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Journal of Emergency Nursing Jan 2020
Review
Topics: Cholinesterase Inhibitors; Delirium; Emergency Nursing; Humans; Muscarinic Antagonists; Neurotoxicity Syndromes; Physostigmine
PubMed: 31918808
DOI: 10.1016/j.jen.2019.09.002 -
Biosensors & Bioelectronics Feb 20212,3,9,10,16,17,23,24-Octakis (4-methyl-2,6-bis((prop-2-yn-1-yloxy)methyl)phenoxy) phthalocyaninato zinc(II) (Pc) bearing sixteen terminal ethynyl groups was synthesized...
2,3,9,10,16,17,23,24-Octakis (4-methyl-2,6-bis((prop-2-yn-1-yloxy)methyl)phenoxy) phthalocyaninato zinc(II) (Pc) bearing sixteen terminal ethynyl groups was synthesized and attached to SWCNT (Single-walled carbon nanotube) covalently to obtain three dimensional porous hybrid material (SWCNT-Pc 3D) and its copper complex (Cu-SWCNT-Pc 3D). The structural characterization and electrochemical sensor features of the Cu-SWCNT-Pc hybrid towards to physostigmine pesticide were performed. A fast, direct and suitable determination method for physostigmine detection was offered. The designed sensor, Cu-SWCNT-Pc 3D/GCE (glassy carbon electrode) shows sensitivity ca 1.8, 4.3 and 2.8 times more than that of SWCNT/GCE, SWCNT-Pc-noncovalent/GCE and SWCNT-Pc 3D/GCE in terms of peak heights while bare and Pc/GCE had almost no voltammetric response to 2 μM physostigmine in PBS at a pH of 7.0. The limit of detection and quantification of physostigmine determination with Cu-SWCNT-Pc 3D/GCE were found to be 53 and 177 nM in the range of 0.1-4.8 μM, respectively. This study demonstrated that the modification of the GCE with Cu-SWCNT-Pc 3D as an electrochemical sensor was acted as catalytic role toward physostigmine presence of other interfering pesticides as high sensitivity and selectivity. The electrochemical determination of physostigmine in real samples was performed under the optimized conditions, also accuracy of the electrochemical determination method was evaluated with HPLC as a standard determination method.
Topics: Biosensing Techniques; Copper; Electrodes; Indoles; Isoindoles; Limit of Detection; Nanotubes, Carbon; Pesticides; Physostigmine; Zinc
PubMed: 33246678
DOI: 10.1016/j.bios.2020.112819 -
Journal of Applied Toxicology : JAT Jan 2019Organophosphorus compounds (OPCs), inhibitors of acetylcholinesterase (AChE), are useful agents as pesticides, but also represent a serious health hazard. Standard... (Review)
Review
Organophosphorus compounds (OPCs), inhibitors of acetylcholinesterase (AChE), are useful agents as pesticides, but also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators (pralidoxime, obidoxime) is unsatisfactory. Better therapeutic results are obtained, when reversible AChE inhibitors are administered before OPC exposure. This review summarizes the history of such a pretreatment approach and sums up a set of experiments undertaken in search of compounds that are efficacious when given before a broad range of OPCs. The prophylactic efficacy of 10 known AChE inhibitors, either already used clinically for different indications (physostigmine, pyridostigmine, ranitidine, tiapride, tacrine, amiloride, metoclopramide, methylene blue) or developed for possible therapeutic use in the future (7-methoxytacrine, K-27) was compared, when administered before exposure to six chemically diverse OPCs in the same experimental setting: ethyl-paraoxon, methyl-paraoxon, diisopropylfluorophosphate, terbufos sulfone, azinphos-methyl and dicrotophos. The experimental oxime K-27 was the most efficacious compound, affording best protection, when administered before terbufos sulfone, azinphos-methyl and dicrotophos, second best before ethyl- and methyl-paraoxon exposure and third best before diisopropylfluorophosphate administration. This ranking was similar to that of physostigmine, which was superior to the Food and Drug Administration-approved pretreatment for soman with pyridostigmine. Tiapride, amiloride, metoclopramide, methylene blue and 7-methoxytacrine did not achieve protection. No correlation was observed between the IC of the reversible AChE inhibitors and their protective efficacy. These studies indicate that K-27 can be considered a very promising broad-spectrum prophylactic agent in case of imminent organophosphate exposure, which may be related to its AChE reactivating activity rather than its AChE inhibition.
Topics: Animals; Cholinesterase Inhibitors; Humans; Models, Animal; Organophosphate Poisoning; Organophosphates; Pre-Exposure Prophylaxis
PubMed: 30027640
DOI: 10.1002/jat.3662 -
Toxicology Sep 2018Physostigmine and its analogues neostigmine, pyridostigmine and rivastigmine are carbamates nowadays used in many indications, including antidotal effects against... (Comparative Study)
Comparative Study
BACKGROUND
Physostigmine and its analogues neostigmine, pyridostigmine and rivastigmine are carbamates nowadays used in many indications, including antidotal effects against antimuscarinic poisonings, reversal of competitive neuromuscular block, myasthenia gravis, Alzheimer's disease and prophylaxis against nerve agent intoxications. Use of these medicinal carbamates, but also of carbamate insecticides, created need for research into the potential and mechanisms of action of several antidotes against carbamate poisonings, including anticholinergics and oximes.
AIM
The goal of this experimental study was to ascertain the life-preserving potential of anticholinergics atropine, hexamethonium and d-tubocurarine, oxime HI-6 and their combinations in rats poisoned with physostigmine or pyridostigmine.
MATERIALS AND METHODS
Experiments were performed in Wistar rats. Carbamates were injected subcutaneously (sc) and antidotes intramuscularly (im). Median lethal dose (LD) in animals treated with antidotes were compared to the ones in saline-treated rats and protective ratios (PRs) were calculated. Atropine (5, 10 and 20 mg/kg), hexamethonium (5, 10 and 20 mg/kg), d-tubocurarine (0.005, 0.010 and 0.020 mg/kg) and oxime HI-6 (25, 50 and 100 mg/kg) were used as monotherapies and in dual combinations, where atropine was the obligatory antidote. Biochemical experiments consisted in measuring of the cholinesterase activities in brain, whole blood and diaphragm in rats 5, 15, 30, 60, 120 and 240 min after poisoning with 0.8 LD of physostigmine or pyridostigmine.
RESULTS
All the tested antidotes assured some degree of protection against the two carbamates. Atropine and hexamethonium produced better protection in physostigmine-poisoned rats, while d-tubocurarine and HI-6 were more efficacious in pyridostigmine-intoxicated animals. Oxime HI-6 50 mg/kg reactivated acetylcholinesterase (AChE) in brain inhibited by physostigmine and in diaphragm inhibited by pyridostigmine.
CONCLUSIONS
Mechanism of physostigmine-induced lethal effect is predominantly central and it involves inhibition of brain AChE, while pyridostigmine produces the same effect exclusively outside the central nervous system, by inhibiting AChE in the respiratory muscles. As a consequence, increasing doses of atropine and their combination with hexamethonium assure excellent protection against physostigmine toxicity, while the best protection against pyridostigmine is provided by a strictly peripherally acting antinicotinic d-tubocurarine and bispyridinium oxime HI-6. The oxime acts as antidote against physostigmine and pyridostigmine poisoning by reactivating AChE in the brain and diaphragm, respectively.
Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Brain; Cholinergic Antagonists; Cholinesterase Reactivators; Diaphragm; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Activation; GPI-Linked Proteins; Hexamethonium; Male; Neurotoxicity Syndromes; Oximes; Physostigmine; Pyridinium Compounds; Pyridostigmine Bromide; Rats, Wistar; Tubocurarine
PubMed: 30176331
DOI: 10.1016/j.tox.2018.08.017 -
Neuropsychopharmacology : Official... Mar 2023The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few...
The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the β-subunit containing nicotinic acetylcholine receptor (β*-nAChR) partial agonist radioligand (-)-[F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (V) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-[F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[F]flubatine V, consistent with increased cortical acetylcholine levels reducing the number of β*-nAChR sites available for (-)-[F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[F]flubatine V was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.
Topics: Animals; Male; Female; Acetylcholine; Acetylcholinesterase; Physostigmine; Positron-Emission Tomography; Brain; Receptors, Nicotinic; Cognition; Cholinergic Agents; Smoking
PubMed: 36681758
DOI: 10.1038/s41386-023-01535-1 -
Cognitive, Affective & Behavioral... Dec 2020Seasonal variations in environmental light influence switches between moods in seasonal affective disorder (SAD) and bipolar disorder (BD), with depression arising...
Seasonal variations in environmental light influence switches between moods in seasonal affective disorder (SAD) and bipolar disorder (BD), with depression arising during short active (SA) winter periods. Light-induced changes in behavior are also seen in healthy animals and are intensified in mice with reduced dopamine transporter expression. Specifically, decreasing the nocturnal active period (SA) of mice increases punishment perseveration and forced swim test (FST) immobility. Elevating acetylcholine with the acetylcholinesterase inhibitor physostigmine induces depression symptoms in people and increases FST immobility in mice. We used SA photoperiods and physostigmine to elevate acetylcholine prior to testing in a probabilistic learning task and the FST, including reversing subsequent deficits with nicotinic and scopolamine antagonists and targeted hippocampal adeno-associated viral administration. We confirmed that physostigmine also increases punishment sensitivity in a probabilistic learning paradigm. In addition, muscarinic and nicotinic receptor blockade attenuated both physostigmine-induced and SA-induced phenotypes. Finally, viral-mediated hippocampal expression of human AChE used to lower ACh levels blocked SA-induced elevation of FST immobility. These results indicate that increased hippocampal acetylcholine neurotransmission is necessary for the expression of SA exposure-induced behaviors. Furthermore, these studies support the potential for cholinergic treatments in depression. Taken together, these results provide evidence for hippocampal cholinergic mechanisms in contributing to seasonally depressed affective states induced by short day lengths.
Topics: Acetylcholine; Acetylcholinesterase; Animals; Hippocampus; Mice; Photoperiod; Physostigmine
PubMed: 32794101
DOI: 10.3758/s13415-020-00824-2 -
Toxicology in Vitro : An International... Mar 2019The purpose of these studies was to develop ex vivo tissue-based and in vitro cell-based assays using multi-electrode array (MEA) technology to predict seizure liability...
The purpose of these studies was to develop ex vivo tissue-based and in vitro cell-based assays using multi-electrode array (MEA) technology to predict seizure liability at the early stage of preclinical studies. Embryonic rat hippocampal neurons and adult rat hippocampal slices were used in these studies. Spontaneous activity in cultured neurons and evoked field potentials in hippocampal brain slices were recorded using MEA technology. Six seizurogenic compounds bicuculline, pentylenetetrazole, picrotoxin, gabazine, 4-Aminopyridine and BMS-A increased field potential area and peak number in brain slices and spontaneous spike activity in hippocampal neurons. Physostigmine, another seizurogenic compound, had no effect on brain slices at lower concentrations (0.1, 1, and 10 μM), and mildly increased field potential area at 100 μM. However, physostigmine induced multiple peaks in evoked field potential starting at 10 μM. Physostigmine showed greater potency in the cultured neuron assay, and increased spike rates in the nanomolar range. Two seizurogenic compounds, BMS-B and BMS-C increased the spontaneous activity in hippocampal neurons, but did not increase area and peak number of field potentials in brain slices. These findings suggest that MEA technology and rat hippocampal brain slices or rat embryonic hippocampal neurons, may be useful as early, predictive in vitro assays for seizure liability.
Topics: Animals; Cells, Cultured; Convulsants; Drug Evaluation, Preclinical; Electrodes; Hippocampus; Neurons; Rats, Sprague-Dawley; Seizures
PubMed: 30528373
DOI: 10.1016/j.tiv.2018.12.001 -
Medical Science Monitor : International... Dec 2021BACKGROUND Major depressive disorder (MDD) is the leading cause of disability around the world. It is generally agreed that the central cholinergic system plays an...
BACKGROUND Major depressive disorder (MDD) is the leading cause of disability around the world. It is generally agreed that the central cholinergic system plays an important role in emotional regulation. Acetylcholine (ACh) is now a new target for antidepressants. Therefore, the aim of this study was to evaluate the effect of acupuncture on depressive behaviors, cholinergic tones, and synaptic plasticity in the prefrontal cortex (PFC) in chronic unpredictable mild stress (CUMS). MATERIAL AND METHODS We randomly divided 36 male Sprague-Dawley (SD) rats into the Normal group, Stress group, Physostigmine+stress (Phys+stress) group, and Electroacupuncture+physostigmine+stress (EA+Phys+stress) group. Rats underwent CUMS exposure for 42 days. After 28 days of CUMS, rats received physostigmine or EA treatment for 2 weeks. Rats in the Phys+stress and EA+Phys+stress group received an intraperitoneal injection of physostigmine (TOCRIS, UK, 5 mg/kg) daily. Rats in the EA+Phys+stress group also received EA stimulation at GV 20 (Baihui), GV 29 (Yintang), LI 4 (Hegu), and LR 3 (Taichong) daily for 2 weeks. RESULTS We found that EA ameliorated weight loss and the depressive-like behaviors in the sucrose preference test, novelty-suppressed feeding test, and open-field test. There was significantly decreased expression of ACh and increased expression of acetylcholinesterase (AChE) after EA treatment. Consistent with the behavior tests and cholinergic tones, there were increased spine density and expressions of synaptic proteins, including brain-derived neurotrophic factor (BDNF), glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), postsynaptic density protein 95 (PSD95), and synapsin I in the PFC. CONCLUSIONS The results suggest that EA can reverse the depressive-like behaviors and synaptic deficits induced by hyper-cholinergic tone during chronic stress via the modulation of hyper-cholinergic tone.
Topics: Acetylcholine; Acetylcholinesterase; Animals; Blotting, Western; Cholinesterase Inhibitors; Depression; Electroacupuncture; Male; Neuronal Plasticity; Open Field Test; Physostigmine; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Stress, Psychological
PubMed: 34924558
DOI: 10.12659/MSM.933833 -
Neurological Sciences : Official... Feb 2024Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia. The early diagnosis of AD is an important factor for the... (Review)
Review
OBJECTIVE
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia. The early diagnosis of AD is an important factor for the control of AD progression. Electroencephalography (EEG) can be used for early diagnosis of AD. Acetylcholinesterase inhibitors (AChEIs) are also used for the amelioration of AD symptoms. In this systematic review, we reviewed the effect of different AChEIs including donepezil, rivastigmine, tacrine, physostigmine, and galantamine on EEG patterns in patients with AD.
METHODS
PubMed electronic database was searched and 122 articles were found. After removal of unrelated articles, 24 articles were selected for the present study.
RESULTS
AChEIs can decrease beta, theta, and delta frequency bands in patients with AD. However, conflicting results were found for alpha band. Some studies have shown increased alpha frequency, while others have shown decreased alpha frequency following treatment with AChEIs. The only difference was the type of drug.
CONCLUSIONS
We found that studies reporting the decreased alpha frequency used donepezil and galantamine, while studies reporting the increased alpha frequency used rivastigmine and tacrine. It was suggested that future studies should focus on the effect of different AChEIs on EEG bands, especially alpha frequency in patients with AD, to compare their effects and find the reason for their different influence on EEG patterns. Also, differences between the effects of AChEIs on oligodendrocyte differentiation and myelination may be another important factor. This is the first article investigating the effect of different AChEIs on EEG patterns in patients with AD.
Topics: Humans; Cholinesterase Inhibitors; Alzheimer Disease; Donepezil; Rivastigmine; Galantamine; Acetylcholinesterase; Tacrine; Piperidines; Indans; Phenylcarbamates
PubMed: 37843690
DOI: 10.1007/s10072-023-07114-y -
The Journal of Emergency Medicine Oct 2023Anticholinergic toxicity is a common cause of delirium in emergency department patients. The standard antidotal treatment for anticholinergic toxicity is physostigmine....
BACKGROUND
Anticholinergic toxicity is a common cause of delirium in emergency department patients. The standard antidotal treatment for anticholinergic toxicity is physostigmine. Physostigmine functions as a reversible acetylcholinesterase inhibitor that readily crosses the blood-brain barrier. Rivastigmine is another member of this class currently approved for the treatment of Alzheimer's disease and Parkinson's disease. Rivastigmine also crosses the blood-brain barrier and has been found to be effective in the management of anticholinergic toxicity in limited case reports.
CASE REPORT
A 61-year-old women presented to the emergency department via emergency medical services with altered mental status and a Glasgow Coma Scale score of 8 out of 15. She was found down near multiple medication bottles, including diphenhydramine and dicyclomine. Her physical examination was consistent with anticholinergic toxicity with mydriasis, obtundation, and warm flushed skin. In addition to standard resuscitation, she received two doses of rivastigmine 3 mg via nasogastric tube. After the second dose she was alert and oriented. She was admitted to the intensive care unit and had a rivastigmine patch applied. She was deemed back to her baseline 27 h after presentation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although the standard antidotal treatment for anticholinergic toxicity is physostigmine, there is a national shortage of this medication. In the absence of this standard antidote, it is reasonable for emergency physicians to use rivastigmine as an alternative treatment. This can be delivered orally or via nasogastric tube with dosing each hour until resolution of symptoms. Alternatively, in consultation with toxicology, it may be reasonable to use transdermal rivastigmine, as it provides consistent drug absorption for 24 h.
Topics: Humans; Female; Middle Aged; Rivastigmine; Physostigmine; Cholinergic Antagonists; Acetylcholinesterase; Cholinesterase Inhibitors; Antidotes; Anticholinergic Syndrome; Delirium; Transdermal Patch
PubMed: 37716903
DOI: 10.1016/j.jemermed.2023.06.008