Nerve Agents’ Surrogates: Invaluable Tools for Development of Acetylcholinesterase Reactivators

2019 ◽  
Vol 23 (14) ◽  
pp. 1539-1559 ◽  
Author(s):  
Samir F. de A. Cavalcante ◽  
Alessandro B. C. Simas ◽  
Kamil Kuča
Keyword(s):  
Organophosphorus Compounds ◽  
Nerve Agents ◽  
Toxic Chemicals ◽  
Restricted Class ◽  
Pharmaceutical Substances ◽  
Chemical Weapons Convention ◽  
Organophosphorus Poisoning ◽  
Cholinesterase Reactivators ◽  
Terrorist Acts ◽  
Acetylcholinesterase Reactivators

The use of nerve agents as warfare and in terrorist acts has drawn much attention from the governments and societies. Such toxic organophosphorus compounds are listed in Chemical Weapons Convention as Schedule 1 chemicals. The discussion about the chemical identity of the elusive Novichok agents, more potent compounds than best known G- and V-Agents, which have been implicated in recent rumorous assassination plots, clearly demonstrating the importance of the matter. Furthermore, accidents with pesticides or misuse thereof have been a pressing issue in many countries. In this context, the continued development of novel cholinesterase reactivators, antidotes for organophosphorus poisoning, a rather restricted class of pharmaceutical substances, is warranted. Testing of novel candidates may require use of actual nerve agents. Nonetheless, only a few laboratories comply with the requirements for storing, possession and manipulation of such toxic chemicals. To overcome such limitations, nerve agents’ surrogates may be a useful alternative, as they undergo the same reaction with cholinesterases, yielding similar adducts, allowing assays with novel antidote candidates, among other applications.

scholarly journals Synthesis routes of CeO2 nanoparticles dedicated to organophosphorus degradation: a benchmark

CrystEngComm ◽  
2020 ◽  
Vol 22 (10) ◽  
pp. 1725-1737 ◽  
Author(s):  
Isabelle Trenque ◽  
Greta Camilla Magnano ◽  
Jan Bárta ◽  
Frédéric Chaput ◽  
Marie Alexandrine Bolzinger ◽  
...  
Keyword(s):  
Organophosphorus Compounds ◽  
Nerve Agents ◽  
Ceo2 Nanoparticles ◽  
Military Conflicts ◽  
Synthesis Routes ◽  
Terrorist Acts

Exposure to nerve agents, in military conflicts or terrorist acts, requires efficient decontamination systems. CeO2 nanoparticles appear efficient against organophosphorus compounds, thus we performed a benchmark on the available synthesis routes.

scholarly journals Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning / Usporedno određivanje učinkovitosti bispiridinijevih oksima pri trovanju paraoksonom

2015 ◽  
Vol 66 (2) ◽  
pp. 129-134 ◽  
Author(s):  
Suzana Žunec ◽  
Božica Radić ◽  
Kamil Kuča ◽  
Kamil Musilek ◽  
Ana Lucić Vrdoljak
Keyword(s):  
Therapeutic Efficacy ◽  
Standard Therapy ◽  
Organophosphorus Compounds ◽  
Nerve Agents ◽  
Therapeutic Efficiency ◽  
Hi 6 ◽  
Comparative Determination

Abstract The inability of standard therapy to provide adequate protection against poisoning by organophosphorus compounds (pesticides and nerve agents) motivated us to search for new, more effective oximes. We investigated the pharmacotoxicological properties of six experimental K-oximes (K027, K033, K048, K074, K075, and K203) in vivo. The therapeutic efficacy of K-oximes (at doses of 5 or 25 % of their LD50) combined with atropine was assessed in paraoxon-poisoned mice and compared with conventionally used oximes HI-6 and TMB-4. The bisoxime K074 was the most toxic (LD50=21.4 mg kg-1) to mice, while monoxime K027 was the least toxic (LD50=672.8 mg kg-1). With the exception of K033, all of the tested K-oximes showed better therapeutic efficiency than HI-6 and TMB-4. K027 and K048 stood out by demonstrating low acute toxicities and ensuring protective indices ranging from 60.0 to 100.0 LD50 of paraoxon. Taking into account that these two oximes showed a similar therapeutic efficacy regardless of the applied doses, our results suggest that K027 and K048 could be antidotes for paraoxon intoxication.

scholarly journals LDH LEVEL IN ACUTE ORGANOPHOSPHORUS POISONING AND ITS RELATION WITH SEVERITY AND MORTALITY: A TERTIARY CARE HOSPITAL EXPERIENCE

2021 ◽  
Vol 5 (4) ◽  
Author(s):  
Suresh Kumar Nagar ◽  
Maniram Kumhar ◽  
V. B. Singh ◽  
Mayank Srivastav
Keyword(s):  
Organophosphorus Compounds ◽  
Tertiary Care ◽  
Crop Protection ◽  
Serum Lactate ◽  
Spectrophotometric Analysis ◽  
Serum Lactate Dehydrogenase ◽  
Care Hospital ◽  
Significant Difference ◽  
Organophosphorus Poisoning ◽  
Acute Organophosphorus Poisoning

Background: Organophosphorus compounds have been widely used for a few decades in agriculture for crop protection and pest control. In India Organophosphorus poisoning is the most common. The objective of our study was to measure the  LDH Level in acute organophosphorus poisoning Methods: This study was conducted among minimum 100 patients acute organophosphorus poisoning admitted in Casualty ward, MICU and attending medical ward of JLN hospital, Ajmer during Aug 2018 to July 2020. Serum lactate dehydrogenase estimation by spectrophotometric analysis using Beckman Coalter AU 680 Results: These were significantly higher among deaths on day 1 and 3(810±372.99 and 1027.09±458.26, respectively) in comparison to survivors on day 1 and 3 (538.18±300.42 and 365.19±175.49, respectively). Significant difference was found between mean values of different levels of severity of LDH on day 1 and 3. Conclusion: In conclusion, this study found that Serum LDH can be used as biomarker in diagnosis or stratifying severity of acute OP poisoning, as it is cheap and easily available, especially in developing countries. Serial measurements of serum LDH levels in acute OP poisoning can predict the prognosis. Keywords: LDH, OP poisoning, Severity

scholarly journals Catalytic Degradation of Nerve Agents

Catalysts ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 881
Author(s):  
Agatino Zammataro ◽  
Rossella Santonocito ◽  
Andrea Pappalardo ◽  
Giuseppe Trusso Sfrazzetto
Keyword(s):  
World War Ii ◽  
Acute Toxicity ◽  
Organophosphorus Compounds ◽  
Organophosphorus Pesticides ◽  
Lethal Effect ◽  
Nerve Agents ◽  
Catalytic Degradation ◽  
World War ◽  
Degradation Reactions ◽  
Chemical Hydrolysis

Nerve agents (NAs) are a group of highly toxic organophosphorus compounds developed before World War II. They are related to organophosphorus pesticides, although they have much higher human acute toxicity than commonly used pesticides. After the detection of the presence of NAs, the critical step is the fast decontamination of the environment in order to avoid the lethal effect of these organophosphorus compounds on exposed humans. This review collects the catalytic degradation reactions of NAs, in particular focusing our attention on chemical hydrolysis. These reactions are catalyzed by different catalyst categories (metal-based, polymeric, heterogeneous, enzymatic and MOFs), all of them described in this review.

scholarly journals Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 436 ◽  
Author(s):  
Alexandre A. de Castro ◽  
Letícia C. Assis ◽  
Flávia V. Soares ◽  
Kamil Kuca ◽  
Daniel A. Polisel ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Broad Spectrum ◽  
The Past ◽  
Cholinesterase Reactivators ◽  
Key Enzyme ◽  
Patent Literature ◽  
Cholinergic Syndrome ◽  
Op Nerve Agents ◽  
Acetylcholinesterase Reactivators ◽  
Made In

Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.

scholarly journals Multiomic Analysis of Zebrafish Models of Acute Organophosphorus Poisoning With Different Severity

2019 ◽  
Vol 171 (1) ◽  
pp. 211-220
Author(s):  
Benjamin Piña ◽  
Tamar Ziv ◽  
Melissa Faria ◽  
Shani Ben-Lulu ◽  
Eva Prats ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Organophosphorus Compounds ◽  
Cholinergic Neurons ◽  
Acetylcholinesterase Inhibitors ◽  
Chemical Models ◽  
Organophosphorus Poisoning ◽  
Important Therapeutic Target ◽  
Acute Organophosphorus Poisoning ◽  
Integrative Omics

Abstract Organophosphorus compounds are acetylcholinesterase inhibitors used as pesticides and chemical warfare nerve agents. Acute organophosphorus poisoning (acute OPP) affects 3 million people, with 300 000 deaths annually worldwide. Severe acute OPP effects include overstimulation of cholinergic neurons, seizures, status epilepticus, and finally, brain damage. In a previous study, we developed 3 different chemical models of acute OPP in zebrafish larvae. To elucidate the complex pathophysiological pathways related to acute OPP, we used integrative omics (proteomic, transcriptomics, and metabolomics) on these 3 animal models. Our results show that these stochastic, apparently disparate morphological phenotypes can result from almost linear concentration-response variations in molecular levels. Results from the multiomics analysis strongly suggest that endoplasmic reticulum stress might play a central role in the pathophysiology of severe acute OPP, emphasizing the urgent need of further research on this molecular pathway. Endoplasmic reticulum stress could be an important therapeutic target to be included in the treatment of patients with severe acute OPP.

scholarly journals Effect of organophosphorus compounds on the external respiratory function in rats during intratracheal and intraperitoneal administration

2021 ◽  
Author(s):  
Anastasiya A. Kryazhevskikh ◽  
Aleksey A. Kryazhevskikh ◽  
Svetlana N. Subbotina ◽  
Nataliia A. Sklyarova
Keyword(s):  
Respiratory Failure ◽  
Respiratory Function ◽  
Organophosphorus Compounds ◽  
Intraperitoneal Administration ◽  
Toxic Chemicals ◽  
Organophosphate Poisoning ◽  
Toxic Chemical ◽  
Intratracheal Administration ◽  
Chemical Factors ◽  
Lethal Doses

Due to the increasing influence of chemical factors on the human body, the experiment has been conducted using organophosphorus compounds (OPC) to stimulate poisoning cases in the production facilities. Given that the development of respiratory failure is a specific organophosphate poisoning symptom, a comparative analysis of external respiratory function (ERF) in rats with intratracheal and intraperitoneal administration of diisopropyl fluorophosphates (DFP) has been carried out. During the research, the average lethal doses of the toxic chemicals have been established, the conditions of DFP intoxication have been modeled. Thus, LD16 was 0.284 mg/kg by intratracheal administration, 1.6 mg/kg by intraperitoneal administration. Experimental data have shown that the intratracheal intake of OPC causes the development of respiratory failure in the first minutes after poisoning. The return of the ERF indicators to the background values was noted a day after poisoning. With the intraperitoneal administration of the toxic chemical, the rate of development of ERF disorders was lower, toxic effects persisted for two days. The data obtained can be used to make appropriate recommendations for the prevention of accidents and non-emergency cases in a production facility.

scholarly journals Kajian Toksikologi dan Penanggulangan Senjata Kimia

2020 ◽  
pp. 25-32
Author(s):  
Mariana Raini
Keyword(s):  
Arms Control ◽  
Toxic Chemicals ◽  
Chemical Weapons ◽  
Environmental Damage ◽  
Chemical Weapon ◽  
Military Operations ◽  
Injury Death ◽  
Chemical Weapons Convention ◽  
Control Chemical ◽  
And Control

A chemical weapon is defined as a substance that is intended for use in military and non- military operations to kill, seriously injure or otherwise incapacitate people, or to harm or destroy their habitat or economy. Chemical weapons can be made by toxic chemicals reaction. Chemical weapons misused may lead to terror, injury, death and environmental damage The Chemical Weapons Convention (CWC) is an arms control agreement which outlaws the production, stockpiling and use of chemical weapons. C WC is the Convention on the Prohibition of the Development, Production, Stoclqoiling and Use of Chemical Weapons and on their Destruction. This article describe how to idenlijji chemical weapons, sign and symptom of their toxicity, impact and the chemical weapons convention, in order to handle and control chemical weapons release.

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