Rivastigmine for the management of anticholinergic delirium.

INTRODUCTION: Anticholinergic agents are commonly taken in overdose, often causing delirium. The spectrum of anticholinergic delirium ranges from mild agitation to severe behavioural disturbance. Physostigmine is an effective treatment for anticholinergic delirium, but its availability is limited. As rivastigmine is readily available, it has been used to manage anticholinergic delirium; however, there is limited research investigating its use. METHOD: This was a retrospective review of patients with anticholinergic delirium treated in two toxicology units with rivastigmine (oral capsule or transdermal patch) from January 2019 to June 2023. The primary outcome was the use of further parenteral treatment (sedation or physostigmine) for delirium post rivastigmine administration. RESULTS: Fifty patients were administered rivastigmine for the management of anticholinergic delirium. The median age was 36 years (interquartile range: 25-49 years) and 27 (54 per cent) were females. Features consistent with anticholinergic toxicity included tachycardia in 44 (88 per cent) and urinary retention requiring catheterisation in 40 (80 per cent). Forty-three patients (86 per cent) were treated with physostigmine before rivastigmine administration. Twenty-two were managed with transdermal rivastigmine (most commonly 9.5 mg/24 hour patch), and 28 with oral rivastigmine 6 mg. Further parenteral sedation and/or physostigmine treatment were required more often in patients given transdermal than oral rivastigmine [16/22 (73 per cent) versus 9/28 (32 per cent), P = 0.010)]. No patients had bradycardia or gastrointestinal symptoms following rivastigmine administration. One patient with a history of epilepsy had a seizure, 1.5 hours post physostigmine administration and 7 hours post transdermal rivastigmine. DISCUSSION: Rivastigmine has been increasingly used for the management of patients with anticholinergic delirium, due to the lack of availability of physostigmine. In this case series, rivastigmine transdermal patch appeared to be less effective than oral rivastigmine capsules, likely due to its slow onset of action and/or insufficient dose. CONCLUSION: Rivastigmine can be used to treat anticholinergic delirium. In our case series oral rivastigmine appeared more effective than transdermal rivastigmine.

[Eserine, in Crooked House and Curtain].

Eserine, well-known as physostigmine, is classified as an alkaloid. It is a cholinesterase inhibitor and appears in Agatha Christie's novel entitled, Crooked House and Curtain: Poirot's Last Case. In clinical medicine, eserine was used as an ophthalmic treatment for glaucoma and considered as a treatment for myasthenia gravis, Alzheimer's disease, and hereditary cerebellar ataxias. Currently, it is used as a treatment for anticholinergic poisoning.

Oral and Transdermal Rivastigmine for the Treatment of Anticholinergic Delirium: A Case Report.

BACKGROUND: Anticholinergic toxicity is a common cause of delirium in emergency department patients. The standard antidotal treatment for anticholinergic toxicity is physostigmine. Physostigmine functions as a reversible acetylcholinesterase inhibitor that readily crosses the blood-brain barrier. Rivastigmine is another member of this class currently approved for the treatment of Alzheimer's disease and Parkinson's disease. Rivastigmine also crosses the blood-brain barrier and has been found to be effective in the management of anticholinergic toxicity in limited case reports. CASE REPORT: A 61-year-old women presented to the emergency department via emergency medical services with altered mental status and a Glasgow Coma Scale score of 8 out of 15. She was found down near multiple medication bottles, including diphenhydramine and dicyclomine. Her physical examination was consistent with anticholinergic toxicity with mydriasis, obtundation, and warm flushed skin. In addition to standard resuscitation, she received two doses of rivastigmine 3 mg via nasogastric tube. After the second dose she was alert and oriented. She was admitted to the intensive care unit and had a rivastigmine patch applied. She was deemed back to her baseline 27 h after presentation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although the standard antidotal treatment for anticholinergic toxicity is physostigmine, there is a national shortage of this medication. In the absence of this standard antidote, it is reasonable for emergency physicians to use rivastigmine as an alternative treatment. This can be delivered orally or via nasogastric tube with dosing each hour until resolution of symptoms. Alternatively, in consultation with toxicology, it may be reasonable to use transdermal rivastigmine, as it provides consistent drug absorption for 24 h.

Diphenhydramine-Induced Antimuscarinic Delirium Treated with Physostigmine and Transdermal Rivastigmine.

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.

Electroacupuncture Ameliorates Depressive-Like State and Synaptic Deficits Induced by Hyper-Cholinergic Tone During Chronic Stress in Rats.

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.

Pharmacological support to anti-arthritic prospective of physostigmine: a new approach.

Rheumatoid arthritis (RA) is a slowly progressing inflammatory autoimmune disease. Several features are involved in the RA pathogenesis in addition to environmental and genetic factors. Previously it has been reported that acetyl cholinesterase (AChE) activity is enhanced in old age and may contribute in the progression of RA. The current experimental work was projected to assess the activity of physostigmine (a cholinesterase inhibitor) for treatment of RA. In vitro and in vivo approaches were used for such evaluation. However, enzyme linked immunosorbent assays (ELISA) was performed to determine the concentrations of Prostaglandins E2 (PGE2) and tumor necrosis factor-α in arthritic rats after treatment with physostigmine. Moreover, anti-oxidant assays were employed to calculate the level of super oxide dismutase (SOD) and catalase peroxidase (CAT) in tissue of treated animals. The results claimed the dose dependent protective and stabilizing effect of physostigmine on denaturation of albumin (egg and bovine serum) protein and human red blood cell membrane, respectively, through in vitro studies. Furthermore, the physostigmine (10 and 20 mg/kg) significantly (p < 0.001) reduced the swelling of paw after induction of arthritis with formaldehyde or complete Freund's adjuvant (CFA) as compared to arthritic control animals. Moreover, significant (p < 0.001) reduction in the levels of inflammatory markers (PGE2 and TNF-α) at doses of 10 and 20 mg/kg of physostigmine has been observed in ELISA test. Likewise, there was a prominent rise in levels of SOD and CAT in animals treated with physostigmine. These findings pharmacologically conclude the anti-arthritic effect of physostigmine.

The Use of Physostigmine in the Diagnosis and Treatment of Anticholinergic Toxicity After Olanzapine Overdose: Literature Review and Case Report.

BACKGROUND: Second-generation antipsychotic agents are commonly used by clinicians for the treatment of various psychiatric and medical conditions. Despite their presumed safety, an overdose with olanzapine may lead to the development of anticholinergic toxicity. The anticholinergic toxidrome is characterized by both central and peripheral physical findings. Central anticholinergic syndrome, a term used to describe the symptoms that arise from reduced cholinergic activity in the central nervous system, is characterized primarily by signs and symptoms consistent with hyperactive delirium. Signs of peripheral anticholinergia include mydriasis and blurred vision, tremors, ataxia, fever/hyperthermia, flushed and dry skin, dry oral mucosa, decreased bowel sounds, constipation, and urinary retention, among other symptoms. In extreme cases, central anticholinergic syndrome can be associated with seizures, coma, respiratory failure, and cardiovascular collapse. OBJECTIVE: To provide scientific evidence regarding the efficacy and safety of physostigmine use in cases of anticholinergic toxicity. METHODS: We conducted a comprehensive review of the published literature on the symptoms, diagnosis, and treatment of anticholinergic toxicity. RESULTS: Currently the recommended treatment for olanzapine overdose, as is the case of most severe anticholinergic toxicity cases, involves supportive care, along with cardiac, neurological, and respiratory status monitoring. In addition, we detail the symptoms characteristic of anticholinergic toxicity, using the case of a patient experiencing central anticholinergic syndrome after an overdose with olanzapine. CONCLUSION: Physostigmine, a tertiary acetylcholinesterase inhibitor, can be used to assist in the both the diagnosis and management of severe anticholinergic toxicity associated with an olanzapine overdose, which might be applicable to the antimuscarinic toxidrome associated with the ingestion of agents with significant anticholinergic activity.

The history of acetylcholinesterase inhibitors in the treatment of myasthenia gravis.

The beneficial effects of acetylcholinesterase inhibitors for the treatment of myasthenia gravis (MG) was a major discovery that came about through one young physician putting together a string of previous observations. To understand how this discovery came to light, we must first go back to earlier times when men hunted by bow-and-arrow to capture their prey. The substance used to poison the prey was eventually was identified as curare. Centuries later, a connection was made between the physiological effects of curare and a disease entity with no known pathological mechanism or treatment, myasthenia gravis. In 1935, house officer Dr. Mary Walker was the first physician to try physostigmine in the treatment of MG, which had previously been used to treat curare poisoning. What she saw was a dramatic improvement in the symptoms experienced in patients with MG, and thus became the first documented case of use of physostigmine, an acetylcholinesterase inhibitor, in the treatment of MG. This article is a summary of the history of the use of acetylcholinesterase inhibitors in the treatment of myasthenia gravis. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

A randomized trial comparing physostigmine vs lorazepam for treatment of antimuscarinic (anticholinergic) toxidrome.

BACKGROUND: Toxicity from antimuscarinic agents precipitates a constellation of signs and symptoms; two of the most significant are agitation and delirium. Benzodiazepines are commonly used for treatment; physostigmine is also effective but is underutilized due to concerns for safety and short duration of action. The objective of this study was to compare lorazepam to physostigmine for the treatment of antimuscarinic delirium and agitation. METHODS: This was a blinded, randomized clinical trial in patients presenting for antimuscarinic toxidrome. Inclusion criteria were: ≥10-<18 years old, at least one central and two peripheral antimuscarinic symptoms, delirium and moderate agitation. Subjects were randomized to either (1) lorazepam bolus (0.05 mg/kg) followed by a 4-h normal saline infusion, or (2) physostigmine 0.02 mg/kg bolus followed by a 4-h physostigmine infusion (0.02 mg/kg/h). Primary outcomes were the control of delirium and agitation after bolus and during the infusion. RESULTS: Ten (53%) subjects were enrolled in the lorazepam arm, 9 (47%) in the physostigmine arm. Diphenhydramine was the most common agent ingested (16, 84%). Fewer patients receiving physostigmine had delirium after the initial bolus (44% vs 100%, p = 0.01) and at the 4th hour of infusion (22% vs 100%, p < 0.001) compared to patients who received lorazepam. There was a significant decrease in agitation scores in the physostigmine arm compared to the lorazepam arm after the initial bolus (89% vs 30%, p = 0.02), but no difference at the 4th hour of infusion (p > 0.99). There were no seizures, bradycardia, bronchorrhea, bronchospasm, intubation, or cardiac dysrhythmias. CONCLUSION: Physostigmine was superior to lorazepam in controlling antimuscarinic delirium and agitation after bolus dosing, and control of delirium after a 4-h infusion. There were no serious adverse events in either treatment arm. Physostigmine bolus and infusion should be considered in adolescent patients with significant delirium and agitation from antimuscarinic agents.

Perioperative use of physostigmine to reduce opioid consumption and peri-incisional hyperalgesia: a randomised controlled trial.

BACKGROUND: Several studies have shown that cholinergic mechanisms play a pivotal role in the anti-nociceptive system by acting synergistically with morphine and reducing postoperative opioid consumption. In addition, the anti-cholinesterase drug physostigmine that increases synaptic acetylcholine concentrations has anti-inflammatory effects. METHODS: In this randomised placebo-controlled trial including 110 patients undergoing nephrectomy, we evaluated the effects of intraoperative physostigmine 0.5 mg h-1 i.v. for 24 h on opioid consumption, hyperalgesia, pain scores, and satisfaction with pain control. RESULTS: Physostigmine infusion did not affect opioid consumption compared with placebo. However, the mechanical pain threshold was significantly higher (2.3 [sd 0.3]) vs 2.2 [0.4]; P=0.0491), and the distance from the suture line of hyperalgesia (5.9 [3.3] vs 8.5 [4.6]; P=0.006), wind-up ratios (2.2 [1.5] vs 3.1 [1.5]; P=0.0389), and minimum and maximum postoperative pain scores at 24 h (minimum 1.8 [1.0] vs 2.4 [1.2]; P=0.0451; and maximum 3.2 [1.4] vs 4.2 [1.4]; P=0.0081) and 48 h (minimum 0.9 [1.0] vs 1.6 [1.1]; P=0.0101; and maximum 2.0 [1.5] vs 3.2 [1.6]; P=0.0029) were lower in the study group. Pain Disability Index was lower and satisfaction with pain control was higher after 3 months in the physostigmine group. CONCLUSIONS: In contrast to previous trials, physostigmine did not reduce opioid consumption. As pain thresholds were higher and hyperalgesia and wind-up lower in the physostigmine group, we conclude that physostigmine has anti-hyperalgesic effects and attenuates sensitisation processes. Intraoperative physostigmine may be a useful and safe addition to conventional postoperative pain control. CLINICAL TRIAL REGISTRATION: EudraCT number 2012-000130-19.

Prophylactic Physostigmine for Extreme and Refractory Adult Emergence Delirium, Aimed at Increasing Patient Safety and Reducing Health Care Workplace Violence: A Case Report.

Emergence delirium is a well-known phenomenon that may be encountered after general anesthesia. A common approach to this issue is to risk stratify patients preoperatively and treat them postoperatively if emergence delirium occurs. We present the case of a patient with Barrett esophagus and a history of severe and refractory emergence delirium, who was successfully treated prophylactically with physostigmine, resulting in decreased risk of harm to the patient, trauma to the perioperative staff, and a safer and more positive recovery.

[Update - intoxications in critical care medicine]. / Update ­ Intoxikationen in der Intensivmedizin.

While monitoring and symptomatic care is sufficient for most intoxicated patients, some develop life threatening symptoms. We present recent changes in the recommendations of the treatment in patients with calcium channel blocker, beta blocker and high dose paracetamol intoxications. Additionally, new insights in the efficacy and safety of the use of physostigmine in anticholinergic patients and beta blockers in cocaine intoxication are discussed as well as the specific considerations in the resuscitation of intoxicated patients.

[Analytical investigation of a suspected case of drug-facilitated crime]. / Säker och känslig analysmetodik viktig vid misstänkta fall av ofrivillig drogning.

Sometimes it is suspected that people have been involuntary exposed to drugs, usually by spiked drinks. A young woman was transported to an emergency department by ambulance. Her clinical symptoms (decreased consciousness, mydriasis, confusion, hallucinations and urine retention) indicated anticholinergic syndrome that was effectively treated with the antidote physostigmine. A urine sample tested negative for common narcotic drugs and alcohol, but an extended toxicological analysis of the urine revealed the presence of the alkaloid scopolamine. Scopolamine occurs naturally in Solanaceae plants and is used in some medications. The woman reported that the symptoms had appeared soon after she was offered tea by a male acquaintance. The analytical results along with the woman's story indicated that she had been subjected to a drug-facilitated crime. The results further demonstrate that in suspected cases of involuntary drug exposure, testing should cover a wide panel of relevant drugs, otherwise poisoning may be missed.

Computational insight into the anticholinesterase activities and electronic properties of physostigmine analogs.

Aim: Alzheimer's disease (AD) is known to be themajor cause of dementia among the elderly. The structural properties and binding interactions of the AD drug physostigmine (-)-phy, and its analogues (-)-hex and (-)-phe and (+)-phe, were examined, as well as their impact on the conformational changes of two different AD target enzymes AChE and BChE. Materials & methods: The conformational changes were studied using molecular dynamics and structural properties using Quantum mechanics. Results & conclusions: The binding free energy (ΔGbind) and the change in the free energy surface (FES) computed from the funnel metadynamics (FMD) simulation, both support the idea that inhibitors (-)-phe and (-)-hex have better binding activities toward enzyme AChE, and that (-)-phe is stronger in binding than the present AD drug (-)-phy.

Continuous infusion of physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling.

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 ±â€¯2.81 ng/mL (mean ±â€¯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 (EC50) 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.

(-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer's disease challenged mice.

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.

In Vivo Effects of Neostigmine and Physostigmine on Neutrophil Functions and Evaluation of Acetylcholinesterase and Butyrylcholinesterase as Inflammatory Markers during Experimental Sepsis in Rats.

INTRODUCTION: Recent studies have shown that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may serve as important diagnostic and therapeutic targets in sepsis. Since polymorphonuclear neutrophils (PMNs) play a pivotal role in the early phase of sepsis, we evaluated the potential therapeutic effects of cholinesterase inhibitors on PMN functions during cecal ligation and puncture- (CLP-) induced sepsis and investigated the roles of AChE and BChE as inflammatory markers under standardized experimental conditions. METHODS: Sham surgery or CLP was performed in male Wistar rats (n = 60). Animals were randomized into four groups: physostigmine, 100 µg/kg; neostigmine, 75 µg/kg; 0.9% saline (control group); and sham group, each applied four times over 24 h. The levels of reactive oxygen species (ROS) production and CD11b/CD62l expression were quantified by flow cytometry at t = 0, 6, 15, 20, and 24 h. Blood gas analysis as well as AChE and BChE activity levels was measured by validated point-of-care measurements. Clinical scores and survival times were determined. RESULTS: CLP induced a significant increase in ROS production and CD11b upregulation by rat PMNs. Treatment with physostigmine or neostigmine significantly reduced ROS production and CD11b upregulation by PMNs 20 h after CLP induction. In physostigmine-treated animals, survival times were significantly improved compared to the control animals, but not in neostigmine-treated animals. While AChE activity significantly decreased in the control animals at t > 6 h, AChE activity did not change in the sham group. BChE activity decreased at t > 20 h in the control animals. CONCLUSION: While AChE activity may serve as an acute inflammatory marker, BChE activity shows a delayed decrease. Administration of centrally acting physostigmine in CLP-induced sepsis in rats has protective effects on PMN functions and improves survival times, which may be of interest in clinical practice.

Datura and Brugmansia plants related antimuscarinic toxicity: an analysis of poisoning cases reported to the Taiwan poison control center.

INTRODUCTION: Datura and Brugmansia plants, especially Datura species, have been used for their hallucinogenic effects in the United States and Europe; whereas Datura plants have been used as a traditional medicine in many Asian countries. This study was conducted to better understand the pattern and outcome of Datura/Brugmansia plant related poisoning in Taiwan. METHODS: This is a retrospective case series study of all cases with Datura/Brugmansia exposure reported to the Taiwan Poison Control Center between 1986 and 2015. Data for patients with relevant poisoning were reviewed and abstracted. Logistic regression analysis was used to identify potential predictors of the severity of poisoning; bivariate analysis was employed to assess the effectiveness of physostigmine in the treatment of Datura/Brugmansia poisoning. RESULTS: A total of 203 cases involving 114 Datura exposures and 89 Brugmansia suaveolens exposures were eligible for analysis. Using Datura/Brugmansia for a medicinal purpose by the patients without consulting Chinese medicine practitioners was the most common reason of poisoning (81.2%); whereas only 2% of the patients were poisoned after medicinal use associated with the prescription from Chinese medicine practitioners. None of the 203 patients had used Datura/Brugmansia plant for recreational purpose. Most frequently observed clinical effect was mydriasis (53.2%), followed by confusion (40%), tachycardia (35.5%), dry mouth (35.5%), dizziness (34%), dry skin (32.5%), and delirium (31%). Seventy-three cases (36%) had severe effects; none of them died. Misidentification of the plants and ingestion of plant parts other than flowers were positively associated with the severity of poisoning. Forty patients (19.7%) received physostigmine therapy and patients receiving physostigmine had an earlier resolution of central nervous system toxicity than those who did not. CONCLUSIONS: Medicinal use without consulting Chinese medicine practitioners is the main reason for Datura/Brugmansia poisoning in Taiwan. Consumption of parts other than flowers and misidentification of the plants predicted the severity of poisoning in this study. Patients who received physostigmine appear to have earlier improvement in the central nervous system effects. No adverse events were reported from physostigmine administration.