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This document is a compilation of summaries of four different articles from various medical journals. The first article discusses the use of a two-bag N-acetylcysteine (NAC) system for acetaminophen poisoning, comparing its effectiveness and safety to the FDA-approved three-bag system. The second article examines the use of physostigmine in the treatment of anticholinergic toxicity, finding that patients treated with physostigmine alone were less likely to be intubated. The third article explores the use of dexmedetomidine in non-intubated patients, concluding that it is a safe and useful adjunct in the care of agitated toxicological patients. The fourth article compares the acute effects of mescaline, lysergic acid diethylamide (LSD), and psilocybin in a randomized, double-blind, placebo-controlled study, finding that the subjective experiences were similar at the studied doses. These articles provide valuable insights for toxicologists and poison centers in the treatment of various toxicological conditions. [Extracted from the article]

(-)-Phenserine ("phenserine") and (+)-phenserine (posiphen; buntanetap) are longer-acting enantiomeric analogs of physostigmine with demonstrated promise in the treatment of Alzheimer's and Parkinson's diseases. Both enantiomers have short plasma half-lives, and their pharmacokinetics might be improved through the use of either once or twice-daily administration of an extended-release dosage form. Phenserine was observed to form a colored degradation product in near-neutral and alkaline pH environments, and at pH 7, the half-life of posiphen was determined to be ~ 9 h (40 °C). To limit luminal degradation which would reduce bioavailability, a gastroretentive tablet composed of a polyethylene oxide-xanthan gum matrix was developed. When placed in simulated gastric fluid (pH 1.2), approximately 70% of the phenserine was released over a 12 h period, and no degradants were detected in the release medium. In comparison, a traditional hydrophilic-matrix, extended-release tablet showed measurable amounts of phenserine degradation in a pH 7.2 medium over an 8 h release interval. These results confirm that a gastroretentive tablet can reduce the luminal degradation of phenserine or posiphen by limiting exposure to neutral pH conditions while providing sustained release of the drug over at least 12 h. Additional advantages of the gastroretentive tablet include reduced gastric and intestinal concentrations of the drug resulting from the slower release from the gastroretentive tablet which may also limit the occurrence of the dose-limiting GI side effects previously observed with immediate-release phenserine capsules. [ABSTRACT FROM AUTHOR]

Introduction: Physostigmine fell out of widespread use in the 1980s due to safety concerns; however, more recent research has demonstrated that its safety profile is better than previously thought. These studies have mainly included adults. We theorized that improved safety data may lead to more acceptance. Our objectives, therefore, were to characterize current frequency of use of physostigmine in pediatric patients as well as to study adverse effect rates in a national pediatric patient population. Methods: The National Poison Data System was queried for cases of patients aged 0–18 years that involved single-substance exposures to antimuscarinic xenobiotics that were reported to a poison center between January 1, 2000, and December 31, 2020. Cases were stratified into groups by therapy received: benzodiazepines alone, benzodiazepines and physostigmine, physostigmine alone, or no physostigmine or benzodiazepines. Patient demographics, clinical effects, and medical outcomes were analyzed. Results: A total of 694,132 cases were reviewed, and 150,075 were included for analysis. Nearly 5% (7562/150,075) of patients received specific pharmacological therapy with benzodiazepines, physostigmine, or both. A benzodiazepine as a single agent was the most frequently used pharmacologic therapy (92% of 7562). Among patients receiving any pharmacological therapy, only 8.3% (n = 627) of patients received physostigmine. Frequency of serious outcomes significantly increased across the study period among patients receiving benzodiazepines alone or with physostigmine. There was no increase in serious outcomes among patients receiving only physostigmine. Conclusions: Physostigmine frequency of use was low overall, but when used, was associated with less severe outcomes when compared to benzodiazepines. [ABSTRACT FROM AUTHOR]

Physostigmine is an effective antidote for antimuscarinic delirium. There is little evidence for its use to reverse delirium following second generation antipsychotic exposure. The purpose of this study is to describe the safety and effectiveness of physostigmine in reversing delirium from second generation antipsychotic exposure. This is a retrospective cohort study of all patients reported to a single regional poison center treated with physostigmine following a second generation antipsychotic exposure from January 1, 2000 to April 15, 2021. The poison center electronic medical record was queried to identify cases and for data abstraction. The primary outcome was the positive response rate to physostigmine, as determined by two trained abstractors. Secondary outcomes included physostigmine dosing, and adverse events. Of 147 charts reviewed, 138 individual patients were included, and the response to physostigmine was reported in 128 patients. The most common second-generation antipsychotic exposure was quetiapine (97; 70.3 percent). A positive response to physostigmine was noted in 106/128 (82.8 percent) patients [95 percent confidence interval 68.9–83.6 percent]. Median number of physostigmine doses was 1 (interquartile range 1–3; range 1–9). The median total physostigmine dose received was 2 mg (interquartile range 2–6 mg; range 0.15–30 mg). The positive physostigmine response rate for patients with an antimuscarinic co-ingestion was not significantly different compared to patients with a different co-ingestion or no co-ingestion (25/34 versus 81/94; P = 0.09). Adverse events were reported in four (2.9 percent) patients, including one death. A positive response to physostigmine to treat antimuscarinic delirium from second generation antipsychotic exposure was reported in 82.8 percent of patients, which is similar to previous physostigmine studies. Adverse events were infrequent, and included diaphoresis (one 0.7 percent), seizure (one; 0.7 percent), and bradycardia (one; 0.7 percent). One (0.7%) patient suffered a cardiac arrest 60 minutes after receiving physostigmine to treat antimuscarinic delirium following having received increasing clozapine doses over the previous month. In this study, physostigmine appears to be a safe and effective treatment for antimuscarinic delirium from second generation antipsychotic exposure. Further studies are needed to validate the safety and effectiveness of physostigmine for this indication. [ABSTRACT FROM AUTHOR]

From 2019 to 2020, antihistamines were found in 15% of all US drug overdose deaths, often co-administered with fentanyl, with 3.6% of overdose deaths due to antihistamines alone. The most common antihistamine found in all these reported deaths is diphenhydramine, a ubiquitous, over-the-counter and clinically important medication. Currently, there is no antidote for diphenhydramine overdose. This review summarizes the adverse health effects and current emergency medicine treatments for diphenhydramine. Several emergency medicine case reports are reviewed, and the efficacy and outcomes of a variety of treatments are compared. The treatments reviewed include the more traditional antihistamine overdose therapeutics physostigmine and sodium bicarbonate, as well as newer ones such as donepezil, dexmedetomidine, and lipid emulsion therapy. We conclude that more study is needed to determine the ideal therapeutic approach to treating antihistamine overdoses. [ABSTRACT FROM AUTHOR]

Background: Juvenile myasthenia gravis (MG) is a rare autoimmune neuromuscular disorder and has a varied presentation in childhood making it a diagnostic challenge. Clinical Description: An 8-year-old girl presented to the pediatric emergency with multiple episodes of falling, drooling of saliva, dysphagia, and bilateral ptosis. Within a few hours of admission, she had acute deterioration, developed respiratory failure, and was put on ventilatory support. Management and Outcome: A myasthenic crisis was suspected and a neostigmine challenge test was done. She was managed in the emergency with atropine, neostigmine, intravenous immunoglobulin, and supportive care. Subsequently, she achieved complete remission with steroids, physostigmine, and oral mycophenolate mofetil over the next 6 weeks. Conclusion: Juvenile MG may rarely be the cause of generalized muscular weakness. A strong suspicion of myasthenic crisis must be kept in case of sudden deterioration involving bulbar and respiratory muscles, in a patient with neurologic weakness. Early intervention in this rare condition can be lifesaving.

Testing of cholinesterase, the enzyme that hydrolyzed acetylcholine, on the leaf surface of woody plants was done by the histochemical methods with Ellman reagent, Fast Red TR, and azo analogue of Ellman reagent dithio-bis-(p-phenyleneazo)-bis-(1-oxy-8-chloro-3,6) sodium disulfate, shortly DTPDD reagent. Last dye test was seen visually and under microscope. Inhibitors of cholinesterase neostigmine and physostigmine decreased the hydrolysis of acetylthiocholine by the cells. Presence of enzyme on plant surface shows its possible participation in allelopatic reactions between organisms containing and releasing acetylcholine. [ABSTRACT FROM AUTHOR]

Introduction: Sudden onset of reduced consciousness, psychomotor agitation and mydriasis are all indicative of an anticholinergic toxidrome. It is important to note that numerous drugs, as well as certain herbs and plants, possess anticholinergic properties. Case description: An 84-year-old female patient had sudden nocturnal onset of uncoordinated hand movements and altered mental status. Shortly after, the patient’s 83-year-old husband developed symptoms of dysarthria, gait ataxia, vertigo, and delirium. Conclusion: Anticholinergic syndrome consists of a combination of central and peripheral anticholinergic symptoms. Physostigmine given intravenously resulted in rapid reversal of symptoms. Thorn apple seeds had been accidentally ingested and were identified as the cause.

Anticholinergic toxicity is commonly encountered in the emergency department. However, the availability of physostigmine, a central acetylcholinesterase inhibitor used to reverse anticholinergic delirium, has been significantly limited due to national drug shortages in the United States. Several articles have explored the viability of rivastigmine as an alternative treatment in these patients. A 33-year-old man presented to the emergency department after a suspected suicide attempt. The patient was found with an empty bottle of diphenhydramine at the scene. On arrival, he was tachycardic and delirious, with dilated and nonreactive pupils and dry skin. As the clinical picture was highly suggestive of anticholinergic toxicity, the patient was treated with oral rivastigmine at a starting dose of 4.5 mg to reverse his anticholinergic delirium. Although a repeat dose was required, his delirium resolved without recurrence. Why Should an Emergency Physician Be Aware of This? Oral rivastigmine has been applied successfully here and in other case reports to reverse anticholinergic delirium with the benefit of prolonged agitation control. Emergency physicians may consider this medication in consultation with a specialist, with initial doses starting at 4.5–6 mg, if encountering anticholinergic delirium when physostigmine is not available. [ABSTRACT FROM AUTHOR]

AbstractTreatment of antimuscarinic toxicity has become more difficult in the United States due to an ongoing national shortage of physostigmine. Rivastigmine has emerged as an alternative, off-label therapy due to its similar mechanism of action as a reversible, centrally-acting acetylcholinesterase inhibitor. We present a case of a diphenhydramine overdose where the patient exhibited classic central antimuscarinic delirium characterized by inattention, floccillation, and deficits in spatial planning manifested by the inability to properly draw a clock. These symptoms rapidly resolved after treatment with oral rivastigmine.

ObjectiveRecent clinical trials targeting amyloid beta (Aβ) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments.BackgroundAD and DS share several characteristic manifestations. DS is caused by trisomy of whole or part of chromosome 21; this chromosome contains about 233 protein-coding genes, including APP. Recent evidence points to a defining role for increased expression of the gene for APP and for its 99 amino acid C-terminal fragment (C99, also known as β-CTF) in dysregulating the endosomal/lysosomal system. The latter is critical for normal cellular function and in neurons for transmitting neurotrophic signals.New/updated hypothesisWe hypothesize that the increase in APP gene dose in DS initiates a process in which increased levels of full-length APP (fl-APP) and its products, including β-CTF and possibly Aβ peptides (Aβ42 and Aβ40), drive AD pathogenesis through an endosome-dependent mechanism(s), which compromises transport of neurotrophic signals. To test this hypothesis, we carried out studies in the Ts65Dn mouse model of DS and examined the effects of Posiphen, an orally available small molecule shown in prior studies to reduce fl-APP. In vitro, Posiphen lowered fl-APP and its C-terminal fragments, reversed Rab5 hyperactivation and early endosome enlargement, and restored retrograde transport of neurotrophin signaling. In vivo, Posiphen treatment (50 mg/kg/d, 26 days, intraperitoneal [i.p.]) of Ts65Dn mice was well tolerated and demonstrated no adverse effects in behavior. Treatment resulted in normalization of the levels of fl-APP, C-terminal fragments and small reductions in Aβ species, restoration to normal levels of Rab5 activity, reduced phosphorylated tau (p-tau), and reversed deficits in TrkB (tropomyosin receptor kinase B) activation and in the Akt (protein kinase B [PKB]), ERK (extracellular signal-regulated kinase), and CREB (cAMP response element-binding protein) signaling pathways. Remarkably, Posiphen treatment also restored the level of choline acetyltransferase protein to 2N levels. These findings support the APP gene dose hypothesis, point to the need for additional studies to explore the mechanisms by which increased APP gene expression acts to increase the risk for AD in DS, and to possible utility of treatments to normalize the levels of APP and its products for preventing AD in those with DS.Major challenges for the hypothesisImportant unanswered questions are: (1) When should one intervene in those with DS; (2) would an APP-based strategy have untoward consequences on possible adaptive changes induced by chronically increased APP gene dose; (3) do other genes present on chromosome 21, or on other chromosomes whose expression is dysregulated in DS, contribute to AD pathogenesis; and (4) can one model strategies that combine the use of an APP-based treatment with those directed at other AD phenotypes including p-tau and inflammation.Linkage to other major theoriesThe APP gene dose hypothesis interfaces with the amyloid cascade hypothesis of AD as well as with the genetic and cell biological observations that support it. Moreover, upregulation of fl-APP protein and products may drive downstream events that dysregulate tau homeostasis and inflammatory responses that contribute to propagation of AD pathogenesis.

Loss of neuropeptide Y (NPY)-expressing interneurons in the hippocampus and decaying cholinergic neuromodulation are thought to contribute to impaired cognitive function during aging. However, the interaction of these two neuromodulatory systems in maintaining hippocampal synaptic plasticity during healthy aging has not been explored so far. Here we report profound sex differences in the Neuropeptide-Y (NPY) levels in the dorsal dentate gyrus (DG) with higher NPY concentrations in the male mice compared to their female counterparts and a reduction of NPY levels during aging specifically in males. This change in aged males is accompanied by a deficit in theta burst-induced long-term potentiation (LTP) in the medial perforant path-to-dorsal DG (MPP-DG) synapse, which can be rescued by enhancing cholinergic activation with the acetylcholine esterase blocker, physostigmine. Importantly, NPYergic transmission is required for this rescue of LTP. Moreover, exogenous NPY application alone is sufficient to recover LTP induction in aged male mice, even in the absence of the cholinergic stimulator. Together, our results suggest that in male mice NPYergic neurotransmission is a critical factor for maintaining dorsal DG LTP during aging. [ABSTRACT FROM AUTHOR]

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.

The synaptic homeostasis theory of sleep proposes that low neurotransmitter activity in sleep optimizes memory consolidation. We tested this theory by asking whether increasing acetylcholine levels during early sleep would weaken motor memory consolidation. We trained separate groups of adult mice on the rotarod walking task and the single pellet reaching task, and after training, administered physostigmine, an acetylcholinesterase inhibitor, to increase cholinergic tone in subsequent sleep. Post-sleep testing showed that physostigmine impaired motor skill acquisition of both tasks. Home-cage video monitoring and electrophysiology revealed that physostigmine disrupted sleep structure, delayed non-rapid-eye-movement sleep onset, and reduced slow-wave power in the hippocampus and cortex. Additional experiments showed that: (1) the impaired performance associated with physostigmine was not due to its effects on sleep structure, as 1 h of sleep deprivation after training did not impair rotarod performance, (2) a reduction in cholinergic tone by inactivation of cholinergic neurons during early sleep did not affect rotarod performance, and (3) stimulating or blocking muscarinic and nicotinic acetylcholine receptors did not impair rotarod performance. Taken together, the experiments suggest that the increased slow wave activity and inactivation of both muscarinic and nicotinic receptors during early sleep due to reduced acetylcholine contribute to motor memory consolidation.

From 2019 to 2020, antihistamines were found in 15% of all US drug overdose deaths, often co-administered with fentanyl, with 3.6% of overdose deaths due to antihistamines alone. The most common antihistamine found in all these reported deaths is diphenhydramine, a ubiquitous, over-the-counter and clinically important medication. Currently, there is no antidote for diphenhydramine overdose. This review summarizes the adverse health effects and current emergency medicine treatments for diphenhydramine. Several emergency medicine case reports are reviewed, and the efficacy and outcomes of a variety of treatments are compared. The treatments reviewed include the more traditional antihistamine overdose therapeutics physostigmine and sodium bicarbonate, as well as newer ones such as donepezil, dexmedetomidine, and lipid emulsion therapy. We conclude that more study is needed to determine the ideal therapeutic approach to treating antihistamine overdoses.

Treatment of antimuscarinic toxicity has become more difficult in the United States due to an ongoing national shortage of physostigmine. Rivastigmine has emerged as an alternative, off-label therapy due to its similar mechanism of action as a reversible, centrally-acting acetylcholinesterase inhibitor. We present a case of a diphenhydramine overdose where the patient exhibited classic central antimuscarinic delirium characterized by inattention, floccillation, and deficits in spatial planning manifested by the inability to properly draw a clock. These symptoms rapidly resolved after treatment with oral rivastigmine. [ABSTRACT FROM AUTHOR]

Antimuscarinic delirium (AD), a potentially life-threatening condition frequently encountered by emergency physicians, results from poisoning with antimuscarinic agents. Treatment with physostigmine and benzodiazepines is the mainstay of pharmacotherapy, and use of dexmedetomidine and non-physostigmine centrally-acting acetylcholinesterase inhibitors (cAChEi) such as rivastigmine has also been described. Unfortunately, these medications are subject to drug shortages which negatively impact the ability to provide appropriate pharmacologic treatment of patients with AD. Drug shortage data were retrieved from the University of Utah Drug Information Service (UUDIS) database from January 2001 through December 2021. Shortages of first-line agents used to treat AD (physostigmine and parenteral benzodiazepines) and second-line agents (dexmedetomidine and non-physostigmine cAChEi) were examined. Drug class, formulation, route of administration, reason for shortage, shortage duration, generic status, and whether the drug was a single-source product (made by only one manufacturer) were extracted. Shortage overlap and median shortage durations were calculated. Twenty-six shortages impacting drugs used to treat AD were reported to UUDIS from January 1, 2001 to December 31, 2021. Median shortage duration for all medication classes was 6.0 months. Four shortages were unresolved at the end of the study period. The single medication most often on shortage was dexmedetomidine, however benzodiazepines were the most common medication class on shortage. Twenty-five shortages involved parenteral formulations, and one shortage involved the transdermal patch formulation of rivastigmine. The majority (88.5%) of shortages involved generic medications, and 50% of products on shortage were single-source. The most common reported reason for shortage was a manufacturing issue (27%). Shortages were often prolonged and, in 92% of cases, overlapped temporally with other shortages. Shortage frequency and duration increased during the second half of the study period. Shortages of agents used in the treatment of AD were common during the study period and affected all agent classes. Shortages were often prolonged and multiple shortages were ongoing at study period end. Multiple concurrent shortages involving different agents occurred, which could hamper substitution as a means of mitigating shortage. Healthcare stakeholders must develop innovative patient- and institution-specific solutions in times of shortage and work to build resilience into the medical product supply chain to minimize future shortages of drugs used for treatment of AD. • Shortages of drugs used to treat antimuscarinic delirium are common. • Twenty-six shortages occurred from 2001 to 2021. • Shortages were often prolonged and overlapping. • Multiple drug classes were affected, hampering substitution. • Shortages may negatively impact patient care. [ABSTRACT FROM AUTHOR]

Introduction: Recurrent physostigmine shortages present a challenge to healthcare providers treating antimuscarinic delirium. Other centrally acting acetylcholinesterase inhibitors such as rivastigmine may represent a therapeutic alternative or adjunct during physostigmine shortage; however, previous reports of use have not documented serum antimuscarinic toxin concentrations, limiting evaluation of effectiveness. Combination therapy with physostigmine and rivastigmine has not been described. In this report, the authors present a case of diphenhydramine-induced antimuscarinic delirium with elevated diphenhydramine serum concentrations treated with physostigmine and transdermal rivastigmine without observed adverse effect. Case Report: A 48-year-old female presented to an emergency department after ingesting 3.75 g (41.2 mg/kg) of diphenhydramine. She had antimuscarinic delirium with a presenting serum diphenhydramine concentration of 1500 ng/mL (therapeutic range, 25–112 ng/mL) and required two doses of physostigmine to avert intubation prior to intensive care unit (ICU) admission. At hospital hour 22, in the ICU, antimuscarinic delirium persisted but no further physostigmine was available due to hospital shortage. Therefore, a 9.5-mg transdermal rivastigmine patch was applied. By hospital hour 24, her delirium had resolved. A serum diphenhydramine concentration at hospital hour 25 was elevated at 760 ng/mL. Transdermal rivastigmine was discontinued at hospital hour 48 without recurrent delirium. Despite persistent normal mental status after rivastigmine discontinuation, the patient had a dry mouth, difficulty urinating, and mydriasis until hospital day 5. She never developed muscarinic toxicity. Discussion: Transdermal rivastigmine may be a useful treatment alternative or adjunct during physostigmine shortage for antimuscarinic delirium and has a long duration of action without aspiration risk. Muscarinic toxicity was not observed. [ABSTRACT FROM AUTHOR]

Impaired consciousness is a frequent phenomenon after general anesthesia. In addition to the classical causes (e.g., overhang of sedatives), an impairment of consciousness can also be an adverse side effect of drugs. Many drugs used in anesthesia can trigger these symptoms. Alkaloids, such as atropine can trigger a central anticholinergic syndrome, opioids can promote the occurrence of serotonin syndrome and the administration of a neuroleptic can lead to neuroleptic malignant syndrome. These three syndromes are difficult to diagnose due to the individually very heterogeneous symptoms. Mutual symptoms, such as impaired consciousness, tachycardia, hypertension and fever further complicate the differentiation between the syndromes; however, more individual symptoms, such as sweating, muscle tension or bowl sounds can be helpful in distinguishing these syndromes. The time from the trigger event can also help to differentiate the syndromes. The central anticholinergic syndrome is the fastest to appear, usually taking just a few of hours from trigger to clinical signs, serotonin syndrome takes several hours up to 1 day to show and neuroleptic malignant syndrome usually takes days. The clinical symptoms can range from mild to life-threatening. Generally, mild cases are treated with discontinuation of the trigger and extended observation. More severe cases can require specific antidotes. The specific treatment recommended for central anticholinergic syndrome is physostigmine with an initial dose of 2 mg (0.04 mg/kg body weight, BW) administered over 5 min. For serotonin syndrome an initial dose of 12 mg cyproheptadine followed by 2 mg every 2 h is recommended (maximum 32 mg/day or 0.5 mg/kgBW day−1) but this medication is only available in Germany as an oral formulation. For neuroleptic malignant syndrome 25–120 mg dantrolene (1–2.5 mg/kgBW maximum 10 mg/kgBW day−1) is the recommended treatment. [ABSTRACT FROM AUTHOR]

Physostigmine (Phs) is a reversible inhibitor of acetylcholinesterase (AChE) that penetrates the blood–brain barrier (BBB) and could be used to protect the central nervous system (CNS) against the effects of nerve agents. For prophylactic effectiveness, long, steady, and adequate inhibition of AChE activity by Phs is needed to broadly protect against the CNS effects of nerve agents. Here, we evaluated the efficacy of transdermal patches containing Phs and procyclidine (PC) as prophylactic agents. Patches (25 cm2) containing 4.4 mg Phs and 17.8 mg PC had a protective ratio of approximately 78.6-fold in rhesus monkeys challenged with VX nerve agent and given an antidote. Physiologically based pharmacokinetic model in conjunction with an indirect pharmacodynamic (PBPK/PD) was developed for Phs and scaled to rhesus monkeys. The model was able to reproduce the concentration profile and inhibitory effect on AChE of Phs in monkeys, as evidenced by correlation coefficients of 0.994 and 0.992 for 25 cm2 and 49 cm2 patches, respectively (i.e., kinetic data), and 0.989 and 0.968 for 25 cm2 and 49 cm2 patches, respectively (i.e., dynamic data). By extending the monkey PBPK/ PD model to humans, the effective human dose was predicted to be five applications of a 25 cm2 patch (i.e., 22 mg Phs), and two applications of a 49 cm2 patch (i.e., 17.4 mg Phs). Therefore, given that patch application of Phs in rhesus monkeys has a prolonged effect (namely, AChE inhibition of 19.6% for the 25 cm2 patch and 23.0% for the 49 cm2 patch) for up to 216 h, patch formulation of Phs may provide similar protection against nerve agent intoxication in humans. [ABSTRACT FROM AUTHOR]

AbstractGlycopyrronium is an antimuscarinic drug that is available in a moist towelette preparation for the treatment of primary axillary hyperhidrosis, which is characterized by excessive sweating on the palms, soles of feet, and axillary region. Antimuscarinic toxicity is uncommon with therapeutic use. A 25-year-old female presented to the emergency department with urinary retention and visual changes after initiating topical glycopyrronium tosylate therapeutically. She was tachycardic with a heart rate of 115 beats/min and required a Foley catheter for urinary retention of over 1200 mL. She received 1.5 mg physostigmine for antimuscarinic symptoms and her heart rate improved. Despite treatment, she required a Foley catheter for four days with eventual improvement. This case demonstrates side effects of an unusual preparation of glycopyrronium and the need to take a detailed topical medication history in patients with antimuscarinic symptoms.

Anticholinergics are substances that antagonize the activity of the neurotransmitter acetylcholine. Anticholinergic syndrome (AS) occurs following a suicidal overdose, accidental drug intake, drug incompatibilities, and intake of multiple drugs simultaneously. Herein, we present two patients who were brought to the emergency room in a delirium state and were diagnosed with AS, presented other symptoms of anticholinergic toxidrome, and were treated with physostigmine.

The asexual freshwater planarian Dugesia japonica has emerged as a medium-throughput alternative animal model for neurotoxicology. We have previously shown that D. japonica are sensitive to organophosphorus pesticides (OPs) and characterized the in vitro inhibition profile of planarian cholinesterase (DjChE) activity using irreversible and reversible inhibitors. We found that DjChE has intermediate features of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Here, we identify two candidate genes (Djche1 and Djche2) responsible for DjChE activity. Sequence alignment and structural homology modeling with representative vertebrate AChE and BChE sequences confirmed our structural predictions, and show that both DjChE enzymes have intermediate sized catalytic gorges and disrupted peripheral binding sites. Djche1 and Djche2 were both expressed in the planarian nervous system, as anticipated from previous activity staining, but with distinct expression profiles. To dissect how DjChE inhibition affects planarian behavior, we acutely inhibited DjChE activity by exposing animals to either an OP (diazinon) or carbamate (physostigmine) at 1 µM for 4 days. Both inhibitors delayed the reaction of planarians to heat stress. Simultaneous knockdown of both Djche genes by RNAi similarly resulted in a delayed heat stress response. Furthermore, chemical inhibition of DjChE activity increased the worms' ability to adhere to a substrate. However, increased substrate adhesion was not observed in Djche1/Djche2 (RNAi) animals or in inhibitor-treated day 11 regenerates, suggesting this phenotype may be modulated by other mechanisms besides ChE inhibition. Together, our study characterizes DjChE expression and function, providing the basis for future studies in this system to dissect alternative mechanisms of OP toxicity.

Central cholinergic systems regulate the hypothalamic-pituitary-adrenal (HPA) axis differentially in males and females (sexual diergism). We previously investigated the role of muscarinic receptors in this regulation by administering physostigmine (PHYSO), an acetylcholinesterase inhibitor, to male and female rats pretreated with scopolamine (SCOP), a nonselective muscarinic antagonist. SCOP pretreatment enhanced adrenocorticotropic hormone (ACTH) and corticosterone (CORT) responses in both sexes, but males had greater ACTH responses while females had greater CORT responses. In the present study, we further explored the role of muscarinic receptor subtypes in HPA axis regulation by administering PHYSO to male and female rats following SCOP or various doses of either the M1 or the M2 selective muscarinic receptor antagonists, pirenzepine (PIREN) or methoctramine (METHO). Blood was sampled before and at multiple times after PHYSO. ACTH and CORT were determined by highly specific immunoassays. M1 antagonism by PIREN prior to PHYSO resulted in sustained, dose-dependent increases in ACTH and CORT: ACTH responses were similar in both sexes, and CORT responses were greater in females. M2 antagonism by METHO prior to PHYSO resulted in overall decreases in ACTH and CORT: ACTH and CORT responses were higher in females but lower in both sexes than the hormone responses following PIREN or SCOP pretreatment. Area under the curve analyses supported these findings. These results suggest that specific muscarinic receptor subtypes differentially influence the HPA axis in a sexually diergic manner.

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. 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. 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. [ABSTRACT FROM AUTHOR]

Included on the World Health Organization Model Lists of Essential Medicines, atropine remains a cornerstone medication that is used for a myriad of clinical indications. Systemically, atropine carries indications for the treatment of asymptomatic and symptomatic bradycardia, reduction of salivation and bronchial secretions prior to surgery, and as an antidote for a variety of poisoning agents (i.e., carbamate or organophosphate insecticides, nerve agents, muscarine-containing mushrooms). Topically, atropine is administered via the ophthalmic route for the treatment of cycloplegia, mydriasis, and amblyopia or may be administered sublingually to treat chronic sialorrhea. As an anticholinergic, supratherapeutic concentrations of atropine result in a toxidrome typical of other anticholinergic medication overdoses. However, it is easy to overlook atropine as the causative agent when being administered topically, potentially resulting in an unnecessarily extensive and complicated workup. This case report describes the systemic absorption of atropine administered through the ophthalmic route at normal doses, resulting in stroke-like symptoms in an adolescent male. Upon identifying that the patient was being treated with atropine ophthalmic drops prior to hospital arrival, a dose of intravenous physostigmine was administered, resulting in complete reversal of all toxidrome symptoms. [ABSTRACT FROM AUTHOR]

The effect of dose-dependent activation of cholinoreactive structures on the severity of sinus bradycardia occurring in some intact newborn rats during the first weeks after birth was analyzed in non-narcotized one-day-old (P1) and 16-day-old (P16) rats. The parameters of low-amplitude bradycardic oscillations of heart rhythm in norm and after administration of the acetylcholinesterase inhibitor physostigmine (eserine) in different doses (1/100, 1/10, and 3/4LD50) to rats were studied. The maximum increase in the power of low-amplitude brady-cardic oscillations was achieved during moderate activation of cholinoreactive structures after injection of eserine in a dose of 1/10LD50. Further increase in acetylcholine level led to disappearance of the sinus rhythm and development of pathological bradycardia. The data obtained indicate the immaturity of the mechanisms of heart rhythm regulation in rats immediately after birth. During activation of cholinoreactive structures, the severity of bradycardia oscillations increases exponentially at P1 and has an inverse exponential character at P16, which indicates a high risk of cardiac rhythmogenesis disorders and dysrhythmia development in newborn rats under conditions of excessive enhancement of cholinergic activation. [ABSTRACT FROM AUTHOR]

Physostigmine, or eserine, is an alkaloid found in the Calabar bean (eséré), Physostigma venenosum (Balfour). The scientific discovery of physostigmine played a pivotal role in our understanding of chemical neurotransmission and the emergence of pharmacology as a science. The Efik people of Old Calabar, in present day Cross River State of Nigeria, used the bean as an ordeal poison to determine if persons accused of certain allegations such as witchcraft were guilty or innocent. Scottish missionaries working in Old Calabar witnessed eséré ordeal trials and attended to patients inadvertently poisoned by the plant. Perplexed by the ordeal trials and concerned for their patients, the missionaries sent reports of their observations and samples of the beans to scientists back in Britain for study. Evaluations of the plant material for its chemical constituents and biological activity led to the discovery of its active principle, physostigmine. Further explorations with physostigmine led to the discovery of acetylcholine and chemical neurotransmission, and the Nobel Prize for Physiology or Medicine in 1936. From a classic practice of ethno-jurisprudence, the world came to understand the chemical basis of synaptic transmission, and the nature of substrate-enzyme and ligand-receptor interactions as underlying principles in biochemistry and pharmacology. Numerous medicines including physostigmine have been developed based on these principles and are being used in current pharmacotherapy. The rich history of eséré plant and its physostigmine alkaloid anchors a compelling story of the role natural products have played in the discovery of modern therapeutic agents. Moreover, the story highlights the reality that probably many more medicinal plants in Africa remain to be explored for their chemical constituents as potential leads in breakthrough drug discovery. [ABSTRACT FROM AUTHOR]

Audience: Emergency medicine residents, internal medicine residents, family medicine residents, community physicians, pediatricians, toxicology fellows Introduction: There are over 600 compounds which contain anticholinergic properties.1 Medications with anticholinergic properties include antihistamines, atropine, tricyclic antidepressants, antipsychotics, topical mydriatics, antispasmodics, sleep aids, and cold preparations.1-4 Plants that possess anticholinergic properties such as jimson weed, and street drugs cut with anticholinergics such as scopolamine are sources of accidental or intentional ingestion.1,2,4 Anticholinergic toxicity can cause a myriad of signs and symptoms, including agitation, seizures, hyperthermia, cardiac dysrhythmias, and death. Since poisoning from anticholinergic medications is frequently encountered in the emergency department, is it essential that emergency physicians be familiar with how to manage this toxidrome. This simulation case will allow the learner to evaluate and manage a patient presenting with anticholinergic toxicity. Educational Objectives: By the end of this simulation case, learners will be able to: 1) describe the classic clinical presentation of anticholinergic toxicity, 2) discuss common medications and substances that may lead to anticholinergic toxicity, 3) recognize the electrocardiogram (ECG) findings in anticholinergic toxicity that require specific therapy, and 4) review the management of anticholinergic toxicity. Educational Methods: This simulation is taught using a high-or moderate-fidelity manikin. Research Methods: The educational content was evaluated by the learners immediately after completion and debriefing of the scenario. This case was initially piloted with approximately twenty emergency medicine residents. The group was comprised of first, second-, and third-year residents from a three-year emergency medicine residency. The efficacy of the content was assessed by oral feedback. Results: Overall, the case was well received by learners, who felt it was useful and were engaged throughout the session. The overall feedback was positive and the case was well-received by learners. Discussion: This scenario was eventually tested on over 100 learners over the course of several years, and the overall feedback was positive. It was found to be effective when debriefing sessions using various debriefing techniques (such as advocacy/inquiry) were utilized to discuss both the learners' performance in the case, as well as the debriefing pearls (located at the end of this manuscript). Topics: Anticholinergic toxicity, altered mental status, toxicology. [ABSTRACT FROM AUTHOR]

Introduction Anticholinergic syndrome (AS) is a complication that can appear due to different drugs with antimuscarinic effects, such as antihistamines, alkaloids, antipsychotics, tricyclic antidepressives or anesthetics, and it is characterized by urinary retention, dry mouth and skin, mydriasis, low-grade fever, and confusion or coma. Objectives To describe a clinical case of AS admitted to our hospital. Methods We present a case report of a patient with schizophrenia who presented an anticholinergic syndrome. We also searched for previous studies of AS using a pubmed query. Results A 53-year-old male was admitted for a psychotic decompensation to another hospital in Barcelona. The usual treatment at home was amisulpride 1200mg/d, olanzapine 30mg/d and lormetazepam, and haloperidol 6mg/d and clotiapine 40mg/d were added to treat the decompensation. Then, the patient started to present mydriasis, mucocutaneous dryness, low-grade fever, slight hypertension and tachycardia, repeated retentions of urine, confusion, unintelligible speech and agitation, so he was referred to our hospital. Once he was admitted, haloperidol was withdrawn and support measures (bladder catheterization, fluid therapy, etc.) were applied. After a few days, most of the mentioned alterations were stabilized, but the psychotic symptoms, such as thought and behavioural disorganization, persisted and required electroconvulsive therapy, with subsequent improvement. Conclusions AS is a relatively frequent side effect of psychiatric medication, which diagnosis is clinical, so, we must be capable to identify it and initiate early treatment to prevent possible complications. The first step, as reflected in the case described, is to stop the causative drugs, and apply support measures. Additionally, physostigmine can be used, as it is an effective antidote. Disclosure No significant relationships.

The article focuses on toxicology and presents advice for emergency clinicians. Topics include the importance of seeking support from readily accessible resources and treating illicit drugs with supportive care; and the use of activated charcoal, the administration of naloxone in opioid overdose cases along with guidance on the use of sodium bicarbonate in the treatment of toxic ingestions.

Atropa belladonna (deadly nightshade) is a poisonous herb that can be especially seen in Northern regions of our country and cause anticholinergic toxic syndrome (ATS) when consumed. ATS can be seen when consuming the plant which contains atropine or in overdose of psychoactive drugs containing atropine (such as antipsychotics, tricyclic antidepressants). A 65-year-old female patient was admitted to emergency service with the clinic of agitation, speech disorder and consciousness change. It was learned that she consumed atropa belladonna fruits about an hour ago. She was followed up with the diagnosis of ATS and treated with conservative approach. A 58-year-old male patient was admitted to the emergency servise due to impaired consciousness, agitation, difficulty in speaking, vomiting and fever. He also ate the same fruits with his relative, case 1. He also followed up with a diagnosis of ATS and treated with both conservative approach and physostigmine. Consuming atropa belladonna fruits and leaves can lead to ATS and life-threatening consequences can be seen in severe toxicity. Early diagnosis and treatment are important in prognosis. Physostigmine must be kept in mind in cases who does not benefit from conservative approach. [ABSTRACT FROM AUTHOR]

Abstract Hyoscine butylbromide–induced pyschosis, though rare, should be considered in a child presenting with deteriorating cognitive functions and psychotic features acutely as evident in our case of a 9‐year‐old child taking hyoscine for her non‐specific abdominal pain.

Hyoscyamus niger, commonly known as henbane, contains potent alkaloids that can cause anticholinergic toxicity when ingested. This case report describes a 35-year-old male gardener who presented with confusion, hallucinations, dry mouth, and dilated pupils after consuming parts of the plant. The patient was treated with rehydration, activated charcoal, and physostigmine, leading to rapid clinical improvement. This case highlights the importance of recognizing plant-based poisonings and the efficacy of physostigmine in managing anticholinergic syndrome. Public awareness and education on the dangers of unfamiliar plants are essential to prevent accidental ingestions., Competing Interests: Declaration of conflicting interestsThe author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Glycopyrronium is an antimuscarinic drug that is available in a moist towelette preparation for the treatment of primary axillary hyperhidrosis, which is characterized by excessive sweating on the palms, soles of feet, and axillary region. Antimuscarinic toxicity is uncommon with therapeutic use. A 25-year-old female presented to the emergency department with urinary retention and visual changes after initiating topical glycopyrronium tosylate therapeutically. She was tachycardic with a heart rate of 115 beats/min and required a Foley catheter for urinary retention of over 1200 mL. She received 1.5 mg physostigmine for antimuscarinic symptoms and her heart rate improved. Despite treatment, she required a Foley catheter for four days with eventual improvement. This case demonstrates side effects of an unusual preparation of glycopyrronium and the need to take a detailed topical medication history in patients with antimuscarinic symptoms. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to assess the influence of adrenomedullary secretion on the plasma glucose, lactate, and free fatty acids (FFAs) during running exercise in rats submitted to intracerebroventricular (i.c.v.) injection of physostigmine (PHY). PHY i.c.v. was used to activate the central cholinergic system. Methods: Wistar rats were divided into sham-saline (sham-SAL), sham-PHY, adrenal medullectomy-SAL, and ADM-PHY groups. The plasma concentrations of glucose, lactate, and FFAs were determined immediately before and after i.c.v. injection of 20 μL of SAL or PHY at rest and during running exercise on a treadmill. Results: The i.c.v. injection of PHY at rest increased plasma glucose in the sham group, but not in the ADM group. An increase in plasma glucose, lactate, and FFAs mobilization from adipose tissue was observed during physical exercise in the sham-SAL group; however, the increase in plasma glucose was greater with i.c.v. PHY. Moreover, the hyperglycemia induced by exercise and PHY in the ADM group were blunted by ADM, whereas FFA mobilization was unaffected. Conclusion: These results indicate that there is a dual metabolic control by which activation of the central cholinergic pathway increases plasma glucose but not FFA during rest and exercise, and that this hyperglycemic response is dependent on adrenomedullary secretion. [ABSTRACT FROM AUTHOR]

Anticholinergics are substances that antagonize the activity of the neurotransmitter acetylcholine. Anticholinergic syndrome (AS) occurs following a suicidal overdose, accidental drug intake, drug incompatibilities, and intake of multiple drugs simultaneously. Herein, we present two patients who were brought to the emergency room in a delirium state and were diagnosed with AS, presented other symptoms of anticholinergic toxidrome, and were treated with physostigmine. [ABSTRACT FROM AUTHOR]