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Oxime Research
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
The chain linking two quaternary nitrogens in bispyridinium oximes exerts a great effect on the reactivating efficacy, although this part of the oxime does not play any role in the dephosphylation process. It is a major factor in influencing oxime access to the active site of AChE and its reactivation rates. The length of the linker between both pyridinium rings (for bisquaternary pyridinium reactivators) plays an important role in its potency to reactivate nerve agent–inhibited AChE (Kuca et al., 2003c; Pang et al., 2003). There is relationship between the length of the n-methylene linkage chain and the type of nerve agent used for inhibition. The optimal length of the reactivator’s linker for satisfactory potency to reactivate tabun, sarin, or VX-inhibited AChE is three or four methylenes. On the other hand, one methylene group seems to be the most potent for the reactivation of cyclosarin-inhibited AChE. Unfortunately, this rule is satisfied only in the case of n-methylene linkage chains and oxime groups in position four at the pyridinium ring. Compounds with oxygen, sulfur, or other structural fragments differing from the methylene that are incorporated into the linker and compounds with different positions of oxime groups do not fulfill this rule (Acharya et al., 2009b; Musilek et al., 2005, 2006b; Oh et al., 2006; Pang et al., 2003). These differences could be caused by the presence of the free electrons in the linker and subsequent interactions of this part of the reactivator’s molecule with the inside of the enzyme cavity. An important structural factor influencing the reactivation process could also be the “rigidity” of the linking chain. Due to the rigidity of the linker, the spatial orientation of the pyridinium rings in the enzyme cavity is limited. Compounds with a certain level of rigidity of the linker were synthesized with the aim of elucidating the influence of rigidity on reactivation potency. Z- and E-but-2-ene and ortho-, meta-, and para-xylene moieties were inserted into the linkage chain (Musilek et al., 2005, 2006b, 2007b).
Influence of experimental end point on the therapeutic efficacy of the antinicotinic compounds MB408, MB442 and MB444 in treating nerve agent poisoned mice – a comparison with oxime-based treatment
Published in Toxicology Mechanisms and Methods, 2020
Jiri Kassa, Christopher M. Timperley, Mike Bird, A. Christopher Green, John E. H. Tattersall
The therapeutic efficacies of the antidotes studied on the experimental end point in the case of cyclosarin poisoning are summarized in Table 4. Cyclosarin-poisoned mice showed a wide spectrum of clinical signs of poisoning including salivation, lachrymation, nose secretion and tonic-clonic convulsions within a few minutes. The distribution of times to death differed slightly between treatment groups. While all deaths occurred within the first 6 h in the experimental group with antidotal treatment involving atropine alone, or atropine in combination with the oxime HI-6 or MB444, the other treatments (atropine in combination with MB408 or MB442) prevented some deaths before more than 6 h.
Gadolinium-based contrast agents: in vitro paraoxonase 1 inhibition, in silico studies
Published in Drug and Chemical Toxicology, 2021
Şükrü Beydemir, Cüneyt Türkeş, Ahmet Yalçın
Living things have been intertwined with chemicals throughout their lives. These chemicals can be many different drugs and other compounds as well as water, air, and foods having vital importance. On the other hand, many toxic compounds are also encountered that living things are exposed. Among the most toxic chemicals in the world, organophosphorus compounds (OPs) are in the first order (Heath 1992). Although OPs were initially developed to be used as insecticides, they have been unfortunately used as chemical warfare agents due to their strong toxicity (Ballantyne and Marrs 2017). The most known of these are tabun, sarin, soman, and cyclosarin as well as insecticides, paraoxon, parathion, and tetraethyl pyrophosphate (Nurulain 2011). Due to effects on the nervous system of the OP chemicals, particularly irreversible inhibition of the acetylcholinesterase has been taken into account by scientists, very seriously (Silva Filho et al.2004, Saint-André et al.2011). Paraoxonase 1 (PON1), a serum enzyme, is a critical OP hydrolyzer in metabolism (Demir and Beydemir 2015, Işık et al.2015). The high-density lipoprotein (HDL) associated enzyme hydrolyzes several OPs used as insecticides particularly paraoxon, as well as nerve agents (e.g., sarin, soman, and tabun) (Costa et al.2005, Beydemir and Demir 2017, Caglayan et al.2019). PON1 containing 354 amino acids is a calcium-dependent antioxidant enzyme. It plays a role in the pathogenesis of various inflammatory diseases including diabetes, and atherosclerosis. It also protects HDL and LDL against oxidative stress (Demir and Köksal 2019, Taslimi et al.2019). Also, PON1 Q192R and M55L polymorphisms have been directly linked with the development of cancer between lung adenocarcinoma and squamous cell carcinoma tissues (Aldonza et al.2017).
Novichok: a murderous nerve agent attack in the UK
Published in Clinical Toxicology, 2018
J. Allister Vale, Timothy C. Marrs, Robert L. Maynard
Nerve agents are a group of highly toxic organophosphorus compounds developed, first, in Germany in the late 1930s and 1940s and, after World War II, in many other countries [6]. They are related to organophosphorus pesticides though they have a very much higher human acute toxicity than commonly used pesticides. The best investigated nerve agents include tabun (GA), sarin (GB), soman (GD) and VX but others, for example, GE, GF (cyclosarin), VE, VG, VM and VR, are also known [7].