Performance characteristics allow for confinement of a CRISPR toxin-antidote gene drive for population suppression in a reaction-diffusion model.

Gene drive alleles that can bias their own inheritance could engineer populations for control of disease vectors, invasive species and agricultural pests. There are successful examples of suppression drives and confined modification drives, but developing confined suppression drives has proven more difficult. However, CRISPR-based toxin-antidote dominant embryo (TADE) suppression drive may fill this niche. It works by targeting and disrupting a haplolethal target gene in the germline with its gRNAs while rescuing this target. It also disrupts a female fertility gene by driving insertion or additional gRNAs. Here, we used a reaction-diffusion model to assess drive performance in continuous space, where outcomes can be substantially different from those in panmictic populations. We measured drive wave speed and found that moderate fitness costs or target gene disruption in the early embryo from maternally deposited nuclease can eliminate the drive's ability to form a wave of advance. We assessed the required release size, and finally we investigated migration corridor scenarios. It is often possible for the drive to suppress one population and then persist in the corridor without invading the second population, a potentially desirable outcome. Thus, even imperfect variants of TADE suppression drive may be excellent candidates for confined population suppression.

Tetraploid interspecific hybrids between Asian and African rice species restore fertility depending on killer-protector loci for hybrid sterility.

Interspecific F1 hybrids between Asian (Oryza sativa) and African rice (Oryza glaberrima) exhibit severe sterility caused by the accumulation of hybrid sterility genes/loci at 15 or more loci. The mechanisms underlying the hybrid sterility genes are largely unknown; however, a few genes associated with the killer-protector system, which is the system most frequently associated with hybrid sterility genes, have been identified. We previously produced fertile plants as tetraploids derived from diploid interspecific F1 hybrids through anther culture; therefore, it was suggested that hybrid sterility could be overcome following tetraploidization. We investigated whether tetraploid interspecific plants produced by crossing are fertile and tested the involvement of hybrid sterility genes in the process. Fertile tetraploid interspecific F1 hybrid plants were obtained by crossing two tetraploids of Oryza sativa and Oryza glaberrima. To elucidate the relationships between pollen fertility and the hybrid sterility loci in the tetraploid F1 microspores, we performed genetic analyses of the tetraploid F2 hybrids and diploid plants obtained from the microspores of tetraploid interspecific hybrids by anther culture. The result suggested that the tetraploid interspecific hybrids overcame pollen and seed infertility based on the proportion of loci with the killer-protector system present in the tetraploids. The heterozygous hybrid sterility loci with the killer-protector system in the tetraploid segregate the homozygous killed allele (16.7-21.4%), with more than three-quarters of the gametes surviving. We theoretically and experimentally demonstrated that fertile rice progenies can be grown from tetraploid interspecific hybrids.

Deletion of Glyoxalase 1 Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.

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.

Protective effects of Panax ginseng as a medical food against chemical toxic agents: molecular and cellular mechanisms.

Humans are exposed to different types of toxic agents, which may directly induce organ malfunction or indirectly alter gene expression, leading to carcinogenic and teratogenic effects, and eventually death. Ginseng (Panax ginseng) is the most valuable of all medicinal herbs. Nevertheless, specific data on the antidotal mechanisms of this golden herb are currently unavailable. Based on the findings of in vitro, in vivo, and clinical studies, this review focused on the probable protective mechanisms of ginseng and its major components, such as protopanaxadiols, protopanaxatriols, and pentacyclic ginsenosides against various chemical toxic agents. Relevant articles from 2000 to 2023 were gathered from PubMed/Medline, Scopus, and Google Scholar. This literature review shows that P. ginseng and its main components have protective and antidotal effects against the deteriorative effects of pesticides, pharmaceutical agents, including acetaminophen, doxorubicin, isoproterenol, cyclosporine A, tacrolimus, and gentamicin, ethanol, and some chemical agents. These improvements occur through multi-functional mechanisms. They exhibit antioxidant activity, induce anti-inflammatory action, and block intrinsic and extrinsic apoptotic pathways. However, relevant clinical trials are necessary to validate the mentioned effects and translate the knowledge from basic science to human benefit, fulfilling the fundamental goal of all toxicologists.

Antidote-controlled DNA aptamer modulates human factor IXa activity.

Thrombosis leads to elevated mortality rates and substantial medical expenses worldwide. Human factor IXa (HFIXa) protease is pivotal in tissue factor (TF)-mediated thrombin generation, and represents a promising target for anticoagulant therapy. We herein isolated novel DNA aptamers that specifically bind to HFIXa through systematic evolution of ligands by exponential enrichment (SELEX) method. We identified two distinct aptamers, seq 5 and seq 11, which demonstrated high binding affinity to HFIXa (Kd = 74.07 ± 2.53 nM, and 4.93 ± 0.15 nM, respectively). Computer software was used for conformational simulation and kinetic analysis of DNA aptamers and HFIXa binding. These aptamers dose-dependently prolonged activated partial thromboplastin time (aPTT) in plasma. We further rationally optimized the aptamers by truncation and site-directed mutation, and generated the truncated forms (Seq 5-1t, Seq 11-1t) and truncated-mutated forms (Seq 5-2tm, Seq 11-2tm). They also showed good anticoagulant effects. The rationally and structurally designed antidotes (seq 5-2b and seq 11-2b) were competitively bound to the DNA aptamers and effectively reversed the anticoagulant effect. This strategy provides DNA aptamer drug-antidote pair with effective anticoagulation and rapid reversal, developing advanced therapies by safe, regulatable aptamer drug-antidote pair.

Seven- and thirty-day mortality in digoxin poisoning: Results from the DIGITOX study.

BACKGROUND: Digoxin poisonings are relatively common and potentially fatal, requiring immediate therapeutic intervention, with special attention to the patient's hemodynamic status and the presence of electrocardiographic and electrolytic disturbances. OBJECTIVE: To identify factors associated with seven-day and thirty-day mortality in digoxin poisoning. DESIGN, SETTINGS AND PARTICIPANTS: A retrospective, observational, multicenter study was conducted across 15 Hospital Emergency Departments (HED) in Spain. All patients over 18 years of age who presented to participating HEDs from 2015 to 2021 were included. The inclusion criteria encompassed individuals meeting the criteria for digoxin poisoning, whether acute or chronic. OUTCOMES MEASURE AND ANALYSIS: To identify independent factors associated with 7-day and 30-day mortality, a multivariate analysis was conducted. This analysis included variables of clinical significance, as well as those exhibiting a trend (p < 0.1) or significance in the bivariate analysis. MAIN FINDINGS: A total of 658 cases of digoxin poisoning were identified. Mortality rates were 4.5% (30 patients) at seven days and 11.1% (73 patients) at thirty days. Regarding 7-day mortality, the mean age of deceased patients was comparable to survivors (84.7 (8.9) vs 83.9 (7.9) years; p = ns). The multivariate analysis revealed that factors independently associated with 7-day mortality encompassed the extent of dependence assessed by the Barthel Index (BI 60-89 OR 0.28; 95% CI 0.10-0.77; p = 0.014 and BI>90 OR 0.22; 95% CI 0.08-0.63; p = 0.005), the identification of ventricular arrhythmias (OR 1.34; 95% CI 1.34-25.21; p = 0.019), and the presence of circulatory (OR 2.84; 95% CI 1.19-6.27; p = 0.019) and neurological manifestations (OR 2.67; 95% CI 1.13-6.27; p = 0.025). Factors independently associated with 30-day mortality encompassed extent of dependence (BI 60-89 OR 0.37; 95% CI 0.20-0.71; p = 0.003 and BI>90 OR 0.18; 95% CI 0.09-0.39; p < 0.001) and the identification of circulatory (OR 2.13; 95% CI 1.10-4.15; p = 0.025) and neurological manifestations (OR 2.39; 95% CI 1.25-3.89; p = 0.006). CONCLUSIONS: The study identifies the degree of dependency assessed by the Barthel Index and the presence of cardiovascular and neurological symptoms as independent predictors of both 7-day and 30-day mortality. Additionally, the detection of ventricular arrhythmia is also an independent factor for 7-day mortality.

Efficacy and Safety of Glycopyrrolate in the Management of Organophosphate and Carbamate Poisoning: A Systematic Review.

OBJECTIVE: There is a lack of evidence on the effectiveness of antidotes in the management of organophosphate and carbamate (OPC) poisoning. We aimed to review the efficacy and safety of glycopyrrolate in the management of OPC poisoning. METHODOLOGY: Databases such as PubMed, Scopus, Embase, and Cochrane Library were extensively searched from inception to November 2022 and updated till October 2023. Interventional, observational, and descriptive studies assessing the efficacy and safety of glycopyrrolate administered in any dose, route, and duration for the management of OPC poisoning published in the English language were considered for this review. The treatment with any other regimen that did not include glycopyrrolate was regarded as the comparator. The survival, intensive care unit (ICU) days and ventilatory outcomes were considered efficacy outcomes, and adverse effects were considered safety outcomes. Suitable quality assessment tools were used to assess the risk of bias in the included studies. Two independent reviewers were involved in the study selection, data extraction, and quality assessment and any discrepancies were resolved through mutual discussion or consultation with a third reviewer. RESULTS: A total of 9 studies (2 RCTs, 4 cohorts, 1 case series, and 2 case reports) out of 591 nonduplicate records were considered for this review. Overall, the RCTs were observed to have a moderate quality, and observational studies and descriptive studies were found to have good quality. All the included studies used atropine administration as a standard treatment option along with glycopyrrolate. The OPC patients treated with glycopyrrolate had a fewer hospitalization days with comparable recovery and ventilatory outcomes than those that had not been treated with glycopyrrolate. The occurrence of adverse events and complications was lower in the glycopyrrolate group than in the control group. CONCLUSION: Currently, there is a lack of comparative studies to recommend the use of glycopyrrolate in OPC poisoning, and further interventional studies are required to make an evidencebased recommendation on this topic.

An approach to the management of acute poisoning in emergency settings.

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.

Identification and Biological Evaluation of a Novel Small-Molecule Inhibitor of Ricin Toxin.

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.

In vivo treatment of zinc phosphide poisoning by administration of mesoporous silica nanoparticles as an effective antidote agent.

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.

Is there a role for the laboratory monitoring in the management of specific antidotes of direct oral anticoagulants?

Given the growing number of patients receiving direct oral anticoagulant (DOAC), patients requiring rapid neutralization is also increasing in case of major bleedings or urgent surgery/procedures. Idarucizumab is commercialized as a specific antidote to dabigatran while andexanet alfa has gained the Food and Drug Administration and the European Medicines Agency approval as an oral anti-factor Xa inhibitors antidote. Other antidotes or hemostatic agents are still under preclinical or clinical development, the most advanced being ciraparantag. DOAC plasma levels measurement allows to appropriately select patient for antidote administration and may prevent unnecessary prescription of expensive molecules in some acute clinical settings. However, these tests might be inconclusive after some antidote administration, namely andexanet alfa and ciraparantag. The benefit of laboratory monitoring following DOAC reversal remains unclear. Here, we sought to provide an overview of the key studies evaluating the safety and efficacy of DOAC reversal using the most developed/commercialized specific antidotes, to discuss the potential role of the laboratory monitoring in the management of patients receiving DOAC specific antidotes and to highlight the areas that deserve further investigations in order to establish the exact role of laboratory monitoring in the appropriate management of DOAC specific antidotes.

CB1 Receptor Negative Allosteric Modulators as a Potential Tool to Reverse Cannabinoid Toxicity.

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.

Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP.

Introduction: 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. Methods: 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. Results: 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. Discussion: 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.

Intratracheal cobinamide (vitamin B12 analog) administration increases survivability in rabbits exposed to a lethal dose of inhaled hydrogen sulfide.

BACKGROUND: Hydrogen sulfide is a highly toxic, flammable, and colorless gas. Hydrogen sulfide has been identified as a potential terrorist chemical threat agent in mass-casualty events. Our previous studies showed that cobinamide, a vitamin B12 analog, effectively reverses the toxicity from hydrogen sulfide poisoning. In this study, we investigate the effectiveness of intratracheally administered cobinamide in treating a lethal dose hydrogen sulfide gas inhalation and compare its performance to saline control administration. METHODS: A total of 53 pathogen-free New Zealand White rabbits were used for this study. Four groups were compared: (i) received no saline solution or drug intratracheally (n = 15), (ii) slow drip saline intratracheally (n = 15), (iii) fast drip saline intratracheally (n = 15), and (iv) slow drip cobinamide intratracheally (n = 8). Blood pressure was continuously monitored, and deoxy- and oxyhemoglobin concentration changes were monitored in real-time in vivo using continuous wave near-infrared spectroscopy. RESULTS: The mean (± standard deviation) weight for all animals (n = 53) was 3.87 ± 0.10 kg. The survival rates of the slow cobinamide and the fast saline groups were 75 percent and 60 percent, respectively, while the survival rates in the slow saline and control groups were 26.7 percent and 20 percent, respectively. A log-rank (Mantel-Cox) test showed that survival in fast saline and slow cobinamide groups were significantly greater than those of no saline control and slow saline groups (P < 0.05). The slow and no saline control groups were not significantly different (P = 0.59). The slow cobinamide group did significantly better than the slow saline group (P = 0.021). DISCUSSION: The ability to use intratracheal cobinamide as an antidote to hydrogen sulfide poisoning is a novel approach to mass-casualty care. The major limitations of this study are that it was conducted in a single species at a single inhaled hydrogen sulfide concentration. Repeated investigations in other species and at varying levels of hydrogen sulfide exposure will be needed before any definitive recommendations can be made. CONCLUSIONS: We demonstrated that intratracheal cobinamide and fast saline drip improved survival for hydrogen sulfide gas inhalation in rabbit models. Although further study is required, our results suggest that intratracheal administration of cobinamide and fast saline may be useful in hydrogen sulfide mass-casualty events.

Antidotal Effects of the Antihistamine Diphenhydramine Against Cholinesterase Inhibitor Poisoning: A Meta-Analysis of Median Lethal Doses in Experimental Animals.

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.

Rivastigmine for the management of anticholinergic delirium.

INTRODUCTION: Anticholinergic agents are commonly taken in overdose, often causing delirium. The spectrum of anticholinergic delirium ranges from mild agitation to severe behavioural disturbance. Physostigmine is an effective treatment for anticholinergic delirium, but its availability is limited. As rivastigmine is readily available, it has been used to manage anticholinergic delirium; however, there is limited research investigating its use. METHOD: This was a retrospective review of patients with anticholinergic delirium treated in two toxicology units with rivastigmine (oral capsule or transdermal patch) from January 2019 to June 2023. The primary outcome was the use of further parenteral treatment (sedation or physostigmine) for delirium post rivastigmine administration. RESULTS: Fifty patients were administered rivastigmine for the management of anticholinergic delirium. The median age was 36 years (interquartile range: 25-49 years) and 27 (54 per cent) were females. Features consistent with anticholinergic toxicity included tachycardia in 44 (88 per cent) and urinary retention requiring catheterisation in 40 (80 per cent). Forty-three patients (86 per cent) were treated with physostigmine before rivastigmine administration. Twenty-two were managed with transdermal rivastigmine (most commonly 9.5 mg/24 hour patch), and 28 with oral rivastigmine 6 mg. Further parenteral sedation and/or physostigmine treatment were required more often in patients given transdermal than oral rivastigmine [16/22 (73 per cent) versus 9/28 (32 per cent), P = 0.010)]. No patients had bradycardia or gastrointestinal symptoms following rivastigmine administration. One patient with a history of epilepsy had a seizure, 1.5 hours post physostigmine administration and 7 hours post transdermal rivastigmine. DISCUSSION: Rivastigmine has been increasingly used for the management of patients with anticholinergic delirium, due to the lack of availability of physostigmine. In this case series, rivastigmine transdermal patch appeared to be less effective than oral rivastigmine capsules, likely due to its slow onset of action and/or insufficient dose. CONCLUSION: Rivastigmine can be used to treat anticholinergic delirium. In our case series oral rivastigmine appeared more effective than transdermal rivastigmine.

Management of DOAC-related bleeding in cancer patients: a single center-case series.

Venous thromboembolism (VTE) and stroke carry significant mortality and morbidity in cancer patients. Direct oral anticoagulants (DOACs) have been demonstrated to be effective for the treatment of VTE and prevention of stroke in atrial fibrillation (AF). Bleeding rates are variable and are based on the cancer type and the patient's specific risk factors. There are approved specific antidotes for DOAC-associated bleeding. Other strategies are available for bleeding reversal, including the use of prothrombin complex concentrate (PCC). No randomized studies have compared head-to-head the efficacy and safety of reversal agents. We aim to examine the safety and effectiveness of hemostatic agents in cancer patients with DOAC-related major bleeding. A retrospective chart review study of patients at MD Anderson Cancer Center with DOAC-related major bleeding between 2014 and 2019. Bleeding severity and clinical hemostasis were described based on ISTH guidelines and the Sarode criteria, respectively. The rates of thrombotic complications and mortality at 30-day from the index bleeding event were described. We identified 23 patients with DOAC-related major bleeding; 14 patients received PCC and 9 patients received andexanet alfa. The most common sites of bleeding were the gastrointestinal tract and intracranial. Effective hemostasis and 30-day mortality were similar to reported results from other reports of outcomes of reversal agents for DOAC related-bleeding in non-cancer patients. One patient in each treatment group experienced a thrombotic event. Further larger scale studies are needed to confirm our findings in cancer patients.

Thallium - poisoner's poison: An overview and review of current knowledge on the toxicological effects and mechanisms.

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.

Physicochemical and pharmacotechnical characterization of Prussian blue for future Prussian blue oral dosage forms formulation.

Ferric hexacyanoferrate, Fe4 [Fe(CN)6]3 · xH2O, known as Prussian blue (PB), has proven its effectiveness as an antidote in cases of accidental poisoning or poisoning caused by radioactive materials such as cesium (Cs) and thallium (Tl); which due to their solubility in water, when absorbed by the human body, cause serious damage to vital organs. The local development of a drug with PB as an active ingredient arises as a response to the civil and military needs established within the Ministry's pharmacy request for national defense. This fact contemplates the circumstances related to public health protection in the nuclear, radiological, biological and chemical (NRBQ) of the emergency institutions in health and national security. In this paper and by using various analytical techniques, the characterization of the locally synthesized PB with pharmaceutical quality has been described, as a first step to predict its behavior in the preparation of a drug that contains it as an active ingredient. The research findings demonstrate that locally synthesized PB is suitable for use in oral dosage forms, enabling the local development of drug formulations incorporating PB, thus being able to potentially become a main resource in the treatment of Cs and Tl poisoning in any accidental or intended of the population. This development opens up the possibility of creating drug formulations that incorporate PB at a local level, making it a potentially significant resource in the treatment of Cs and Tl poisoning. The ability to locally produce and utilize PB in oral dosage forms could be crucial in addressing cases of accidental or intentional exposure within the population. This advancement not only contributes to the scientific understanding of PB but also holds promising implications for practical applications in public health and emergency situations.