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Experimental & Applied Acarology Jun 2021The non-target toxicity and resistance problems of acetylcholinesterase (AChE) insecticides, such as organophosphates and carbamates, are of growing concern. To explore...
The non-target toxicity and resistance problems of acetylcholinesterase (AChE) insecticides, such as organophosphates and carbamates, are of growing concern. To explore the potential targets for achieving inhibitor selectivity, the AChE structures at or near the catalytic pocket of Tetranychus urticae (TuAChE), honey bees, and humans were compared. The entrances to the AChE catalytic pocket differ significantly because of their different peripheral sites. The role of these potential mite-specific sites in AChE function was further elucidated by site-directed mutagenesis of these sites and then examining the catalytic activities of TuAChE mutants. The spider mite E, H, and V active sites are important for AChE function. By further analyzing their physostigmine inhibitory properties and the detailed interaction between physostigmine and TuAChE, the peripheral site H locating near the gorge entrance, and S at the oxyanion hole, affects substrate and inhibitor trafficking. The discovery of conserved mite-specific residues in Tetranychus will enable the development of safer, effective pesticides that target residues present only in mite AChEs, potentially offering effective control against this important agricultural pest.
Topics: Acetylcholinesterase; Animals; Carbamates; Insecticides; Mites; Tetranychidae
PubMed: 33914192
DOI: 10.1007/s10493-021-00624-4 -
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 -
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 -
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 -
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 -
Journal of Biomolecular Structure &... Dec 2023Alzheimer's disease (AD) is a complex neurodegenerative disorder involving cognitive dysfunction like short-term memory and behavioral changes as the disease progresses... (Review)
Review
Alzheimer's disease (AD) is a complex neurodegenerative disorder involving cognitive dysfunction like short-term memory and behavioral changes as the disease progresses due to other unaltered physiological factors. The solution for this problem is Multi-targeted Drugs (MTDs), which can affect multiple determinants to realize the multifunctional effects. Acetylcholinesterase (AChE) inhibitors donepezil, rivastigmine, galantamine, and N-methyl-D-aspartate (NMDA) receptor antagonist memantine are FDA-approved drugs used to treat AD symptomatically. The key objective of this review is to understand multitargeted bioactive natural molecules that could be considered as leads for further development as effective drugs for treating AD, along with understanding its pharmacology and structure-activity relationship (SAR). Understanding the molecular mechanism of the AD pathophysiology, the role of existing drugs, treatment of AD via amyloid beta (Aβ) plaque, and neurofibrillary tangle (NFT) inhibition by natural bioactive molecules were also discussed in the review. The current quest and recent advancements with natural bioactive compounds like physostigmine, resveratrol, curcumin, and catechins, along with the study of SAR, were reported in the present study. This review summarises the structural properties required for bioactive natural molecules to show anti-Alzheimer's activity by emphasizing on SAR of several bioactive natural molecules targeting various AD pathologies, their key molecular interactions that are critical for target specificity, their role as multitargeted ligands, used with adjunctive therapy for AD followed by related US patents granted recently. This article highlights the significance of the structural features of natural bioactive molecules in the treatment of AD and establishes a connection between them.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Acetylcholinesterase; Cholinesterase Inhibitors; Structure-Activity Relationship
PubMed: 36579430
DOI: 10.1080/07391102.2022.2158136 -
Journal of Pineal Research Aug 2023Arylacetamide deacetylase (AADAC) is a deacetylation enzyme present in the mammalian liver, gastrointestinal tract, and brain. During our search for mammalian enzymes...
Arylacetamide deacetylase (AADAC) is a deacetylation enzyme present in the mammalian liver, gastrointestinal tract, and brain. During our search for mammalian enzymes capable of metabolizing N-acetylserotonin (NAS), AADAC was identified as having the ability to convert NAS to serotonin. Both human and rodent recombinant AADAC proteins can deacetylate NAS in vitro, although the human AADAC shows markedly higher activity compared with rodent enzyme. The AADAC-mediated deacetylation reaction can be potently inhibited by eserine in vitro. In addition to NAS, recombinant hAADAC can deacetylate melatonin (to form 5-methoxytryptamine) and N-acetyltryptamine (NAT) (to form tryptamine). In addition to the in vitro deacetylation of NAS by the recombinant AADAC proteins, liver (mouse and human) and brain (human) extracts were able to deacetylate NAS; these activities were sensitive to eserine. Taken together, these results demonstrate a new role for AADAC and suggest a novel pathway for the AADAC-mediated metabolism of pineal indoles in mammals.
Topics: Animals; Humans; Mice; Carboxylic Ester Hydrolases; Mammals; Melatonin; Physostigmine; Serotonin
PubMed: 37002641
DOI: 10.1111/jpi.12870 -
British Journal of Clinical Pharmacology Nov 2021HTL0009936 is a selective M muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
HTL0009936 is a selective M muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF).
METHODS
Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests.
RESULTS
Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine.
CONCLUSIONS
HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.
Topics: Aged; Area Under Curve; Cholinergic Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Receptors, Cholinergic
PubMed: 33891333
DOI: 10.1111/bcp.14872