Phosphonylierte aldoxime. Hemmwirkung auf acetylcholinesterase und hydrolytischer abbau

Nenner, M

doi:10.1016/0006-2952(74)90329-3

Cited by 25 publications

(11 citation statements)

References 9 publications

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“…The data from previous investigations support the assumption that POX formed during the reactivation of paraoxon-, sarin-, VX-and soman-inhibited human AChE by obidoxime, at human-relevant concentrations (Erdmann et al 1965;Thiermann et al 1999), does impair the net reactivation at physiological AChE concentrations Nenner 1974;Schoene 1973;, whereas no deviation from pseudo first-order reactivation kinetics could be observed with tabun-and cyclosarin-inhibited AChE (Worek et al 1998a(Worek et al , 1998b. The present data indicate that there is also no POX effect with VR-inhibited AChE.…”

Section: Discussionsupporting

confidence: 61%

“…POXs have been found to be extremely potent cholinesterase inhibitors (Ashani et al 2003;de Jong and Ceulen 1978;Harvey et al 1986;Lamb et al 1964;Leader et al 1999;Nenner 1974;Schoene 1973); therefore, a rapid decay of generated POX is crucial for effective reactivation. The stability of POX is strongly dependent on the position of the aldoxime function in the pyridinium oxime.…”

Section: Discussionmentioning

confidence: 99%

“…This may be attributed to rapid dealkylation (''ageing'') of the phosphonylated AChE (Aldridge and Reiner 1972) or to a certain inaccessibility of the oximes to the active site of AChE. In addition, an inspection of the reactivation scheme for the removal by oximes of the phosphyl moiety from the enzyme points to another factor, which can also affect the reactivation process (Eyer 1996;Wilson and Ginsburg 1955) Harvey et al 1986;Lamb et al 1964;Nenner 1974;Schoene 1973), being one or two orders of magnitude more potent than their parent OPs. A closer look at the reactivation scheme reveals that the forward reaction is usually of pseudo first-order form ( (Harvey et al 1984;Scaife 1959; and phosphorylated AChE (Worek et al 1999a).…”

Section: Introductionmentioning

confidence: 97%

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Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Herkenhoff

Szinicz

Rastogi³

et al. 2004

Archives of Toxicology

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The reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) by oximes results inevitably in the formation of highly reactive phosphyloximes (POX), which may re-inhibit the enzyme. An impairment of net reactivation by stable POX was found with 4-pyridinium aldoximes, e.g. obidoxime, and a variety of OP compounds. In this study the effect of organophosphorus hydrolase (OPH), organophosphorus acid anhydrolase (OPAA) and diisopropylfluorophosphatase (DFPase) on obidoxime-induced reactivation of human acetylcholinesterase (AChE) inhibited by different OPs was investigated. Reactivation of paraoxon-, sarin-, soman- and VX-inhibited AChE by obidoxime was impaired by POX-induced re-inhibition whereas no deviation of pseudo first-order kinetics was observed with tabun, cyclosarin and VR. OPH prevented (paraoxon) or markedly reduced the POX-induced re-inhibition (VX, sarin, soman), whereas OPAA and DFPase were without effect. Additional experiments with sarin-inhibited AChE indicate that the POX hydrolysis by OPH was concentration-dependent. The activity of OP-inhibited AChE was not affected by OPH in the absence of obidoxime. In conclusion, OPH may be a valuable contribution to the therapeutic regimen against OP poisoning by accelerating the degradation of both the parent compound, OP, and the reaction product, POX.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Herkenhoff

Szinicz

Rastogi³

et al. 2004

Archives of Toxicology

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“…POXs were identiWed as highly toxic anticholinesterases, even 10-to 100-fold more toxic than their parent compounds (Hackley et al 1959;Lamb et al 1964Lamb et al , 1965Schoene 1973;Nenner 1974;de Jong and Ceulen 1978;Harvey et al 1984Harvey et al , 1986Worek et al 2000). The stability of the POX intermediate seems to be an important factor determining the velocity of the direct reaction.…”

Section: Discussionmentioning

confidence: 99%

“…However, the studies are hardly to compare, since the authors did not only use diVerent methods, OPCs, and oximes, but also diVerent buVers, pH values, temperatures, and reactant concentrations (Hackley et al 1959;Lamb et al 1965;Okonek 1972;Nenner 1974;Harvey et al 1986; Waser et al…”

Section: Introductionmentioning

confidence: 99%

Direct reaction of oximes with crotylsarin, cyclosarin, or VX in vitro

et al. 2006

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The direct reaction of seven pyridinium oximes with the organophosphorus compounds (OPCs) crotylsarin, cyclosarin, and VX was studied by spectrophotometry. This method allows to quantify diVerent parameters: (a) the half-life times (t 1/2 ) of the oxime-OPC reactions on the basis of the changes in the absorption at the zwitterion (betaine) peak maximum, (b) the Wrst-and second-order rate constants (k 1 , k 2 ), and (c) the maximum reaction velocities (v max ). The results of the study show that the reaction velocity of the nerve agents with any of the oximes investigated decreased in the order crotylsarin > cyclosarin > VX. The comparison of the reaction rates of the three therapeutically used oximes (2-PAM, obidoxime, HI 6) with the respective OPC gave the highest rate for crotylsarin and cyclosarin with obidoxime and to a similar degree with HI 6, while in the case of VX the most reactive oxime was HI 6. The reaction velocity of the nerve agents with the monopyridinium oxime 2-PAM was lower as compared to the bispyridinium oximes (obidoxime, HI 6). The results obtained with the two sarin analogues indicate that the direct reaction with 2-PAM, obidoxime, or HI 6 could be used for non-corrosive decontamination purposes, especially, if sensitive biological surfaces like skin, mucous membranes, or wounds are considered. However, in view of the concentrations of nerve agents and oximes, which could be expected during OPC poisoning in man, the maximum reaction velocities would not be high enough to contribute markedly to the detoxication of nerve agents in vivo.

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Insektizide und Nervengase: Vergiftung und Therapie

Stark

1984

Chemie in nserer Zeit

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Es hatte so gejuckt und weil es doch Schadlinge waren, diese Lause, hatte er sich halt den Kopf mit diesem Schadlingsbekampfungsmittel eingerieben. Der Bauer, der das bei seiner Einlieferung in die Klinik erzahlte, hatte kurz nach seiner Radikalkur ganz enge Pupillen bekommen, leichte ziehende Augenschmer-Zen, seine Nase fing an zu laufen und das Atmen wurde schwer. Diagnose: Mittelschwere Organophosphat-Vergiftung. Das ist kein Einzelfall, sondern eines der vielen Beispiele, wie durch Unwissenheit, Unvernunft oder Leichtsinn Unfalle durch die weltweit angewendeten Insektenvertilgungsmittel (Insektizide) vorkommen. Chemie in umerer Zeit 118. Jahrg. 1984 / Nu. 3 0009-28;51/84/0306-0096 $ 02.;50/0 0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984

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Phosphonylierte aldoxime. Hemmwirkung auf acetylcholinesterase und hydrolytischer abbau

Cited by 25 publications

References 9 publications

Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Direct reaction of oximes with crotylsarin, cyclosarin, or VX in vitro

Insektizide und Nervengase: Vergiftung und Therapie

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