Side effects of physostigmine as a pretreatment in guinea pigs

Philippens, Ingrid H.C.H.M.; Wolthuis, Otto L.; Busker, Ruud W.; Langenberg, J.P.; Melchers, B.P.C.

doi:10.1016/0091-3057(96)83115-7

Cited by 34 publications

(16 citation statements)

References 14 publications

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“…In this study no change in ASR or PPI was found after sarin administration, even though red blood cell ChE activity was significantly decreased. Differences in the modulation of ASR by organophosphates among rodent species (mice, rats and guinea-pigs) have been described by many authors (Scremin et al, 2003;Philippens et al, 1996Philippens et al, , 1997Jones and Shannon, 2000). These studies together with our results indicate the involvement of other than cholinergic systems in this modulation.…”

Section: Discussionsupporting

confidence: 60%

Delayed behavioral and endocrine effects of sarin and stress exposure in mice

Mach

Grubbs

Price

et al. 2007

J of Applied Toxicology

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The organophosphorus agent sarin is a potent inhibitor of acetylcholinesterase. Experiments tested the influence of exposure to low doses of sarin along with psychological stress on delayed behavioral and endocrine changes in mice. Motor activity, acoustic startle response (ASR), pre-pulse inhibition (PPI) of ASR, activity of cholinesterase in blood and catecholamine levels in adrenals were evaluated after low dose sarin exposure (3 x 0.4 LD50 subcutaneously) combined with chronic intermittent stress in C57BL/6J mice. While sarin alone produced depression of motor activity, no interaction of the stress with sarin exposure was observed. Cholinesterase activity was significantly reduced 24 h after exposure to sarin; however, the basal activity was re-established 3 weeks later. The combination of low dose sarin exposure and stress produced delayed behavioral change manifested as excessive grooming together with endocrine alterations in adrenals 7 weeks after exposure. The size of the adrenals in the combined exposure group was increased and the concentration of catecholamines was significantly decreased. In conclusion, these findings indicate that sarin in low doses is more dangerous when combined with shaker stress inducing delayed behavioral and endocrine changes.

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Section: Discussionsupporting

confidence: 60%

Delayed behavioral and endocrine effects of sarin and stress exposure in mice

Mach

Grubbs

Price

et al. 2007

J of Applied Toxicology

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“…Originally we had chosen physostigmine because it is widely used experimentally and has been proposed for use against chemical warfare agents (Phillippens, 1996), since it gains access to the CNS, and may give better protection than pyridostigmine (which does not as readily cross the blood brain barrier). Unfortunately, two rats died when given physostigmine (1 mg/kg or 0.3 mg/kg) in combination with MK-801 (3 mg/kg).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, given the risks chemical warfare attacks, it is probable that military use of AChEIs may still be necessary, based on studies showing their effectiveness against such exposures (Leadbeater, 1985;Phillippens, et al, 1996). In addition, some AChEIs are highly potent or have a long duration of action, such that even low levels of AChEIs might be problematic when co-administered with NMDA antagonists.…”

Section: Figurementioning

confidence: 99%

Neuronal Degeneration in the Cingulate Gyrus: NMDA Antagonists and Anticholinesterases

Wilson¹

2000

PsycEXTRA Dataset

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Due QUALITY is&smmD 4 REPORT DOCUMENTATION PAGEForm Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and The goal of this study is to understand the interaction between drugs that are antagonists at the NMDA receptor subtype of glutamate receptors and drugs that are anticholinesterases. Previous research showed that NMDA antagonists are neurotoxic in the cingulate/retrosplenial cortex and that this toxicity was enhanced by muscarinic cholinergic agonists. We hypothesized that anticholinesterases would also enhance the toxicity of these compounds.We have used three approaches in this study: 1) We used intracellular electrophysiology; 2) We used imaging of brain slices treated with voltage sensitive dyes; 3) We used a stain (Fluro-Jade) which identifies dying neurons.Each of these approaches showed that NMDA antagonism produces excitability and/or neurotoxicity in these brain areas.Surprisingly, the anticholinesterase pyridostigmine appears to be inhibitory and preliminary studies suggest that it may protect against NMDA antagonist neurotoxicity.Our second year of experiments will continue this line of research. SUBJECT TERMS Neurotoxin IntroductionThe key objectives of these studies are to determine the neurotoxic risks of combining inhibitors of acetylcholinesterase (AChE) enzymes and blockers of N-methyl-D-aspartate receptor or channels (NMDAr/c). As more drugs are being developed that are NMDAr/c antagonists, therapeutic combinations are likely to occur in military or civilian settings. For example, these may be used in combination to prevent toxicity from chemical warfare that act on AChE enzymes (e.g., soman), or to treat symptoms of exposure to these agents. There are three approaches with which we are attacking these objectives:1. We have used electrophysiological studies, including patch clamp recordings of single neurons, to test the hypotheses proposed regarding the mechanisms by which NMDA r/c antagonist-mediated toxicity occurs. We used rat brain slices that include posterior cingulate/retrosplenial cortecies (PC/RSC) and parietal cortex to test the hypothesis that MK-801 produces neurotoxicity by disrupting GABAergic inhibition, and that this disruption is greater in the PC/RSC than other cortical areas. Our results are consistent with these hypotheses. Specifically, it has been hypothesized that a decrease in excitatory drive to interneurons caused by NMDA antagonists could result in disinhibition of principal cells and, in turn, this disinhibition (and resultin...

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“…그러나 physostigmine은 반감기(혈액속에서)가 짧 고 유효 약물농도범위(therapeutic index)가 좁아서 DDS (Drug Delivery System) 제제화에 대한 연구가 집중되 었다 [17～20] . 또한 physostigmine은 저농도에서 행동독성 (behaviorally toxic)이 있는 것으로 알려졌는데 [20,21] , 이 러한 문제점은 항콜린성 약물을 복합투여함에 의해 해결될 수 있음이 입증되었다 [22,23] . 독성은 서로 상쇄 되는 반면 약효는 상승되는 매우 이상적인 연구결과 들이 다수 보고 되었다 [20,24～31] .…”

Section: 서 론unclassified

Investigation of the Pharmacological Mechanisms and the R&D of Medical Countermeasures Against Nerve Agent Poisoning

Cho

2011

Journal of the Korea Institute of Military Science and Technolo

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Nerve agents are irreversible inhibitors of the cholinesterase enzyme. Exposure causes a progression of toxic signs, including hypersecretions, fasciculations, tremor, convulsions, respiratory distress, epileptiform seizures, brain injuries and death. A combined regimen of prophylaxis and therapy is the most effective medical countermeasure for dealing with the threat of nerve agent poisoning to military personnel. In this paper, the author investigated the updated technologies regarding various pre-and post-treatment drugs for nerve agents detoxification which are under development in several countries including Korea. Some characteristics of active ingredients in the formulations of drugs, their action mechanisms, and effectiveness were analyzed. Additionally, part of experimental data on the transdermal patch studied in ADD using beagle dogs was introduced.

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Side effects of physostigmine as a pretreatment in guinea pigs

Cited by 34 publications

References 14 publications

Delayed behavioral and endocrine effects of sarin and stress exposure in mice

Delayed behavioral and endocrine effects of sarin and stress exposure in mice

Neuronal Degeneration in the Cingulate Gyrus: NMDA Antagonists and Anticholinesterases

Investigation of the Pharmacological Mechanisms and the R&D of Medical Countermeasures Against Nerve Agent Poisoning

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