The design of MB327, a bispyridinium compound that ameliorates the nicotinic effects of acute organophosphorus nerve agent (NA) intoxication, followed an observation made by the German pharmacologist Klaus Schoene in the 1970s, who noted therapeutic activity in bispyridinium molecules missing the usual oxime group, CHNOH. Some of these compounds protected mice against soman. One structurally related to obidoxime called HY10 had this action. Its oxime moieties were capped by tert-butyl groups: CH=NOtBu. We modified HY10 by changing the bridge between the pyridinium units from a dimethylene ether to a trimethylene group (CH2OCH2 → CH2CH2CH2) and prepared a novel relative of trimedoxime, called LB1, whose synthesis and stereochemistry are described. Unlike obidoxime or trimedoxime, LB1 because of its capped oxime groups, cannot directly reactivate NA inhibited acetylcholinesterase. Its antidotal activity in mice is now reported. The therapeutic efficacy of LB1, atropine alone, atropine with LB1, atropine with an oxime (HI-6, obidoxime or trimedoxime), and atropine with an oxime and LB1, was studied by determining the LD50 values of the NAs soman, sarin, or tabun in mice treated with these compounds or mixtures. LB1 exceeded MB327 in toxicity and its activity was insufficient for a useful addition to the current standard antidotal treatment (protective ratio data are compared to those of MB327). Although this study produced largely negative biological results, the therapeutically beneficial mechanism of the effective bispyridinium non-oxime analogues is unclear, and has been demonstrated only in vivo. The present study points out directions in structural optimisation unlikely to yield the desired therapeutic outcomes and provides a literature review that could promote creative thinking for the design of widely-desirable non-oxime therapeutics for anticholinesterase inhibitors.
- MeSH
- Acetylcholinesterase metabolism MeSH
- Antidotes * chemical synthesis chemistry pharmacology therapeutic use MeSH
- Atropine therapeutic use pharmacology MeSH
- Cholinesterase Inhibitors toxicity MeSH
- Mice MeSH
- Nerve Agents * toxicity MeSH
- Organophosphorus Compounds * toxicity MeSH
- Oximes chemistry MeSH
- Pyridinium Compounds * chemical synthesis chemistry therapeutic use pharmacology MeSH
- Soman toxicity MeSH
- Trimedoxime chemistry chemical synthesis pharmacology therapeutic use MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The castor plant (Ricinus communis) is primarily known for its seeds, which contain a unique fatty acid called ricinoleic acid with several industrial and commercial applications. Castor seeds also contain ricin, a toxin considered a chemical and biological warfare agent. Despite years of investigation, there is still no effective antidote or vaccine available. However, some progress has been made, and the development of an effective treatment may be on the horizon. To provide an updated overview of this issue, we have conducted a comprehensive review of the literature on the current state of research in the fight against ricin. This review is based on the reported research and aims to address the challenges faced by researchers, as well as highlight the most successful cases achieved thus far. Our goal is to encourage the scientific community to continue their efforts in this critical search.
- MeSH
- Antidotes * chemistry pharmacology MeSH
- Chemical Warfare Agents chemistry MeSH
- Humans MeSH
- Ricin * antagonists & inhibitors chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
A benzodiazepine, diazepam, has been the leading antidote for seizures caused by nerve agents, the most toxic chemical weapons of mass destruction, since the 1960s. However, its limitations have often brought questions about its usefulness. Extensive effort has been devoted into exploring alternatives, such as other benzodiazepines, anticholinergics, or glutamate antagonists. However, only few showed clear clinical benefit. The only two options to ultimately reach clinical milestones are Avizafone, a water-soluble prodrug of diazepam adopted by the French and UK armed forces, and intramuscular midazolam, adopted by the US Army. The recently FDA-approved new intramuscular application of midazolam brought several advantages, such as rapid onset of action, short duration with predictable pharmacokinetics, increased water solubility for aqueous injectable solutions, and prolonged storage stability. Herein, we discuss the pitfalls and prospects of using midazolam as a substitute in anticonvulsant therapy with a particular focus on military purposes in combat casualty care. We have also considered and discussed several other alternatives that are currently at the experimental level. Recent studies have shown the superiority of midazolam over other benzodiazepines in the medical management of poisoned casualties. While its use in emergency care is straightforward, the proper dose for soldiers under battlefield conditions is questionable due to its sedative effects.
- MeSH
- Anticonvulsants * administration & dosage therapeutic use MeSH
- Diazepam * administration & dosage MeSH
- Humans MeSH
- Midazolam * administration & dosage MeSH
- Nerve Agents * MeSH
- Seizures * drug therapy chemically induced MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Hledání optimálního nastavení podmínek chemické analýzy je zpravidla zdlouhavý proces. Tento článek k tomuto účelu navrhuje využití neuronových sítí, zejména ve vztahu k určení optimální podmínek pro analýzu zkoumaných látek s využitím technologie LC/MS/MS a ESI ionizací, a to na základě znalosti jejich základních vlastností, označených jako univerzální deskriptory. Práce se soustředí na nalezení takových podmínek analýzy, kdy dochází k maximalizaci signálu iontu prekurzoru. Práce se zabývá zejména otázkou, zda lze výsledky zjištěné na jednom typu analytu použít k neurální interpolační predikci optimálních podmínek analytů podobných.
The search for the optimal instrumental settings of conditions in chemical analysis is typically a lengthy process. This article proposes the use of neural networks for this purpose, particularly in relation to determining the optimal conditions for the analysis of substances under study using LC/MS/MS and ESI technologies, based on the knowledge of their fundamental properties, referred to as universal descriptors. The work focuses on finding such analysis conditions that maximize the precursor ion signal. The paper specifically addresses the question of whether the results obtained from one type of analyte can be used for neural-interpolated prediction of optimal conditions for similar analytes.
- MeSH
- Chemical Warfare Agents chemistry MeSH
- Chemistry Techniques, Analytical methods MeSH
- Chromatography, Liquid methods MeSH
- Spectrometry, Mass, Electrospray Ionization methods MeSH
- Mass Spectrometry methods MeSH
- Humans MeSH
- Neural Networks, Computer MeSH
- Organophosphates * chemistry analysis MeSH
- Check Tag
- Humans MeSH
The search for the optimal instrumental settings of conditions in chemical analysis is typically a lengthy process. This article proposes the use of neural networks for this purpose, particularly in relation to determining the optimal conditions for the analysis of substances under study using LC/MS/MS and ESI technologies, based on the knowledge of their fundamental properties, referred to as universal descriptors. The work focuses on finding such analysis conditions that maximize the precursor ion signal. The paper specifically addresses the question of whether the results obtained from one type of analyte can be used for neural-interpolated prediction of optimal conditions for similar analytes.
- MeSH
- Chemical Warfare Agents analysis chemistry MeSH
- Chemistry Techniques, Analytical methods MeSH
- Chromatography, Liquid methods MeSH
- Spectrometry, Mass, Electrospray Ionization methods MeSH
- Mass Spectrometry methods MeSH
- Humans MeSH
- Neural Networks, Computer MeSH
- Organophosphates * analysis chemistry MeSH
- Check Tag
- Humans MeSH
- MeSH
- History, 19th Century MeSH
- History, 20th Century MeSH
- Injections, Intravenous history MeSH
- Poisons history toxicity MeSH
- Physicians history MeSH
- Humans MeSH
- Capital Punishment * history methods MeSH
- Inventions history MeSH
- Famous Persons MeSH
- Check Tag
- History, 19th Century MeSH
- History, 20th Century MeSH
- Humans MeSH
- Geographicals
- Czech Republic MeSH
- United States MeSH
- MeSH
- Chemical Warfare Agents MeSH
- Humans MeSH
- Military Medicine * trends MeSH
- Research Design * trends MeSH
- Check Tag
- Humans MeSH
The extreme toxicity of nerve agents and the broad spectrum of their physical and chemical properties, enabling the use of these agents in a variety of tactical situations, is a continuing challenge in maintaining the knowledge and capability to detect them, as well as in finding new effective methods. Despite significant advances in the instrumentation of the analysis of nerve agents, relatively simple methods based on the evaluation of colour signals (absorption and fluorescence), in particular those using the cholinesterase reaction, continue to be of importance. This review provides a brief presentation of the current status of these simple methods, with an emphasis on military applications, and illustrates the high interest of the professional community in their further development. At the same time, it also contains some peculiarities (high reliability and durability, resistance to extreme climatic conditions, work in deployed means of protection, low purchase prices, economic availability especially in a state of war, etc.) that the authors believe research and development of simple methods and means for the detection of nerve agents should respect.
- MeSH
- Cholinesterases MeSH
- Nerve Agents * analysis MeSH
- Reproducibility of Results MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
"Novichok" refers to a new group of nerve agents called the A-series agents. Their existence came to light in 2018 after incidents in the UK and again in 2020 in Russia. They are unique organophosphorus-based compounds developed during the Cold War in a program called Foliant in the USSR. This review is based on original chemical entities from Mirzayanov's memoirs published in 2008. Due to classified research, a considerable debate arose about their structures, and hence, various structural moieties were speculated. For this reason, the scientific literature is highly incomplete and, in some cases, contradictory. This review critically assesses the information published to date on this class of compounds. The scope of this work is to summarize all the available and relevant information, including the physicochemical properties, chemical synthesis, mechanism of action, toxicity, pharmacokinetics, and medical countermeasures used to date. The environmental stability of A-series agents, the lack of environmentally safe decontamination, their high toxicity, and the scarcity of information on post-contamination treatment pose a challenge for managing possible incidents.
- MeSH
- Drug Contamination * MeSH
- Nerve Agents * toxicity MeSH
- Organophosphorus Compounds MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Organophosphorus compounds (OPs) involving life-threatening nerve agents (NA) have been known for several decades. Despite a clear mechanism of their lethality caused by the irreversible inhibition of acetylcholinesterase (AChE) and manifested via overstimulation of peripheral nicotinic and muscarinic acetylcholine (ACh) receptors, the mechanism for central neurotoxicity responsible for acute or delayed symptoms of the poisoning has not been thoroughly uncovered. One of the reasons is the lack of a suitable model. In our study, we have chosen the SH-SY5Y model in both the differentiated and undifferentiated state to study the effects of NAs (GB, VX and A234). The activity of expressed AChE in cell lysate assessed by Ellman's method showed 7.3-times higher activity in differentiated SH-SY5Y cells in contrast to undifferentiated cells, and with no involvement of BuChE as proved by ethopropazine (20 μM). The activity of AChE was found to be, in comparison to untreated cells, 16-, 9.3-, and 1.9-times lower upon A234, VX, and GB (100 μM) administration respectively. The cytotoxic effect of given OPs expressed as the IC50 values for differentiated and undifferentiated SH-SY5Y, respectively, was found 12 mM and 5.7 mM (A234), 4.8 mM and 1.1 mM (VX) and 2.6 mM and 3.8 mM (GB). In summary, although our results confirm higher AChE expression in the differentiated SH-SY5Y cell model, the such higher expression does not lead to a more pronounced NA cytotoxic effect. On the contrary, higher expression of AChE may attenuate NA-induced cytotoxicity by scavenging the NA. Such finding highlights a protective role for cholinesterases by scavenging Novichoks (A-agents). Second, we confirmed the mechanism of cytotoxicity of NAs, including A-agents, can be ascribed rather to the non-specific effects of OPs than to AChE-mediated effects.
- MeSH
- Acetylcholinesterase metabolism MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Nerve Agents * MeSH
- Neuroblastoma * MeSH
- Neurotoxicity Syndromes * etiology MeSH
- Antineoplastic Agents * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
