Structural and Biochemical Insights into the Inhibition of Human Acetylcholinesterase by G-Series Nerve Agents and Subsequent Reactivation by HI-6

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.

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HPLC Analysis of HI‐6 Dichloride and Dimethanesulfonate—Antidotes against Nerve Agents and Organophosphorus Pesticides

Analytical Letters ◽

10.1080/00032710701588531 ◽

2007 ◽

Vol 40 (14) ◽

pp. 2783-2787 ◽

Cited By ~ 41

Author(s):

Daniel Jun ◽

Kamil Kuca ◽

Petr Stodulka ◽

Vit Koleckar ◽

Bohuslav Dolezal ◽

...

Keyword(s):

Hplc Analysis ◽

Organophosphorus Pesticides ◽

Nerve Agents ◽

Hi 6

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The role of the oximes HI-6 and HS-6 inside human acetylcholinesterase inhibited with nerve agents: a computational study

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2017.1389307 ◽

2017 ◽

Vol 36 (13) ◽

pp. 3444-3452 ◽

Cited By ~ 4

Author(s):

Teobaldo Cuya ◽

Arlan da Silva Gonçalves ◽

Jorge Alberto Valle da Silva ◽

Teodorico C. Ramalho ◽

Kamil Kuca ◽

...

Keyword(s):

Computational Study ◽

Nerve Agents ◽

Hi 6

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Optimal Choice of Acetylcholinesterase Reactivators for Antidoral Treatment of Nerve Agent Intoxication

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2016.78 ◽

2010 ◽

Vol 53 (4) ◽

pp. 207-211 ◽

Cited By ~ 9

Author(s):

Jiří Bajgar

Keyword(s):

Nerve Agents ◽

Nerve Agent ◽

Optimal Choice ◽

Simple Type ◽

Hi 6 ◽

Acetylcholinesterase Reactivators ◽

Better Than

The studies dealing with mechanism of organophosphates (OP)/nerve agent action, prophylaxis and treatment of intoxications is a very hot topic at present. Though the research is very intensive, unfortunately, up to now, there is not universal or significantly better reactivator sufficiently effective against all nerve agents/OP when compared with presently available oximes (pralidoxime, methoxime, obidoxime, trimedoxime, HI-6). The use of the most effective reactivator (HI-6) using simple type of autoinjector (e.g. ComboPen) is strictly limited because of decomposition of HI-6 in solution. Thanks to better solubility it is clear that another salt of HI-6 (dimethanesulfonate, HI-6 DMS) is more convenient for the use as antidote against nerve agents in the autoinjector than HI-6 chloride (Cl). It was clearly demonstrated that reactivation potency of HI-6 DMS in comparison with HI-6 Cl in vivo was the same and bioavailability of HI-6 DMS is better than that of HI-6 Cl. Three chambered autoinjector allows administration of all three antidotes (atropine, reactivator, diazepam) simultaneously. Moreover, the content of chambers can be changed according to proposed requirements. Possible way to solve the problem of universal reactivator could be the use of two reactivators. Three chambered autoinjector is an ideal device for this purpose.

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Preparation of Oxime HI-6 (Dichloride and Dimethanesulphonate) - Antidote against Nerve Agents

Defence Science Journal ◽

10.14429/dsj.58.1660 ◽

2008 ◽

Vol 58 (3) ◽

pp. 399-404 ◽

Cited By ~ 8

Author(s):

Kamil Kuca ◽

Petr Stodulka ◽

Martina Hrabinova ◽

Petra Hanusova ◽

Daniel Jun ◽

...

Keyword(s):

Nerve Agents ◽

Hi 6

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Neuroprotective Effects of Antidotes in Soman-Poisoned Rats

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2019.155 ◽

1999 ◽

Vol 42 (4) ◽

pp. 127-131 ◽

Cited By ~ 2

Author(s):

Jiří Kassa ◽

Marie Koupilová

Keyword(s):

Motor Activity ◽

Automatic Measurement ◽

Nerve Agents ◽

The Other ◽

Sublethal Dose ◽

Neuroprotective Effects ◽

Hi 6 ◽

Other Hand ◽

Functional Observational Battery

1. The neuroprotective effects of antidotes (atropine, obidoxime/atropine mixture, HI-6/atropine mixture) on rats poisoned with soman at a sublethal dose (48 μg/kg i.m.; 60% of LD50 value) were studied. The neurotoxicity was monitored using a functional observational battery (FOB) and an automatic measurement of motor activity. The neurotoxicity of soman was monitored at 24h and 7d following soman poisoning. 2. The results indicate that atropine alone and the oxime HI-6 in combination with atropine seem to be effective antidotal treatment for the elimination of soman-induced neurotoxicity in the case of sublethal poisonings. 3. On the other hand, the combination of obidoxime with atropine appears to be practically ineffective in diminishing neurotoxic soman-induced symptoms. 4. Dealing with neuroprotective effects of antidotes, the oxime HI-6 in combination with atropine seems to be more suitable antidotal mixture than obidoxime in combination with atropine even in the case of sublethal poisoning with nerve agents.

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Evaluation of Potency of Known Oximes (Pralidoxime, Trimedoxime, HI-6, Methoxime, Obidoxime) to in vitro Reactivate Acetylcholinesterase Inhibited by Pesticides (Chlorpyrifos and Methylchlorpyrifos and Nerve Agent (Russian VX)

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2017.83 ◽

2007 ◽

Vol 50 (3) ◽

pp. 203-206 ◽

Cited By ~ 1

Author(s):

Kamil Musílek ◽

Kamil Kuča ◽

Daniel Jun

Keyword(s):

Organophosphorus Pesticides ◽

Nerve Agents ◽

Nerve Agent ◽

Hi 6 ◽

Acetylcholinesterase Reactivators

Nerve agents and pesticides belong to the group of organophosphates. They are able to inhibit irreversibly the enzyme acetylcholinesterase (AChE). Acetylcholinesterase reactivators were designed for the treatment of nerve agent intoxications. Their potency to reactivate pesticide-inhibited AChE was many times evaluated. In this study, five commonly used AChE reactivators (pralidoxime, methoxime, HI-6, obidoxime, trimedoxime) for the reactivation of AChE inhibited by two pesticides (chlorpyrifos and methylchlorpyrifos) were used. Russian VX (nerve agent) as a member of nerve agents’ family was taken for comparison. Obtained results show that oximes developed against nerve agent intoxication are less effective for intoxication with organophosphorus pesticides. Especially, methylchlorpyrifos-inhibited AChE was found to be poorly reactivated by the compounds used.

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A Comparison of the Potency of the Oxime HLö-7 and Currently Used Oximes (HI-6, Pralidoxime, Obidoxime) to Reactivate Nerve Agent-Inhibited Rat Brain Acetylcholinesterase by in vitro Methods

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2018.36 ◽

2005 ◽

Vol 48 (2) ◽

pp. 81-86 ◽

Cited By ~ 14

Author(s):

Kamil Kuča ◽

Jiří Cabal ◽

Jiří Kassa ◽

Daniel Jun ◽

Martina Hrabinová

Keyword(s):

Rat Brain ◽

Nerve Agents ◽

Nerve Agent ◽

The Other ◽

In Vitro Evaluation ◽

In Vitro Methods ◽

Hi 6 ◽

Hlö 7 ◽

Brain Acetylcholinesterase

1. The efficacy of the oxime HLö-7 and currently used oximes (pralidoxime, obidoxime, HI-6) to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun, cyclosarin, VX) was tested by in vitro methods. 2. Both H oximes (HLö-7, HI-6) were found to be more efficacious reactivators of sarin and VX-inhibited acetylcholinesterase than pralidoxime and obidoxime. On the other hand, their potency to reactivate tabun-inhibited acetylcholinesterase is very low and does not reach the reactivating efficacy of obidoxime. In the case of cyclosarin, the oxime HI-6 was only found to be able to sufficiently reactivate cyclosarin-inhibited acetylcholinesterase in vitro. 3. Thus, the oxime HLö-7 does not seem to be more efficacious reactivator of nerve agent-inhibited acetylcholinesterase than HI-6 according to in vitro evaluation of their reactivation potency and, therefore, it is not more suitable to be introduced for antidotal treatment of nerve agent-exposed people than HI-6.

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Efficacies of Atropine/2-PAM and Atropine/HI-6 in Treating Monkeys Intoxicated with Organophosphonate Nerve Agents

International Journal of Toxicology ◽

10.1080/109158197227314 ◽

1997 ◽

Vol 16 (1) ◽

pp. 9-20 ◽

Cited By ~ 8

Author(s):

C. T. Olson ◽

R. G. Menton ◽

R. C. Riser ◽

M. C. Matthews ◽

R. R. Stotts ◽

...

Keyword(s):

Experimental Design ◽

Treatment Regimen ◽

Rhesus Monkeys ◽

Lethal Dose ◽

Nerve Agents ◽

Free Base ◽

Treatment Results ◽

Median Lethal Dose ◽

Hi 6 ◽

Male Rhesus

The efficacies of atropine (ATR)/ 2-PAM and ATRl HI-6 in treating male rhesus monkeys injected with the neurotoxic organophosphonate (OP) agents GA, GB, GD, GF, or VX were compared. Experiments were conducted using no more than 8 monkeys per OP and treatment regimen. Doses were selected using a modified up-and-down experimental design, challenging one monkey per day per OP and treatment. Results were used to approximate the median lethal dose (MLD) for groups of treated monkeys or monkeys given only a vehicle following challenge with an OP. Mortality and signs of intoxication with each treatment were statistically compared. Doses of 2-PAM (25.7 mgl kg) or HI-6 (50 mgl kg) and atropine (0.4 mg free base! kg) were given in a single intramuscular (IM) injection 1 min following challenge with an OP. Strong and well-defined relationships between agent dose and 10-h lethality were observed in untreated animals. The 10-h IM OP MLDs for untreated monkeys were estimated to be 80, 43, 8.0, 22, and 7.4 μg/kg for GA, GB, GD, GF, and VX, respectively. No statistical differences w ere found between AT Rl 2-PAM and AT Rl HI-6 treatment efficacies in preventing lethality for any of the OPs. Both oxime combinations appear to provide protection against a 2 × 10-h MLD of GA, GF, or VX; only

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