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Chemistry of Antidotes
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Chemistry of Antidotes

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

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 18715

Special Issue Editors

Prof. Dr. Pascal Houzé

E-Mail Website
Guest Editor
Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France
Interests: analytical toxicology; clinical toxicology; metabolomics; proteomic
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Frédéric J. Baud

E-Mail 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

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Keywords

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

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Published Papers (5 papers)

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Research

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15 pages, 3591 KiB  
Article
Safety and Efficacy of New Oximes to Reverse Low Dose Diethyl-Paraoxon-Induced Ventilatory Effects in Rats
by Maya Kayouka, Pascal Houzé, Marc Lejay, Frédéric J. Baud and Kamil Kuca
Molecules 2020, 25(13), 3056; https://doi.org/10.3390/molecules25133056 - 3 Jul 2020
Cited by 2 | Viewed by 2163
Abstract
Background: Oximes are used in addition to atropine to treat organophosphate poisoning. However, the efficiency of oximes is still a matter of debate. In vitro experiments suggested than new oximes are more potent than the commercial oximes. However, the antidotal activity of new [...] Read more.
Background: Oximes are used in addition to atropine to treat organophosphate poisoning. However, the efficiency of oximes is still a matter of debate. In vitro experiments suggested than new oximes are more potent than the commercial oximes. However, the antidotal activity of new oximes has not been assessed in vivo. Methods: The aim of this work was to assess the safety and efficiency of new oximes compared to pralidoxime in a rat model of diethyl paraoxon-induced non-lethal respiratory toxicity. Results: Safety study of oximes showed no adverse effects on ventilation in rats. KO-33, KO-48, KO-74 oximes did not exhibit significant antidotal effect in vivo. In contrast, KO-27 and BI-6 showed evidence of antidotal activity by normalization of respiratory frequency and respiratory times. KO-27 became inefficient only during the last 30 min of the study. In contrast, pralidoxime demonstrated to be inefficient at 30 min post injection. Inversely, the antidotal activity of BI-6 occurred lately, within the last 90 min post injection. Conclusion: This study showed respiratory safety of new oximes. Regarding, the efficiency, KO-27 revealed to be a rapid acting antidote toward diethylparaoxon-induced respiratory toxicity, meanwhile BI-6 was a late-acting antidote. Simultaneous administration of these two oximes might result in a complete and prolonged antidotal efficiency. Full article
(This article belongs to the Special Issue Chemistry of Antidotes)
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13 pages, 921 KiB  
Article
Combined Pre- and Posttreatment of Paraoxon Exposure
by Dietrich E Lorke, Syed M Nurulain, Mohamed Y Hasan, Kamil Kuča and Georg A Petroianu
Molecules 2020, 25(7), 1521; https://doi.org/10.3390/molecules25071521 - 27 Mar 2020
Cited by 12 | Viewed by 2772
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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9 pages, 2519 KiB  
Article
Pharmacokinetics of Two Chlorine-Substituted Bis-Pyridinium Mono-Aldoximes with Regenerating Effect on Butyrylcholinesterase
by Huba Kalász, Zoltán Szimrók, Gellért Karvaly, Jennifer Adeghate and Kornélia Tekes
Molecules 2020, 25(5), 1250; https://doi.org/10.3390/molecules25051250 - 10 Mar 2020
Cited by 2 | Viewed by 2530
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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21 pages, 5098 KiB  
Article
Biodegradation of Organophosphorus Compounds Predicted by Enzymatic Process Using Molecular Modelling and Observed in Soil Samples Through Analytical Techniques and Microbiological Analysis: A Comparison
by Monique Cardozo, Joyce S. F. D. de Almeida, Samir F. de A. Cavalcante, Jacqueline R. S. Salgado, Arlan S. Gonçalves, Tanos C. C. França, Kamil Kuca and Humberto R. Bizzo
Molecules 2020, 25(1), 58; https://doi.org/10.3390/molecules25010058 - 23 Dec 2019
Cited by 13 | Viewed by 3193
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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27 pages, 1011 KiB  
Review
An Appraisal of Antidotes’ Effectiveness: Evidence of the Use of Phyto-Antidotes and Biotechnological Advancements
by Christiana Eleojo Aruwa, Yusuf Ola Mukaila, Abdulwakeel Ayokun-nun Ajao and Saheed Sabiu
Molecules 2020, 25(7), 1516; https://doi.org/10.3390/molecules25071516 - 26 Mar 2020
Cited by 6 | Viewed by 7318
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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