RESUMEN
RATIONALE: Anesthetics are widely used for optimizing surgical conditions, postoperative pain management, and treating various chronic pain conditions. Tetracaine and decamethonium are representative drugs of local anesthetics and neuromuscular blocking agents, respectively. However, overdose and toxicity of the drugs always lead to serious adverse events. Thus, there is a strong demand for effective antidotes. METHODS: The binding interactions of amide naphthotubes with tetracaine and decamethonium were systematically studied using 1H NMR, ITC, and DFT calculations. The antidotal effects of amide naphthotube to tetracaine toxicity were assessed in vitro and in vivo, and the mechanism of detoxification was explored at a cellular level. Additionally, mouse models were established to evaluate the reversal activities of amide naphthotube on decamethonium-induced mortality and muscle relaxation, and the reversal mechanism was investigated through pharmacokinetic experiments. RESULTS: We have demonstrated that the anti-isomer of amide naphthotube exhibits significant binding affinities towards tetracaine (K a = 1.89×107 M-1) and decamethonium (K a = 1.01×107 M-1) in water. The host displayed good biocompatibility both in vitro and in vivo. The administration of amide naphthotube following tetracaine overdose in mouse models notably increased the overall survival rate, indicating its effective antidotal properties. The host could reverse the tetracaine-induced Na+ channels blockage at the cellular level. Moreover, the injection of amide naphthotube also reversed the mortality and paralysis induced by decamethonium in mouse models following a pharmacokinetic mechanism. CONCLUSION: An emerging artificial receptor, amide naphthotube, has strong binding affinities towards tetracaine and decamethonium. It functions as a supramolecular antidote for tetracaine poisoning and a reversal agent for decamethonium by selectively sequestering these compounds in vivo.
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Antídotos , Tetracaína , Animales , Tetracaína/farmacología , Tetracaína/química , Ratones , Antídotos/farmacología , Antídotos/química , Amidas/química , Amidas/farmacología , Masculino , Anestésicos Locales/farmacología , Anestésicos Locales/química , Humanos , Bloqueantes Neuromusculares/química , Bloqueantes Neuromusculares/farmacologíaRESUMEN
ABSTRACT: The effects of the calcium sensitizer levosimendan on hemodynamics and survival in guinea pigs intoxicated with the calcium blockers verapamil or diltiazem were evaluated in a randomized controlled study. One hundred four animals were randomized to be intoxicated with either verapamil (2.0 mg/kg) or diltiazem (4.5 mg/kg) and thereafter further randomized into 6 groups which received either saline (control), 3 different regimes of levosimendan, calcium chloride, and levosimendan combined with calcium chloride. The hemodynamics and survival of the animals were followed for 60 minutes after intoxication.The negative inotropic effect of calcium blockers was seen as a decrease by over 70% of the positive derivative of the left ventricular pressure. This was reversed by levosimendan. Moreover, both verapamil and diltiazem-induced marked hypotension (-69% and -63% of the baseline value, respectively) which was also reversed by levosimendan. The combined levosimendan and calcium chloride treatment had a synergistic effect in reversing verapamil or diltiazem-induced deterioration in hemodynamics.Both verapamil and diltiazem intoxications decreased the survival rate of guinea pigs to 13%. Levosimendan addition improved survival dose-dependently up to a survival rate of 75% and 88% in the verapamil and diltiazem groups, respectively. Low dose of levosimendan combined with calcium chloride improved survival in verapamil and diltiazem group to 88% and 100%, respectively.In conclusion, the administration of levosimendan improved hemodynamics and survival in calcium channel blocker intoxicated guinea pigs. The synergistic effect of levosimendan and calcium chloride suggests that this combination could be an effective antidote in calcium channel blocker intoxications.
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Antídotos , Bloqueadores de los Canales de Calcio , Diltiazem , Hidrazonas , Piridazinas , Simendán , Verapamilo , Animales , Simendán/farmacología , Cobayas , Bloqueadores de los Canales de Calcio/farmacología , Hidrazonas/farmacología , Piridazinas/farmacología , Diltiazem/farmacología , Verapamilo/farmacología , Antídotos/farmacología , Masculino , Hemodinámica/efectos de los fármacos , Cloruro de Calcio , Cardiotónicos/farmacología , Sinergismo Farmacológico , Modelos Animales de Enfermedad , Quimioterapia Combinada , Tasa de SupervivenciaAsunto(s)
Analgésicos Opioides , Humanos , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/farmacología , Antídotos/farmacología , Antídotos/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Antagonistas de Narcóticos/farmacología , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/prevención & controlRESUMEN
BACKGROUND: Prompt acetylcysteine treatment with standard doses (300 mg/kg over 21 h in divided doses) is almost universally effective in preventing hepatotoxicity after paracetamol (acetaminophen) overdose. However, hepatotoxicity is reported despite early treatment when paracetamol concentrations exceed 300 mg/L (1,985 µmol/L) at 4 h. Prior studies evaluating high-dose acetylcysteine to treat high-risk ingestions have shown mixed results. We compared outcomes in patients with high-risk ingestions receiving standard or high-dose acetylcysteine. METHODS: Records from a single poison center were reviewed from 1 January 2017 to 31 December 2022. We included cases of acute paracetamol ingestion treated with intravenous acetylcysteine with an initial paracetamol concentration above the "300 mg/L" (1,985 µmol/L) line on the Rumack-Matthew nomogram. We compared standard and high-dose acetylcysteine groups by odds ratios and multivariable logistic regression. We defined hepatotoxicity as aminotransferase activity >1,000 U/L. RESULTS: We included 190 cases. Fifty-six percent received standard-dose acetylcysteine while 44% received high-dose acetylcysteine. Treatment within 8 h yielded no difference in hepatotoxicity between groups (odds ratio 1.67, 95% CI 0.067-42.3). Among patients treated after 8 h, hepatoxicity was more common in the high-dose group (odds ratio 3.39, 95% CI 1.25-9.2) though odds of liver failure were similar (odds ratio 2.78, 95% CI 0.89-8.69). Eighty-eight percent of patients with hepatotoxicity had elevated aminotransferase activity at presentation. No patient died or received a liver transplant. DISCUSSION: Rates of hepatotoxicity were low in patients treated within 8 h regardless of acetylcysteine dose. Unexpectedly, high-dose acetylcysteine treatment was associated with an increased odds of hepatoxicity in those treated after 8 h, but most had abnormal aminotransferase activities at presentation and there was no difference in rates of liver failure. Limitations include the use of retrospective, voluntarily reported poison center data. CONCLUSIONS: Prompt treatment with acetylcysteine, regardless of dose, prevented hepatotoxicity in high-risk paracetamol ingestion.
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Acetaminofén , Acetilcisteína , Enfermedad Hepática Inducida por Sustancias y Drogas , Sobredosis de Droga , Humanos , Acetilcisteína/uso terapéutico , Acetilcisteína/administración & dosificación , Acetaminofén/envenenamiento , Acetaminofén/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Masculino , Femenino , Sobredosis de Droga/tratamiento farmacológico , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Antídotos/administración & dosificación , Antídotos/uso terapéutico , Adulto Joven , Analgésicos no Narcóticos/envenenamiento , Analgésicos no Narcóticos/administración & dosificación , Relación Dosis-Respuesta a Droga , Centros de Control de Intoxicaciones/estadística & datos numéricos , AdolescenteRESUMEN
Aluminum phosphide (AlP) is the main component of rice tablets (a pesticide), which produces phosphine gas (PH3) when exposed to stomach acid. The most important symptoms of PH3 toxicity include, lethargy, tachycardia, hypotension, and cardiac shock. It was shown that Iodine can chemically react with PH3, and the purpose of this study is to investigate the protective effects of Lugol solution in poisoning with rice tablets. Five doses (12, 15, 21, 23, and 25 mg/kg) of AlP were selected, for calculating its lethal dose (LD50). Then, the rats were divided into 4 groups: AlP, Lugol, AlP + Lugol, and Almond oil (as a control). After 4 h, the blood pressure and electrocardiogram (ECG) were recorded, and blood samples were obtained for biochemical tests, then liver, lung, kidney, heart, and brain tissues were removed for histopathological examination. The results of the blood pressure showed no significant changes (P > 0.05). In ECG, the PR interval showed a significant decrease in the AlP + Lugol group (P < 0.05). In biochemical tests, LDH, Ca2+, Creatinine, ALP, Mg2+, and K+ represented significant decreases in AlP + Lugol compared to the AlP group (P < 0.05). Also, the administration of Lugol's solution to AlP-poisoned rats resulted in a significant decrease in malondialdehyde levels and a significant increase in catalase activity (P < 0.05). Histopathological evaluation indicates that Lugol improves changes in the lungs, kidneys, brain, and heart. Our results showed that the Lugol solution could reduce tissue damage and oxidative stress in AlP-poisoned rats. We assume that the positive effects of Lugol on pulmonary and cardiac tissues are due to its ability to react directly with PH3.
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Compuestos de Aluminio , Fosfinas , Ratas Wistar , Animales , Fosfinas/toxicidad , Compuestos de Aluminio/toxicidad , Masculino , Estrés Oxidativo/efectos de los fármacos , Biomarcadores/sangre , Modelos Animales de Enfermedad , Presión Sanguínea/efectos de los fármacos , Antídotos/farmacología , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Electrocardiografía , Intoxicación/prevención & control , Antioxidantes/farmacología , Plaguicidas/toxicidad , Comprimidos , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Ratas , Dosificación Letal Mediana , Miocardio/patología , Miocardio/metabolismo , YodurosRESUMEN
The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.
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Acetilcolinesterasa , Sustancias para la Guerra Química , Inhibidores de la Colinesterasa , Reactivadores de la Colinesterasa , Agentes Nerviosos , Oximas , Compuestos de Piridinio , Oximas/farmacología , Acetilcolinesterasa/metabolismo , Reactivadores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/toxicidad , Compuestos de Piridinio/farmacología , Sustancias para la Guerra Química/toxicidad , Agentes Nerviosos/toxicidad , Compuestos de Pralidoxima/farmacología , Compuestos Organotiofosforados/toxicidad , Animales , Antídotos/farmacologíaRESUMEN
BACKGROUND: Ethylene glycol poisoning causes metabolic acidosis, organ injury, and death. Ethylene glycol testing is unavailable in many areas. Our laboratory uses an automated glycerol dehydrogenase enzymatic assay to screen for ethylene glycol. We sought to determine how often ethylene glycol results were available within 12 h of the first dose of fomepizole. METHODS: Records from a single poison center were reviewed from December 2016 to December 2019. Cases were identified by searching for cases that received fomepizole. Outcomes included whether results were available within 12 h, and the turnaround time from time of laboratory order to result. RESULTS: Of the 125 cases of suspected toxic alcohol poisoning identified, 73 had screening for ethylene glycol by enzymatic assay. Results were available within 12 h of the initial fomepizole dose in 58 (79%) cases with a median turnaround time of 391 min. DISCUSSION: We have demonstrated clinically acceptable turnaround times using an automated screening ethylene glycol assay. The major limitations include lack of approval for this test at this time, the use of voluntarily reported poison center data, and lack of assessment of patient outcomes. CONCLUSION: Enzymatic screening for ethylene glycol yielded results within 12 h in 79% of cases.
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Glicol de Etileno , Fomepizol , Glicol de Etileno/envenenamiento , Humanos , Factores de Tiempo , Estudios Retrospectivos , Pruebas de Enzimas/métodos , Centros de Control de Intoxicaciones/estadística & datos numéricos , Antídotos , Masculino , FemeninoRESUMEN
BACKGROUND: Snake bites cause considerable morbidity and mortality worldwide, yet evidence from low- and middle-income countries remains fragmented. This is particularly the case in Eastern Mediterranean Region where available data on snake bites is relatively weak. Without reliable data, it is difficult to make the case for greater visibility and investment to address the snakebite burden in this Region. A scoping review was therefore conducted to summarize evidence on snake bites in countries of the Eastern Mediterranean. METHODOLOGY/PRINCIPAL FINDINGS: The review employed manual and electronic searching methods of four databases plus Google Scholar, ultimately including 196 records from 20 countries published between 2000 and 2023. More than half originated from Iran, Morocco, and Pakistan. Many records lacked information on permanent sequalae, disability, snake species, and types and sources of antivenoms. When identified, offending snakes belonged to 30 species. Use of more than 12 types of antivenoms were described across the Region, and some were not specific to indigenous species. CONCLUSION/SIGNIFICANCE: Despite the relatively large number of publications identified, the data were concentrated in just a few countries in the Region, and there was little or no information available for the remainder. As is the case worldwide, disability associated with snake bites was poorly characterized and quantified across the Region. There is an urgent need for concrete action at national and regional levels to enhance epidemiological surveillance, research, and the collection of clinical, disability and outcomes data to inform policy and public health investment. Greater regional cooperation and collaboration is also crucial for addressing this neglected disease throughout the Region.
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Antivenenos , Mordeduras de Serpientes , Serpientes , Mordeduras de Serpientes/epidemiología , Mordeduras de Serpientes/tratamiento farmacológico , Antivenenos/uso terapéutico , Humanos , Animales , Antídotos/uso terapéutico , Región Mediterránea/epidemiología , Irán/epidemiología , Pakistán/epidemiologíaRESUMEN
Snakebites affect about 1.8 million people annually. The current standard of care involves antibody-based antivenoms, which can be difficult to access and are generally not effective against local tissue injury, the primary cause of morbidity. Here, we used a pooled whole-genome CRISPR knockout screen to define human genes that, when targeted, modify cell responses to spitting cobra venoms. A large portion of modifying genes that conferred resistance to venom cytotoxicity was found to control proteoglycan biosynthesis, including EXT1, B4GALT7, EXT2, EXTL3, XYLT2, NDST1, and SLC35B2, which we validated independently. This finding suggested heparinoids as possible inhibitors. Heparinoids prevented venom cytotoxicity through binding to three-finger cytotoxins, and the US Food and Drug Administration-approved heparinoid tinzaparin was found to reduce tissue damage in mice when given via a medically relevant route and dose. Overall, our systematic molecular dissection of cobra venom cytotoxicity provides insight into how we can better treat cobra snakebite envenoming.
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Venenos Elapídicos , Mordeduras de Serpientes , Animales , Humanos , Mordeduras de Serpientes/tratamiento farmacológico , Ratones , Antídotos/farmacologíaRESUMEN
INTRODUCTION: Physostigmine is an effective antidote for antimuscarinic delirium. There is little evidence for its use to reverse delirium following second generation antipsychotic exposure. The purpose of this study is to describe the safety and effectiveness of physostigmine in reversing delirium from second generation antipsychotic exposure. METHODS: This is a retrospective cohort study of all patients reported to a single regional poison center treated with physostigmine following a second generation antipsychotic exposure from January 1, 2000 to April 15, 2021. The poison center electronic medical record was queried to identify cases and for data abstraction. The primary outcome was the positive response rate to physostigmine, as determined by two trained abstractors. Secondary outcomes included physostigmine dosing, and adverse events. RESULTS: Of 147 charts reviewed, 138 individual patients were included, and the response to physostigmine was reported in 128 patients. The most common second-generation antipsychotic exposure was quetiapine (97; 70.3 percent). A positive response to physostigmine was noted in 106/128 (82.8 percent) patients [95 percent confidence interval 68.9-83.6 percent]. Median number of physostigmine doses was 1 (interquartile range 1-3; range 1-9). The median total physostigmine dose received was 2 mg (interquartile range 2-6 mg; range 0.15-30 mg). The positive physostigmine response rate for patients with an antimuscarinic co-ingestion was not significantly different compared to patients with a different co-ingestion or no co-ingestion (25/34 versus 81/94; P = 0.09). Adverse events were reported in four (2.9 percent) patients, including one death. DISCUSSION: A positive response to physostigmine to treat antimuscarinic delirium from second generation antipsychotic exposure was reported in 82.8 percent of patients, which is similar to previous physostigmine studies. Adverse events were infrequent, and included diaphoresis (one 0.7 percent), seizure (one; 0.7 percent), and bradycardia (one; 0.7 percent). One (0.7%) patient suffered a cardiac arrest 60 minutes after receiving physostigmine to treat antimuscarinic delirium following having received increasing clozapine doses over the previous month. CONCLUSIONS: In this study, physostigmine appears to be a safe and effective treatment for antimuscarinic delirium from second generation antipsychotic exposure. Further studies are needed to validate the safety and effectiveness of physostigmine for this indication.
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Antipsicóticos , Delirio , Fisostigmina , Centros de Control de Intoxicaciones , Humanos , Fisostigmina/uso terapéutico , Estudios Retrospectivos , Delirio/tratamiento farmacológico , Delirio/inducido químicamente , Antipsicóticos/uso terapéutico , Antipsicóticos/efectos adversos , Femenino , Masculino , Centros de Control de Intoxicaciones/estadística & datos numéricos , Adulto , Persona de Mediana Edad , Antídotos/uso terapéutico , Antídotos/administración & dosificación , Inhibidores de la Colinesterasa/uso terapéutico , Anciano , Adulto Joven , Estudios de CohortesRESUMEN
Abstract: Medication errors pose significant risks to patients' health, representing a relevant social and economic issue for the healthcare system. This study focuses on the life-threatening consequences of an overdose of intravenous lipid emulsion (ILE), used as an antidote for suspected bupivacaine intoxication in a young woman undergoing hip surgery. Shortly after administration of the local anesthetic, the woman experienced cardiac arrest and was admitted to the intensive care unit with severe respiratory failure, metabolic acidosis and deep coma. Despite medical intervention, her condition worsened, leading the medical team to administer ILE for suspected bupivacaine intoxication. The patient's condition did not improve and ultimately resulted in death. The autopsy highlighted a widespread presence of oily material in the vascular system, compatible with an overdose of ILE. At a checking, medical records reported a dose of ILE that was 4-fold higher than the recommended dose in this off-label indication. This case report highlights the important need for healthcare professionals to understand the risks of using ILE as an antidote. Adequate monitoring of these "sentinel events" and their critical evaluation can lead to the implementation of specific clinical risk management protocols to reduce the risk for the patient and contain healthcare costs.
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Antídotos , Bupivacaína , Emulsiones Grasas Intravenosas , Humanos , Emulsiones Grasas Intravenosas/uso terapéutico , Emulsiones Grasas Intravenosas/administración & dosificación , Femenino , Resultado Fatal , Bupivacaína/administración & dosificación , Antídotos/uso terapéutico , Antídotos/administración & dosificación , Adulto , Anestésicos Locales/administración & dosificación , Anestésicos Locales/envenenamiento , Sobredosis de Droga , Paro Cardíaco/inducido químicamente , Errores de Medicación , Acidosis/inducido químicamente , Acidosis/tratamiento farmacológicoRESUMEN
N-acetylcysteine (NAC) is regarded as an effective treatment of paracetamol overdoses. However, in cases of "massive" paracetamol overdoses, recent studies indicate that patients may not be sufficiently treated with the standard dose of NAC (300 mg/kg over 20-21 h). The subject is further complicated because "massive overdoses" and "high-risk" are defined differently; some studies use the ingested amount (e.g., >40 g), and some studies use blood concentrations of paracetamol and transaminases. This narrative review investigates whether high-dose NAC significantly decreases the risk of hepatotoxicity in patients with massive paracetamol overdoses. Three observational studies were analysed; one study with 373 patients found no significant difference (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.49-3.29). One study with 79 patients found a significant difference (OR: 0.27, 95% CI: 0.08-0.94). The third study with 89 patients found a significant difference in hepatoxicity between the groups (p = 0.043). There are no solid evidence to support that treatment with high-dose NAC significantly reduces the rate of hepatotoxicity in patients presenting with massive paracetamol overdoses. Differences in inclusion criteria in the included studies make the studies incomparable. This paper shows that standardized inclusion is needed to determine whether a high-dose NAC regimen should be included in clinical practice.
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Acetaminofén , Acetilcisteína , Enfermedad Hepática Inducida por Sustancias y Drogas , Sobredosis de Droga , Acetilcisteína/administración & dosificación , Acetilcisteína/uso terapéutico , Humanos , Acetaminofén/envenenamiento , Acetaminofén/administración & dosificación , Sobredosis de Droga/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Analgésicos no Narcóticos/envenenamiento , Analgésicos no Narcóticos/administración & dosificación , Antídotos/administración & dosificación , Antídotos/uso terapéutico , Relación Dosis-Respuesta a Droga , Estudios Observacionales como AsuntoRESUMEN
Organophosphorus (OP) poisoning is a significant cause of morbidity and mortality worldwide. Recent research has explored new approaches to improving treatment options, which present several challenges. This study aimed to evaluate the role of fresh frozen plasma (FFP) as an adjunctive therapy for acute OP intoxication. A prospective single-blinded randomized clinical trial was conducted on patients of both sexes admitted to the Intensive Care Unit (ICU) of the Poison Control Center at Ain Shams University Hospital (PCC-ASUH) with acute OP toxicity during the period from the beginning of August 2022 to the end of July 2023. According to the Peradeniya score, Group I consisted of 48 patients (52%) with moderate OP poisoning, and Group II consisted of 44 patients (48%) with severe OP poisoning. Patients in the moderate group were assigned to receive either standard treatment (Group Ia, n = 24) or standard treatment plus FFP (Group Ib, n = 24). In addition, patients in the severe group were assigned to receive either standard treatment (Group IIa, n = 22) or standard treatment plus FFP (Group IIb, n = 22). A total of 46 patients received FFP transfusion. The authors demonstrated that the early use of a total of nine packs of FFP (250 mL each) over three consecutive days significantly reduced the total doses of atropine and oximes, the total hospitalization period, and the requirement for mechanical ventilation in patients with OP poisoning, both in the moderate and severe groups.
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Intoxicación por Organofosfatos , Plasma , Humanos , Femenino , Masculino , Intoxicación por Organofosfatos/terapia , Adulto , Persona de Mediana Edad , Método Simple Ciego , Estudios Prospectivos , Transfusión de Componentes Sanguíneos , Adulto Joven , Antídotos/uso terapéuticoAsunto(s)
Benzodiazepinas , Flumazenil , Unidades de Cuidado Intensivo Neonatal , Mioclonía , Humanos , Flumazenil/uso terapéutico , Mioclonía/inducido químicamente , Recién Nacido , Benzodiazepinas/efectos adversos , Moduladores del GABA/uso terapéutico , Moduladores del GABA/efectos adversos , Masculino , Femenino , AntídotosRESUMEN
Nerve agents are a class of lethal neurotoxic chemicals used in chemical warfare. In this review, we have discussed a brief history of chemical warfare, followed by an exploration of the historical context surrounding nerve agents. The article explores the classification of these agents, their contemporary uses, their toxicity mechanisms, and the disadvantages of the current treatment options for nerve agent poisoning. It then discusses the possible application of enzymes as prophylactics against nerve agent poisoning, outlining the benefits and drawbacks of paraoxonase- 1. Finally, the current studies on paraoxonase-1 are reviewed, highlighting that several challenges need to be addressed in the use of paraoxonase-1 in the actual field and that its potential as a prophylactic antidote against nerve agent poisoning needs to be evaluated. The literature used in this manuscript was searched using various electronic databases, such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, Google Patent, and books using the keywords chemical warfare agent, butyrylcholinesterase, enzyme, nerve agent, prophylactic, and paraoxonase-1, with the time scale for the analysis of articles between 1960 to 2023. The study has suggested that concerted efforts by researchers and agencies must be made to develop effective countermeasures against NA poisoning and that paraoxonase-1 has suitable properties for the development of efficient prophylaxis against NA poisoning.
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Arildialquilfosfatasa , Sustancias para la Guerra Química , Agentes Nerviosos , Arildialquilfosfatasa/metabolismo , Arildialquilfosfatasa/uso terapéutico , Humanos , Sustancias para la Guerra Química/envenenamiento , Sustancias para la Guerra Química/toxicidad , Agentes Nerviosos/envenenamiento , Agentes Nerviosos/toxicidad , Animales , Antídotos/uso terapéutico , Antídotos/farmacologíaRESUMEN
BACKGROUND: Cyanide poisoning poses a significant threat to burn patients exposed to smoke in residential or workplace fires, leading to central nervous system dysfunction, hemodynamic instability, cardiovascular collapse, and death. Prompt administration of an effective antidote is critical. Hydroxocobalamin, a form of vitamin B12, is the gold standard treatment for cyanide toxicity, by binding to cyanide molecules and converting them into non-toxic cyanocobalamin that is eliminated by the kidneys. This mechanism is distinct from previous cyanide antidotes, which induce the formation of methemoglobin to bind to cyanide. Recent case studies have reported elevated methemoglobin levels after hydroxocobalamin administration, raising concerns regarding its safety. The current study investigates smoke inhalation patients treated with hydroxocobalamin at a single institution Burn Unit in hopes of enhancing our understanding of the complexities surrounding cyanide antidote therapy. METHODS: After Institutional Board Approval, a retrospective cohort study was conducted. Our sample comprised burn patients with inhalation injury admitted to a single institution from 2013 to 2023 and treated with hydroxocobalamin for suspected cyanide toxicity. We also analyzed a matched control cohort of similar patients with inhalation injury not treated with hydroxocobalamin. We analyzed changes and peaks in methemoglobin levels, lactate levels, blood urea nitrogen (BUN) and creatinine, ventilator days, % total body surface area (TBSA), various types of medications and dressings, and mortality. Statistical analyses included t-tests, chi-square, linear and logistic regressions, and correlation analysis. RESULTS: In the study, 36 patients with suspected inhalation injury were treated with hydroxocobalamin at the Los Angeles General (LAG) Burn Unit from 2013 to 2023, who were matched to 32 control patients with inhalation injury who were not treated with hydroxocobalamin. Demographic and baseline characteristics showed no statistically significant differences between the groups, including age, gender, BMI, and %TBSA. No significant differences were found in initial, final, peak, or change in methemoglobin levels. The study also revealed no significant disparities in initial lactate levels, mortality, kidney function tests, ventilator days, surgeries, or use of medications/treatments (e.g., Silvadene dressings, Vitamin C) between the two groups. When controlling for covariates, multiple linear regression analysis (age, gender, and %TBSA) indicated that hydroxocobalamin administration was not significantly associated with changes in methemoglobin or mortality. Increased %TBSA, however, was linked to elevated lactate levels. CONCLUSIONS: Our investigation sought to assess the potential risks associated with hydroxocobalamin administration in burn patients with concomitant inhalation injury. Contrary to our initial hypothesis, we found no statistically significant differences in methemoglobinemia, lactate levels, mortality, or kidney function. The influence of other factors, such as methemoglobinemia-inducing drugs or hydroxocobalamin's interference with co-oximetry, adds complexity. Although elevated methemoglobin levels were observed in some cases, their clinical significance was limited. However, this study's limitations, particularly the rarity of inhalation injury cases with concern for cyanide toxicity, warrant consideration. Further research is required to comprehensively elucidate the impact of hydroxocobalamin administration on burn patients' outcomes.
Asunto(s)
Algoritmos , Antídotos , Cianuros , Hidroxocobalamina , Metahemoglobinemia , Lesión por Inhalación de Humo , Humanos , Hidroxocobalamina/uso terapéutico , Masculino , Femenino , Metahemoglobinemia/inducido químicamente , Metahemoglobinemia/tratamiento farmacológico , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Lesión por Inhalación de Humo/tratamiento farmacológico , Antídotos/uso terapéutico , Estudios de Casos y Controles , Complejo Vitamínico B/uso terapéutico , Creatinina/sangre , Quemaduras por Inhalación/tratamiento farmacológico , Quemaduras por Inhalación/complicaciones , Anciano , Metahemoglobina/metabolismo , Metahemoglobina/análisis , Estudios de CohortesRESUMEN
Numerous toxins threaten humans, but specific antidotes are unavailable for most of them. Although CRISPR screening has aided the discovery of the mechanisms of some toxins, developing targeted antidotes remains a significant challenge. Recently, we established a systematic framework to develop antidotes by combining the identification of novel drug targets by using a genome-wide CRISPR screen with a virtual screen of drugs approved by the US Food and Drug Administration. This approach allows for a comprehensive understanding of toxin mechanisms at the whole-genome level and facilitates the identification of promising antidote drugs targeting specific molecules. Here, we present step-by-step instructions for executing genome-scale CRISPR-Cas9 knockout screens of toxins in HAP1 cells. We also provide detailed guidance for conducting an in silico drug screen and an in vivo drug validation. By using this protocol, it takes ~4 weeks to perform the genome-scale screen, 4 weeks for sequencing and data analysis, 4 weeks to validate candidate genes, 1 week for the virtual screen and 2 weeks for in vitro drug validation. This framework has the potential to accelerate the development of antidotes for a wide range of toxins and can rapidly identify promising drug candidates that are already known to be safe and effective. This could lead to the development of new antidotes much more quickly than traditional methods, protecting lives from diverse toxins and advancing human health.
Asunto(s)
Antídotos , Sistemas CRISPR-Cas , Simulación por Computador , Antídotos/farmacología , Humanos , Evaluación Preclínica de Medicamentos/métodos , AnimalesRESUMEN
Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood-brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10-30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.
Asunto(s)
Acetilcolinesterasa , Butirilcolinesterasa , Humanos , Butirilcolinesterasa/metabolismo , Butirilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Ligandos , Oximas/química , Oximas/farmacología , Reactivadores de la Colinesterasa/farmacología , Reactivadores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Colestenonas/farmacología , Colestenonas/química , Cinética , Sarín/química , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/química , Proteínas Ligadas a GPI/antagonistas & inhibidores , Antídotos/farmacología , Antídotos/química , Colesterol/metabolismo , Colesterol/química , Compuestos OrganofosforadosRESUMEN
METHODS: This study was designed as a cross-sectional, observational, retrospective study. The variables of the study were paracetamol overdose, demographic information, poisoning mechanisms, clinical, laboratory findings, and clinical progression of the cases. The cases compared in whom treatment was initiated within the first 8 hours after poisoning and those in whom it was not. χ 2 , t test, and logistic regression analyses were conducted at appropriate facilities. RESULTS: Three hundred forty-eight cases were included in the study. N-AC treatment was initiated within the first 8 hours after poisoning in 322 cases (92.5%), and 26 cases received N-AC treatment after 8 hours after poisoning. Liver toxicity developed in 6 cases (1.7%), and indications for liver transplantation were met in 36 cases (10.3%). Among the 26 cases for which treatment was not initiated within the first 8 hours, 18 cases (69.2%) had indications for liver transplantation ( P < 0.01). It was found that N-AC within the first 8 hours reduced the risk by 43 times ( P = 0.02) and being older than 6 years, being admitted to the intensive care unit, and having alanine aminotransferase values above 1000 U/L increased the risk significantly ( P = 0.009, P = 0.005, P < 0.001). When a receiver operating characteristic curve was plotted for the 4th-hour blood acetaminophen level to predict liver transplantation, a value of 684.5 µg/mL emerged with 89% sensitivity and 93% specificity (area under the curve, 0.951). CONCLUSIONS: As a result, this study demonstrates the protective effect of early-initiated N-AC therapy on liver toxicity in pediatric acetaminophen poisoning cases. It also highlights a significant impact of gastrointestinal decontamination methods.
Asunto(s)
Acetaminofén , Acetilcisteína , Enfermedad Hepática Inducida por Sustancias y Drogas , Humanos , Acetaminofén/envenenamiento , Estudios Retrospectivos , Femenino , Masculino , Estudios Transversales , Niño , Preescolar , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Acetilcisteína/uso terapéutico , Lactante , Analgésicos no Narcóticos/envenenamiento , Sobredosis de Droga , Antídotos/uso terapéutico , Trasplante de Hígado , Adolescente , HígadoRESUMEN
A 53-year-old male patient presented to a regional hospital Emergency Department approximately 2 h post an intentional ingestion of Coopers Instant Wetting Powder Sheep Dip (66% arsenic trioxide, 23% sulphur and 0.42% rotenone), mixed in 600 mL water, as a suicide attempt. On arrival to the Emergency Department, the patient had nausea, vomiting and diarrhoea. Seven hours post ingestion, hypotension developed (BP 90/60 mmHg) and intravenous fluids were commenced. He later developed QTc prolongation. He was treated with 2,3-Dimercapto-1-propanesulfonic acid (DMPS) and N-acetylcysteine and improved without development of neurology. Further investigation of NAC efficacy in humans in the setting of acute arsenic poisoning is required and the optimal duration of treatment and dosing needs to be established. This case highlights an uncommon poisoning which presented to the Emergency Department, the acute symptoms of arsenic toxicity and considerations for management.