Antiplatelet treatment is one of the pillars of contemporary therapy in acute coronary syndromes. It is based on dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 receptor inhibitor. Antiaggregatory treatment reduces ischemic events, but at cost of increased bleeding rates. As a result of irreversible inhibition of platelet P2Y12 receptors, the antiplatelet action of clopidogrel and prasugrel is prolonged for the lifespan of thrombocytes and lasts up to 7 days. The antiaggregatory effect of ticagrelor may persist up to 5 days despite its reversible nature of P2Y12 receptor inhibition. These pharmacodynamic properties may prove problematic in patients requiring immediate reversal of antiplatelet effects due to severe or life-threatening bleeding, or in presence of indications for an urgent surgery. The current review summarizes available knowledge on different strategies of restoring platelet function in patients treated with ticagrelor. Non-specific methods are discussed, including platelet transfusion, human albumin supplementation and hemadsorption. Finally, bentracimab, the first specific antidote for ticagrelor, and in fact against any antiplatelet agent, is described.

OBJECTIVE: In 2012, the Commission on Human Medicines mandated lowering the acetaminophen toxicity nomogram treatment threshold in the UK to 100 µg/ml at 4 h post-ingestion. The present study aim was to evaluate biochemical and liver toxicity patterns in patients who presented with acetaminophen overdose and had low serum acetaminophen concentrations (<150 µg/ml).
METHODS: Patients admitted to the emergency department with a clear history of acute acetaminophen overdose with or without other medication or ethanol were consecutively enrolled into this retrospective cohort study. Patients with serum acetaminophen concentration >150 µg/ml or an unknown ingestion time were excluded. Data were extracted from electronic medical records and are presented as mean ± SD or median (interquartile range).
RESULTS: A total of 103 patients were included (median age, 17 [4-21] years) and 80 (78%) were female. The median ingested acetaminophen dose was 5000 (2850-7650) mg. At baseline, the median serum acetaminophen concentration was 42 (4.5-64.8) µg/ml, and median alanine aminotransferase and aspartate aminotransferase levels were 22 (17-28) and 27 (16-45) IU/L, respectively. Twenty patients were treated with acetylcysteine, with none developing adverse reactions. No patient developed hepatotoxicity, including patients with initial multiple product ingestion or other risk factors.
CONCLUSIONS: Patients presenting with an acute acetaminophen overdose with acetaminophen level <150 µg/ml, including patients with other risk factors, are at low risk of hepatotoxicity.

Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events, culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC), has a narrow therapeutic window, and early treatment is essential for a satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end products (AGEs) and the consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase 1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in the APAP-mediated activation of RAGE and downstream cell death cascades. Constitutive Glo-1-knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were used as tools. Our findings showed elevated oxidative stress resulting from the activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild-type controls. A unique feature of the hepatic necrosis in GKO mice was the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than the inflammation seen in the wild type. The GSH surrogate and general antioxidant ψ-GSH alleviated APAP toxicity irrespective of the Glo-1 status, suggesting that oxidative stress is the primary driver of APAP toxicity. Overall, the exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against the initial stages of APAP overdose.

Mesoporous silica nanoparticles (MSNs) are highly advanced engineered particles with increased surface area and extreme adsorption capacity for various molecules. Herein, two types of MSNs were synthesized and applied as adsorbents for phosphine gas. One was without functional groups (MSN), and the other was post-modified with boric acid (MSN-BA). The structures of MSN and boric acid-modified MSN with high surface areas of about 1025 and 650 m2/g, respectively, were defined. MSN was found to have particles with sizes around 30 nm by transmission electron microscopy (TEM). In the present study, MSNs were used as an antidote to phosphorus poisoning, and zinc phosphide (phosphorus) powder was used as the toxic and lethal agent. In vivo analysis was carried out on rats to demonstrate the ability of MSNs to chemisorb phosphine gas. In the survival percentage assessment, Phos-poisoned animals were kept alive after treatment with MSNs, and the MSN-BA-treated group (dose of 5 mg/kg) was shown to have a 60 % survival rate. Blood serum analysis showed that MSNs have a high potential to alleviate organ blood damage, and serum biomarkers dropped sharply while phosphine-poisoned animals were treated with MSN-BA.

While the opioid crisis has justifiably occupied news headlines, emergency rooms are seeing many thousands of visits for another cause: cannabinoid toxicity. This is partly due to the spread of cheap and extremely potent synthetic cannabinoids that can cause serious neurological and cardiovascular complications-and deaths-every year. While an opioid overdose can be reversed by naloxone, there is no analogous treatment for cannabis toxicity. Without an antidote, doctors rely on sedatives, with their own risks, or \'waiting it out\' to treat these patients. We have shown that the canonical synthetic \'designer\' cannabinoids are highly potent CB1 receptor agonists and, as a result, competitive antagonists may struggle to rapidly reverse an overdose due to synthetic cannabinoids. Negative allosteric modulators (NAMs) have the potential to attenuate the effects of synthetic cannabinoids without having to directly compete for binding. We tested a group of CB1 NAMs for their ability to reverse the effects of the canonical synthetic designer cannabinoid JWH018 in vitro in a neuronal model of endogenous cannabinoid signaling and also in vivo. We tested ABD1085, RTICBM189, and PSNCBAM1 in autaptic hippocampal neurons that endogenously express a retrograde CB1-dependent circuit that inhibits neurotransmission. We found that all of these compounds blocked/reversed JWH018, though some proved more potent than others. We then tested whether these compounds could block the effects of JWH018 in vivo, using a test of nociception in mice. We found that only two of these compounds-RTICBM189 and PSNCBAM1-blocked JWH018 when applied in advance. The in vitro potency of a compound did not predict its in vivo potency. PSNCBAM1 proved to be the more potent of the compounds and also reversed the effects of JWH018 when applied afterward, a condition that more closely mimics an overdose situation. Lastly, we found that PSNCBAM1 did not elicit withdrawal after chronic JWH018 treatment. In summary, CB1 NAMs can, in principle, reverse the effects of the canonical synthetic designer cannabinoid JWH018 both in vitro and in vivo, without inducing withdrawal. These findings suggest a novel pharmacological approach to at last provide a tool to counter cannabinoid toxicity.

The plant-derived toxin ricin is classified as a type 2 ribosome-inactivating protein (RIP) and currently lacks effective clinical antidotes. The toxicity of ricin is mainly due to its ricin toxin A chain (RTA), which has become an important target for drug development. Previous studies have identified two essential binding pockets in the active site of RTA, but most existing inhibitors only target one of these pockets. In this study, we used computer-aided virtual screening to identify a compound called RSMI-29, which potentially interacts with both active pockets of RTA. We found that RSMI-29 can directly bind to RTA and effectively attenuate protein synthesis inhibition and rRNA depurination induced by RTA or ricin, thereby inhibiting their cytotoxic effects on cells in vitro. Moreover, RSMI-29 significantly reduced ricin-mediated damage to the liver, spleen, intestine, and lungs in mice, demonstrating its detoxification effect against ricin in vivo. RSMI-29 also exhibited excellent drug-like properties, featuring a typical structural moiety of known sulfonamides and barbiturates. These findings suggest that RSMI-29 is a novel small-molecule inhibitor that specifically targets ricin toxin A chain, providing a potential therapeutic option for ricin intoxication.

The impact of poisoning can differ significantly depending on the specific substance consumed. Identifying toxic substances in a patient is crucial to obtaining a thorough medical history. Frontline healthcare providers in the emergency department often handle patients presenting with poisoning. Their clinical presentation can vary depending on their dose, duration of exposure, and pre-existing medical conditions. Initially, poisoning management entails administering supportive care such as absorption and enhancing the elimination of poison with charcoal and antidote administration after identifying the poisoning substances. This article aims to provide a basic overview of the concepts involved in evaluating and managing these individuals.

UNASSIGNED: Fentanyl and fentanyl analogs (F/FA) have become increasingly common adulterants in counterfeit prescription pills and illicit street drug mixtures due to their ease of synthesis and exceedingly high potency. The ongoing epidemic of fatal overdoses fueled by F/FA continues to highlight the need for longer-acting therapies than naloxone (NLX), the current gold-standard for reversing opioid overdoses, which shows limited efficacy to prevent renarcotization associated with F/FA toxicity. A novel opioid reversal agent based on covalent naloxone nanoparticles (cNLX-NP) has been shown to blunt fentanyl-induced respiratory depression out to 48 hr, demonstrating its potential therapeutic utility. The purpose of this study was to characterize how rapidly cNLX-NP reverses fentanyl-induced respiratory effects as well as the duration of its protective effects.
UNASSIGNED: Sprague Dawley male rats (n=6/group) were tested on an oximeter for baseline percent arterial oxygen saturation (%SaO2) challenged with 0.1 mg/kg SC fentanyl and 15 min later given 10 mg/kg IM doses of NLX, nalmefene (NLMF), or cNLX-NP and continuously monitored via oximetry for 10 minutes. One week later the experiment was repeated using a 1:1 mixture of NLX:cNLX-NP as the reversal agent in the rats that previously received NLX alone.
UNASSIGNED: While both NLX and NLMF rapidly reversed %SaO2 to baseline within 1 min, rats that received cNLX-NP did not return to >90% SaO2 levels until 9 min after administration. Similarly, heart and breath rates returned to baseline within 1 min of treatment with NLX and NLMF but did not return to baseline until 10 minutes after cNLX-NP administration. In contrast, NLX:cNLX-NP reversed all fentanyl-induced respiratory depressive effects within one minute.
UNASSIGNED: While cNLX-NP alone may not sufficiently reverse F/FA overdose in a timely manner, mixing free NLX with cNLX-NP can provide a mechanism to both rapidly reverse fentanyl-related effects and maintain extended protection against synthetic opioid toxicity. These data support further development of cNLX-NP as a fast-acting and long-lasting antidote to treat F/FA-induced respiratory depression and overdose, and potentially prevent renarcotization in humans.

The H1-antihistamine diphenhydramine antagonizes cholinesterase inhibitor poisoning in various animal species. One aspect of acute antidotal actions of diphenhydramine is increasing the median lethal doses (LD50) of toxicants. The objective of this meta-analysis was to assess the antidotal action of diphenhydramine against short-term toxicity (LD50) of cholinesterase inhibitors in experimental animals. The experimental studies selected were according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. They were conducted in laboratory animals (mice, rats, and chicks) to determine acute LD50 values of cholinesterase inhibitors (organophosphates, carbamates, and imidocarb) under the influence of diphenhydramine vs. controls. Twenty-eight records were selected from 12 studies on mice (n= 242), rats (n= 27), and young chicks (n= 128). The forest plot of randomized two-group meta-analysis assessed effect size, subgroup analysis, drapery prediction, heterogeneity, publication bias-funnel plot as well as one-group proportions meta-analysis of percent protection. Diphenhydramine significantly increased the combined effect size (i.e. increased LD50) in intoxicated experimental animals in comparison to controls (-3.71, standard error (SE) 0.36, 95%CI -4.46, -2.97). The drapery plot proposed a wide range of confidence intervals. The I2 index of heterogeneity of the combined effect size was high at 81.03% (Q= 142.3, p < 0.0001). Galbraith regression also indicated data heterogeneity; however, the normal quantile plot indicated no outliers. Subgroup analysis indicated significantly high heterogeneity with organophosphates (I2 = 63.72%) and carbamates (I2 = 76.41%), but low with imidocarb (I2 = 51.48%). The funnel plot and Egger regression test (t= -13.7, p < 0.0001) revealed publication bias. The median of the diphenhydramine protection ratio was 1.655, and the related forest plot of one group proportion meta-analysis revealed a statistically high level of protection (0.594, SE 0.083, 95%CI 0.432, 0.756), with high heterogeneity (I2= 99.86). The risk of bias assessment was unclear, while the total score (16 out of 20) of each study leaned towards the side of the low risk of bias. In conclusion, the meta-analysis of LD50 values indicated that diphenhydramine unequivocally protected experimental animals from the acute toxicity of cholinesterase inhibitors. The drug could be an additional antidote against acute poisoning induced by cholinesterase inhibitors, but a word of caution: it is not to be considered as a replacement for the standard antidote atropine sulfate. Further studies are needed to examine the action of diphenhydramine on adverse chronic effects of cholinesterase inhibitors.

Thallium (Tl) is one of the most toxic metals and its historic use in homicides has led it to be known as \"the poisoner\'s poison.\" This review summarizes the methods for identifying Tl and determining its concentrations in biological samples in recently reported poisoning cases, as well as the toxicokinetics, toxicological effects, toxicity mechanisms, and detoxication methods of Tl. Recent findings regarding Tl neurotoxicological pathways and toxicological effects of Tl during pregnancy are also presented. Confirmation of elevated Tl concentrations in blood, urine, or hair is indispensable for diagnosing Tl poisoning. The kidneys show the highest Tl concentration within 24 h after ingestion, while the brain shows the highest concentration thereafter. Tl has a very slow excretion rate due to its large distribution volume. Following acute exposure, gastrointestinal symptoms are observed at an early stage, and neurological dysfunction is observed later: Tl causes the most severe damage in the central nervous system. Alopecia and Mees\' lines in the nails are observed within 1 month after Tl poisoning. The toxicological mechanism of Tl is considered to be interference of vital potassium-dependent processes with Tl+ because its ionic radius is similar to that of K+, as well as inhibition of enzyme reactions by the binding of Tl to -SH groups, which disturbs vital metabolic processes. Tl toxicity is also related to reactive oxygen species generation and mitochondrial dysfunction. Prussian blue is the most effective antidote, and metallothionein alone or in combination with Prussian blue was recently reported to have cytoprotective effects after Tl exposure. Because Tl poisoning cases are still reported, early determination of Tl in biological samples and treatment with an antidote are essential.