Oximes: Reactivators of phosphorylated acetylcholinesterase and antidotes in therapy against tabun poisoning

Kovarik, Zrinka; Čalić, Maja; Šinko, Goran; Bosak, Anita; Berend, Suzana; Vrdoljak, Ana Lucić; Radić, Božica

doi:10.1016/j.cbi.2008.04.011

Cited by 38 publications

(32 citation statements)

References 19 publications

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“…Like other previously tested oximes, K203 showed no signifi cant reactivation of tabun-inhibited BChE (14,16). Even after 20 h, the reactivation maximum was only 30 %.…”

Section: In Vitro K203 Interactions With Cholinesterasesmentioning

confidence: 52%

“…Recently we obtained promising results on in vitro reactivation of human AChE inhibited by tabun and antidotal treatment of tabun-poisoned mice with bispyridinium oximes (13)(14)(15)(16)(17)(18). In this paper we tested the reactivation and antidotal potency of bispyridinium oxime K203, which is an analogue of the most effi cient oxime from our previous studies, K048 (Figure 1) (13,14).…”

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confidence: 99%

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Evaluation of Oxime K203 as Antidote in Tabun Poisoning

Kovarik

Vrdoljak

Berend

et al. 2009

Archives of Industrial Hygiene and Toxicology

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We studied bispyridinium oxime K203 [(E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyimino methylpyridinium)-but-2-ene dibromide] with tabun-inhibited human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and its antidotal effect on tabun-poisoned mice and rats in vivo. We compared it with oximes K048 and TMB-4, which have proven the most effi cient oxime antidotes in tabun poisoning by now. Tabun-inhibited AChE was completely reactivated by K203, with the overall reactivation rate constant of 1806 L mol -1 min -1 . This means that K203 is a very potent reactivator of tabun-inhibited AChE. In addition, K203 reversibly inhibited AChE (K i = 0.090 mmol L ), and exhibited its protective effect against phosphorylation of AChE by tabun in vitro. In vivo, a quarter of the LD 50 K203 dose insured survival of all mice after the application of as many as 8 LD 50 doses of tabun, which is the highest dosage obtained compared to K048 and TMB-4. Moreover, K203 showed high therapeutic potency in tabun-poisoned rats, preserving cholinesterase activity in rat plasma up to 60 min after poisoning. This therapeutic improvement obtained by K203 in tabun-poisoning places this oxime in the spotlight for further development.

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“…Like other previously tested oximes, K203 showed no signifi cant reactivation of tabun-inhibited BChE (14,16). Even after 20 h, the reactivation maximum was only 30 %.…”

Section: In Vitro K203 Interactions With Cholinesterasesmentioning

confidence: 52%

mentioning

confidence: 99%

Evaluation of Oxime K203 as Antidote in Tabun Poisoning

Kovarik

Vrdoljak

Berend

et al. 2009

Archives of Industrial Hygiene and Toxicology

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“…24,31 Oxime functional group is essential for reactivation process. For POX-inhibited AChE, at least one oxime group in position four (30) seemed to be beneficial, when compared to related compounds with the oxime in position two (17,28) or three (18,29), especially for 10 µM. Compounds with oxime group in position 3 were much less effective (26 compared to 25 and 27) that was formerly explained by increased pKa of 3-positioned oxime.…”

Section: Resultsmentioning

confidence: 99%

“…16 Reactivators are monoquaternary or bisquaternary pyridinium salts, which bear an oxime (hydroxy- iminomethyl) group in the molecule. 17,18 Dissociated oximate anion is able to attack to the covalent bond in the AChE-OPC complex and restores the enzyme function. 19 The pralidoxime (1, 2-hydroxyiminomethyl-1-methylpyridinium chloride), HI-6 (2, 1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride) obidoxime (3, 1,3-bis(4-hydroxyiminomethylpyridinium)-2-oxapropane dichloride) are commercially available oxime reactivators 20 ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

In vitro Screening of Oxime Reactivators on the Model of Paraoxon-inhibited Acetylcholinesterase-SAR Study

Holas¹,

Musílek²,

Pohanka³

et al. 2010

Bulletin of the Korean Chemical Society

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Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Standard in vitro test was chosen using a rat brain homogenate as the source of AChE. Screening of reactivation potency was performed with two concentration of reactivator (1000 µM and 10 µM). Results were compared to established reactivators pralidoxime, methoxime, HI-6, trimedoxime and obidoxime. More than 30 novel reactivators performed equal or better reactivation ability of POX-inhibited AChE compared to currently used reactivators. The structure-activity relationship for reactivators of paraoxon-inhibited AChE was developed.

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“…Pretreatment with oximes is possible, because oximes in addition to their reactivation potency also act as protectors of AChE against phosphorylation, by reversible inhibition of the enzyme 11,12 . Based on our promising results from previous studies with K-oximes [13][14][15][16][17] , we decided to test the two most potent AChE reactivators, oximes K074 and K048, in combination with atropine in the pretreatment and therapy of tabun-poisoned mice. This study was conducted to determine whether oxime In vivo experimental approach to treatment against tabun poisoning and atropine in pretreatment would improve the efficacy of a standard therapy regimen.…”

Section: Introductionmentioning

confidence: 99%