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Special Issue "Chemistry of Antidotes"

A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: 31 August 2020.

Special Issue Editors

Prof. Dr. Pascal Houzé
Website
Guest Editor
Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie, 75006 Paris, France
Interests: toxicology; pharmacology; organosphosphates; animal experimentation; antidotes; clinical studies
Prof. Dr. Frédéric J. Baud
Website
Guest Editor
Hôpital Necker Enfants Malades, Paris, France
Interests: analytical toxicology; pharmacology; organosphosphates; animal experimentation; antidotes; clinical studies

Special Issue Information

Dear Colleagues,

An antidote can be defined as a substance intended to neutralize the effects of a poison, a toxin or even a virus. To counteract the effects of a toxin or virus, vaccines are perfect examples of antidotes. In the field of toxicology, most intoxications require symptomatic management and, exceptionally, antidote treatment. In a toxicological context, certain antidotes may affect the kinetics of the toxin (toxicokinetic action), for example by modifying its absorption, distribution or elimination. On the other hand, other antidotes have a toxicodynamic action, displacing the toxin from its target (the action of flunitrazepam in benzodiazepine poisonings). Many antidotes have proved their therapeutic efficacy, such as 4-methylpyrazole for toxic alcohol poisoning, atropine for organophosphorus poisonings or metal chelators. Others have not proven with certainty their effectiveness (chloroquine and digitalis intoxication) or have a counter-action (pralidoxime and organophosphates compounds).

This Special Issue seems to me to be an opportunity to provide an update on antidotes by addressing different axes, such as the synthesis of new antidotes, new therapeutic applications, experimentation with animal and in vitro studies, etc. Finally, an analytical approach to methods of measuring antidotes in different biological matrices could complete this issue and address a topic rarely reported in the literature.

Prof. Dr. Pascal Houzé
Prof. Dr. Frédéric J. Baud
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Antidotes
  • Analytical méthodes
  • Experimental studies
  • In vitro evaluation
  • New compounds synthesis
  • Toxicology
  • Antivernoms

Published Papers (4 papers)

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Research

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Open AccessArticle
Combined Pre- and Posttreatment of Paraoxon Exposure
Molecules 2020, 25(7), 1521; https://doi.org/10.3390/molecules25071521 - 27 Mar 2020
Abstract
Aims: Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. [...] Read more.
Aims: Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome. Methods: Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure. Results: Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens. Conclusions: Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter. Full article
(This article belongs to the Special Issue Chemistry of Antidotes)
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Open AccessArticle
Pharmacokinetics of Two Chlorine-Substituted Bis-Pyridinium Mono-Aldoximes with Regenerating Effect on Butyrylcholinesterase
Molecules 2020, 25(5), 1250; https://doi.org/10.3390/molecules25051250 - 10 Mar 2020
Abstract
Our aim was to find chlorine-substituted antidotes against organophosphate poisoning and compare their pharmacokinetics to their parent compound, K-203. White male Wistar rats were intramuscularly injected with K-203, K-867 or K-870. Serum, brain, kidneys, liver, lung, eyes, and testes tissues were taken after [...] Read more.
Our aim was to find chlorine-substituted antidotes against organophosphate poisoning and compare their pharmacokinetics to their parent compound, K-203. White male Wistar rats were intramuscularly injected with K-203, K-867 or K-870. Serum, brain, kidneys, liver, lung, eyes, and testes tissues were taken after 5, 15, 30, 60, and 120 min and analyzed using reversed-phase high-performance liquid chromatography. K-203, K-867, or K-870 was present in every tissue that was analyzed, including the serum, the eyes, testes, liver, kidneys, lungs, and the brain. The serum levels of K-867 and K-870 (chlorine-substituted derivatives of K-203) were nearly constant between 15 and 30 min, while their parent compound (K-203) showed peak level at 15 min after the administration of 30 µmol/rat. Neither K-203, nor K-867 or K-870 were toxic at a dose of 100 µmol/200 g in rats. Chlorine-substitution of K-867 and K-870 produced limited absorbance and distribution compared to their parent compound, K203. Full article
(This article belongs to the Special Issue Chemistry of Antidotes)
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Open AccessArticle
Biodegradation of Organophosphorus Compounds Predicted by Enzymatic Process Using Molecular Modelling and Observed in Soil Samples Through Analytical Techniques and Microbiological Analysis: A Comparison
Molecules 2020, 25(1), 58; https://doi.org/10.3390/molecules25010058 - 23 Dec 2019
Cited by 1
Abstract
Organophosphorus compounds (OP) are chemicals widely used as pesticides in different applications such as agriculture and public health (vector control), and some of the highly toxic forms have been used as chemical weapons. After application of OPs in an environment, they persist for [...] Read more.
Organophosphorus compounds (OP) are chemicals widely used as pesticides in different applications such as agriculture and public health (vector control), and some of the highly toxic forms have been used as chemical weapons. After application of OPs in an environment, they persist for a period, suffering a degradation process where the biotic factors are considered the most relevant forms. However, to date, the biodegradation of OP compounds is not well understood. There are a plenty of structure-based biodegradation estimation methods, but none of them consider enzymatic interaction in predicting and better comprehending the differences in the fate of OPs in the environment. It is well known that enzymatic processes are the most relevant processes in biodegradation, and that hydrolysis is the main pathway in the natural elimination of OPs in soil samples. Due to this, we carried out theoretical studies in order to investigate the interactions of these OPs with a chosen enzyme—the phosphotriesterase. This one is characteristic of some soils’ microorganisms, and has been identified as a key player in many biodegradation processes, thanks to its capability for fast hydrolyzing of different OPs. In parallel, we conducted an experiment using native soil in two conditions, sterilized and not sterilized, spiked with specific amounts of two OPs with similar structure—paraoxon-ethyl (PXN) and O-(4-nitrophenyl) O-ethyl methylphosphonate (NEMP). The amount of OP present in the samples and the appearance of characteristic hydrolysis products were periodically monitored for 40 days using analytical techniques. Moreover, the number of microorganisms present was obtained with plate cell count. Our theoretical results were similar to what was achieved in experimental analysis. Parameters calculated by enzymatic hydrolysis were better for PXN than for NEMP. In soil, PXN suffered a faster hydrolysis than NEMP, and the cell count for PXN was higher than for NEMP, highlighting the higher microbiological toxicity of the latter. All these results pointed out that theoretical study can offer a better comprehension of the possible mechanisms involved in real biodegradation processes, showing potential in exploring how biodegradation of OPs relates with enzymatic interactions. Full article
(This article belongs to the Special Issue Chemistry of Antidotes)
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Review

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Open AccessReview
An Appraisal of Antidotes’ Effectiveness: Evidence of the Use of Phyto-Antidotes and Biotechnological Advancements
Molecules 2020, 25(7), 1516; https://doi.org/10.3390/molecules25071516 - 26 Mar 2020
Abstract
Poisoning is the greatest source of avoidable death in the world and can result from industrial exhausts, incessant bush burning, drug overdose, accidental toxication or snake envenomation. Since the advent of Albert Calmette’s cobra venom antidote, efforts have been geared towards antidotes development [...] Read more.
Poisoning is the greatest source of avoidable death in the world and can result from industrial exhausts, incessant bush burning, drug overdose, accidental toxication or snake envenomation. Since the advent of Albert Calmette’s cobra venom antidote, efforts have been geared towards antidotes development for various poisons to date. While there are resources and facilities to tackle poisoning in urban areas, rural areas and developing countries are challenged with poisoning management due to either the absence of or inadequate facilities and this has paved the way for phyto-antidotes, some of which have been scientifically validated. This review presents the scope of antidotes’ effectiveness in different experimental models and biotechnological advancements in antidote research for future applications. While pockets of evidence of the effectiveness of antidotes exist in vitro and in vivo with ample biotechnological developments, the utilization of analytic assays on existing and newly developed antidotes that have surpassed the proof of concept stage, as well as the inclusion of antidote’s short and long-term risk assessment report, will help in providing the required scientific evidence(s) prior to regulatory authorities’ approval. Full article
(This article belongs to the Special Issue Chemistry of Antidotes)
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