�ber die Permeation von14C-Obidoxim durch die sog. Blut-Hirnschranke von M�usen und Ratten

A, Falb; Erdmann, W. D.

doi:10.1007/bf00577819

Cited by 32 publications

(4 citation statements)

References 12 publications

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“…The presence of oximes in the brain was demonstrated by Sakurada [47] using microdialysis detection of pralidoxime. Similar observation was described by Falb and Erdmann for radiolabelled obidoxime [48] or Cassel using HPLC for demonstration of HI-6 presence in the brain [49].…”

Section: Selective Effect Of the Reactivatorssupporting

confidence: 81%

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

Bajgar

Kuča

Jun³

et al. 2007

CDM

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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.

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Section: Selective Effect Of the Reactivatorssupporting

confidence: 81%

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

Bajgar

Kuča

Jun³

et al. 2007

CDM

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“…Using 14 C labeled obidoxime (12), however, Falb and Erdmann [120] observed higher plasma levels in rats than in mice, with central nervous system concentrations amounting to 3-5% of plasma levels in both species. They observed that central nervous system penetration of obidoxime (12) depended on the choice of anesthetic, but were unable to detect an influence of organophosphate (paraoxon, (6)) administration upon brain entry of obidoxime (12).…”

Section: Brain Entry Of Oximesmentioning

confidence: 95%

Entry of Oximes into the Brain: A Review

Lorke

Kalász

Petroianu

et al. 2008

CMC

175

120

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The passage of hydrophilic drugs, such as oxime acetylcholinesterase reactivators, into the central nervous system is restricted by the blood-brain and the blood-cerebrospinal fluid barriers. The present review summarizes morphological and functional properties of the blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain interface and reviews the existing data on brain entry of oximes. Due to the virtual absence of transcytosis, lack of fenestrations and unique properties of tight junctions in brain endothelial cells, the blood-brain barrier only allows free diffusion of small lipophilic molecules. Various carriers transport hydrophilic compounds and extrude potentially toxic xenobiotics. The blood-cerebrospinal fluid barrier is formed by the choroid plexus epithelium, whose tight junctions are more permeable than those of brain endothelial cells. The major function of plexus epithelium cells is active transport of ions for the production of the cerebrospinal fluid. The cerebrospinal fluid-brain interface is not a biological barrier and allows free diffusion. However, in contrast to passage via the blood-brain barrier or the blood-cerebrospinal fluid barrier, direct penetration from the cerebrospinal fluid into the brain is very slow, since much longer distances have to be covered. A bulk flow of brain interstitial fluid and cerebrospinal fluid speeds up exchange between these two fluid compartments. Oximes, by reactivating acetylcholinesterase, are important adjunct therapeutics in organophosphate poisoning. They are very hydrophilic and therefore cannot diffuse freely into the central nervous system. Changes in brain acetylcholinesterase activity, oxime concentration and some biological effects elicited by oxime administration in the periphery indicate, however, that oximes can gain access to the brain to a certain degree, probably by carrier-mediated transport, reaching in the brain about 4-10% of their respective plasma levels. The clinical relevance of this effect is hotly debated. Possible strategies to improve brain penetration of oximes are discussed.

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“…(2). for radiolabelled obidoxime [48] or Cassel using HPLC for demonstration of HI-6 presence in the brain [49]. Pralidoxime, trimedoxime, obidoxime, methoxime, and HI-6 are available for clinical purposes (in some cases limited for military use only), other compounds are under research and/or development.…”

Section: Is It Really Fact?mentioning

confidence: 99%

Treatment of Organophosphate Intoxication Using Cholinesterase Reactivators:Facts and Fiction

Bajgar¹,

Fusek²,

Kuča³

et al. 2007

MRMC

137

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Basic part of the current standard treatment of organophosphate (OP) agent poisoning is administration of cholinesterase reactivators. It includes different types of oximes with a similar basic structure differing by the number of pyridinium rings and by the position of the oxime group in the pyridinium ring. Oximes hydrolytically cleave the organophosphates from acetylcholinesterase (AChE), restoring enzymatic function. This reactivation of AChE is dependent on the type of the agent and, on the reactivator used. From the common oximes, mono- and bisquaternary pyridinium oximes are more or less frequently used in clinical practice such as pralidoxime, obidoxime, trimedoxime, and HI-6. Though there are data on a good therapeutic effects of reactivators, some attempts to undermine 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 with the aim to resolve the question on their effective use, possible repeated administration in the treatment of OP poisoning, 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. An universality of oximes able to reactivate AChE inhibited by all OP is questioned and trends (molecular modelling using neural network, structure-activity relationship, combination of reactivation and anticholinergic properties in one molecule) for future research are characterized.

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�ber die Permeation von14C-Obidoxim durch die sog. Blut-Hirnschranke von M�usen und Ratten

Cited by 32 publications

References 12 publications

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

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

Entry of Oximes into the Brain: A Review

Treatment of Organophosphate Intoxication Using Cholinesterase Reactivators:Facts and Fiction

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