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- Physostigmine is the Antidote for Anticholinergic Syndrome. [JOURNAL ARTICLE]
- J Med Toxicol 2014 Oct 23.
- Response: Physostigmine May Not Be the Only Option for Treating Anticholinergic Syndrome. [JOURNAL ARTICLE]
- J Med Toxicol 2014 Oct 21.
- Corticosterone and corticotropin-releasing factor acutely facilitate gamma oscillations in the hippocampus in vitro. [JOURNAL ARTICLE]
- Eur J Neurosci 2014 Oct 13.
Stressful experiences do not only cause peripheral changes in stress hormone levels, but also affect central structures such as the hippocampus, implicated in spatial orientation, stress evaluation, and learning and memory. It has been suggested that formation of memory traces is dependent on hippocampal gamma oscillations observed during alert behaviour and rapid eye movement sleep. Furthermore, during quiescent behaviour, sharp wave-ripple (SW-R) activity emerges. These events provide a temporal window during which reactivation of memory ensembles occur. We hypothesized that stress-responsive modulators, such as corticosterone (CORT), corticotropin-releasing factor (CRF) and the neurosteroid 3α, 21-dihydroxy-5α-pregnan-20-one (THDOC) are able to modulate gamma oscillations and SW-Rs. Using in vitro hippocampal slices, we studied acute and subacute (2 h) impact of these agents on gamma oscillations in area cornu ammonis 3 of the ventral hippocampus induced by acetylcholine (10 μm) combined with physostigmine (2 μm). CORT increased the gamma oscillations in a dose-dependent fashion. This effect was mediated by glucocorticoid receptors. Likewise, CRF augmented gamma oscillations via CRF type 1 receptor. Lastly, THDOC was found to diminish cholinergic gamma oscillations in a dose-dependent manner. Neither CORT, CRF nor THDOC modulated gamma power when pre-applied for 1 h, 2 h before the induction of gamma oscillations. Interestingly, stress-related neuromodulators had rather mild effects on spontaneous SW-R compared with their effects on gamma oscillations. These data suggest that the alteration of hippocampal gamma oscillation strength in vitro by stress-related agents is an acute process, permitting fast adaptation to new attention-requiring situations in vivo.
- Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: assessment using azinphos-methyl. [JOURNAL ARTICLE]
- J Appl Toxicol 2014 Sep 3.
Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors before organophosphorous compound (OPC) exposure can reduce OPC-induced mortality. However, pyridostigmine, the only substance employed for such prophylaxis, is merely efficacious against a limited number of OPCs. In search of more efficacious and broad-range alternatives, we have compared in vivo the ability of five reversible AChE inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and K-27) to reduce mortality induced by the OPC azinphos-methyl. Protection was quantified using Cox analysis by determining the relative risk (RR) of death in rats that were administered these AChE inhibitors in equitoxic dosage (25% of LD01 ) 30 min before azinphos-methyl exposure. Azinphos-methyl-induced mortality was significantly reduced by all five tested compounds as compared with the reference group that was only exposed to azinphos-methyl without prior pre-treatment (RR = 1). The most efficacious prophylactic agents were K-27 (RR = 0.15) and physostigmine (RR = 0.21), being significantly more efficacious than ranitidine (RR = 0.62) and pyridostigmine (RR = 0.37). Pre-treatment with tacrine (RR = 0.29) was significantly more efficacious than pre-treatment with ranitidine, but the difference between tacrine and pyridostigmine was not significant. Our results indicate that prophylactic administration of the oxime K-27 may be a promising alternative in cases of imminent OPC exposure. Copyright © 2014 John Wiley & Sons, Ltd.
- Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase. [JOURNAL ARTICLE]
- Bioorg Med Chem 2014 Jun 26.
A series of cyclic acyl guanidine with carbamate moieties have been synthesized and evaluated in vitro for their AChE and BChE inhibitory activities. Structure-activity relationships identified compound 23 as a nanomolar and selective BChE inhibitor, while compound 32 exhibited nanomolar and selective AChE inhibition, selectivity depending on both the structure of the carbamate substituent as well as the position of guanidines-N substitution. The velocity of enzyme carbamoylation was analyzed and showed similar behavior to physostigmine. Phenolic compounds formed after carbamate transfer to the active site of cholinesterases showed additional neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation.
- Evaluation of the sensitivity of the novel α4β2* nicotinic acetylcholine receptor PET radioligand (18) F-(-)-NCFHEB to increases in synaptic acetylcholine levels in rhesus monkeys. [JOURNAL ARTICLE]
- Synapse 2014 Jul 17.
Objective: (18) F-(-)-NCFHEB (also known as (18) F-(-)-Flubatine) is a new radioligand to image α4β2* nicotinic acetylcholine receptors in vivo with positron emission tomography (PET), with faster kinetics than previous radioligands such as (18) F-2-F-A85380. The goal of this study was to assess the sensitivity of (18) F-(-)-NCFHEB-PET to increases in synaptic acetylcholine concentration induced by acetylcholinesterase inhibitors. Methods: Two rhesus monkeys were scanned four times each on a Focus 220 scanner: first at baseline, then during two bolus plus infusions of physostigmine (0.06-0.28 mg/kg), and finally following a bolus injection of donepezil (0.25 mg/kg). The arterial input function and the plasma free fraction fP were measured. (18) F-(-)-NCFHEB volume of distribution VT was estimated using the multilinear analysis MA1 and then normalized by plasma free fraction fP . Results: (18) F-(-)-NCFHEB fP was 0.89±0.04. At baseline, (18) F-(-)-NCFHEB VT /fP ranged from 7.9±1.3 mL plasma/cm(3) tissue in the cerebellum to 34.3±8.4 mL plasma/cm(3) tissue in the thalamus. Physostigmine induced a dose-dependent reduction of (18) F-(-)-NCFHEB VT /fP of 34±9% in the putamen, 32±8% in the thalamus, 25±8% in the cortex, and 23±10% in the hippocampus. With donepezil, (18) F-(-)-NCFHEB VT /fP was reduced by 24±2%, 14+3% and 14±5%, 10±6% in the same regions. Conclusion: (18) F-(-)-NCFHEB can be used to detect changes in synaptic acetylcholine concentration and is a promising tracer to study acetylcholine dynamics with shorter scan durations than previous radioligands. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
- Investigation into the role of the cholinergic system in radiation-induced damage in the rat liver and ileum. [JOURNAL ARTICLE]
- J Radiat Res 2014 Jun 8.
It has been previously shown that acetylcholine (ACh) may affect pro-inflammatory and anti-inflammatory cytokines. The role of the cholinergic system in radiation-induced inflammatory responses and tissue damage remains unclear. Therefore, the present study was designed to determine the radio-protective properties of the cholinergic system in the ileum and the liver of rats. Rats were exposed to 8-Gy single-fraction whole-abdominal irradiation and were then decapitated at either 36 h or 10 d post-irradiation. The rats were treated either with intraperitoneal physiological saline (1 ml/kg), physostigmine (80 µg/kg) or atropine (50 μg/kg) twice daily for 36 h or 10 d. Cardiac blood samples and liver and ileal tissues were obtained in which TNF-α, IL-1β and IL-10 levels were assayed using ELISA. In the liver and ileal homogenates, caspase-3 immunoblots were performed and myeloperoxidase (MPO) activity was analyzed. Plasma levels of IL-1β and TNF-α increased significantly following radiation (P < 0.01 and P < 0.001, respectively) as compared with non-irradiated controls, and physostigmine treatment prevented the increase in the pro-inflammatory cytokines (P < 0.01 and P < 0.001, respectively). Plasma IL-10 levels were not found to be significantly changed following radiation, whereas physostigmine augmented IL-10 levels during the late phase (P < 0.01). In the liver and ileum homogenates, IL-1β and TNF-α levels were also elevated following radiation, and this effect was inhibited by physostigmine treatment but not by atropine. Similarly, physostigmine also reversed the changes in MPO activity and in the caspase-3 levels in the liver and ileum. Histological examination revealed related changes. Physostigmine experiments suggested that ACh has a radio-protective effect not involving the muscarinic receptors.
- Surgery-induced changes in rat IL1β and acetylcholine metabolism: role of physostigmine. [JOURNAL ARTICLE]
- Clin Exp Pharmacol Physiol 2014 May 29.
Pharmacological enhancement of cholinergic activities by administering physostigmine is known to induce protective effects. It is unclear, however, whether the impact of physostigmine on inflammation and acetylcholine metabolism is related to different types of surgical intervention or to anesthesia alone. To determine this, rats were subjected to partial liver resection (PLR) or sham surgery. A control group only received anesthesia. Half of each treatment group received a single intraoperative dose of physostigmine; the others received placebo. Acetylcholine esterase (ACHE) activity and IL1β and acetylcholine (ACH) concentrations were determined. Both PLR and sham operation induced a time-dependent increase in plasma concentration of IL1β (3.9 and 4.8-fold) as compared to rats that received anesthesia alone. In rat brain, IL1β had increased by about twofold after surgery as compared to controls. Blood ACHE was transiently decreased after surgery. Brain ACHE activity increased 1.3-fold (p=0.014) only after PLR; consequently, the cerebral ACH concentration was significantly reduced. Physostigmine administration significantly reduced IL1β and ACHE levels. Cerebral ACH concentration was markedly increased from 543.9±121.5 (placebo) to 653.5±93.3 ng mg(-1) protein (p<0.001) after administering physostigmine. We conclude that a single dose of physostigmine intraoperatively had a sustained anti-inflammatory effect up to 120 min after injection that was especially pronounced under the conditions of PLR surgery. In addition to its protective peripheral action, physostigmine exerts neuroprotective action by increasing levels of the neurotransmitter ACH. This article is protected by copyright. All rights reserved.
- Microcirculatory Effects of Physostigmine on Experimental Burn Edema. [JOURNAL ARTICLE]
- J Burn Care Res 2014 May 12.
In order to further understand the role of the cholinergic anti-inflammatory pathway, the authors determined the effects of burn plasma from donor rats (DRs) on the microvascular circulation of healthy recipient rats and whether these could be altered by pretreatment with physostigmine (PT).DRs underwent thermal injury (100°C water, 12 seconds, 30% BSA) for positive controls. For negative controls DRs underwent sham burn (same procedure but water at 37°C). DR-plasma (harvested 4 hours posttrauma) was transferred to healthy rats. Bolus injection of PT (70 μg/kg body weight) was performed 15 minutes before starting the infusion of DR-plasma in the study group. Intravital microscopy was performed in mesenteric venules (0/60/120 minutes). Edema was assessed by FITC-albumin extravasation. Additionally, leukocyte rolling and sticking (cells/mm) as well as hemodynamic parameters were assessed.Burn plasma transfer significantly increases albumin extravasation in healthy individuals when compared with sham-burn treatment. Additional bolus administration of PT (70 μg/kg body weight) to burn plasma treatment reduces plasma extravasation to sham-burn levels. PT also attenuates leukocyte-endothelial interactions. After 120 minutes no significant changes in the systemic circulation (mean arterial pressure, heart rate, wall shear rate) were found between the groups.Burn plasma transfer results in significant increases in plasma extravasation and leukocyte-endothelial wall adherence, which are reversed by pretreatment with PT. These results suggest that the cholinergic anti-inflammatory pathway may play a role in the microcirculatory response to thermal injury.
- Use of a Physostigmine Continuous Infusion for the Treatment of Severe and Recurrent Antimuscarinic Toxicity in a Mixed Drug Overdose. [JOURNAL ARTICLE]
- J Med Toxicol 2014 May 6.
Physostigmine was once a widely used antidote for the treatment of antimuscarinic toxicity. However, reports describing the association of physostigmine with asystole and seizures in severe tricyclic antidepressant poisoning resulted in a decrease in use. Recent literature has demonstrated that physostigmine is a safe and effective antidote for the treatment of antimuscarinic toxicity. There are only two previously published articles regarding the use of physostigmine administered as a continuous intravenous infusion for persistent antimuscarinic toxicity. We present a case of physostigmine continuous infusion for the treatment of antimuscarinic symptoms in a polydrug overdose due to the ingestion of diphenhydramine along with bupropion, citalopram, acetaminophen, and naproxen.A 13-year-old female presented with hyperthermia, myoclonus and rigidity, hallucinations, severe agitation, and antimuscarinic toxicity including inability to sweat after a polydrug overdose. Several doses of lorazepam were administered followed by physostigmine which produced resolution of hallucinations and attenuation of the antimuscarinic symptoms including perspiration, temperature improvement, and decreased agitation. After periods of improvement and recurrence of antimuscarinic effects, a continuous infusion of physostigmine was administered at 2 mg/h and continued for almost 8 h to maintain attenuation of symptoms. GABAergic agents including lorazepam and phenobarbital were used later in the hospital course for presumed symptoms of serotonergic and adrenergic toxicity after resolution of antimuscarinic effects. The patient did not experience any adverse effects of physostigmine administration.Physostigmine administered as a continuous infusion may be a reasonable treatment option for severe and recurrent symptoms related to antimuscarinic toxicity.