Comparison of Reactivating and Therapeutic Efficacy of Two Salts of the Oxime HI‐6 against Tabun, Soman and Cyclosarin in Rats

Kassa, Jiřı́; Jun, Daniel; Kuča, Kamil; Bajgar, Jiří

doi:10.1111/j.1742-7843.2007.00126.x

Cited by 13 publications

(10 citation statements)

References 24 publications

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“…In atropine (10)-pretreated rats, HI-6 (15) raised the LD 50 of soman (3) 5.7 times and additional intracerebroventricular injections of HI-6 (15) failed to enhance this protection further [101]. This may, however, not come as a surprise, because HI-6 (15) is unable to reactivate soman (3)-inhibited brain acetylcholinesterase [102][103][104]. Sarin (2) induced hypothermia, which is considered to be the result of muscarinic receptor stimulation in the hypothalamus, can be effectively antagonized by HI-6 (15) [108].…”

Section: Brain Entry Of Oximesmentioning

confidence: 70%

“…Pralidoxime (11) was found to be unable to reactivate brain acetylcholinesterase after sarin (2) intoxication [100], whereas HI-6 (15) only reactivated acetylcholinesterase in the central nervous system after inhibition by sarin (2), but not by soman (3) or tabun (1) [4,[101][102][103][104]. On the other hand, one of the newly developed oximes (K-74 (18)) was shown to be an efficacious reactivator of tabun-inhibited acetylcholinesterase in the brain [103].…”

Section: Brain Entry Of Oximesmentioning

confidence: 97%

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Entry of Oximes into the Brain: A Review

Lorke

Kalász

Petroianu

et al. 2008

CMC

175

120

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The passage of hydrophilic drugs, such as oxime acetylcholinesterase reactivators, into the central nervous system is restricted by the blood-brain and the blood-cerebrospinal fluid barriers. The present review summarizes morphological and functional properties of the blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain interface and reviews the existing data on brain entry of oximes. Due to the virtual absence of transcytosis, lack of fenestrations and unique properties of tight junctions in brain endothelial cells, the blood-brain barrier only allows free diffusion of small lipophilic molecules. Various carriers transport hydrophilic compounds and extrude potentially toxic xenobiotics. The blood-cerebrospinal fluid barrier is formed by the choroid plexus epithelium, whose tight junctions are more permeable than those of brain endothelial cells. The major function of plexus epithelium cells is active transport of ions for the production of the cerebrospinal fluid. The cerebrospinal fluid-brain interface is not a biological barrier and allows free diffusion. However, in contrast to passage via the blood-brain barrier or the blood-cerebrospinal fluid barrier, direct penetration from the cerebrospinal fluid into the brain is very slow, since much longer distances have to be covered. A bulk flow of brain interstitial fluid and cerebrospinal fluid speeds up exchange between these two fluid compartments. Oximes, by reactivating acetylcholinesterase, are important adjunct therapeutics in organophosphate poisoning. They are very hydrophilic and therefore cannot diffuse freely into the central nervous system. Changes in brain acetylcholinesterase activity, oxime concentration and some biological effects elicited by oxime administration in the periphery indicate, however, that oximes can gain access to the brain to a certain degree, probably by carrier-mediated transport, reaching in the brain about 4-10% of their respective plasma levels. The clinical relevance of this effect is hotly debated. Possible strategies to improve brain penetration of oximes are discussed.

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Section: Brain Entry Of Oximesmentioning

confidence: 70%

Section: Brain Entry Of Oximesmentioning

confidence: 97%

Entry of Oximes into the Brain: A Review

Lorke

Kalász

Petroianu

et al. 2008

CMC

175

120

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show abstract

“…Thus, bis-pyridinium reactivators can occupy both sites (peripheral aromatic site and catalytic anionic site) and confer the compounds inhibitory ability towards AChE as confirmed in our study. The connecting linker does not play a direct role in the dephosphonylation process; however, it is important in distribution, elimination, and AChE reactivation rates (e.g., in the binding mechanism) [19]. …”

Section: Resultsmentioning

confidence: 99%

“…Tri or tetra-carbon linkers appear to be the most suitable for the reactivation process of soman, tabun, or cyclosarin-inhibited AChE [19] (Figure 2, n = 3,4). These derivatives of trimedoxime (compound 6 ) were prepared by Musilek et al and superior reactivation ability was confirmed for them over trimedoxime [20].…”

Section: Resultsmentioning

confidence: 99%

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

Šepsová

Karasová

Korábečný

et al. 2013

IJMS

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Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

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“…The obtained results in that investigation have been encouraging. 146 Nucleophilic reactivation of phosphylated AChE by an oxime occurs through the mechanism described in Figure 14. Usually, it is considered that the oxime reacts in the deprotonated form (oximate) in nucleophilic reactivation, as represented in Figure 14.…”

Section: Treatment and Antidotes For Nerve Agentsmentioning

confidence: 99%

Organophosphorus compounds as chemical warfare agents: a review

Delfino¹,

Ribeiro²,

Figueroa‐Villar³

2009

J. Braz. Chem. Soc.

233

178

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Os agentes de guerra química constituem uma das maiores ameaças do mundo moderno. Dentre estes, destacam-se os agentes neurotóxicos, em virtude de sua alta letalidade e periculosidade. Eles são compostos organofosforados que atuam pela inibição da enzima acetilcolinesterase, a qual é fundamental no processo de transmissão de impulsos nervosos. Existem várias formas de tratamento para a intoxicação por organofosforados, mas nenhuma delas é eficaz contra todos os agentes conhecidos ou contra todos os seus efeitos. Esta revisão tem como foco o uso de compostos organofosforados como agentes neurotóxicos de guerra química. Após uma breve introdução histórica, será feita uma discussão sobre as principais características estruturais e biológicas da acetilcolinesterase, seguida por uma revisão das propriedades dos compostos organofosforados e da sua aplicação como agentes de guerra química. Por fim, serão discutidas as formas de tratamento contra estes agentes, com ênfase nas oximas usadas para reativar a acetilcolinesterase inibida.Chemical warfare agents constitute one of the greatest threats in the modern world. Among them, the neurotoxic agents are of special interest due to their high lethality and danger. Neurotoxic agents are organophosphorus compounds that act by inhibiting the enzyme acetylcholinesterase, which is fundamental for the control of transmission of nervous impulses. There are several ways of treating intoxication by organophosphorus compounds, but none of them is efficient against all the known neurotoxic agents or against all of their effects. This review focus on the use of organophosphorus compounds as neurotoxic chemical warfare agents. After a brief historical introduction, it will be done a discussion about the structural and biological characteristics of acetylcholinesterase, followed by a review of the properties of organophosphorus compounds and their application as chemical warfare agents. Finally, the ways of treatment against intoxication with these agents will be discussed, with emphasis on the oximes used for reactivating the inhibited acetylcholinesterase.

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Comparison of Reactivating and Therapeutic Efficacy of Two Salts of the Oxime HI‐6 against Tabun, Soman and Cyclosarin in Rats

Cited by 13 publications

References 24 publications

Entry of Oximes into the Brain: A Review

Entry of Oximes into the Brain: A Review

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

Organophosphorus compounds as chemical warfare agents: a review

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