Rivastigmine for treatment-refractory posttraumatic stress disorder: a systematic review.

We conducted a systematic review evaluating the efficacy of rivastigmine augmentation for treatment-refractory posttraumatic stress disorder (PTSD). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The databases Ovid MEDLINE, PubMed, CINAHL, and EMBASE were searched using key words: 'rivastigmine' OR 'Exelon' OR 'rivastigmine augmentation' OR 'Exelon augmentation' AND 'posttraumatic stress disorder*' OR 'post-traumatic stress disorder*' OR 'PTSD' OR 'combat disorder*' OR 'post-traumatic symptoms'. The asterisk specified plural forms of the relevant word. Four papers were identified, comprising one double-blind randomised controlled trial, one non-controlled open trial, one case series (presenting three case studies), and one paper with two case studies. The randomised controlled trial found no statistically significant difference in efficacy, using the PTSD CheckList-Military Version as the relevant outcomes measure, between the active add-on rivastigmine interventions and placebo or treatment as usual. The open trial, although reporting relatively positive outcomes, had a weak study design and lacked reporting of key information, including participant sex and age and pre-rivastigmine PTSD measures. The assessment of efficacy was based on participants' reporting of subjective benefits, and clinician-rating using a Clinical Global Impression, rather than established PTSD assessments scales. Although the five case studies reported improvement in PTSD symptoms, there were confounding factors and limitations in clinical and demographic data, warranting caution regarding attributed benefits. There is a lack of methodologically robust evidence supporting the efficacy of add-on rivastigmine for the treatment of refractory PTSD. Additional research may help in further evaluating its possible clinical efficacy.

Sex, environment, and death rate in a dementia cohort: a seven-years Bayesian survival analysis using medications data from a contaminated area in Italy.

Introduction: Studies have analyzed the effects of industrial installations on the environment and human health in Taranto, Southern Italy. Literature documented associations between different variables and dementia mortality among both women and men. The present study aims to investigate the associations between sex, environment, age, disease duration, pandemic years, anti-dementia drugs, and death rate. Methods: Data from the regional medication registry were used. All women and men with an anti-dementia medication between 2015 and 2021 were included and followed-up to 2021. Bayesian mixed effects logistic and Cox regression models with time varying exposures were fitted using integrated nested Laplace approximations and adjusting for patients and therapy characteristics. Results: A total of 7,961 person-years were observed. Variables associated with lower prevalence of acetylcholinesterase inhibitors (AChEIs) medication were male sex (OR 0.63, 95% CrI 0.42-0.96), age 70-79 years (OR 0.17, 95% CrI 0.06-0.47) and ≥ 80 years (OR 0.08, 95% CrI 0.03-0.23), disease duration of 2-3 years (OR 0.43, 95% CrI 0.32-0.56) and 4-6 years (OR 0.21, 95% CrI 0.13-0.33), and pandemic years 2020 (OR 0.50, 95% CrI 0.37-0.67) and 2021 (OR 0.47, 95% CrI 0.33-0.65). Variables associated with higher mortality were male sex (HR 2.14, 95% CrI 1.75-2.62), residence in the contaminated site of national interest (SIN) (HR 1.25, 95% CrI 1.02-1.53), age ≥ 80 years (HR 6.06, 95% CrI 1.94-18.95), disease duration of 1 year (HR 1.50, 95% CrI 1.12-2.01), 2-3 years (HR 1.90, 95% CrI 1.45-2.48) and 4-6 years (HR 2.21, 95% CrI 1.60-3.07), and pandemic years 2020 (HR 1.38, 95% CrI 1.06-1.80) and 2021 (HR 1.56, 95% CrI 1.21-2.02). Variables associated with lower mortality were therapy with AChEIs alone (HR 0.69, 95% CrI 0.56-0.86) and in combination with memantine (HR 0.54, 95% CrI 0.37-0.81). Discussion: Male sex, age, disease duration, and pandemic years appeared to be associated with lower AChEIs medications. Male sex, residence in the SIN of Taranto, age, disease duration, and pandemic years seemed to be associated with an increased death rate, while AChEIs medication seemed to be associated with improved survival rate.

Preoperative management and postoperative complications in 9 dogs undergoing surgical treatment of thymic-associated myasthenia gravis.

Objective: Thymoma-associated paraneoplastic syndromes in dogs and cats include myasthenia gravis, hypercalcemia, exfoliative dermatitis, erythema multiforme, T-cell lymphocytosis, myocarditis, anemia, and polymyositis. Paraneoplastic myasthenia gravis (MG) is the most commonly reported paraneoplastic syndrome in dogs with thymic epithelial tumors. The objective of this study was to examine cases of canine thymic-associated MG treated surgically, with the specific objective of providing an updated clinical picture of the preoperative management, postoperative complications, and outcomes of these cases. Animals: Nine dogs with paraneoplastic MG underwent surgical removal of a thymic epithelial tumor. Procedure: Medical records of dogs with MG that received surgical treatment of a thymic epithelial tumor between January 1, 2012 and October 1, 2022 were obtained from 4 veterinary teaching hospitals. Descriptions of perioperative MG management, complications, and outcomes were reported. Results: Six of the 9 dogs received medical therapy for MG, with either a cholinesterase inhibitor (4 dogs) or a cholinesterase inhibitor and immunosuppressive agent (2 dogs), before surgery. The median duration of medical therapy for MG before surgery was 7.5 d (range: 2 to 60 d). Three of 9 dogs experienced immediate postoperative complications and were euthanized. Six of 9 dogs (66.6%) survived to discharge and 3 of 6 dogs that survived to discharge were alive at the time of writing. At the time of writing, 3 of 6 dogs had complete resolution of clinical signs attributable to MG and 2 of 6 had partial resolution. The median time from surgery to resolution of clinical signs of MG in these dogs was 63 d (range: 2 to 515 d). Conclusion: Dogs with thymic epithelial tumors and paraneoplastic MG are at a high risk for perioperative complications. Clinical relevance: The findings of this study corroborate previous literature stating that paraneoplastic MG is a poor prognostic indicator for dogs with thymic epithelial tumors, while also highlighting the variation in approaches to clinical management of thymic-associated MG in veterinary medicine and the lack of established protocols guiding perioperative management.

Prise en charge préopératoire et complications postopératoires chez 9 chiens subissant un traitement chirurgical de la myasthénie grave associée au thymus. Objectif: Les syndromes paranéoplasiques associés au thymome chez le chien et le chat comprennent la myasthénie grave, l'hypercalcémie, la dermatite exfoliative, l'érythème polymorphe, la lymphocytose à cellules T, la myocardite, l'anémie et la polymyosite. La myasthénie paranéoplasique (MG) est le syndrome paranéoplasique le plus fréquemment rapporté chez les chiens atteints de tumeurs épithéliales thymiques. L'objectif de cette étude était d'examiner les cas de MG canine associée au thymus traités chirurgicalement, dans le but spécifique de fournir un tableau clinique actualisé de la prise en charge préopératoire, des complications postopératoires et des résultats de ces cas. Animaux: Neuf chiens atteints de MG paranéoplasique ont subi l'ablation chirurgicale d'une tumeur épithéliale thymique. Procédure: Les dossiers médicaux des chiens atteints de MG ayant reçu un traitement chirurgical d'une tumeur épithéliale thymique entre le 1er janvier 2012 et le 1er octobre 2022 ont été obtenues auprès de 4 hôpitaux universitaires vétérinaires. Des descriptions de la prise en charge péri-opératoire de la MG, des complications et des résultats ont été rapportées. Résultats: Six des 9 chiens ont reçu un traitement médical pour la MG, avec soit un inhibiteur de la cholinestérase (4 chiens), soit un inhibiteur de la cholinestérase et un agent immunosuppresseur (2 chiens), avant la chirurgie. La durée médiane du traitement médical de la MG avant la chirurgie était de 7,5 jours (plage : 2 à 60 jours). Trois des neuf chiens ont présenté des complications postopératoires immédiates et ont été euthanasiés. Six des 9 chiens (66,6 %) ont survécu jusqu'à leur sortie et 3 des 6 chiens qui ont survécu jusqu'à leur sortie étaient en vie au moment de la rédaction. Au moment de la rédaction de cet article, 3 chiens sur 6 présentaient une résolution complète des signes cliniques attribuables à la MG et 2 chiens sur 6 présentaient une résolution partielle. Le délai médian entre l'intervention chirurgicale et la résolution des signes cliniques de MG chez ces chiens était de 63 jours (plage : 2 à 515 jours). Conclusion: Les chiens atteints de tumeurs épithéliales thymiques et de MG paranéoplasique présentent un risque élevé de complications périopératoires. Pertinence clinique: Les résultats de cette étude corroborent la littérature antérieure indiquant que la MG paranéoplasique est un indicateur de mauvais pronostic pour les chiens atteints de tumeurs épithéliales thymiques, tout en soulignant également la variation des approches de prise en charge clinique de la MG associée au thymus en médecine vétérinaire et le manque de protocoles établis de gestion guidant les interventions périopératoires.(Traduit par Dr Serge Messier).

Analysis of events from sudden isolated dysarthria to diagnosis of myasthenic crisis: myasthenia gravis mimicking acute lacunar stroke-a case report.

BACKGROUND: Myasthenic crisis (MC) is a life-threatening complication of myasthenia gravis (MG), necessitating ventilation. Achieving a safe and timely diagnosis of myasthenic crisis with atypical, isolated presentation is a considerable challenge particularly in elderly patients, where myasthenia gravis can present with isolated dysarthria in rare instances, giving a clinical impression of lacunar stroke. CASE PRESENTATION: We present a compelling case of a 73-year-old Caucasian female presenting with abrupt onset of isolated dysarthria. Despite initial treatment for a presumed lacunar stroke, subsequent evaluations led to her diagnosis of a myasthenic crisis. Within 72 h of admission, the patient developed dysphagia and shortness of breath, requiring supplemental oxygen. The case highlights the sequential progression of events from the atypical presentation of isolated dysarthria and its course to the management of a myasthenic crisis. CONCLUSION: Our reported case focuses on the discussion of myasthenia that mimicked a lacunar stroke and was finally diagnosed at a critical time of medical crisis. This case highlights the imperative notion that isolated dysarthria in elderly individuals warrants vigilant monitoring for possible myasthenia gravis, given the low incidence of lacunar stroke presenting with only dysarthria.

Acquired Risk Factors that Influence Risk for Dementia and Possibly Alzheimer Disease.

Various medicinal agents aimed at improving Alzheimer disease (AD) include cholinesterase inhibitors, memantine, aducanumab, and antioxidants. These medications are typically prescribed once AD is diagnosed in the clinical setting in order to slow progression. Though initiating treatment after being diagnosed with AD is important, significance should be placed on recognizing known acquired risk factors in order to potentially decrease the likelihood of developing dementia and perhaps specifically AD. This article summarizes the acquired factors that influence risk for dementia.

Ceanothanes Derivatives as Peripheric Anionic Site and Catalytic Active Site Inhibitors of Acetylcholinesterase: Insights for Future Drug Design.

Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system and particularly in the formation of amyloid plaques; therefore, the inhibition of AChE has become one of the most promising strategies for the treatment of AD, particularly concerning AChE inhibitors that interact with the peripheral anionic site (PAS). Ceanothic acid isolated from the Chilean Rhamnaceae plants is an inhibitor of AChE through its interaction with PAS. In this study, six ceanothic acid derivatives were prepared, and all showed inhibitory activity against AChE. The structural modifications were performed starting from ceanothic acid by application of simple synthetic routes: esterification, reduction, and oxidation. AChE activity was determined by the Ellmann method for all compounds. Kinetic studies indicated that its inhibition was competitive and reversible. According to the molecular coupling and displacement studies of the propidium iodide test, the inhibitory effect of compounds would be produced by interaction with the PAS of AChE. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the ceanothane derivatives were performed using the Swiss ADME tool.

Cholinesterase Inhibition and Antioxidative Capacity of New Heteroaromatic Resveratrol Analogs: Synthesis and Physico-Chemical Properties.

The targeted compounds in this research, resveratrol analogs 1-14, were synthesized as mixtures of isomers by the Wittig reaction using heterocyclic triphenylphosphonium salts and various benzaldehydes. The planned compounds were those possessing the trans-configuration as the biologically active trans-resveratrol. The pure isomers were obtained by repeated column chromatography in various isolated yields depending on the heteroaromatic ring. It was found that butyrylcholinesterase (BChE) was more sensitive to the heteroaromatic resveratrol analogs than acetylcholinesterase (AChE), except for 6, the methylated thiophene derivative with chlorine, which showed equal inhibition toward both enzymes. Compounds 5 and 8 achieved the highest BChE inhibition with IC50 values of 22.9 and 24.8 µM, respectively. The same as with AChE and BChE, methylated thiophene subunits of resveratrol analogs showed better enzyme inhibition than unmethylated ones. Two antioxidant spectrophotometric methods, DPPH and CUPRAC, were applied to determine the antioxidant potential of new heteroaromatic resveratrol analogs. The molecular docking of these compounds was conducted to visualize the ligand-active site complexes' structure and identify the non-covalent interactions responsible for the complex's stability, which influence the inhibitory potential. As ADME properties are crucial in developing drug product formulations, they have also been addressed in this work. The potential genotoxicity is evaluated by in silico studies for all compounds synthesized.

Antioxidant and Anti-Inflammatory Profiles of Two Mexican Heteropterys Species and Their Relevance for the Treatment of Mental Diseases: H. brachiata (L.) DC. and H. cotinifolia A. Juss. (Malpighiaceae).

Depression and anxiety are recognized as the most common mental diseases worldwide. New approaches have considered different therapeutic targets, such as oxidative stress and the inflammation process, due to their close association with the establishment and progression of mental diseases. In the present study, we evaluated the antioxidant and anti-inflammatory activities of the methanolic extracts of the plant species Heteropterys brachiata and Heteropterys cotinifolia and their main compounds, chlorogenic acid and rutin, as potential complementary therapeutic tools for the treatment of anxiety and depression, since the antidepressant and anxiolytic activities of these methanolic extracts have been shown previously. Additionally, we also evaluated their inhibitory activity on the enzyme acetylcholinesterase (AChE). Our results revealed that both species exhibited potent antioxidant activity (>90%) through the TBARS assay, while by means of the DPPH assay, only H. cotinifolia exerted potent antioxidant activity (>90%); additionally, low metal chelating activity (<40%) was detected for all samples tested in the ferrozine assay. The methanolic extracts of H. brachiata and H. cotinifolia exhibited significant anti-inflammatory activities in the TPA-induced ear edema, while only H. cotinifolia exerted significant anti-inflammatory activities in the MPO assay (>45%) and also exhibited a higher percentage of inhibition on AChE of even twice (>80%) as high as the control in concentrations of 100 and 1000 µg/mL. Thus, the potent antioxidant and inflammatory properties and the inhibition of AChE may be involved in the antidepressant activities of the species H. cotinifolia, which would be positioned as a candidate for study in drug development as an alternative in the treatment of depression.

Vegan and Vegetarian Soups Are Excellent Sources of Cholinesterase Inhibitors.

BACKGROUND: The cholinesterase theory stands as the most popular worldwide therapy for Alzheimer's disease (AD). Given the absence of a cure for AD, a plant-based diet has been repeatedly shown as positive in the prevention of AD, including exploring ready-made products in stores and the development of new functional foods. GOAL: This study compared the anti-acetyl- and butyrylcholinesterase activity of thirty-two Polish market soups and five newly formulated soups intended to be functional. Additionally, the research aimed to assess the significance of animal content, distinguishing between vegan and vegetarian options, in cholinesterase inhibition. MATERIALS AND METHODS: The anticholinesterase activity was investigated using a spectrophotometric method, and the inhibitory activity was expressed as % inhibition of the enzyme. The study categorized soups into three groups based on ingredients: those containing animal-derived components, vegetarian soups and vegan soups. RESULTS: Soups exhibited varying levels of activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), indicating differences in their compositions. Composition appeared to be the primary factor influencing anticholinesterase activity, as soups within each group showed significant variability in activity levels. While some commercial soups demonstrated notable anticholinesterase activity, they did not surpass the effectiveness of the optimized soups developed in the laboratory. Certain ingredients were associated with higher anticholinesterase activity, such as coconut, potato, onion, garlic, parsley and various spices and herbs. CONCLUSIONS: Vegetarian and vegan soups exhibited comparable or even superior anticholinesterase activity compared to animal-derived soups, highlighting the importance of plant-based ingredients. The study underscores the need for further research to explore the mechanisms underlying the anticholinesterase activity of soups, including the impact of ingredient combinations and processing methods.

Expanding Knowledge about the Influence of Citral on Cognitive Functions-In Vitro, In Vivo and Ex Vivo Studies.

Citral, a common monoterpene found in numerous plants, is an interesting compound that has been shown to have various biological activities. Although it is widely distributed in nature and there are many studies presenting its biological activities, its anti-neurodegenerative activity, especially under in vivo conditions, is very poorly understood. Thus, this paper aimed to deepen knowledge about citral activity towards factors and symptoms of neurodegeneration. To accomplish this, several comprehensive tests were conducted, including the estimation of butyrylcholinesterase inhibition, the evaluation of hepatotoxicity and the detection of oxidative stress and lipid peroxidation in vitro, as well as an in vivo behavioral assessment using mice models. Additionally, ex vivo determination of level of the compound in the brain and blood of a tested animal was undertaken. The results obtained revealed that citral is able to inhibit butyrylcholinesterase activity and protect hepatic cells against oxidative stress and lipid peroxidation in vitro. Moreover, behavioral tests in vivo indicated that citral (50 mg/kg) improves memory processes associated with acquisition (passive avoidance test), both in acute and subchronic administration. Additionally, we found that the administration of citral at 25 mg/kg and 50 mg/kg did not significantly affect the locomotor activity. Beyond the aforementioned, gas chromatography-mass spectrometry analysis revealed the presence of the compound in the blood and brain after subchronic administration of citral. Taken together, the results obtained in vitro, in vivo and ex vivo clearly indicate that citral is a promising monoterpene that can potentially be used towards cognition improvement.

Synthesis, biological evaluation, molecular docking, and MD simulation of novel 2,4-disubstituted quinazoline derivatives as selective butyrylcholinesterase inhibitors and antioxidant agents.

Alzheimer's disease is the most prevalent neurodegenerative disorder characterized by significant memory loss and cognitive impairments. Studies have shown that the expression level and activity of the butyrylcholinesterase enzyme increases significantly in the late stages of Alzheimer's disease, so butyrylcholinesterase can be considered as a promising therapeutic target for potential Alzheimer's treatments. In the present study, a novel series of 2,4-disubstituted quinazoline derivatives (6a-j) were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes, as well as for their antioxidant activities. The biological evaluation revealed that compounds 6f, 6h, and 6j showed potent inhibitory activities against eqBuChE, with IC50 values of 0.52, 6.74, and 3.65 µM, respectively. These potent compounds showed high selectivity for eqBuChE over eelAChE. The kinetic study demonstrated a mixed-type inhibition pattern for both enzymes, which revealed that the potent compounds might be able to bind to both the catalytic active site and peripheral anionic site of eelAChE and eqBuChE. In addition, molecular docking studies and molecular dynamic simulations indicated that potent compounds have favorable interactions with the active sites of BuChE. The antioxidant screening showed that compounds 6b, 6c, and 6j displayed superior scavenging capabilities compared to the other compounds. The obtained results suggest that compounds 6f, 6h, and 6j are promising lead compounds for the further development of new potent and selective BuChE inhibitors.

A Comparison of Phenolic, Flavonoid, and Amino Acid Compositions and In Vitro Antioxidant and Neuroprotective Activities in Thai Plant Protein Extracts.

The leaves of mulberry, Azolla spp., sunflower sprouts, cashew nut, and mung bean are considered rich sources of plant protein with high levels of branched-chain amino acids. Furthermore, they contain beneficial phytochemicals such as antioxidants and anti-inflammatory agents. Additionally, there are reports suggesting that an adequate consumption of amino acids can reduce nerve cell damage, delay the onset of memory impairment, and improve sleep quality. In this study, protein isolates were prepared from the leaves of mulberry, Azolla spp., sunflower sprouts, cashew nut, and mung bean. The amino acid profile, dietary fiber content, phenolic content, and flavonoid content were evaluated. Pharmacological properties, such as antioxidant, anticholinesterase, monoamine oxidase, and γ-aminobutyric acid transaminase (GABA-T) activities, were also assessed. This study found that concentrated protein from mung beans has a higher quantity of essential amino acids (52,161 mg/100 g protein) compared to concentrated protein from sunflower sprouts (47,386 mg/100 g protein), Azolla spp. (42,097 mg/100 g protein), cashew nut (26,710 mg/100 g protein), and mulberry leaves (8931 mg/100 g protein). The dietary fiber content ranged from 0.90% to 3.24%, while the phenolic content and flavonoid content ranged from 0.25 to 2.29 mg/g and 0.01 to 2.01 mg/g of sample, respectively. Sunflower sprout protein isolates exhibited the highest levels of dietary fiber (3.24%), phenolic content (2.292 ± 0.082 mg of GAE/g), and flavonoids (2.014 mg quercetin/g of sample). The biological efficacy evaluation found that concentrated protein extract from sunflower sprouts has the highest antioxidant activity; the percentages of inhibition of 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical were 20.503 ± 0.288% and 18.496 ± 0.105%, respectively. Five plant-based proteins exhibited a potent inhibition of acetylcholinesterase (AChE) enzyme activity, monoamine oxidase (MAO) inhibition, and GABA-T ranging from 3.42% to 24.62%, 6.14% to 20.16%, and 2.03% to 21.99%, respectively. These findings suggest that these plant protein extracts can be used as natural resources for developing food supplements with neuroprotective activity.

Reactivation by novel pyridinium oximes of rat serum and skeletal muscle acetylcholinesterase inhibited by organophosphates.

The treatment of organophosphate (OP) anticholinesterases currently lacks an effective oxime reactivator of OP-inhibited acetylcholinesterase (AChE) which can penetrate the blood-brain barrier (BBB). Our laboratories have synthesized novel substituted phenoxyalkyl pyridinium oximes and tested them for their ability to promote survival of rats challenged with lethal doses of nerve agent surrogates. These previous studies demonstrated the ability of some of these oximes to promote 24-h survival to rats challenged with a lethal level of highly relevant surrogates for sarin and VX. The reactivation of OP-inhibited AChE in peripheral tissues was likely to be a major contributor to their efficacy in survival of lethal OP challenges. In the present study, twenty of these novel oximes were screened in vitro for reactivation ability for AChE in rat skeletal muscle and serum using two nerve agent surrogates: phthalimidyl isopropyl methylphosphonate (PIMP, a sarin surrogate) and 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate). The oximes demonstrated a range of 23%-102% reactivation of AChE in vitro across both tissue types. Some of the novel oximes tested in the present study demonstrated the ability to more effectively reactivate AChE in serum than the currently approved oxime, 2-PAM. Therefore, some of these novel oximes have the potential to reverse AChE inhibition in peripheral target tissues and contribute to survival efficacy.

Rapid identification of chemical components and screening of acetylcholinesterase inhibitors from Dalbergia odorifera based on mass defect and diagnostic ion filtering strategy, affinity ultrafiltration, and liquid chromatography-tandem mass spectrometry.

Dalbergia odorifera is a natural product rich in pharmacological ingredients, but the comprehensive characterization and rapid profiling of active components remain a challenge. Thus, an integrated data mining and identification strategy was exploited to efficiently identify the chemical constituents and screen acetylcholinesterase inhibitors (AChEIs) through affinity ultrafiltration and ultra-high-performance liquid chromatography-mass spectrometry (AUF-UHPLC-MS). As a result, polygonal mass defect filtering, diagnostic product ions, and neutral loss rules were created for rapid structural classification and component identification. A total of 140 flavonoids were tentatively characterized, including 41 isoflavonoids, 23 flavanones, 21 isoflavans, 19 flavones and flavonols, 13 neoflavonoids, 11 isoflavanones, seven flavone glycosides, and five chalcones. Subsequently, six natural AChEIs including tectorigenin, fisetin, dalbergin, pterostilbene, isoliquiritigenin, and biochanin A were screened out using AUF-UHPLC-MS and molecular docking. Meanwhile, the AChE inhibitory activities of the six compounds were assessed in vitro, tectorigenin, fisetinand, and dalbergin have moderate inhibitory activity. In conclusion, a novel strategy for systematic characterization and further screening of active compounds in natural products was established, which provides a material basis for quality control of Dalbergia odorifera.

Physostigmine reversal of delirium from second generation antipsychotic exposure: a retrospective cohort study from a regional poison center.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSIONS: 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.

Brain targeting efficacy of novel drug delivery system in the treatment of Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD), a common degenerative disease of the central nervous system in the elderly, has become the third largest health killer after cardiovascular and cerebrovascular diseases and tumors. Based on the fact that Alzheimer's disease is a disease with multiple etiologies and complex pathology, a single target is bound to have a limited curative effect, and the synergy of multiple links and multiple targets is expected to achieve a better curative effect. The aim of this study is to investigate the brain targeting of a drug modified by chitosan, based on the new nanodrug delivery system for treating Alzheimer's disease developed by the research group. MATERIALS AND METHODS: Chitosan with good biocompatibility, biosorption, and degradation products that can protect and promote the regeneration of nerve cells was selected to combine with galantamine, a natural representative cholinesterase inhibitor, to develop a new nano drug delivery system for nasal delivery of anti-Alzheimer's disease with a multi-target synergistic effect. Synchronous analysis was conducted on the blood and brain tissue drug concentrations after intravenous and nasal administration of the original drug solution and system solution. The brain targeting index (DTI) is used to evaluate the brain targeting effect of the nano-drug delivery system after intranasal administration. RESULTS: The blood concentration of galantamine original drug solution and galantamine system solution after intravenous injection and nasal show that in the two administration methods of intravenous injection and nasal administration, under the same administration method, the time point of the system reaching the highest blood drug concentration is much higher than that of the original drug. The content of galantamine in plasma samples and tissue samples indicate that after intravenous administration and intranasal administration of the galantamine system, at the same time point, the drug concentration in brain tissue was far greater than that of the original drug of galantamine, and the duration was also longer. The concentration of drugs in brain tissue decreased gradually in the order of olfactory bulb, olfactory tract, brain, and cerebellum. In the brain tissues of the olfactory bulb, olfactory tract, cerebrum, and cerebellum, the drug concentration of the galantamine system after intravenous injection is lower than that after nasal administration. CONCLUSIONS: This study concludes that compared with the original drug solution, the nano drug delivery system has significant brain targeting for nasal administration, and intravenous injection also has brain targeting. In the olfactory bulb, olfactory tract, brain, and cerebellum, the brain targeting index at the olfactory bulb is the highest, and the targeting is the best.

Synthesis, biological evaluation, theoretical calculations, QSAR and molecular docking studies of novel arylaminonaphthols as potent antioxidants and BChE inhibitors.

A completely green protocol was developed for the synthesis of a series of arylaminonaphthol derivatives in the presence of N-ethylethanolamine (NEEA) as a catalyst under ultrasonic irradiation and solventless conditions. The major assets of this methodology were the use of non-toxic organic medium, available catalyst, mild reaction condition, and good to excellent yield of desired products. All of the synthesized products were screened for their in vitro antioxidant activity using DPPH, ABTS, and Ferric-phenanthroline assays and it was found that most of them are potent antioxidant agents. Also, their butyrylcholinesterase inhibitory activity has been investigated in vitro. All tested compounds exhibited potential inhibitory activity toward BuChE when compared to standard reference drug galantamine, however, compounds 4r, 4u, 4 g and 4x gave higher butyrylcholinesterase inhibitory with IC50 values of 14.78 ± 0.65 µM, 16.18 ± 0.50 µM, 20.00 ± 0.50 µM, and 20.28 ± 0.08 µM respectively. On the other hand, we employed density functional theory (DFT), calculations to analyze molecular geometry and global reactivity descriptors, and MESP analysis to predict electrophilic and nucleophilic attacks. A quantitative structure-activity relationship (QSAR) investigation was conducted on the antioxidant and butyrylcholinesterase properties of 25 arylaminonaphthol derivatives, resulting in robust and satisfactory models. To evaluate their anti-Alzheimer's activity, compounds 4 g, 4q, 4r, 4u, and 4x underwent docking simulations at the active site of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing why these compounds displayed superior activity, consistent with the biological findings.

Discovery of cinnamamide/ester triazole hybrids as potential treatment for Alzheimer's disease.

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.

Synthesis, insecticidal Activity, and molecular docking analysis of some benzo[h]quinoline derivatives against Culex pipiens L. Larvae.

Some heterocycles bearing a benzo[h]quinoline moiety were synthesized through treating a 3-((2-chlorobenzo[h]quinolin-3-yl)methylene)-5-(p-tolyl)furan-2(3H)-one with four nitrogen nucleophiles comprising ammonium acetate, benzylamine, dodecan-1-amine, and 1,2-diaminoethane. Also, thiation reactions of furanone and pyrrolinone derivatives were investigated. The insecticidal activity of these compounds against mosquito larvae (Culex pipiens L.) was evaluated. All tested compounds exhibited significant larvicidal activity, surpassing that of the conventional insecticide chlorpyrifos. In silico docking analysis revealed that these compounds may act as acetyl cholinesterase (AChE) inhibitors, potentially explaining their larvicidal effect. Additionally, interactions with other neuroreceptors, such as nicotinic acetylcholine receptor and sodium channel voltage-gated alpha subunit were also predicted. The results obtained from this study reflected the potential of benzo[h]quinoline derivatives as promising candidates for developing more effective and sustainable mosquito control strategies. The ADME (absorption, distribution, metabolism, and excretion) analyses displayed their desirable drug-likeness and oral bioavailability properties.

Changes in motor behavior and lumbar motoneuron morphology following repeated chlorpyrifos exposure in rats.

Chlorpyrifos is an organophosphate pesticide associated with numerous health effects including motor performance decrements. While many studies have focused on the health effects following acute chlorpyrifos poisonings, almost no studies have examined the effects on motoneurons following occupational-like exposures. The main objective of this study was to examine the broad effects of repeated occupational-like chlorpyrifos exposures on spinal motoneuron soma size relative to motor activity. To execute our objective, adult rats were exposed to chlorpyrifos via oral gavage once a day, five days a week for two weeks. Chlorpyrifos exposure effects were assessed either three days or two months following the last exposure. Three days following the last repeated chlorpyrifos exposure, there were transient effects in open-field motor activity and plasma cholinesterase activity levels. Two months following the chlorpyrifos exposures, there were delayed effects in sensorimotor gating, pro-inflammatory cytokines and spinal lumbar motoneuron soma morphology. Overall, these results offer support that subacute repeated occupational-like chlorpyrifos exposures have both short-term and longer-term effects in motor activity, inflammation, and central nervous system mechanisms.