparable to the other reversal agents. Conclusions In this in vitro study the 80% dose of aPCC (40 IU/kg) reversed the anticoagulant effect of apixaban more effectively than the corresponding dose of rFVIIa and PCC both in WB (CT) and PPP (peak, ETP).

Essentials Reversal of anticoagulant effects of dabigatran may occur despite application of idarucizumab. Monitoring of dabigatran level after antidote application is crucial to detect rebound. Repeated doses of idarucizumab may be necessary in cases of massive dabigatran accumulation. Combination of antidote application and renal replacement therapy may offer additional benefit. Summary Idarucizumab is a monoclonal antibody fragment designed for reversing the anticoagulant effects of dabigatran. Administration is recommended as two intravenous boluses of 2.5 g within 15 min of each other or as a single 5 g bolus. However, in certain situations a second dose of the drug could be necessary. We report the case of a 77-year-old man, treated with dabigatran for paroxysmal atrial fibrillation. He presented at our department with acute renal failure, concomitant massive dabigatran accumulation and subsequent acute gastrointestinal bleeding. Fifty minutes after the administration of idarucizumab, the dabigatran plasma concentration decreased from a peak of 1630 ng ml-1 to a level below the detection limit of 30 ng ml-1 and bleeding stopped. Eight hours after administration, the dabigatran plasma level started to increase up to 1560 ng ml-1 (96% of the maximum value obtained), accompanied by a further drop in hemoglobin. Concomitant hemodialysis and hemofiltration led to a continuous decrease in dabigatran plasma levels. However, sepsis and multiorgan failure ensued, which led to death. With this case report we raise the question of whether massive dabigatran accumulation requires repeated doses of idarucizumab, or alternatively, if the combination of antidote with hemodialysis/renal replacement therapy is advisable in order to remove circulating levels of dabigatran.

Abtbract Ethnopharmacological relevance Aconite root is very poisonous; causes cardiac arrhythmias, ventricular fibrillation and ventricular tachycardia. There is no specific antidote for aconite poisoning. In Ayurveda, dehydrated borax is mentioned for management of aconite poisoning. Aim of the study The investigation evaluated antidotal effect of processed borax against acute and sub-acute toxicity, cardiac toxicity and neuro-muscular toxicity caused by raw aconite. Materials and methods For acute protection Study, single dose of toxicant (35 mg/kg) and test drug (22.5 mg/kg and 112.5 mg/kg) was administered orally, and then 24 h survival of animals was observed. The schedule was continued for 30 days in sub-acute protection Study with daily doses of toxicant (6.25 mg/kg), test drug (22.5 mg/kg and 112.5 mg/kg) and vehicle. Hematological and biochemical tests of blood and serum, histopathology of vital organs were carried out. The cardiac activity Study was continued for 30 days with daily doses of toxicant (6.25 mg/kg), test drug (22.5 mg/kg), processed borax solution (22.5 mg/kg) and vehicle; ECG was taken after 1 h of drug administration on 1TB, 15th and on 30th day. For neuro-muscular activity Study, the leech dorsal muscle response to 2.5 µg of acetylcholine followed by response of toxicant at 25 µg and 50 µg doses and then response of test drug at 25 µg dose were recorded. Results Protection index indicates that treated borax gave protection to 50% rats exposed to the lethal dose of toxicant in acute protection Study. Most of the changes in hematological, biochemical parameters and histopathological Study induced by the toxicant in sub-acute protection Study were reversed significantly by the test drug treatment. The ventricular premature beat and ventricular tachyarrhythmia caused by the toxicant were reversed by the test drug indicate reversal of toxicant induced cardio-toxicity. The acetylcholine induced contractions in leech muscle were inhibited by toxicant and it was reversed by test drug treatment. Conclusion The processed borax solution is found as an effective protective agent to acute and sub-acute aconite poisoning, and aconite induced cardiac and neuro-muscular toxicity. Processed borax at therapeutic dose (22.5 mg/kg) has shown better antidotal activity profile than five times more than therapeutic dose (112.5 mg/kg).

The plant toxin ricin is considered a potential bioterror agent against which there is no available antidote. To date, neutralizing antibodies are the most promising post-exposure treatment for ricin intoxication, yet so far they were shown to be effective only when given within several hours post exposure. As part of an ongoing effort to develop efficient ricin-countermeasures, we tested whether high-affinity antibodies that were previously isolated from immunized non-human primates, may confer effective post-exposure therapy for ricin-intoxicated mice treated at late time-points after exposure. While each antibody is capable of providing high protection rate by itself, a formulation consisting of three neutralizing antibodies that target different epitopes was tested to provide therapeutic coverage against different variants of the malicious pathogen. Indeed, the tri-antibody based cocktail was highly effective, its administration resulting in very high survival rates (>70%) when animals were treated as late as 48 h post exposure and significant protection (>30%) even at 72 h. This study establishes for the first time that anti-ricin antibodies can serve as a highly effective antidote at such late time-points after exposure. From the clinical point of view, the extended therapeutic window documented here is of high importance allowing adequate time to accurately identify the causative agent and may permit initiation of life-saving treatment with these antibodies even after the onset of clinical signs.

Toxins are natural or chemical poisonous substances with severe side effects on health. Humans are generally exposed by widespread toxic contaminations via air, soil, water, food, fruits and vegetables. Determining a critical antidote agent with extensive effects on different toxins is an ultimate goal for all toxicologists. Traditional medicine is currently perceived as a safe and natural approach against toxins. In this regard, we focused on the protective effects of green tea (Camellia sinensis) and its main components such as catechin, epicatechin, epicatechin gallate, gallocatechin, epigallocatechin and epigallocatechin gallate as a principal source of antioxidants against both natural and chemical toxins. This literate review demonstrates that protective effects of green tea and its constituents were mainly attributed to their anti-oxidative, radical scavenging, chelating, anti-apoptotic properties and modulating inflammatory responses. Although, some studies reveal they have protective effects by increasing toxin metabolism and neutralizing PLA2, proteases, hyaluronidase and l-amino acid oxidase enzymes.

Poisoning is commonly encountered in acute medical practice and can involve toxicity arising from exposure to any one of a large number of different drugs or chemicals. Clinical toxidromes can help to define particular toxicological mechanisms so that appropriate treatments can be considered. The electrocardiogram and arterial blood gas are particularly important assessing poisoned patients, and laboratory drug confirmation plays a role in some situations. Oral activated charcoal is capable of reducing the gastrointestinal absorption of a number of drugs and chemicals. A wide range of specific antidotes are available, including acetylcysteine. Generalized strategies that minimize toxicity include haemodialysis and intravenous lipid administration for selected poisonings. Poisons units provide access to specialist expertise and poisoning management advice.

Background Carbon monoxide and cyanide poisoning are important causes of death due to fire. Carbon monoxide is more regularly assessed than cyanide at the site of burn or smoke inhalation treatment due to its ease in assessment and simplicity to treat. Although several forensic studies have demonstrated the significance of cyanide poisoning in fire victims using blood cyanide levels, the association between the cause of cardiac arrest and the concentration of cyanide among fire victims has not been sufficiently investigated. This study aimed to investigate the frequency of cyanide-induced cardiac arrest in fire victims and to assess the necessity of early empiric treatment for cyanide poisoning. Methods This study was a retrospective analysis of fire victims with cardiac arrest at the scene who were transported to a trauma and critical care center, Kyorin University Hospital, from January 2014 to June 2017. Patients whose concentration of cyanide was measured were included. Results Five patients were included in the study; all died despite cardiopulmonary resuscitation. Three of these victims were later found to have lethal cyanide levels (>3 μg/ml). Two of the patients had non-lethal carboxyhemoglobin levels under 50% and might have been saved if hydroxocobalamin had been administered during resuscitation. Conclusion According to our results, cyanide-induced cardiac arrest may be more frequently present among fire victims than previously believed, and early empiric treatment with hydroxocobalamin may improve outcomes for these victims in cases where cardiac arrest is of short duration.

Background: Botulinum neurotoxins (BoNTs) are among the deadliest toxins known to humans. To date, there are no approved drugs to treat botulism after intoxication of the motor neuron. Intensive efforts have been made to develop small-molecule inhibitors, however, few possess noteworthy in vivo efficacy. Methods: The primary rat cerebellar granule neuron (CGN)-based screening was performed to discover novel effective inhibitors against BoNT/A in neural cells. The anti-botulism mechanism of embelin was preliminary studied in the impact of embelin on the main steps of BoNTs intoxication and intracellular duration. The anti-botulism efficacy of natural product embelin on botulinum toxin type A and type B was assessed in BALB/c mouse. Findings: We discovered a promising anti-BoNTs natural poduct embelin, which could protect 80% and 60% of the mice against lethal dose of BoNT/A or BoNT/B at 1 h after toxin exposure, respectively. Moreover, at 8 h after toxin exposure, embelin still protect 30% and 35% of the mice against lethal dose of BoNT/A or BoNT/B. In addition, mechanism analysis proved that embelin could significantly speed up the clearance of BoNTs in neurons. Interpretation: We discovered a promising anti-BoNTs natural product embelin, which could protect mice against lethal dose of BoNTs. The novel botulism antidote will be useful for reducing the morbidity of BoNTs intoxication and have potential biodefense implications. Funding Statement: We acknowledge this work was supported by National Key R&D Program of China (2017YFC1200905), National Key Basic Research Program (973) of China (2015CB554202), and the Beijing Nova Program (Z181100006218111) for funding. Declaration of Interests: The authors declare no competing financial interest. Ethics Approval Statement: The Beijing Institute of Microbiology and Epidemiology Animal Care and Use Committee approved our study protocol. The animal care and use protocol adhered to the regulations of the Institutional Animal Care and Use Committee (IACUC).

Dabigatran is an oral anticoagulant directly acting as thrombin inhibitor. The monoclonal antibody idarucizumab was developed to reverse its anticoagulatory effects after application of a standardized dose. Following administration, dabigatran plasma level rebounds have been reported but its consequences are not fully understood. We report a case of a multiple-trauma patient under dabigatran treatment suffering from secondary bleeding relapse after initially successful reversal with idarucizumab. Stabilisation of the patient's coagulopathy and subsequent bleeding was not achieved until application of an additional dose of idarucizumab. We conclude that patients treated with dabigatran and presenting with active bleeding require close attention to its reversal with standard doses of idarucizumab. Screening for thrombin time was shown beneficial in early detection of dabigatran rebound in this case.

The brain is a critical target for the toxic action of organophosphorus (OP) inhibitors of acetylcholinesterase (AChE) such as the nerve agent sarin. However, the available oxime antidote 2-PAM only reactivates OP-inhibited AChE in peripheral tissues. Monoisonitrosoacetone (MINA), a tertiary oxime, reportedly reactivates AChE in the central nervous system (CNS). The current study investigated whether MINA would be beneficial as a supplemental oxime treatment in preventing lethality and reducing morbidity following lethal sarin exposure, MINA supplement would improve AChE recovery in the body, and MINA would be detectable in the CNS. Guinea pigs were exposed to sarin and treated with atropine sulfate and 2-PAM at one minute. Additional 2-PAM or MINA was administered at 3, 5, 15, or 30 min after sarin exposure. Survival and morbidity were assessed at 2 and 24 h. AChE activity in brain and peripheral tissues was evaluated one hour after MINA and 2-PAM treatment. An in vivo microdialysis technique was used to determine partitioning of MINA into the brain. A liquid chromatography-tandem mass spectrometry method was developed for the analysis of MINA in microdialysates. MINA-treated animals exhibited significantly higher survival and lower morbidity compared to 2-PAM-treated animals. 2-PAM was significantly more effective in reactivating AChE in peripheral tissues, but only MINA reactivated AChE in the CNS. MINA was found in guinea pig brain microdialysate samples beginning at ~10 min after administration in a dose-related manner. The data strongly suggest that a centrally penetrating oxime could provide significant benefit as an adjunct to atropine and 2-PAM therapy for OP intoxication.

Nerve agent exposure is generally treated by an antidote formulation composed of a muscarinic antagonist, atropine sulfate (ATR), and a reactivator of acetylcholinesterase (AChE) such as pralidoxime, obidoxime (OBI), methoxime, trimedoxime or HI-6 and an anticonvulsant. Organophosphates (OPs) irreversibly inhibit AChE, the enzyme responsible for termination of acetylcholine signal transduction. Inhibition of AChE leads to overstimulation of the central and peripheral nervous system with convulsive seizures, respiratory distress and death as result. The present study evaluated the efficacy and pharmacokinetics (PK) of ATR/OBI following exposure to two different VX dose levels. The PK of ATR and OBI administered either as a single drug, combined treatment but separately injected, or administered as the ATR/OBI co-formulation, was determined in plasma of naïve guinea pigs and found to be similar for all formulations. Following subcutaneous VX exposure, ATR/OBI-treated animals showed significant improvement in survival rate and progression of clinical signs compared to untreated animals. Moreover, AChE activity after VX exposure in both blood and brain tissue was significantly higher in ATR/OBI-treated animals compared to vehicle-treated control. In conclusion, ATR/OBI has been proven to be efficacious against exposure to VX and there were no PK interactions between ATR and OBI when administered as a co-formulation.

Drug-induced liver injury (DILI) is the predominant cause of acute liver failure in many countries, which is closely associated with reactive oxygen species (ROS) and inflammation. Although N-acetylcysteine (NAC) is presently the first-choice antidote for DILI, it often fails to benefit the late stage patients due to its narrow therapeutic time window. Herein, we report ceria nanozymes (CeNZs) that simultaneously scavenge reactive oxygen species and generate oxygen for the treatment of acetaminophen-induced liver injury (a typical form of DILI), enabling a prolonged therapeutic time window as compared to NAC. It is found that CeNZs can effectively scavenge ROS in impaired hepatocytes for detoxification. More importantly, CeNZs can generate abundant oxygen based on their catalase (CAT)-mimic activity, thus further alleviating hypoxia and specifically inhibiting the pro-inflammatory macrophages to relieve inflammation for a promoted hepatocyte regeneration of DILI, which is vital for the treatment of late stage DILI when there is already massive hepatocyte necrosis. The dual detoxification and inflammatory regulation by CeNZs for DILI treatment with relatively long therapeutic time window as compared to NAC, together with the revealed mechanism herein, suggesting the future clinical use of CeNZs for DILI treatment, especially for the late stage DILI treatment.

Acute pesticide poisoning in children is rare but potentially serious. Some clinical patterns (toxidromes) are suggestive of the drug class: cholinergic crisis for organophosphate or carbamate insecticides; neurological syndrome for rodenticides; digestive and respiratory syndrome for herbicides. Treatment is symptomatic and only a few patients are treated with an antidote: atropine and pralidoxime for organophosphate insecticides, vitamin K for anticoagulant rodenticides.

Catalytic scavengers of organophosphates (OPs) are considered very promising antidote candidates for preventing the adverse effects of OP intoxication as stand alone treatments. This study aimed at correlating the in-vivo catalytic efficiency ((kcat/KM)[Enzyme]pl), established prior to the OP challenge, with the severity of symptoms and survival rates of intoxicated animals. The major objective was to apply a theoretical approach to estimate a lower limit for (kcat/KM)[Enzyme]pl that will be adequate for establishing the desired kcat/KM value and plasma concentration of efficacious catalytic bioscavengers. Published data sets by our group and others, from in vivo protection experiments executed in the absence of any supportive medicine, were analyzed. The kcat/KM values of eight OP hydrolyzing enzymes and their plasma concentrations in four species exposed to OPs via s.c., i.m. and oral gavage, were analyzed. Our results show that regardless of the OP type and the animal species employed, sign-free animals were observed following bioscavenger treatment provided the theoretically estimated time period required to detoxify 96% of the OP (t96%) in vivo was ≤10 s. This, for example, can be achieved by an enzyme with kcat/KM = 5 × 107 M-1 min-1 and a plasma concentration of 0.4 μM ((kcat/KM)[Enzyme]pl = 20 min-1). Experiments in which animals were intoxicated by i.v. OP injections did not always conform to this rule, and in some cases resulted in high mortality rates. We suggest that in vivo evaluation of catalytic scavengers should avoid the unrealistic bolus i.v. route of OP exposure.