Neurotoxicology
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Treatment of OP poisoning should include careful decontamination of the patient since many OP agents have the potential to contaminate health care providers who care for exposed patients. Pharmacologic therapy consists of atropine, an antagonist of the muscarinic ACh receptor. Administration of atropine should be titrated to the reduction of bronchial secretions, and large doses may be needed, totaling hundreds of grams in some severely poisoned patients. Oximes are compounds that react with and bind to OP agents with higher affinity than the binding between OPs and AChE, and are used to reverse OP-mediated inactivation of the enzyme as well as prevent formation of a permanent covalent bond between the OP and AChE, a process referred to as “ageing.” Different OPs age at different speeds, some occurring within minutes, in which case oximes will be of little benefit. However, the specific OP agent is usually unknown at the time of patient presentation, so empiric therapy with oximes is typically indicated. Pralidoxime is the most commonly used oxime in the United States, though others are used internationally. Severe poisoning can progress to seizures which can be treated with BZD (diazepam is classically cited, but any immediately available BZD can be used) in addition to continued treatment with atropine and general supportive care. The etiology of OP-induced seizures is not well described and may be due to hypoxia.
Battlefield Chemical Inhalation Injury
Jacob Loke in Pathophysiology and Treatment of Inhalation Injuries, 2020
Reactivation of the inhibited enzyme with serine- (cholinesterase active site) directed nucleophiles has been accomplished using quaternary oximes. A wide variety of oximes has been studied. Of these, 2-PAM-C1 (pralidoxime chloride), P2S (pralidoxime methanesulfonate). Toxogonin, and TMB-4 have been most intensively studied (National Research Council, 1984). These substances speed the separation of the phosphorus atom from the active cholinesterase site, freeing the cholinesterase for acetylcholine binding. This process is more difficult if “aging” has occurred, hence the oximes are less effective with OP compounds that age rapidly (e.g., sarin, soman). In the absence of reactivation of the inhibited enzyme, normal metabolic regeneration of fresh cholinesterase must occur. Blood cholinesterase is regenerated at the rate of new red blood cell entry into the peripheral circulation since resynthesis does not occur in circulating red blood cells. Tissue cholinesterase is regenerated more quickly (Austin and James, 1970; Funckes, 1960; Grob and Johns, 1958; Namba and Hiraki, 1958).
Oxime Research
Brian J. Lukey, James A. Romano, Salem Harry in Chemical Warfare Agents, 2019
The search for the most powerful reactivator against all nerve agents led to various structural modifications considering the binding affinity, increased hydrophobicity, reactivation potency, and other requirements. Newly developed oximes can be distinguished on the basis of several structural characteristics (Worek et al., 2013). There are five important structural factors that influence the affinity of the AChE reactivators toward inhibited AChE: (a) the presence of the quaternary nitrogens in the reactivator molecule; (b) the length and shape of the linker between two pyridinium rings; (c) the presence of the oxime group; (d) the position of the oxime group at the pyridinium ring; and (e) the number of oxime groups in the reactivator’s structure.
Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Liliane O. Ortlieb, Ícaro P. Caruso, Nathane C. Mebus-Antunes, Andrea T. Da Poian, Elaine da C. Petronilho, José Daniel Figueroa-Villar, Claudia J. Nascimento, Fabio C. L. Almeida
The oximes 9–18 were prepared by the reaction of hydroxylamine hydrochloride with the corresponding aldehydes, using ethanol (95%) and distilled water as solvents26,55,56. After stirring, the product was vacuum filtered and washed with cold distilled water, leading to compounds obtained in 50–98% yields. The time of stirring (1–36 h) and the yield for each compound is described in Supplementary Material with the spectral assignment data. The mechanism for forming oximes is similar to that of guanylhydrazones, based on the nucleophilic attack of the –NH2 group of hydroxylamine to the –C=O group of the aldehyde, followed by loss of water and formation of the double bond (Supplementary Information, Scheme S2). Compounds 2, 4, 5–11, 13, 14, and 18 are new unpublished agents. Although compounds 1, 3, 12, 15, 16, and 17 have already been reported in the literature, they have never been tested as DENVC inhibitors. All compounds were characterised by infra-red spectroscopy (IR) and NMR (Supplementary Information, Figures S1–S54).
Efficacy of fresh frozen plasma transfusion in comparison with conventional regimen in organophosphate poisoning treatment: a meta-analysis study
Published in Critical Reviews in Toxicology, 2020
Farzad Gheshlaghi, Mahsa Akafzadeh Savari, Rozita Nasiri, Anselm Wong, Awat Feizi, Mohammad Reza Maracy, Gholamali Dorooshi, Rokhsareh Meamar, Nastaran Eizadi-Mood
It is not clear how oximes work, whether they are only useful for patients who are poisoned by specific pesticides or those with moderate poisoning (Eyer 2003). A number of studies have shown that atropine and oximes cannot prevent morbidity and mortality in poisoned patients (Masson et al. 1997; Johnson et al. 2000; Sudakin et al. 2000; Eddleston et al. 2002; Sivagnanam 2002). Generally, oximes are used widely in treating organophosphorus poisoned humans because extensive studies on oximes have shown its protective effects against organophosphorus in vitro. However, the results of in vivo studies on humans are not proved yet and there are no exhaustive meta-analyses to indicate oximes effectiveness (Pawar et al. 2006; Peter et al. 2006; Pazooki et al. 2011). It is only demonstrated that oximes may be useful in moderate to severe poisonings in which the patient has been referred to hospital and received treatment promptly (less than 6 h of exposure) (Pawar et al. 2006). In addition, other studies have shown that oximes are ineffective in organophosphate (OP) poisoning management and also may cause harm. Accordingly, clinicians should be cautious about using oximes in poisoned patients (Eddleston et al. 2002; Peter et al. 2006), and other treatment regimens for organophosphorus poisoning are needed (Peter et al. 2008).
A pilot clinical study of the neuromuscular blocker rocuronium to reduce the duration of ventilation after organophosphorus insecticide poisoning
Published in Clinical Toxicology, 2020
Jeevan Dhanarisi, Fathima Shihana, Kirsi Harju, Fahim Mohamed, Vasundhara Verma, Seyed Shahmy, Paula Vanninen, Olli Kostiainen, Indika Gawarammana, Michael Eddleston
Agricultural organophosphorus (OP) insecticides are widely used in rural regions of low- and middle-income countries [1]. Self-poisoning with these highly hazardous pesticides is responsible for >100,000 deaths, and hundreds of thousands of admissions to intensive care units (ICU) for respiratory support, every year [2–5]. OP compounds inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), causing accumulation of acetylcholine at cholinergic synapses and an “acute cholinergic crisis” that results in bradycardia, hypotension, coma and acute respiratory failure (due to a combination of neuromuscular junction [NMJ] dysfunction, loss of central respiratory drive and bronchorrhoea) [6–9]. Treatment requires the muscarinic antagonist atropine, supportive care and mechanical ventilation [10,11]. The role of oximes is unclear [12,13]. Unfortunately, despite this treatment, many poisoned patients still die.
Related Knowledge Centers
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- Side Chain
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