Some Possibilities to Study New Prophylactics against Nerve Agents

2019 ◽  
Vol 19 (12) ◽  
pp. 970-979 ◽  
Author(s):  
J. Bajgar ◽  
J. Kassa ◽  
T. Kucera ◽  
K. Musilek ◽  
D. Jun ◽  
...  
Keyword(s):  
Cholinesterase Inhibitors ◽  
Chemical Warfare Agents ◽  
Nerve Agents ◽  
Chemical Warfare ◽  
Huperzine A ◽  
Acetylcholinesterase Inhibition ◽  
Effective Prophylaxis ◽  
Warfare Agents

Nerve agents belong to the most dangerous chemical warfare agents and can be/were misused by terrorists. Effective prophylaxis and treatment is necessary to diminish their effect. General principles of prophylaxis are summarized (protection against acetylcholinesterase inhibition, detoxification, treatment “in advance” and use of different drugs). They are based on the knowledge of mechanism of action of nerve agents. Among different examinations, it is necessary to test prophylactic effectivity in vivo and compare the results with protection in vitro. Chemical and biological approaches to the development of new prophylactics would be applied simultaneously during this research. Though the number of possible prophylactics is relatively high, the only four drugs were introduced into military medical practice. At present, pyridostigmine seems to be common prophylactic antidote; prophylactics panpal (tablets with pyridostigmine, trihexyphenidyl and benactyzine), transant (transdermal patch containing HI-6) are other means introduced into different armies as prophylactics. Scavenger commercionally available is Protexia®. Future development will be focused on scavengers, and on other drugs either reversible cholinesterase inhibitors (e.g., huperzine A, gallantamine, physostigmine, acridine derivatives) or other compounds.

scholarly journals In Vitro Interaction of Organophosphono- and Organophosphorothioates with Human Acetylcholinesterase

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3029
Author(s):  
Franz Worek ◽  
Horst Thiermann ◽  
Marianne Koller ◽  
Timo Wille
Keyword(s):  
Human Plasma ◽  
Biological Effects ◽  
Chemical Warfare Agents ◽  
Nerve Agents ◽  
Ache Inhibitors ◽  
Potential Structure ◽  
Warfare Agents ◽  
Op Nerve Agents

The implementation of the Chemical Weapons Convention (CWC) in 1997 was a milestone in the prohibition of chemical warfare agents (CWA). Yet, the repeated use of CWA underlines the ongoing threat to the population. Organophosphorus (OP) nerve agents still represent the most toxic CWA subgroup. Defensive research on nerve agents is mainly focused on the “classical five”, namely tabun, sarin, soman, cyclosarin and VX, although Schedule 1 of the CWC covers an unforeseeable number of homologues. Likewise, an uncounted number of OP pesticides have been produced in previous decades. Our aim was to determine the in vitro inhibition kinetics of selected organophosphono- and organophosphorothioates with human AChE, as well as hydrolysis of the agents in human plasma and reactivation of inhibited AChE, in order to derive potential structure–activity relationships. The investigation of the interactions of selected OP compounds belonging to schedule 1 (V-agents) and schedule 2 (amiton) of the CWC with human AChE revealed distinct structural effects of the P-alkyl, P-O-alkyl and N,N-dialkyl residues on the inhibitory potency of the agents. Irrespective of structural modifications, all tested V-agents presented as highly potent AChE inhibitors. The high stability of the tested agents in human plasma will most likely result in long-lasting poisoning in vivo, having relevant consequences for the treatment regimen. In conclusion, the results of this study emphasize the need to investigate the biological effects of nerve agent analogues in order to assess the efficacy of available medical countermeasures.

scholarly journals Detection Papers with Chromogenic Chemosensors for Direct Visual Detection and Distinction of Liquid Chemical Warfare Agents

Chemosensors ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 30 ◽  
Author(s):  
Vladimír Pitschmann ◽  
Lukáš Matějovský ◽  
Kamila Lunerová ◽  
Michal Dymák ◽  
Martin Urban ◽  
...  
Keyword(s):  
Chemical Warfare Agents ◽  
Nerve Agents ◽  
Chemical Warfare ◽  
Bromocresol Green ◽  
Ph Indicator ◽  
Nitrogen Mustards ◽  
Experimental Development ◽  
Influence Of Water ◽  
Warfare Agents ◽  
Hydrophobic Treatment

This work provides a summary of our results in the area of the experimental development of detection paper for the detection of liquid phase chemical warfare agents (drops, aerosol), the presence of which is demonstrated by the development of characteristic coloring visible to the naked eye. The basis of the detection paper is a cellulose carrier saturated with the dithienobenzotropone monomer (RM1a)–chromogenic chemosensor sensitive to nerve agents of the G type, blister agent lewisite, or choking agent diphosgene. We achieve a higher coloring brilliance and the limit certain interferences by using this chemosensor in the mix of the o-phenylendiamine-pyronine (PY-OPD). We prove that the addition of the Bromocresol Green pH indicator even enables detection of nerve agents of the V type, or, nitrogen mustards, while keeping a high stability of the detection paper and its functions for other chemical warfare agents. We resolve the resistance against the undesirable influence of water by providing a hydrophobic treatment of the carrier surface.

The in vitro efficacy of haemostatic products in the presence of chemical warfare agents—Sulphur mustard (HD) and VX

Toxicology ◽  
2009 ◽  
Vol 262 (1) ◽  
pp. 9-10 ◽  
Author(s):  
Charlotte A. Hall ◽  
Helen L. Lydon ◽  
Christopher H. Dalton ◽  
J. Kevin Chipman ◽  
Robert P. Chilcott ◽  
...  
Keyword(s):  
Chemical Warfare Agents ◽  
Chemical Warfare ◽  
Sulphur Mustard ◽  
Warfare Agents

scholarly journals Electrochemical acetylcholinesterase biosensor for detection of cholinesterase inhibitors: study with eserine

2019 ◽  
pp. 235-240
Keyword(s):  
Gold Electrode ◽  
Cholinesterase Inhibitors ◽  
Electrochemical Biosensor ◽  
Immobilized Enzyme ◽  
Chemical Warfare Agents ◽  
Chemical Warfare ◽  
Initial Reduction ◽  
Warfare Agents ◽  
Ellman’S Method ◽  
Acetylthiocholine Chloride

Cholinesterase inhibitors are widely used as pesticides, as chemical warfare agents and as drugs to treat symptoms of Alzheimer’s disease. Therefore, it is a high need to develop methods for their detection which are fast, sensitive, and reliable. This paper reports a preliminary work in the development of an electrochemical biosensor based on acetylcholinesterase (AChE) which is constructed by immobilization layers – cysteamine/glutaraldehyde/AChE on thin layer gold electrode for detection of cholinesterase inhibitors. Eserine (physostigmine) was used as a test inhibitor. The enzyme immobilization efficacy was evaluated by measuring activity of immobilized enzyme via Ellman’s method. The enzyme activity of the initial reduction of 33% in five days remained after that stable for at least one week. Chronoamperometric response to substrate acetylthiocholine chloride (ATCl) was assumed to follow Michaelis-Menten kinetics. After exposure biosensor to 25 mM eserine for 10 min, 70% inhibition of enzyme was detected. Reactivation factor of inhibited AChE was determined as 0.016 min-1.

Future Considerations for the Medical Management of Nerve-Agent Intoxication

2003 ◽  
Vol 18 (3) ◽  
pp. 208-216 ◽  
Author(s):  
Pål Aas
Keyword(s):  
Chemical Warfare Agents ◽  
Nerve Agents ◽  
Nerve Agent ◽  
Chemical Warfare ◽  
Weapons Of Mass Destruction ◽  
Terrorist Attacks ◽  
International Conflicts ◽  
Mass Destruction ◽  
The World ◽  
Warfare Agents

AbstractThe use of chemical warfare agents against civilians and unprotected troops in international conflicts or by terrorists against civilians is considered to be a real threat, particularly following the terrorist attacks on 11 September 2001 against the World Trade Center in New York and against the Pentagon in Washington, DC. Over the past 10 years, terrorists have been planning to use or have used chemical warfare agents on several occasions around the world, and the attacks in 2001 illustrate their willingness to use any means of warfare to cause death and destruction among civilians. In spite of new international treaties with strong verification measures and with an aim to prohibit and prevent the use of weapons of mass destruction, nevertheless, some countries and terrorist groups have been able to develop, produce, and use such weapons, particularly nerve agents, in domestic terrorist attacks or during warfare in international conflicts. This article reviews current medical therapy for nerve-agent intoxication and discusses possible future improvement of medical therapies.Present medical counter-measures against nerve agents are not sufficiently effective particularly in protecting the brain. Therefore, new and more effective countermeasures must be developed to enable better medical treatment of civilians and military personnel following exposure to nerve agents. Therefore, it is important with an enhanced effort by all countries, to improve and increase research in medical countermeasures, in the development of protective equipment, and in carrying out regular training of medical and emergency personnel as well as of military nuclear, biological, or chemical (NBC) units. Only then will nations be able to reduce the risk from and prevent the use of such weapons of mass destruction (WMD).

Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice

2020 ◽  
Vol 12 (527) ◽  
pp. eaay0356 ◽  
Author(s):  
Venkaiah Betapudi ◽  
Reena Goswami ◽  
Liliya Silayeva ◽  
Deborah M. Doctor ◽  
Nageswararao Chilukuri
Keyword(s):  
Gene Therapy ◽  
Hematological Parameters ◽  
Clinical Signs ◽  
Nerve Agents ◽  
Medical Intervention ◽  
Chemical Warfare ◽  
Paraoxonase 1 ◽  
Behavioral Abnormalities

Chemical warfare nerve agents are organophosphorus chemical compounds that induce cholinergic crisis, leaving little or no time for medical intervention to prevent death. The current chemical treatment regimen may prevent death but does not prevent postexposure complications such as brain damage and permanent behavioral abnormalities. In the present study, we have demonstrated an adeno-associated virus 8 (AAV8)–mediated paraoxonase 1 variant IF-11 (PON1-IF11) gene therapy that offers asymptomatic prophylactic protection to mice against multiple lethal doses of G-type chemical warfare nerve agents, namely, tabun, sarin, cyclosarin, and soman, for up to 5 months in mice. A single injection of liver-specific adeno-associated viral particles loaded with PON1-IF11 gene resulted in expression and secretion of recombinant PON1-IF11 in milligram quantities, which has the catalytic power to break down G-type chemical warfare nerve agents into biologically inactive products in vitro and in vivo in rodents. Mice containing milligram concentrations of recombinant PON1-IF11 in their blood displayed no clinical signs of toxicity, as judged by their hematological parameters and serum chemistry profiles. Our study unfolds avenues to develop a one-time application of gene therapy to express a near-natural and circulating therapeutic PON1-IF11 protein that can potentially protect humans against G-type chemical warfare nerve agents for several weeks to months.

scholarly journals Mineralization of Paraoxon and Its Use as a Sole C and P Source by a Rationally Designed Catabolic Pathway in Pseudomonas putida

2006 ◽  
Vol 72 (10) ◽  
pp. 6699-6706 ◽  
Author(s):  
Matthew de la Peña Mattozzi ◽  
Sundiep K. Tehara ◽  
Thomas Hong ◽  
Jay D. Keasling
Keyword(s):  
Pseudomonas Putida ◽  
Cholinesterase Inhibitors ◽  
Chemical Warfare Agents ◽  
Chemical Warfare ◽  
Catabolic Pathway ◽  
Warfare Agents ◽  
Phosphorus Source ◽  
High Concentrations ◽  
Synthetic Operon ◽  
Heterologous Pathway

ABSTRACT Organophosphate compounds, which are widely used as pesticides and chemical warfare agents, are cholinesterase inhibitors. These synthetic compounds are resistant to natural degradation and threaten the environment. We constructed a strain of Pseudomonas putida that can efficiently degrade a model organophosphate, paraoxon, and use it as a carbon, energy, and phosphorus source. This strain was engineered with the pnp operon from Pseudomonas sp. strain ENV2030, which encodes enzymes that transform p-nitrophenol into β-ketoadipate, and with a synthetic operon encoding an organophosphate hydrolase (encoded by opd) from Flavobacterium sp. strain ATCC 27551, a phosphodiesterase (encoded by pde) from Delftia acidovorans, and an alkaline phosphatase (encoded by phoA) from Pseudomonas aeruginosa HN854 under control of a constitutive promoter. The engineered strain can efficiently mineralize up to 1 mM (275 mg/liter) paraoxon within 48 h, using paraoxon as the sole carbon and phosphorus source and an inoculum optical density at 600 nm of 0.03. Because the organism can utilize paraoxon as a sole carbon, energy, and phosphorus source and because one of the intermediates in the pathway (p-nitrophenol) is toxic at high concentrations, there is no need for selection pressure to maintain the heterologous pathway.

scholarly journals Acute Toxicity and Efficacy of Nanomaterial based Decontamination Formulation Developed for Personal Decontamination against Chemical Warfare Agents

2019 ◽  
Vol 9 (1) ◽  
pp. 40-54
Author(s):  
Anshoo Gautam ◽  
Gangavarapu K. Prasad ◽  
Deeksha Singh ◽  
Rajagopalan Vijayaraghavan
Keyword(s):  
Acute Toxicity ◽  
Skin Irritation ◽  
Chemical Warfare Agents ◽  
Chemical Warfare ◽  
The Body ◽  
Respiratory Pattern ◽  
Histological Evaluation ◽  
Warfare Agents ◽  
Body Weight Index

Background: This study addresses the efficacy of nanomaterials based formulation developed for personal decontamination application against chemical warfare agents and used in Personal Decontamination Kit (PDK). It has the potential to decontaminate the skin of an individual, protective equipment, and small arms contaminated with chemical warfare agents. As this formulation has been developed for personal decontamination, risk of nanomaterial toxicity would always be there while sprinkling or applying to the affected area. It may get into the body through various routes specifically through the inhalation route. Aim: The aim of this study was to evaluate in vivo decontamination efficiency of the formulation and acute inhalation, intratracheal, intranasal, oral, dermal, and intraperitoneal toxicity of the formulation. Materials and Methods: 14 days survival was recorded for the evaluation of decontamination efficiency of this formulation. Various endpoints were considered while assessing the toxicity of Nanomaterial Decontamination Formulation which include Organ Body Weight Index (OBWI), serum biochemical parameters, and respiratory variables like tidal volume, respiratory rate, time of inspiration, time of expiration, etc. LD50 of the formulation were also determined for various routes. As skin is the primary organ to come in contact with the decontaminant, its primary skin irritation response has also been determined in this study. Results and Conclusion: It was found that there is no gross acute toxicity observed at different doses. Though there were some changes in the initial respiratory pattern, they were all later recovered. The preliminary histological evaluation did not show any adverse effect on various organs after exposure with NDF.

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