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The new oral anticoagulants have many advantages over warfarin, but one disadvantage is the inability to rapidly reverse their anticoagulant effects. Andexanet, a small-molecule factor Xa fragment, rapidly lowered levels of rivaroxaban and apixaban in older healthy volunteers. The direct factor Xa inhibitors apixaban, rivaroxaban, and edoxaban are used in the prevention and treatment of thromboembolism. Indications for the use of these agents include the prevention of stroke in patients with nonvalvular atrial fibrillation, the treatment and secondary prevention of deep-vein thrombosis and pulmonary embolism, and the prevention of venous thrombosis after orthopedic surgery. In spite of the demonstrated safety and efficacy of factor Xa inhibitors, as well as their practical advantages over vitamin K antagonists such as warfarin, the lack of a specific antidote to reverse their anticoagulant effects is an important limitation. In clinical trials involving . . .

Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit. We performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 0.88-3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 [21.5%], placebo 24/114 [21.1%], adjusted HR 1.27 [95% CI 0.71-2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit. Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required.

Poisoning is the greatest source of avoidable death in the world and can result from industrial exhausts, incessant bush burning, drug overdose, accidental toxication or snake envenomation. Since the advent of Albert Calmette’s cobra venom antidote, efforts have been geared towards antidotes development for various poisons to date. While there are resources and facilities to tackle poisoning in urban areas, rural areas and developing countries are challenged with poisoning management due to either the absence of or inadequate facilities and this has paved the way for phyto-antidotes, some of which have been scientifically validated. This review presents the scope of antidotes’ effectiveness in different experimental models and biotechnological advancements in antidote research for future applications. While pockets of evidence of the effectiveness of antidotes exist in vitro and in vivo with ample biotechnological developments, the utilization of analytic assays on existing and newly developed antidotes that have surpassed the proof of concept stage, as well as the inclusion of antidote’s short and long-term risk assessment report, will help in providing the required scientific evidence(s) prior to regulatory authorities’ approval.

Fire smoke inhalation represents a major cause of acute mortality in fire incidents, with hydrogen cyanide being a critical contributor to rapid systemic toxicity. This study aimed to establish a controlled smoke inhalation model to characterize cyanide-dominant exposure and to evaluate the prophylactic efficacy of a nebulized antidote combination under acute conditions. A reproducible smoke chamber system was developed to generate cyanide-rich toxic atmospheres. C57BL/6 mice were exposed to controlled cyanide concentrations, followed by prophylactic administration of a nebulized formulation containing hydroxocobalamin and deferoxamine. Survival outcomes were assessed to evaluate the protective effects of the intervention. Controlled cyanide exposure resulted in rapid and dose-dependent lethality. Prophylactic inhalation of the nebulized antidote significantly improved short-term survival compared with untreated controls (p < 0.05), consistent with effective mitigation of cyanide toxicity. In conclusion, this study establishes a reproducible cyanide-focused smoke inhalation model and provides experimental evidence supporting the potential of aerosolized hydroxocobalamin-based prophylaxis as an immediate protective strategy during fire smoke exposure. These findings support the feasibility of rapid, non-invasive intervention aimed at preserving a critical time window for escape and subsequent medical treatment in fire-related emergencies.

Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation 1 , has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers 2 . Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K—a group of naphthoquinones that includes menaquinone and phylloquinone 3 —confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-4 4 , 5 , was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle 6 . The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis. Biochemical and lipidomic analyses identify an anti-ferroptotic function of vitamin K and reveal ferroptosis suppressor protein 1 (FSP1) as the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle.

Remimazolam tosylate (HR-7056) is a novel ester-type benzodiazepine with ultrafast onset of effect. The compound is being developed for sedation induction and maintenance during anesthesia. It was approved for procedural anesthesia in December 2019 by the National Medical Products Administration of China. Previous studies have reported on remimazolam's effects on consciousness and cognition. Although the time to full psychomotor recovery after remimazolam-mediated sedation is critical for decisions regarding hospital discharge, relevant clinical evidence is still lacking. This study investigated the residual psychomotor effects of remimazolam and their recovery from sedating treatment in 2 simulated clinical settings: (1) single-dose administration for sedation initiation; and (2) constant rate infusion for sedation maintenance. A single-ascending-dose, parallel-group, midazolam-controlled study and a 2-way crossover study evaluating the reversal effect of flumazenil versus placebo after a 2-h constant rate infusion were conducted with HR-7056 in 87 Chinese healthy volunteers; the studies used a double-blind, randomized trial design. A battery of psychomotor tests was administered before dosing and several times postdose over 4–6 h. Pharmacokinetic, sedation, and safety assessments were performed throughout the studies. After bolus infusion, the Bispectral Index score decreased in a concentration-dependent manner with HR-7056, accompanied by a sharp drop of Modified Observer's Assessment of Alertness/Sedation score. The recovery of consciousness was much faster with HR-7056 than with midazolam. During the constant rate infusion, the Bispectral Index score was maintained between 40 and 60 with an average plasma remimazolam concentration of ~1000 ng/mL. Subjects' performance in saccadic and smooth pursuit eye movement, body sway, test of choice reaction time, and word recall was significantly impaired after single-dose midazolam and after constant rate infusion of remimazolam. The end-of-infusion injection of flumazenil shortened the median time to full alertness to 3.5 min and effectively reversed psychomotor and cardiovascular dysfunction. The study results showed quicker psychomotor recovery from sedation in the remimazolam-treated group. The moderate and short-lasting residual effect of remimazolam after 2-h conscious sedation proposes a need for psychomotor assessment(s) before hospital discharge. ClinicalTrials.gov identifiers: NCT01970072 and NCT03444480.

High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As2+ are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As2+-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered.

Accidental or suicidal ingestion of the world's most widely used herbicide, paraquat (PQ), may result in rapid multi-organ failure with a 60% fatality rate due to the absence of an effective detoxification solution. Effective, specific antidotes to PQ poisoning have been highly desired. The binding constant of PQ and a synthetic receptor, cucurbit[7]uril (CB[7]), was first determined in various pH environments. The antidotal effects of CB[7] on PQ toxicity were firstly evaluated with cell lines. With mice models, the pharmacokinetics and the biodistribution of PQ in major organs were determined to evaluate the influence of CB[7] on the oral bioavailability of PQ. Major organs' injuries and overall survival rates of the mice were systemically examined to evaluate the therapeutic efficacy of CB[7] on PQ poisoning. We demonstrate that CB[7] may complex PQ strongly under various conditions and significantly reduce its toxicity and . Oral administration of PQ in the presence of CB[7] in a mouse model significantly decreased PQ levels in the plasma and major organs and alleviated major organs' injuries, when compared to those of mice administered with PQ alone. Further studies indicated that oral administration of CB[7] within 2 h post PQ ingestion significantly increased the survival rates and extended the survival time of the mice, in contrast to the ineffective treatment by activated charcoal, which is commonly recommended for PQ decontamination. CB[7] may be used as a specific oral antidote for PQ poisoning by strongly binding with PQ and inhibiting its absorption in the gastrointestinal tracts.

Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure–activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.

Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As such as contaminated water, air, soil, but also food, can cause serious human diseases. The complex mechanism of As toxicity in the human body is associated with the generation of free radicals and the induction of oxidative damage in the cell. One effective strategy in reducing the toxic effects of As is the usage of chelating agents, which provide the formation of inert chelator–metal complexes with their further excretion from the body. This review discusses different aspects of the use of metal chelators, alone or in combination, in the treatment of As poisoning. Consideration is given to the therapeutic effect of thiol chelators such as meso-2,3-dimercaptosuccinic acid, sodium 2,3-dimercapto-1-propanesulfonate, 2,3-dimercaptopropanol, penicillamine, ethylenediaminetetraacetic acid, and other recent agents against As toxicity. The review also considers the possible role of flavonoids, trace elements, and herbal drugs as promising natural chelating and detoxifying agents.