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Chemical Communications (Cambridge,... Aug 2023Here, a redox-neutral palladium-catalyzed photo-induced radical cascade domino Heck reaction of -aryl acrylamide with vinyl arenes is described. A diverse range of...
Here, a redox-neutral palladium-catalyzed photo-induced radical cascade domino Heck reaction of -aryl acrylamide with vinyl arenes is described. A diverse range of bioactive oxindoles, featuring an all-carbon quaternary center, were synthesized. The reaction is proposed to proceed an open-shell intermediate and occurs under mild reaction conditions, exhibiting excellent functional group tolerance. Importantly, the synthesized products can be readily transformed into biologically active molecules, including (±)-physostigmine and (±)-physovenine.
PubMed: 37578259
DOI: 10.1039/d3cc03506a -
Chemistry & Biodiversity Aug 2023Cinnamomum species have applications in the pharmaceutical and fragrance industry for wide biological and pharmaceutical activities. The present study investigates the...
Cinnamomum species have applications in the pharmaceutical and fragrance industry for wide biological and pharmaceutical activities. The present study investigates the chemical composition of the essential oils extracted from two species of Cinnamomum namely C. tamala and C. camphora. Chemical analysis showed E-cinnamyl acetate (56.14 %), E-cinnamaldehyde (20.15 %), and linalool (11.77 %) contributed as the major compounds of the 95.22 % of C. tamala leaves essential oil found rich in phenylpropanoids (76.96 %). C. camphora essential oil accounting for 93.57 % of the total oil composition was rich in 1,8-cineole (55.84 %), sabinene (14.37 %), and α-terpineol (10.49 %) making the oil abundant in oxygenated monoterpenes (70.63 %). Furthermore, the acetylcholinesterase inhibitory activity for both the essential oils was carried out using Ellman's colorimetric method. The acetylcholinesterase inhibitory potential at highest studied concentration of 1 mg/mL was observed to be 46.12±1.52 % for C. tamala and 53.61±2.66 % for C. camphora compared to the standard drug physostigmine (97.53±0.63 %) at 100 ng/ml. These multiple natural aromatic and fragrant characteristics with distinct chemical compositions offered by Cinnamon species provide varied benefits in the development of formulations that could be advantageous for the flavor and fragrance industry.
Topics: Cinnamomum camphora; Cinnamomum; Acetylcholinesterase; Oils, Volatile; Pharmaceutical Preparations; Plant Leaves
PubMed: 37533252
DOI: 10.1002/cbdv.202300666 -
Journal of Research in Medical Sciences... 2023Diphenhydramine (DPH) is an antihistamine medication that in overdose can result in anticholinergic symptoms and serious complications, including arrhythmia and coma. We...
BACKGROUND
Diphenhydramine (DPH) is an antihistamine medication that in overdose can result in anticholinergic symptoms and serious complications, including arrhythmia and coma. We aimed to compare the value of various machine learning (ML) models, including light gradient boosting machine (LGBM), logistic regression (LR), and random forest (RF), in the outcome prediction of DPH poisoning.
MATERIALS AND METHODS
We used the National Poison Data System database and included all of the human exposures of DPH from January 01, 2017 to December 31, 2017, and excluded those cases with missing information, duplicated cases, and those who reported co-ingestion. Data were split into training and test datasets, and three ML models were compared. We developed confusion matrices for each, and standard performance metrics were calculated.
RESULTS
Our study population included 53,761 patients with DPH exposure. The most common reasons for exposure, outcome, chronicity of exposure, and formulation were captured. Our results showed that the average precision-recall area under the curve (AUC) of 0.84. LGBM and RF had the highest performance (average AUC of 0.91), followed by LR (average AUC of 0.90). The specificity of the models was 87.0% in the testing groups. The precision of models was 75.0%. Recall (sensitivity) of models ranged between 73% and 75% with an F1 score of 75.0%. The overall accuracy of LGBM, LR, and RF models in the test dataset was 74.8%, 74.0%, and 75.1%, respectively. In total, just 1.1% of patients (mostly those with major outcomes) received physostigmine.
CONCLUSION
Our study demonstrates the application of ML in the prediction of DPH poisoning.
PubMed: 37496638
DOI: 10.4103/jrms.jrms_602_22 -
Journal of Chromatography. B,... Jun 2023Carbamate pesticides are extensively used in agriculture for their inhibition to acetylcholinesterase and damages to the insects' neural systems. Because of their...
A retrospective screening method for carbamate toxicant exposure based on butyrylcholinesterase adducts in human plasma with ultra-high performance liquid chromatography-tandem mass spectrometry.
Carbamate pesticides are extensively used in agriculture for their inhibition to acetylcholinesterase and damages to the insects' neural systems. Because of their toxicity, human poisoning incidents caused by carbamate pesticide exposure have occurred from time to time. What's more, some lethally toxic carbamate toxicants known as carbamate nerve agents (CMNAs) have been supplemented in Schedule 1 of the Annex on Chemicals in the Chemical Weapons Convention (CWC) by Organisation of the Prohibition of Chemical Weapons (OPCW) from 2020. And some other carbamates, like physostigmine, have been used in clinical treatment as anticholinergic drugs and their misuse may also cause damages to the body. Similar to organophosphorus toxicants, carbamate toxicants would react with butyrylcholinesterase (BChE) in plasma when entering the human body, resulting in the BChE adducts, based on which the exposure of carbamate toxicants could be detected retrospectively. In this study, methylcarbamyl nonapeptide and dimethylcarbamyl nonapeptide from pepsin digestion of BChE adducts were identified with ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in product ion scan mode. Carbofuran was chosen as the target to establish the detection method of carbamate toxicant exposure based on methylcarbamyl nonapeptide digested from methylcarbamyl BChE. Procainamide-gel affinity purification, pepsin digestion and UHPLC-MS/MS analysis in multiple reaction monitoring (MRM) mode were applied. Under the optimized conditions of sample preparation and UHPLC-MS/MS MRM analysis, the limits of detection (LODs) reached 10.0 ng/mL of plasma exposed to carbofuran with satisfactory specificity. The quantitation approach was established with d-carbofuran-exposed plasma as the internal standard (IS) and the linearity range was 30.0-1.00 × 10 nmol/L (R >0.998) with the accuracy of 95.6%-107% and precision of ≤9% relative standard deviation (RSD). The applicability was also evaluated by N,N-dimethyl-carbamates with the LODs of 30.0 nmol/L for pirimicarb-exposed plasma based on dimethylcarbamyl nonapeptide. Because most of carbamate toxicants has methylcarbamyl or dimethylcarbamyl groups, this approach could be applied on the retrospective screening of carbamate toxicant exposure including CMNAs, carbamate pesticides or carbamate drugs. This study could provide an effective means in the fields of CWC verification, toxicological mechanism investigation and down-selection of potential treatment options.
Topics: Humans; Butyrylcholinesterase; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Retrospective Studies; Carbofuran; Acetylcholinesterase; Pepsin A; Nerve Agents; Pesticides
PubMed: 37285767
DOI: 10.1016/j.jchromb.2023.123775 -
Wiener Klinisches Magazin : Beilage Zur... 2023Impaired consciousness is a frequent phenomenon after general anesthesia. In addition to the classical causes (e.g., overhang of sedatives), an impairment of... (Review)
Review
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) 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) is the recommended treatment.
PubMed: 37251531
DOI: 10.1007/s00740-023-00492-1 -
Journal of Medical Toxicology :... Jul 2023
Topics: Humans; Muscarinic Antagonists; Rivastigmine; Physostigmine; Cholinesterase Inhibitors; Delirium
PubMed: 37204613
DOI: 10.1007/s13181-023-00947-1 -
BMJ Open May 2023Preoperative hypoalbuminaemia is associated with adverse outcome, including increased postoperative mortality in cardiovascular surgery, neurosurgery, trauma and... (Observational Study)
Observational Study
OBJECTIVES
Preoperative hypoalbuminaemia is associated with adverse outcome, including increased postoperative mortality in cardiovascular surgery, neurosurgery, trauma and orthopaedic surgery. However, much less is known about the association between preoperative serum albumin and clinical outcomes after liver surgery. In this study, we sought to determine whether hypoalbuminaemia before partial hepatectomy is associated with a worse postoperative outcome.
DESIGN
Observational study.
SETTING
University Medical Centre in Germany.
PARTICIPANTS
We analysed 154 patients enrolled in the perioperative PHYsostigmine prophylaxis for liver resection patients at risk for DELIrium and postOperative cognitive dysfunction (PHYDELIO) trial with a preoperative serum albumin assessment. Hypoalbuminaemia was defined as serum albumin <35 g/L. Subgroups classified as hypoalbuminaemia and non-hypoalbuminaemia consisted of 32 (20.8%) and 122 (79.2%) patients, respectively.
OUTCOME MEASURES
The outcome parameters of interest were postoperative complications according to Clavien (moderate: I, II; major: ≥III), length of intensive care unit (ICU) stay, length of hospital stay and survival rates 1 year after surgery.
RESULTS
Preoperative hypoalbuminaemia was associated with the occurrence of major postoperative complications (OR 3.051 (95% CI 1.197 to 7.775); p=0.019) after adjusting for age, sex, randomisation, American Society of Anesthesiologists physical status, preoperative diagnosis and Child-Pugh class. Both ICU and hospital lengths of stay were significantly prolonged in patients with preoperative hypoalbuminaemia (OR 2.573 (95% CI 1.015 to 6.524); p=0.047 and OR 1.296 (95% CI 0.254 to 3.009); p=0.012, respectively). One-year survival was comparable between patients with and without hypoalbuminaemia.
CONCLUSIONS
We found that low serum albumin before surgery was associated with a worse short-term outcome after partial hepatectomy, which strengthens the prognostic value of serum albumin in the setting of liver surgery.
TRIAL REGISTRATION NUMBERS
ISRCTN18978802 and EudraCT 2008-007237-47.
Topics: Humans; Risk Factors; Hypoalbuminemia; Postoperative Complications; Serum Albumin; Liver; Academic Medical Centers
PubMed: 37202140
DOI: 10.1136/bmjopen-2022-068405 -
Clinical Toxicology (Philadelphia, Pa.) May 2023Exposures to hydroxyzine, a first-generation H1 antihistamine, have increased rapidly over the last two decades. Many assumptions about hydroxyzine poisoning are based...
INTRODUCTION
Exposures to hydroxyzine, a first-generation H1 antihistamine, have increased rapidly over the last two decades. Many assumptions about hydroxyzine poisoning are based on other antihistamines, like diphenhydramine. However, the receptor affinities of hydroxazine suggest that there should be fewer antimuscarinic findings than diphenhydramine.
METHODS
This was a cohort study that compared hydroxyzine and diphenhydramine exposures reported to the National Poison Data System between January 1, 2000, and December 31, 2020, and the Toxicologic Investigators Consortium Core Registry between January 1, 2010, and December 31, 2020. The primary outcome was to assess for antimuscarinic findings in hydroxyzine-poisoned patients, using diphenhydramine-poisoned patients as a comparison group. The secondary outcomes were to assess for markers of overall toxicity. Inclusion criteria were single-substance exposures with known outcomes. Exclusion criteria for National Poison Data System exposures were chronic exposures, unintentional exposures, and patients younger than 12 years old. There were no exclusion criteria for exposures reported to the Toxicologic Investigators Consortium Core Registry.
RESULTS
There were 17,265 hydroxyzine and 102,354 diphenhydramine exposures reported to the National Poison Data System and 134 hydroxyzine and 1,484 diphenhydramine exposures reported to the Toxicologic Investigators Consortium Core Registry that met inclusion criteria. In both datasets, hydroxyzine-poisoned patients had lower rates and relative risk of developing antimuscarinic findings or receiving physostigmine, with the exception of hyperthermia in the Toxicologic Investigators Consortium Core Registry dataset. Coma/central nervous system depression (major), respiratory depression, seizures, ventricular dysrhythmias, intubation, and benzodiazepine administration were less likely in hydroxyzine-poisoned patients, but central nervous system depression (mild) was more likely in exposures reported to the National Poison Data System. The mortality in hydroxyzine-poisoned patients was rare: 0.02% and 0.8% of exposures reported to the National Poison Data System and Toxicologic Investigators Consortium Core Registry, respectively.
DISCUSSION
The clinical manifestations of hydroxyzine exposures are consistent with the pharmacology of hydroxazine. The clinical effects were consistent across two United States national datasets. Clinicians should not generalize the illness script of diphenhydramine exposures to hydroxyzine exposures.
CONCLUSIONS
Hydroxyzine-poisoned patients were less likely to develop antimuscarinic findings than diphenhydramine-poisoned patients. Hydroxyzine-poisoned patients were more likely to have mild central nervous system depression than an antimuscarinic toxidrome.
Topics: Humans; United States; Child; Diphenhydramine; Muscarinic Antagonists; Hydroxyzine; Cohort Studies; Poisons; Poison Control Centers
PubMed: 37194685
DOI: 10.1080/15563650.2023.2200575 -
Journal of Alzheimer's Disease : JAD 2023Perfusion imaging has the potential to identify neurodegenerative disorders in a preclinical stage. However, to correctly interpret perfusion-derived parameters, the...
BACKGROUND
Perfusion imaging has the potential to identify neurodegenerative disorders in a preclinical stage. However, to correctly interpret perfusion-derived parameters, the impact of perfusion modifiers should be evaluated.
OBJECTIVE
In this systematic review, the impact of acute and chronic intake of four acetylcholinesterase inhibitors (AChEIs) on cerebral perfusion in adults was investigated: physostigmine, donepezil, galantamine, and rivastigmine.
RESULTS
Chronic AChEI treatment results in an increase of cerebral perfusion in treatment-responsive patients with Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease dementia in the frontal, parietal, temporal, and occipital lobes, as well as the cingulate gyrus. These effects appear to be temporary, dose-related, and consistent across populations and different AChEI types. On the contrary, further perfusion decline was reported in patients not receiving AChEIs or not responding to the treatment.
CONCLUSION
AChEIs appear to be a potential perfusion modifier in neurodegenerative patients. More research focused on quantitative perfusion in both patients with and without a cholinergic deficit is needed to draw conclusions on whether AChEI intake should be considered when analyzing perfusion data.
Topics: Humans; Cholinesterase Inhibitors; Acetylcholinesterase; Dementia; Piperidines; Indans; Phenylcarbamates; Parkinson Disease; Rivastigmine; Alzheimer Disease; Galantamine; Cognition; Perfusion; Cerebrovascular Circulation
PubMed: 37182871
DOI: 10.3233/JAD-221125 -
Experimental Parasitology Jul 2023Although new nematicides have appeared, the demand for new products less toxic and more efficient for the control of plant-parasitic nematodes are still high....
Although new nematicides have appeared, the demand for new products less toxic and more efficient for the control of plant-parasitic nematodes are still high. Consequently, studies on natural secondary metabolites from plants, to develop new nematicides, have increased. In this work, nineteen extracts from eleven Brazilian plant species were screened for activity against Meloidogyne incognita. Among them, the extracts of Piterogyne nitens showed a potent nematostatic activity. The alkaloid fraction obtained from the ethanol extract of leaves of P. nitens was more active than the coming extract. Due to the promising activity from the alkaloid fraction, three isoprenylated guanidine alkaloids isolated from this fraction, galegine (1), pterogynidine (2), and pterogynine (3) were tested, showing similar activity to the alkaloid fraction, which was comparable to that of the positive control Temik at 250 μg/mL. At lower concentrations (125-50 μg/mL), compound 2 showed to be the most active one. As several nematicides act through inhibition of acetylcholinesterase (AChE), the guanidine alkaloids were also employed in two in vitro AChE assays. In both cases, compound 2 was more active than compounds 1 and 3. Its activity was considered moderated compared to the control (physostigmine). Compound 2 was selected for an in silico study with the electric eel (Electrophorus electricus) AChE, showing to bind mostly to the same site of physostigmine in the AChEs, pointing out that this could be the mechanism of action for this compound. These results suggested that the guanidine alkaloids 1,2 and 3 from P. nitens are promising for the development of new products to control M. incognita, especially guanidine 2, and encourage new investigations to confirm the mechanism of action, as well as to determine the structure-activity relationship of the guanidine alkaloids.
Topics: Acetylcholinesterase; Guanidine; Physostigmine; Alkaloids; Plant Extracts; Fabaceae; Guanidines; Antinematodal Agents; Cholinesterase Inhibitors
PubMed: 37178971
DOI: 10.1016/j.exppara.2023.108542