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

Herkenhoff, S.; Szinicz, L.; Rastogi, Vipin K.; Cheng, Tu-Chen; DeFrank, Joseph; Worek, Franz

doi:10.1007/s00204-004-0547-2

Cited by 19 publications

(18 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This holds true for previously published data obtained with sarin, soman, and tabun (Becker et al 1997). For practical administrations it might be useful to accelerate the third step of the direct reaction, i.e., the degradation of the POXs, by addition of bacterial (Ashani et al 1998;Leader et al 1999;HerkenhoV et al 2004) or human plasma enzymes Worek et al 2000).…”

Section: Resultssupporting

confidence: 70%

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

et al. 2006

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 70%

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

et al. 2006

Self Cite

View full text Add to dashboard Cite

show abstract

“…4). This might be due to the effect of a formation of stable phosphyl oximes with the 4,4′-oxime obidoxime whose inhibitory activity toward AChE is of impact here in a cuvette-based system and delays pseudocatalytic scavenging with obidoxime compared to the 2-oxime HI-6 (Herkenhoff et al 2004). Although AChE binding sites of erythrocytes were adjusted to that of HEGAChE, the decrease in inhibitory activity was faster with erythrocytes and might be due to unspecific side reactions with the intact membrane of erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

Pseudocatalytic scavenging of the nerve agent VX with human blood components and the oximes obidoxime and HI-6

et al. 2016

View full text Add to dashboard Cite

Despite six decades of extensive research in medical countermeasures against nerve agent poisoning, a broad spectrum acetylcholinesterase (AChE) reactivator is not yet available. One current approach is directed toward synthesizing oximes with high affinity and reactivatability toward butyrylcholinesterase (BChE) in plasma to generate an effective pseudocatalytic scavenger. An interim solution could be the administration of external AChE or BChE from blood products to augment pseudocatalytic scavenging with slower but clinically approved oximes to decrease nerve agent concentrations in the body. We here semiquantitatively investigate the ability of obidoxime and HI-6 to decrease the inhibitory activity of VX with human AChE and BChE from whole blood, erythrocyte membranes, erythrocytes, plasma, clinically available fresh frozen plasma and packed red blood cells. The main findings are that whole blood showed a VX concentration-dependent decrease in inhibitory activity with HI-6 being more potent than obidoxime. Using erythrocytes and erythrocyte membranes again, HI-6 was more potent compared to obidoxime. With freshly prepared plasma, obidoxime and HI-6 showed comparable results for the decrease in VX. The use of the clinically available blood products revealed that packed red blood cells showed similar kinetics as fresh erythrocytes. Fresh frozen plasma resulted in a slower and incomplete decrease in inhibitory plasma compared to freshly prepared plasma. In conclusion, the administration of blood products in combination with available oximes augments pseudocatalytic scavenging and might be useful to decrease the body load of persistent, highly toxic nerve agents.

show abstract

“…In general, concentration 10 -4 -10 -5 M can be considered as suitable for AChE reactivation in vitro but at lower concentrations, small but significant reactivation was observed, too [39][40][41][42][43]. It is known from other results that the inhibition and reactivation of AChE in the brain is selective for different OP [1,44,45]. The presence of oximes in the brain was demonstrated by Sakurada [47] using microdialysis detection of pralidoxime.…”

Section: Selective Effect Of the Reactivatorsmentioning

confidence: 95%

“…The brain is wellorganized and complex organ containing different levels of neuromediators and relevant enzymes in various structures of the brain. It is known that the AChE activity varied minimally 14 times between striatum and cerebellum [44]. In toxicodynamic studies, AChE activity in the whole brain homogenate was described [52,53].…”

Section: Selective Effect Of the Reactivatorsmentioning

confidence: 99%

Cholinesterase Reactivators: The Fate and Effects in the Organism Poisoned with Organophosphates/Nerve Agents

Bajgar

Kuča

Jun³

et al. 2007

CDM

View full text Add to dashboard Cite

Understanding the mechanism of action of organophosphates (OP)/nerve agents -irreversible acetylcholinesterase (AChE, EC 3.1.1.7) inhibition at the cholinergic synapses followed by metabolic dysbalance of the organism -two therapeutic principles for antidotal treatment are derived. The main drugs are anticholinergics that antagonize the effects of accumulated acetylcholine at the cholinergic synapses and cholinesterase reactivators (oximes) reactivating inhibited AChE. Anticonvulsants such as diazepam are also used to treat convulsions. Though there are experimental data on a good therapeutic effects of reactivators, some attempts to underestimate the role of reactivators as effective antidotes against OP poisoning have been made. Some arguments on the necessity of their administration following OP poisoning are discussed. Their distribution patterns and some metabolic and pharmacological effects are described with the aim to resolve the question on their effective use, possible repeated administration in the treatment of OP poisonig, their peripheral and central effects including questions on their penetration through the blood brain barrier as well as a possibility to achieve their effective concentration for AChE reactivation in the brain. Reactivation of cholinesterases in the peripheral and central nervous system is described and it is underlined its importance for the survival or death of the organism poisoned with OP. Metabolization and some other effects of oximes (not connected with AChE reactivation) are discussed (e.g. forming of the phosphonylated oxime, parasympatholytic action, hepatotoxicity, behavioral changes etc.). An universality of oximes able to reactivate AChE inhibited by all OP is questioned and therefore, needs of development of new oximes is underlined.

show abstract

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

Cited by 19 publications

References 37 publications

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

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

Pseudocatalytic scavenging of the nerve agent VX with human blood components and the oximes obidoxime and HI-6

Cholinesterase Reactivators: The Fate and Effects in the Organism Poisoned with Organophosphates/Nerve Agents

Contact Info

Product

Resources

About