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Neuroscience and Biobehavioral Reviews Dec 2016The threat of chemical warfare agents like nerve agents requires life saving measures of medical pretreatment combined with treatment after exposure. Pretreatment... (Review)
Review
The threat of chemical warfare agents like nerve agents requires life saving measures of medical pretreatment combined with treatment after exposure. Pretreatment (pyridostigmine) may cause some side effects in a small number of individuals. A comprehensive research on animals has been performed to clarify effects on behavior. The results from these studies are far from unambiguous, since pyridostigmine may produce adverse effects on behavior in animals in relatively high doses, but not in a consistent way. Other animal studies have examined the potential of drugs like physostigmine, galantamine, benactyzine, trihexyphenidyl, and procyclidine, but they all produce marked behavioral impairment at doses sufficient to contribute to protection against a convulsant dose of soman. Attempts have also been made to develop a combination of drugs capable of assuring full protection (prophylaxis) against nerve agents. However, common to all combinations is that they at anticonvulsant doses cause behavioral deficits. Therefore, the use of limited pretreatment doses may be performed without marked side effects followed by post-exposure therapy with a combination of drugs.
Topics: Animals; Benactyzine; Cholinesterase Inhibitors; Humans; Nerve Agents; Procyclidine; Soman
PubMed: 27773692
DOI: 10.1016/j.neubiorev.2016.10.017 -
Acta Medica Iranica Jan 2018Organophosphates (OPs) and carbamates are acetylcholine esterase inhibitors (AChEIs), which can cause seizure and lethality. Anticonvulsant properties of potassium...
Organophosphates (OPs) and carbamates are acetylcholine esterase inhibitors (AChEIs), which can cause seizure and lethality. Anticonvulsant properties of potassium channel openers including cromakalim have been determined in previous studies. In the present experiment, the possible effect of cromakalim on the convulsion and death induced by OPs and carbamates was studied in mice. Dichlorvos (an OP, 50 mg/kg) and physostigmine (a carbamate, 2 mg/kg) were used to induce seizure in animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg was injected 30 min before dichlorvos and physostigmine, and 5 min before glibenclamide (a potassium channel blocker, 1 mg/kg) administration. All injections were performed intraperitoneally. After drugs administration, the onset of convulsion, death, the severity of seizure, and rate of mortality were investigated. Results revealed that both dichlorvos and physostigmine induced seizure activity and lethality in 100% of the animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg significantly increased the latency of both seizure and death (P<0.05). Also, cromakalim decreased the mortality rate induced by dichlorvos and physostigmine (P<0.05). On the other hand, glibenclamide blocked all aspects of the anticonvulsant effect of cromakalim (P<0.05). This study revealed for the first time that cromakalim (a KATP channel opener) diminishes the seizure and death induced by dichlorvos and physostigmine in mice, and introduces a new aspect to manage the patients who suffer from OPs/carbamates-induced seizure.
Topics: Animals; Anticonvulsants; Carbamates; Cromakalim; Dichlorvos; Dose-Response Relationship, Drug; Glyburide; Male; Mice; Organophosphate Poisoning; Physostigmine; Potassium Channels; Seizures
PubMed: 29436790
DOI: No ID Found -
Biomedicine & Pharmacotherapy =... Oct 2019In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive physostigmine salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting.
METHODS
In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM.
RESULTS
Steady state physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%-50.6% of baseline activity during physostigmine salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by physostigmine, with an estimated half maximal effective concentration (EC) of 5.99 ng/mL.
CONCLUSIONS
PK of physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.
Topics: Aged; Cholinesterases; Female; Humans; Male; Middle Aged; Models, Biological; Physostigmine; Shock, Septic
PubMed: 31398669
DOI: 10.1016/j.biopha.2019.109318 -
Military Medicine Dec 2019We present a case of a 66-year-old female who was to undergo a scheduled operation and placed on our institution's ERAS (Enhanced Recovery After Surgery) protocol. The...
We present a case of a 66-year-old female who was to undergo a scheduled operation and placed on our institution's ERAS (Enhanced Recovery After Surgery) protocol. The intraoperative course was unremarkable. The patient developed delayed emergence in the Post-Anesthesia Care Unit. On physical exam, the patient was noted to have a transdermal scopolamine patch adjacent to an area of skin breakdown. She also displayed signs of central anti-cholinergic toxicity including mydriasis and tachycardia. Following removal of the scopolamine patch and administration of physostigmine, her mental status returned to baseline. This interesting case highlights the importance of considering patient specific factors such as age when implementing ERAS protocols perioperatively. It also demonstrates the risks associated with scopolamine and the importance of risk/benefit analysis prior to administration.
Topics: Aged; Female; Humans; Hysterectomy; Mydriasis; Postoperative Complications; Proctectomy; Scopolamine; Skin Absorption
PubMed: 31004425
DOI: 10.1093/milmed/usz086 -
Biomedical Chromatography : BMC Feb 2021Kigelia africana plant is widely used as a herbal remedy in preventing the onset and the treatment of cancer-related infections. With the increase in the research...
UHPLC/GC-TOF-MS metabolomics, MTT assay, and molecular docking studies reveal physostigmine as a new anticancer agent from the ethyl acetate and butanol fractions of Kigelia africana (Lam.) Benth. fruit extracts.
Kigelia africana plant is widely used as a herbal remedy in preventing the onset and the treatment of cancer-related infections. With the increase in the research interest of the plant, the specific chemical compound or metabolite that confers its anticancer properties has not been adequately investigated. The ethyl acetate and butanol fractions of the fruit extracts were evaluated by 2-(4,5-dimethylthiazol-2-yl)-3,5-diphenyl-2H-tetrazolium bromide assay against four different cell lines, with the ethyl acetate fraction having inhibition concentration values of 0.53 and 0.42 μM against Hep G2 and HeLa cells, respectively. More than 235 phytoconstituents were profiled using UHPLC-TOF-MS, while more than 15 chemical compounds were identified using GC-MS from the fractions. Molecular docking studies revealed that physostigmine, fluazifop, dexamethasone, sulfisomidine, and desmethylmirtazapine could favorably bind at higher binding energies of -8.3, -8.6, -8.2, and -8.1 kcal/mol, respectively, better than camptothecin with a binding energy of -7.9 kcal/mol. The results of this study showed that physostigmine interacted well with topoisomerase IIα and had a high score of pharmacokinetic prediction using absorption, distribution, metabolism, excretion, and toxicity profiles, thereby suggesting that drug design using physostigmine as a base structure could serve as an alternative against the toxic side effects of doxorubicin and camptothecin.
Topics: Antineoplastic Agents, Phytogenic; Bignoniaceae; Cell Proliferation; Cell Survival; Chromatography, High Pressure Liquid; Fruit; Gas Chromatography-Mass Spectrometry; HeLa Cells; Hep G2 Cells; Humans; Metabolome; Metabolomics; Molecular Docking Simulation; Physostigmine; Plant Extracts
PubMed: 32895963
DOI: 10.1002/bmc.4979 -
The American Journal of Case Reports Feb 2021BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of...
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Topics: Adult; Antipsychotic Agents; Clozapine; Gastric Lavage; Humans; Male; Physostigmine; Schizophrenia
PubMed: 33591960
DOI: 10.12659/AJCR.929147 -
Clinical Chemistry and Laboratory... Jul 2015Physostigmine, commonly used as an antidote in anticholinergic poisoning, is reported to have additional pharmacological effects, such as activation of the cholinergic...
Revival of physostigmine - a novel HPLC assay for simultaneous determination of physostigmine and its metabolite eseroline designed for a pharmacokinetic study of septic patients.
BACKGROUND
Physostigmine, commonly used as an antidote in anticholinergic poisoning, is reported to have additional pharmacological effects, such as activation of the cholinergic anti-inflammatory pathway in sepsis models. Due to the narrow therapeutic range of physostigmine and its metabolite eseroline, however, the plasma concentrations of these substances need to be determined so as to understand their effect and ensure safety in the treatment of septic patients.
METHODS
To determine physostigmine and its metabolite eseroline, a rapid and sensitive high performance liquid chromatography (HPLC) method has been developed and validated. Spiked plasma samples were cleaned up and concentrated using a simple liquid-liquid extraction (LLE) procedure with N-methylphysostigmine as internal standard. Separation was achieved using reversed-phase HPLC on a Kinetex C18 column with gradient elution and fluorescence detection (254 nm excitation/355 nm emission).
RESULTS
LLE produced clean extracts and a mean recovery of 80.3% for eseroline and 84.9% for physostigmine. The HPLC assay revealed a limit of detection (LOD) of 0.025 ng/mL and a lower limit of quantification (LLOQ) of 0.05 ng/mL for both analytes. Linearity was observed at 0.05-10.0 ng/mL (r²>0.999). Intra- and inter-day precision ranged from 0.7% to 6.6%, and intra- and inter-day accuracy 97.5%-110.0%.
CONCLUSIONS
The presented method is useful for human drug level monitoring of physostigmine and eseroline in accordance with current guidelines. Remarkably low plasma concentrations can be quantified after LLE with gradient elution and fluorescence detection, making this a suitable method for pharmacokinetic studies in a clinical setting.
Topics: Chromatography, High Pressure Liquid; Healthy Volunteers; Humans; Indoles; Liquid-Liquid Extraction; Physostigmine; Shock, Septic
PubMed: 25565546
DOI: 10.1515/cclm-2014-0834 -
Neurobiology of Disease Oct 2019Mild traumatic brain injury (mTBI) is a risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). TBI-derived...
Mild traumatic brain injury (mTBI) is a risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). TBI-derived neuropathologies are promoted by inflammatory processes: chronic microgliosis and release of pro-inflammatory cytokines that further promote neuronal dysfunction and loss. Herein, we evaluated the effect on pre-programmed cell death/neuroinflammation/synaptic integrity and function of (-)-Phenserine tartrate (Phen), an agent originally developed for AD. This was studied at two clinically translatable doses (2.5 and 5.0 mg/kg, BID), in a weight drop (concussive) mTBI model in wild type (WT) and AD APP/PSEN1 transgenic mice. Phen mitigated mTBI-induced cognitive impairment, assessed by Novel Object Recognition and Y-maze behavioral paradigms, in WT mice. Phen fully abated mTBI-induced neurodegeneration, evaluated by counting Fluoro-Jade C-positive (FJC+) cells, in hippocampus and cortex of WT mice. In APP/PSEN1 mice, degenerating cell counts were consistently greater across all experimental groups vs. WT mice. mTBI elevated FJC+ cell counts vs. the APP/PSEN1 control (sham) group, and Phen similarly mitigated this. Anti-inflammatory effects on microglial activation (IBA1-immunoreactivity (IR)) and the pro-inflammatory cytokine TNF-α were evaluated. mTBI increased IBA1-IR and TNF-α/IBA1 colocalization vs. sham, both in WT and APP/PSEN1 mice. Phen decreased IBA1-IR throughout hippocampi and cortices of WT mice, and in cortices of AD mice. Phen, likewise, reduced levels of IBA1/TNF-α-IR colocalization volume across all areas in WT animals, with a similar trend in APP/PSEN1 mice. Actions on astrocyte activation by mTBI were followed by evaluating GFAP, and were similarly mitigated by Phen. Synaptic density was evaluated by quantifying PSD-95+ dendritic spines and Synaptophysin (Syn)-IR. Both were significantly reduced in mTBI vs. sham in both WT and APP/PSEN1 mice. Phen fully reversed the PSD-95+ spine loss in WT and Syn-IR decrease in both WT and APP/PSEN1 mice. To associate immunohistochemical changes in synaptic markers with function, hippocampal long term potentiation (LTP) was induced in WT mice. LTP was impaired by mTBI, and this impairment was mitigated by Phen. In synopsis, clinically translatable doses of Phen ameliorated mTBI-mediated pre-programmed cell death/neuroinflammation/synaptic dysfunction in WT mice, consistent with fully mitigating mTBI-induced cognitive impairments. Phen additionally demonstrated positive actions in the more pathologic brain microenvironment of AD mice, further supporting consideration of its repurposing as a treatment for mTBI.
Topics: Alzheimer Disease; Animals; Brain Concussion; Cell Death; Cerebral Cortex; Disease Models, Animal; Hippocampus; Mice; Mice, Transgenic; Neurons; Physostigmine
PubMed: 31295555
DOI: 10.1016/j.nbd.2019.104528 -
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 -
The Annals of Pharmacotherapy Oct 2019Antimuscarinic delirium is associated with significant morbidity, and its management requires substantial resource allocation, including intubation, restraint, and...
Antimuscarinic delirium is associated with significant morbidity, and its management requires substantial resource allocation, including intubation, restraint, and intensive care unit (ICU) placement. There is controversy over the management of these patients. Physostigmine can rapidly reverse antimuscarinic delirium but has been associated with adverse effects. This study aims to assess the effect of physostigmine use on resource allocation and adverse events. This is a retrospective chart review of patients with an antimuscarinic toxidrome at a single hospital approved by the local institutional review board. A blinded abstractor recorded data from patient charts. Whether the patient was given physostigmine, intubated, restrained, or admitting to critical care was recorded. We recorded instances of seizure, vomiting, or bradycardia. The primary aim was to compare frequency of intubation as a function of physostigmine administration. A total of 141 patients were identified. We found no difference between the groups in age, gender, or initial heart rate; 65 (46%) were given physostigmine, 45 (32%) were admitted to the ICU, and 29 (20%) were intubated. Patients who received physostigmine in the first 24 hours were less likely to be intubated and less likely to be admitted to an ICU. The instance of bradycardia (n = 16), vomiting (n = 27), and seizures (n = 7) was limited, and there were no significant differences between the groups. There were no associations noted between physostigmine administration and adverse effects. This study demonstrated that physostigmine use is associated with decreased resource utilization (including intubation and ICU placement) without increasing rates of bradycardia, vomiting, or seizures.
Topics: Adult; Bradycardia; Cholinergic Antagonists; Critical Care; Delirium; Female; Heart Rate; Humans; Intensive Care Units; Male; Muscarinic Antagonists; Physostigmine; Retrospective Studies; Seizures
PubMed: 31023063
DOI: 10.1177/1060028019846654