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Neurotoxicology
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Sean D. McCann, Trevonne M. Thompson
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
Published in Jacob Loke, 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).
Cholinergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Vishal S. Gulecha, Manoj S. Mahajan, Aman Upaganlawar, Abdulla Sherikar, Chandrashekhar Upasani
Oxime group agents are also useful in the management of organophosphorus poisoning. These drugs govern hydrolysis of enzyme phosphorylated due to binding of organophosphorus. Hydrolytic action of these agents is capable of regenerating the active enzyme that allows dissociation from the complex. Pralidoxime (PAM) and diacetyl monoxime (DAM) are examples of oxime class. PAM is the highly efficient agent for the regeneration of cholinesterase found in neuromuscular junctions (NMJs) of skeletal muscle. PAM is unable to cross BBB; therefore, it is ineffective to overcome central manifestations of organophosphate poisoning (Sharma and Sharma, 2017).
Charged pyridinium oximes with thiocarboxamide moiety are equally or less effective reactivators of organophosphate-inhibited cholinesterases compared to analogous carboxamides
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zuzana Kohoutova, David Malinak, Rudolf Andrys, Jana Svobodova, Miroslav Psotka, Monika Schmidt, Lukas Prchal, Kamil Musilek
The pKa values were determined for compounds K487 (11), K488 (12), K489 (13), pralidoxime (1), asoxime (4) and for parent oximes (5–7). The pKa is an important parameter in pharmaceutical development to rationalise the physicochemical and biopharmaceutical properties of the drug molecule. It allows to detect protonated/deprotonated form of the compound under physiological conditions. In case of oximes deprotonated form so called oximate anion is important, because it is the active form of the oxime reactivator30. Change of amidic group into thioamidic group did not caused significant changes in the pKa values of oxime moiety (Table 1). This result was expected because sulphur does not differ much in electronegativity compared to oxygen. Moreover, thiocarboxamide moiety is far distanced to affect the electron density at the oxime pyridinium ring.
Adrenaline is effective in reversing the inadequate heart rate response in atropine treated organophosphorus and carbamate poisoning
Published in Clinical Toxicology, 2021
Abhishek Samprathi, Binila Chacko, Shilpa Reynal D’sa, Grace Rebekah, C. Vignesh Kumar, Mohammad Sadiq, Punitha Victor, John Prasad, Jonathan Arul Jeevan Jayakaran, John Victor Peter
It is likely that the severity of poisoning played a significant role since mega dose poisoning with concentrated OP and carbamate formulations is common in India and the blunted response to high dose atropine was due to severe cholinesterase suppression. However in our cohort of patients, the butyrylcholinesterase activity was similar in the two groups (Table 1) and there was a lack of association between admission cholinesterase activity and the requirement for high dose atropine (Table 3). However, since red cell cholinesterase more accurately reflects severity of poisoning when compared with butyrylcholinesterase, this would warrant further study. The lack of response to atropine was previously postulated to be due to inadequate dose of oximes or severe poisoning [16]. Oximes were not used in the current study and it is possible that this could have contributed to the need for high dose atropine therapy in some of our patients. Interestingly, this phenomenon has also been reported in patients treated with oximes [12].
Pyridinium-2-carbaldoximes with quinolinium carboxamide moiety are simultaneous reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by nerve agent surrogates
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Hyun Myung Lee, Rudolf Andrys, Jakub Jonczyk, Kyuneun Kim, Avinash G. Vishakantegowda, David Malinak, Adam Skarka, Monika Schmidt, Michaela Vaskova, Kamil Latka, Marek Bajda, Young-Sik Jung, Barbara Malawska, Kamil Musilek
The three-dimensional ligand structures were built with the Corina online tool (Molecular Networks GmbH, Erlangen, Germany & Altamira). Oximes were prepared in the anionic form. Before docking, atom types and protonation states of ligand structures were checked and Gasteiger-Marsili charges were assigned using Sybyl-X 1.1 (Tripos, St. Louis, MO). All proteins used in the docking studies were prepared with ProteinPrepare web service (pH 7.4, without water molecules, including heteroatoms in pKa calculation)21. Docking studies were divided into three parts. In the first part, the inhibition of AChE and BChE by oximes was performed on mouse apo enzymes, i.e. AChE (PDB code: 1J06) and human BChE (PDB code: 1P0I) with the Gold Suite 5.3 (The Cambridge Crystallographic Data Centre, Cambridge, UK). The binding site was defined with all amino acid residues within 15 Å from the serine of the catalytic triad. A standard set of genetic algorithm parameters with a population size of 100 and a number of operations of 100,000 was applied. As a result, 10 ligand conformations were obtained and sorted according to the values of scoring function – GoldScore.