ChemInform Abstract: Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Compounds. Imidazole Derivatives.

Galosi, A.; Deljac, A.; Deljac, V.; Binenfeld, Z.; Maksimović, M.

doi:10.1002/chin.198832176

Cited by 8 publications

(5 citation statements)

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“…In contrast to irinotecan, HI-6 is a poor inhibitor of human erythrocyte AChE in vitro. The IC 50 value of HI-6 indicates low affinity of this compound for AChE, although it contains a quaternary pyridinium moiety in the molecule, which is known to have a certain affinity for human erythrocyte AChE (Bevandić et al, 1985;Galoši et al, 1988). The enzymatic activity decreased by up to 50% when the enzyme was exposed to irinotecan at the concentration of 5.0 × 10 -4 mmol/l, or to HI-6 at 4.2 × 10 -1 mmol/L.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of HI-6 oxime: potential use in protection of human acetylcholinesterase inhibited by antineoplastic drug irinotecan and its cyto/genotoxicity in vitro.

Radić

Vrdoljak²,

Želježić³

et al. 2007

Acta Biochim Pol

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The function of acetylcholinesterase (AChE) is the rapid hydrolysis of the neurotransmitter acetylcholine (ACh), which is involved in the numerous cholinergic pathways in both the central and the peripheral nervous system. Therefore, AChE measurement is of high value for therapy management, especially during the course of intoxication with different chemicals or drugs that inhibit the enzyme. Pyridinium or bispyridinium aldoximes (oximes) are able to recover the activity of the inhibited enzyme. Since their adverse effects are not well elucidated, in this study the efficiency of HI-6 oxime in protection and/or reactivation of human erythrocyte AChE inhibited by the antineoplastic drug irinotecan as well as its cyto/genotoxicity in vitro were investigated. HI-6 was effective in protection of AChE and increased its activity up to 30%; the residual activity after irinotecan inhibition was 7%. Also, it reactivated the enzyme previously inhibited by 50% irinotecan (4.6 microg/ml) applied at 1/4 of the IC50 value. The tested concentrations of HI-6 exhibited acceptable genotoxicity towards white blood cells, as estimated by the alkaline comet assay, DNA diffusion assay and cytogenetic endpoints (structural chromosome aberrations and cytokinesis-block micronucleus assay). The results obtained warrant the further investigation of HI-6 in vivo, as well as its development for possible application in chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Evaluation of HI-6 oxime: potential use in protection of human acetylcholinesterase inhibited by antineoplastic drug irinotecan and its cyto/genotoxicity in vitro.

Radić

Vrdoljak²,

Želježić³

et al. 2007

Acta Biochim Pol

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“…All four compounds are reversible inhibitors of human erythrocyte AChE in vitro . The results indicate low affinity of these compounds for AChE; although all of them contain a quarternary pyridinium moiety in the molecule which is known to have a certain affinity for human erythrocyte AChE: IC 50 for HI‐6 is 2.0×10 −3 moll −1 and IC 50 for TMB‐4 is 8.4×10 −3 moll −1 (Bevandić et al 1985; Galoši et al 1988; ). Compounds III and IV showed a similar in vitro toxic effect on human erythrocyte AChE, which corresponds well to the results of their toxicity obtained with bacterium Pseudomonas putida and on McCoy's cells (Lovrić et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Effect of the tested compounds combined with atropine in respect to currently used oximes TMB-4 and HI-6 upon (subcutaneous) soman a toxicity in male mice. TMB-4 is 8.4¿10 ª3 moll ª1 (Bevandić et al 1985;Galoši et al 1988;). Compounds III and IV showed a similar in vitro toxic effect on human erythrocyte AChE, which corresponds well to the results of their toxicity obtained with bacterium Pseudomonas putida and on McCoy's cells (Lovrić et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Antidotal Efficacy of Pyridinium Chloride Derivatives Against Soman Poisoning

Vrdoljak

Lovrić

Radić

et al. 2006

Basic Clin Pharma Tox

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Acetylcholinesterase (AChE; EC 3.1.1.7.) is an extremely active enzyme necessary for terminating the action of acetylcholine in cholinergic synapses. The aim of this study was to evaluate the efficacy of four mono-pyridinium compounds 1-phenacylpyridinium chloride (I), 1-phenacyl-2-methylpyiridinium chloride (II), 1-benzoylethylpyridinium chloride (III), and 1-benzoylethylpyridinium-4-aldoxime chloride (IV) in the therapy of soman poisoning. Their effect was compared with HI-6 and TMB-4 oximes. The inhibitory potency (IC 50 ) of compounds as well as reactivating (%R) and protective potency (P 50 ) with respect to soman-inhibited AChE were determined for each of the compounds. Their acute intraperitoneal toxicity (LD 50 with 95% confidence limits) was tested in mice and observed for 24 hr. The therapeutic effect was expressed as the protective index and as the therapeutic dose. The tested compounds were found to be reversible inhibitors of AChE. In vivo results show that the tested compounds are relatively toxic (their LD 50 was from 74.9 to 210.0 mg/kg body weight). The best antidotal efficacy was obtained with compound II, which had the highest affinity for AChE (IC 50 was 1.9¿10 ª5 mol l ª1 ) and seems to be an adequate antidote in soman poisoning (its protective index and therapeutic dose were 2.8 and 2, respectively). Our results indicate that its antidotal effect is related to the reactivation or protection of AChE. The type of the substituent in the pyridinium ring generally has a significant influence on toxicity in vitro and in vivo, and on the antidotal efficacy of all new tested compounds.

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“…Numerous publications have been devoted to the investigation of imidazole [388][389][390][391][392][393][394][395][396][397][398][399][400] and pyrazole [401] oximes as antidotes for poisoning by organophosphorus compounds.…”

Section: Other Activitiesmentioning

confidence: 99%

Oximes of five-membered heterocyclic compounds with two heteroatoms 2. Reactions and biological activity (Review)

Абеле

Lukevics

2007

Chem Heterocycl Comp

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ChemInform Abstract: Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Compounds. Imidazole Derivatives.

Cited by 8 publications

References 0 publications

Evaluation of HI-6 oxime: potential use in protection of human acetylcholinesterase inhibited by antineoplastic drug irinotecan and its cyto/genotoxicity in vitro.

Evaluation of HI-6 oxime: potential use in protection of human acetylcholinesterase inhibited by antineoplastic drug irinotecan and its cyto/genotoxicity in vitro.

Antidotal Efficacy of Pyridinium Chloride Derivatives Against Soman Poisoning

Oximes of five-membered heterocyclic compounds with two heteroatoms 2. Reactions and biological activity (Review)

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