Kapon J

References (5)

Title : Efficacy of antidotal treatment against sarin poisoning: the superiority of benactyzine and caramiphen - Raveh_2008_Toxicol.Appl.Pharmacol_227_155
Author(s) : Raveh L , Rabinovitz I , Gilat E , Egoz I , Kapon J , Stavitsky Z , Weissman BA , Brandeis R
Ref : Toxicol Appl Pharmacol , 227 :155 , 2008
Abstract : Sarin, a potent cholinesterase inhibitor, induces an array of toxic effects including convulsions and behavioral impairments. We report here on the protection provided by post-exposure antidotal treatments against a lethal dose of sarin (1.2xLD50) by scopolamine, benactyzine, trihexyphenidyl or caramiphen, administered 5, 10 or 20 min after the initiation of convulsions. A mixture of the oxime TMB4 and atropine (TA) was injected 1 min following poisoning a paradigm that may represent a scenario reminiscent of a terror incident. Surviving TA-treated rats exhibited marked tonic-clonic convulsions, weight loss, poor clinical status and abnormal cognitive performance as assessed by the Morris water maze. Additionally, a dramatic increase in the density of peripheral benzodiazepine receptors (PBRs), a faithful marker for neuronal damage, was noted. Animals treated 5 min after the development of toxic signs with benactyzine, trihexyphenidyl or caramiphen demonstrated control levels of PBR values, whereas scopolamine produced binding densities significantly above basal levels. Examined at the 10-min time point, scopolamine and trihexyphenidyl afforded no protection against brain damage and did not differ from TA-injected rats. All four drugs failed to significantly prevent the alterations when applied 20 min after onset of convulsions. Assessment of learning processes yielded similar results, where caramiphen exibited some protection at the 20-min time point. Our results show that caramiphen and benactyzine, agents with combined anticholinergic and antiglutamatergic pharmacological profiles, offer considerable shielding against sarin, even when their administration is delayed.
ESTHER : Raveh_2008_Toxicol.Appl.Pharmacol_227_155
PubMedSearch : Raveh_2008_Toxicol.Appl.Pharmacol_227_155
PubMedID: 18320638

Title : Viral neuroinvasion as a marker for BBB integrity following exposure to cholinesterase inhibitors - Grauer_2001_Life.Sci_68_985
Author(s) : Grauer E , Ben Nathan D , Lustig S , Kobiler D , Kapon J , Danenberg HD
Ref : Life Sciences , 68 :985 , 2001
Abstract : Exposure to the nerve agent soman, an irreversible cholinesterase (ChE) inhibitor, results in changes in blood-brain barrier permeability attributed to its seizure-induced activity. However, smaller BBB changes may be independent of convulsions. Such minor injury may escape detection. A nonneuroinvasive neurovirulent Sindbis virus strain (SVN) was used as a marker for BBB permeability. Peripheral inoculation of mice with 2 x 10(3) plaque forming units (PFU) caused up to 10(5) PFU/ml viremia after 24 hours with no signs of central nervous system (CNS) infection and with no virus detected in brain tissue. Intra-cerebral injection of as low as 1-5 PFU of the same virus caused CNS infection, exhibited 5-7 days later as hind limb paralysis and death. Soman (0.1-0.7 of the LD50) was administered at peak viremia (1 day following peripheral inoculation). Sublethal soman exposure at as low as 0.1 LD50 resulted in CNS infection 6-8 days following inoculation in 30-40% of the mice. High virus titer were recorded in brain tissue of sick mice while no virus was detected in healthy mice subjected to the same treatment. No changes in the level of viremia or changes in viral traits were observed in the infected mice. The reversible anticholinesterases physostigmine (0.2 mg/kg, s.c.) and pyridostigmine (0.4 mg/kg, i.m.) injected at a dose equal to 0.1 LD50, induced similar results. Thus, both central and peripheral anticholinesterases (anti-ChEs) induce changes in BBB permeability sufficient to allow, at least in some of the mice, the invasion of this otherwise noninvasive but highly neurovirulent virus. This BBB change is probably due to the presence of cholinesterases in the capillary wall. SVN brain invasion served here as a highly sensitive and reliable marker for BBB integrity.
ESTHER : Grauer_2001_Life.Sci_68_985
PubMedSearch : Grauer_2001_Life.Sci_68_985
PubMedID: 11212873

Title : Stress does not enable pyridostigmine to inhibit brain cholinesterase after parenteral administration - Grauer_2000_Toxicol.Appl.Pharmacol_164_301
Author(s) : Grauer E , Alkalai D , Kapon J , Cohen G , Raveh L
Ref : Toxicol Appl Pharmacol , 164 :301 , 2000
Abstract : The peripherally acting cholinesterase inhibitor pyridostigmine was widely used during the Gulf War as a pretreatment against possible chemical warfare attack. Following consistent reports on long-term illness among Gulf War veterans, pyridostigmine was examined for its possible long-term effects. These effects were suggested to be induced by the combination of pyridostigmine administration and stress exposure that allowed this quaternary compound to enter the brain through stress induced changes in blood-brain barrier (BBB) permeability. Recently, pyridostigmine administration was demonstrated to inhibit brain cholinesterase following acute stress in mice. However, the effect was not replicated under similar conditions in guinea pigs. Because of the significant implication of these findings, we tested brain cholinesterase (ChE) inhibition following the administration of pyridostigmine, or the tertiary carbamate physostigmine, with or without stress in mice. Different experiments were performed to examine the contribution of gender, age (young and adults), stress (type and intensity), or strain (CD-1 and FVB/n) parameters. No inhibition of brain ChE was detected in any of these experiments. At the same time, physostigmine induced the expected decrease in brain ChE in all the experiments. Thus, we could not replicate the findings that suggest pyridostigmine can affect brain cholinesterase following stress.
ESTHER : Grauer_2000_Toxicol.Appl.Pharmacol_164_301
PubMedSearch : Grauer_2000_Toxicol.Appl.Pharmacol_164_301
PubMedID: 10799340

Title : Differential effects of anticholinergic drugs on paired discrimination performance - Grauer_1996_Pharmacol.Biochem.Behav_53_463
Author(s) : Grauer E , Kapon J
Ref : Pharmacol Biochem Behav , 53 :463 , 1996
Abstract : Working and reference memory processes were simultaneously evaluated during the performance of a paired discrimination (PD) task in which visual and spatial discrimination trials were combined within the same session. Atropine (1 and 5 mg/kg), scopolamine (0.02-0.20 mg/kg), benactyzine (1-4 mg/kg), trihexyphenidyl (1-10 mg/kg), and aprophen (5-20 mg/kg) were all found to increase the number of errors performed by overtrained rats during the spatial but not during the visual trials. Although all the anticholinergic drugs tested induced specific working memory impairment at low doses, they differentially affected other, simultaneously recorded, behavioral parameters. Thus, while atropine affected most of the recorded parameters, aprophen induced only a mild effect. Benactyzine was found to have the most specific effect on working memory, with only minimal side effects, a combination that supports its use as the preferred psychopharmacological model of working memory impairment.
ESTHER : Grauer_1996_Pharmacol.Biochem.Behav_53_463
PubMedSearch : Grauer_1996_Pharmacol.Biochem.Behav_53_463
PubMedID: 8808159

Title : Human Butyrylcholinesterase as Prophylaxis Treatment against Soman -
Author(s) : Grauer E , Raveh L , Kapon J , Grunwald J , Cohen E , Ashani Y
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :400 , 1995