Comparison of the ability of pyridinium aldoximes to reactivate human red blood cell acetylcholinesterases inhibited by ethyl- and methyl-paraoxon

Georg A. Petroianu, Dietrich E. Lorke, H. Kalász

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Oximes are acetylcholinesterase reactivators of use in poisoning with organophosphorus inhibitors of cholinesterase (OPIChE: (organophosphates and organophosphonates). They are clinically used as an adjunct to atropine in such exposure. Clinical experience with oximes is, however, disappointing. This paper reviews available data concerning the ability of established and new oximes to reactivate cholinesterases inhibited by two differently substituted prototypical organophosphates: ethyl- and methyl-paraoxon. The intrinsic toxicity of oximes is quantified in vitro by measuring the concentration required to inhibit red blood cell (RBC) cholinesterase activity by 50% (IC 50). Reactivation ability is assessed in vitro via the IC 50 shift graph. The slope of the shift graph (tan α) is used to quantify the magnitude of the protective effect (nM IC 50 increase per μM reactivator). The ranking of reactivating potencies of the examined oximes determined with methyl-paraoxon as an inhibitor is essentially the same as the ranking obtained using ethyl-paraoxon as an inhibitor. In the in vitro model used, the presence of ethyl versus methyl substituents does not seem to significantly alter the ability of the examined oximes to reactivate the esterase. In vitro derived results were subsequently validated in vivo in rats using ethyl-paraoxon and methyl-paraoxon as cholinesterase inhibitors and various oximes as reactivators. Mortality data were compared and hazard ratios calculated using Cox proportional hazards model. Overall, the ability of in vitro testing (tan α determinations) to predict in vivo protection by oximes is limited.

Original languageEnglish
Pages (from-to)1359-1369
Number of pages11
JournalCurrent Organic Chemistry
Volume16
Issue number10
DOIs
Publication statusPublished - May 2012

Fingerprint

Oximes
Acetylcholinesterase
Blood
Cells
Organophosphates
Cholinesterase Inhibitors
Cholinesterases
Hazards
Organophosphonates
methylparaoxon
Esterases
Atropine
Toxicity
Rats
Testing

Keywords

  • Cholinesterase
  • DFP
  • Ethyl-paraoxon
  • Methyl-paraoxon
  • Organophosphate
  • Oxime
  • Treatment

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Comparison of the ability of pyridinium aldoximes to reactivate human red blood cell acetylcholinesterases inhibited by ethyl- and methyl-paraoxon. / Petroianu, Georg A.; Lorke, Dietrich E.; Kalász, H.

In: Current Organic Chemistry, Vol. 16, No. 10, 05.2012, p. 1359-1369.

Research output: Contribution to journalArticle

@article{7db30801c05f4c7f8b0278936e76b38b,
title = "Comparison of the ability of pyridinium aldoximes to reactivate human red blood cell acetylcholinesterases inhibited by ethyl- and methyl-paraoxon",
abstract = "Oximes are acetylcholinesterase reactivators of use in poisoning with organophosphorus inhibitors of cholinesterase (OPIChE: (organophosphates and organophosphonates). They are clinically used as an adjunct to atropine in such exposure. Clinical experience with oximes is, however, disappointing. This paper reviews available data concerning the ability of established and new oximes to reactivate cholinesterases inhibited by two differently substituted prototypical organophosphates: ethyl- and methyl-paraoxon. The intrinsic toxicity of oximes is quantified in vitro by measuring the concentration required to inhibit red blood cell (RBC) cholinesterase activity by 50{\%} (IC 50). Reactivation ability is assessed in vitro via the IC 50 shift graph. The slope of the shift graph (tan α) is used to quantify the magnitude of the protective effect (nM IC 50 increase per μM reactivator). The ranking of reactivating potencies of the examined oximes determined with methyl-paraoxon as an inhibitor is essentially the same as the ranking obtained using ethyl-paraoxon as an inhibitor. In the in vitro model used, the presence of ethyl versus methyl substituents does not seem to significantly alter the ability of the examined oximes to reactivate the esterase. In vitro derived results were subsequently validated in vivo in rats using ethyl-paraoxon and methyl-paraoxon as cholinesterase inhibitors and various oximes as reactivators. Mortality data were compared and hazard ratios calculated using Cox proportional hazards model. Overall, the ability of in vitro testing (tan α determinations) to predict in vivo protection by oximes is limited.",
keywords = "Cholinesterase, DFP, Ethyl-paraoxon, Methyl-paraoxon, Organophosphate, Oxime, Treatment",
author = "Petroianu, {Georg A.} and Lorke, {Dietrich E.} and H. Kal{\'a}sz",
year = "2012",
month = "5",
doi = "10.2174/138527212800564277",
language = "English",
volume = "16",
pages = "1359--1369",
journal = "Current Organic Chemistry",
issn = "1385-2728",
publisher = "Bentham Science Publishers B.V.",
number = "10",

}

TY - JOUR

T1 - Comparison of the ability of pyridinium aldoximes to reactivate human red blood cell acetylcholinesterases inhibited by ethyl- and methyl-paraoxon

AU - Petroianu, Georg A.

AU - Lorke, Dietrich E.

AU - Kalász, H.

PY - 2012/5

Y1 - 2012/5

N2 - Oximes are acetylcholinesterase reactivators of use in poisoning with organophosphorus inhibitors of cholinesterase (OPIChE: (organophosphates and organophosphonates). They are clinically used as an adjunct to atropine in such exposure. Clinical experience with oximes is, however, disappointing. This paper reviews available data concerning the ability of established and new oximes to reactivate cholinesterases inhibited by two differently substituted prototypical organophosphates: ethyl- and methyl-paraoxon. The intrinsic toxicity of oximes is quantified in vitro by measuring the concentration required to inhibit red blood cell (RBC) cholinesterase activity by 50% (IC 50). Reactivation ability is assessed in vitro via the IC 50 shift graph. The slope of the shift graph (tan α) is used to quantify the magnitude of the protective effect (nM IC 50 increase per μM reactivator). The ranking of reactivating potencies of the examined oximes determined with methyl-paraoxon as an inhibitor is essentially the same as the ranking obtained using ethyl-paraoxon as an inhibitor. In the in vitro model used, the presence of ethyl versus methyl substituents does not seem to significantly alter the ability of the examined oximes to reactivate the esterase. In vitro derived results were subsequently validated in vivo in rats using ethyl-paraoxon and methyl-paraoxon as cholinesterase inhibitors and various oximes as reactivators. Mortality data were compared and hazard ratios calculated using Cox proportional hazards model. Overall, the ability of in vitro testing (tan α determinations) to predict in vivo protection by oximes is limited.

AB - Oximes are acetylcholinesterase reactivators of use in poisoning with organophosphorus inhibitors of cholinesterase (OPIChE: (organophosphates and organophosphonates). They are clinically used as an adjunct to atropine in such exposure. Clinical experience with oximes is, however, disappointing. This paper reviews available data concerning the ability of established and new oximes to reactivate cholinesterases inhibited by two differently substituted prototypical organophosphates: ethyl- and methyl-paraoxon. The intrinsic toxicity of oximes is quantified in vitro by measuring the concentration required to inhibit red blood cell (RBC) cholinesterase activity by 50% (IC 50). Reactivation ability is assessed in vitro via the IC 50 shift graph. The slope of the shift graph (tan α) is used to quantify the magnitude of the protective effect (nM IC 50 increase per μM reactivator). The ranking of reactivating potencies of the examined oximes determined with methyl-paraoxon as an inhibitor is essentially the same as the ranking obtained using ethyl-paraoxon as an inhibitor. In the in vitro model used, the presence of ethyl versus methyl substituents does not seem to significantly alter the ability of the examined oximes to reactivate the esterase. In vitro derived results were subsequently validated in vivo in rats using ethyl-paraoxon and methyl-paraoxon as cholinesterase inhibitors and various oximes as reactivators. Mortality data were compared and hazard ratios calculated using Cox proportional hazards model. Overall, the ability of in vitro testing (tan α determinations) to predict in vivo protection by oximes is limited.

KW - Cholinesterase

KW - DFP

KW - Ethyl-paraoxon

KW - Methyl-paraoxon

KW - Organophosphate

KW - Oxime

KW - Treatment

UR - http://www.scopus.com/inward/record.url?scp=84861113563&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861113563&partnerID=8YFLogxK

U2 - 10.2174/138527212800564277

DO - 10.2174/138527212800564277

M3 - Article

AN - SCOPUS:84861113563

VL - 16

SP - 1359

EP - 1369

JO - Current Organic Chemistry

JF - Current Organic Chemistry

SN - 1385-2728

IS - 10

ER -