Pharmacological Characterization Research Articles

Pharmacological characteristics and clinical study results of ensitrelvir fumaric acid (XOCOVA® Tablets 125 ‍mg)

Ensitrelvir fumaric acid (Xocova® hereafter ensitrelvir) is a novel anti-SARS-CoV-2 drug for COVID-19. Hokkaido University and Shionogi & Co., Ltd. engaged in joint research targeting SARS-CoV-2 3C-like (3CL) protease at an early stage and started clinical trials in July 2021. In February 2022, an application was filed for manufacture and sales approval for the indication of "SARS-CoV-2 infection,". Ensitrelvir recieved the first emergency regulatory approval from the Ministry of Health, Labour and Welfare (MHLW) in Japan in November 2022, and has obtained standard approval in March 2024. This emergency approval was based on the confirmed safety in a Phase 2/3 study (T1221) conducted in Japan and other Asian countries (Korea and Vietnam) in patients with mild/moderate COVID-19 and the presumed efficacy in Phase 3 Part (SCORPIO-SR), and the standard approval is based on efficacy from the Phase 3 part. In the Phase 3 part, ensitrelvir administered orally 375/125 ‍mg once daily for five days, in patients with irrespective of risk factors for severe complications and vaccination status, demonstrating a significant reduction vs placebo in the time to resolution of five typical Omicron-related symptoms (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness), and also showed a significant reduction in viral RNA on day 4 relative to placebo (P < 0.001). In the Phase 2/3 study, there were no serious adverse events or deaths, indicating good tolerability and safety. We hope that ensitrelvir will contribute as a new treatment option for patients suffering from COVID-19 symptoms.

In vitro and In silico Network Pharmacology Analysis of Eugenol from Syzygium aromaticum Against Escherichia coli

ABSTRACT Background: In this era, Escherichia coli is an ambivalent microbe and commonly causes fecal contamination. Eugenol from clove oil has also demonstrates antibacterial effects that may aid in combating against the microorganisms that cause tooth infections. Aim and Objectives: The current study provides a comprehensive analysis of the pharmacological characteristics of eugenol, a significant bioactive substance extracted from clove (Syzygium aromaticum). The present study aimed to target the genes from E. coli identified through network pharmacology analysis of eugenol and antibiofilm effect of eugenol from clove oil against E. coli. Materials and Methods: In the present study, eugenol was isolated from clove identified through Fourier transform infrared spectroscopy analysis. The antibacterial and antibiofilm activity of eugenol was performed against E. coli were investigated. Targets were identified for Eugenol from clove oil through string database and mapped with E. coli pathway. Molecular docking analysis was carried out for the identified targets and eugenol. Results: The best antibacterial activity of eugenol from clove oil was found against E. coli and evaluated by zone of inhibition and minimum inhibitory concentration analysis at 10 μL. The antibiofilm assay against resistant E. coli was determined by concentration of 10 μL and inhibited in 100% dilution. The top five active targets from E. coli was identified by network pharmacology and docking analysis shows the good binding interaction between targets and eugenol. Conclusion: The research provided in this study lays the foundation for eugenol’s anti-bacterial property with various biofilm forming targets namely Acetyl-CoA acetyltransferase, Acetyl-CoA carboxylase-B, Acetyl-CoA carboxylase-C, Enoyl-[acyl-carrier-protein] reductase [NADH], and 3-oxoacyl-[acyl-carrier-protein] synthase 1. Additional in vivo approach validation is required in future to support the current study.

Pharmacological Characterization of Nigella sativa Extract and the Compound Beta-caryophyllene

Traditional medicines made from medicinal plants are the most abundant biosources of medications. Pharmaceutical medications, synthetic pharmaceuticals, Siddha, Ayurveda, nutraceuticals, and dietary supplements all come from plant sources. In spite of several studies using herbal plants that have shown a strong link between phytochemical, anti-diabetic, and anti-inflammatory content, Nigella sativa—a spice plant of the Ranunculaceae family—showed more significant qualities than its competitors. Numerous pharmacological properties were discovered in both the Nigella sativa essential oil and the seeds. Nigella sativa is considered to be the most powerful antioxidant and medicinal plant with known medicinal properties and therapeutic applications, and it is used as traditional medicine for respiratory, gastrointestinal, rheumatic, and inflammatory disorders. The study was conducted using Nigella sativa and compound Beta caryophyllene to determine the anti-oxidant, invitro-anti-diabetic, anti-inflammatory, and enzymatic and non-enzymatic activity of the ethanolic seed extract of Nigella sativa and compound Beta caryophyllene on Alzheimer's disease because there were no toxic effects or serious side effects observed using animal models or in clinical trials. The antioxidant activity of the compound and the extract was examined to study the qualitative and quantitative analysis of the extract and the compound beta-caryophyllene. Phytochemical screening exhibited secondary metabolites of the extract, such as phenols, flavonoids, steroids, alkaloids, and cardiac glycosides. Nigella sativa extract and its constituents such as beta-caryophyllene, possess a protective effect against toxicity, which is caused by drugs used for treating cancer as well as neurodegenerative disorders. Further, the extract prevents a decrease in hemoglobin levels as well as leukocyte counts. The purpose of the research is to demonstrate that Nigella sativa and the chemical beta-caryophyllene may be employed as medicinal agents and that beta-caryophyllene may have potential cholinesterase inhibitory effects.

Computational Investigation of Bioactive Phytoconstituents as SarS-Cov-2 Main Protease Inhibitors Through Molecular Docking and Interaction Fingerprint Studies

Since 2019, the SARS-CoV-2 infection has continued to cause significant human suffering. Numerous investigations into the viral pathogenesis have led to converging conclusions on how the virus enters and spreads within the host. The main protease (Mpro) of coronaviruses has been considered as an attractive therapeutic target because of its important role in processing polyproteins translated from viral RNA. Many studies discovered that phytoconstituents possess potent antiviral activities. Hence, in the present work, 439 co-crystal ligands of SARS-CoV-2 Mpro were collected and docked with Mpro of SARS-CoV-2 (PDB ID:7AEH) to identify best crystal ligand. Among all the crystal ligands collected, HF0 (7-O-methyl-dihydromyricetin) showed good XP G score -7.872 Kcal/Mol and it was selected as reference to compare the docking scores of phytoconstituents. Then, molecular docking study was performed for 274 antiviral phytoconstituents from various medicinal plants against Mpro of SARS-CoV-2. Molecular docking studies found that seven phytoconstituents exhibited better docking scores than best co-crystal ligand HF0. Among the seven best docked phytoconstituents, 3,4-dicaffeoylquinic acid showed good interactions with key amino acid residues in substrate binding site of Mpro with XPG Score –9.721 Kcal/Mol. Qikprop results indicated that the most phytoconstituents have demonstrated favourable pharmacological characteristics. Interaction fingerprint analysis revealed that all the seven best docked phytoconstituents of the present study bound to Glu166, key residue situated in the centre of the substrate binding site of Mpro resulting in the reduction of the catalytic activity of main protease thus blocking the replication of SARS-CoV-2.

The Impact of Tadbir as a Pre-Application Treatment of Medicinal Plants on Their Chemical Profiles and Biological Activities in Traditional Persian Pharmacy

Based on basic traditional medicine practice, many plants undergo primary treatments to improve their pharmacological characteristics or to attenuate unwanted or unfavorable features of drugs before incorporating them into drug formulations. These treatments are called “Tadbir” in Traditional Persian Medicine (TPM). The purpose of these processes includes but is not limited to eliminating unnecessary compounds, excluding harmful properties such as toxicity and poignancy, and improving their overall natural properties and effectiveness. Here, the effect of vinegar and acetic acid treatment on three herbal specimens, including Carum carvi L. fruits (CC), Trachyspermum ammi (L.) Sprague fruits (TA), and Nigella sativa L. seeds (NS) were investigated. The treated and non-treated samples were subjected to essential oil and methanol extraction. Further, to assess the alterations in the essential oil constituents caused by Tadbir, samples were analyzed by Gas Chromatography/Mass Spectrometry (GC/MS) and HPTLC fingerprinting techniques. Total phenol and flavonoid content and DPPH free radical scavenging activity of methanol extracts were evaluated. As a result of the treatments, TA extracts showed significant rise in phenol and flavonoid contents. Total phenol content increased from 98.50±1.01 in non-treated increased to 181.20±0.27 mg GAE/g Ext. in the vinegar-treated TA fruit extract and total flavonoid showed a rise from 8.97±1.12 to 12.89±0.41 mg QE/g Ext. This may be the reason behind its lower IC50 values in DPPH free radical scavenging assay. Interestingly, Tadbir treatment of TA fruits with 4% acetic acid, lowered the IC50 value from 1019.42±75.65µg/mL in non-treated control to 274.2±17.22 µg/mL; while vinegar caused a lower degree of reduction in IC50 value (369.4±5.54 µg/mL) in DPPH free radical scavenging assay. However, CC fruit extracts, showed a decrease in phenolic content; while demonstrating an increase in flavonoids. Interestingly, phenol and flavonoid contents were significantly enhanced in treated NS seed extracts. The results of all extracts were found significantly different (p&lt;0,05) from each other and the non-treated control. The conclusive results of the present study may partly justify the pre-application of Tadbir treatments of medicinal plants in traditional pharmacy.

Application of Acharas Sapota Linn in Traditional Medicine.

This article offers a thorough analysis of the contemporary application of Achras Sapota Linn, or sapodilla, in conventional medicine. Tropical fruit-bearing Achras Sapota Linn has long been used in many traditional medical systems. The study examines Achras Sapota Linn's phytochemical makeup and pharmacological characteristics with an emphasis on the plant's possible medical uses in the treatment of a range of illnesses. Moreover, it highlights the safety and efficacy characteristics of Achras Sapota Linn and talks about new research and clinical trials that back up its traditional applications. This study also discusses obstacles and potential avenues for further research and application of Achras Sapota Linn in contemporary medicine. All things considered, it emphasizes how important Achras Sapota Linn is to traditional medicine as a therapeutic resource.

Know your molecule: pharmacological characterization of drug candidates to enhance efficacy and reduce late-stage attrition.

Despite advances in chemical, computational and biological sciences, the rate of attrition of drug candidates in clinical development is still high. A key point in the small-molecule discovery process that could provide opportunities to help address this challenge is the pharmacological characterization of hit and lead compounds, culminating in the selection of a drug candidate. Deeper characterization is increasingly important, because the 'quality' of drug efficacy, at least for G protein-coupled receptors (GPCRs), is now understood to be much more than activation of commonly evaluated pathways such as cAMP signalling, with many more 'efficacies' of ligands that could be harnessed therapeutically. Such characterization is being enabled by novel assays to characterize the complex behaviour of GPCRs, such as biased signalling and allosteric modulation, as well as advances in structural biology, such as cryo-electron microscopy. This article discusses key factors in the assessments of the pharmacology of hit and lead compounds in the context of GPCRs as a target class, highlighting opportunities to identify drug candidates with the potential to address limitations of current therapies and to improve the probability of them succeeding in clinical development.

The Dicentrarchus labrax estrogen screen test: A relevant tool to screen estrogen-like endocrine disrupting chemicals in the aquatic environment

In response to the need for the diversification of regulatory bioassays to screen estrogen-like endocrine disrupting chemical (EEDC) in the environment, we propose the use of a reporter gene assay involving all nuclear estrogen receptors from Dicentrarchus labrax (i.e., sbEsr1, sbEsr2a, or sbEsr2b). Named DLES test (D. labrax estrogen screen), it aims at complementing existing standardized in vitro tests by implementing more estrogen receptors notably those that do not originate from humans.Positive responses were obtained with all three estrogen receptors, and—consistently with observations from other species—variations in sensitivity to E2 were measured. Sensitivity and EC50 values could be classified as follows: sbEsr2b < sbEsr2a < sbEsr1. The pharmacological characterization with a human estrogen receptor antagonist (fulvestrant) successfully validated the specific involvement of each sbEsr and evidenced the capacity of the DLES test to highlight antagonist interactions. The DLES test was applied to WWTP contaminant extracts. A positive response was detected in the inflow sample in accordance with the YES test, but not in the outflow sample. Notwithstanding, the DLES test (sbEsr2b) exhibited greater sensitivity for the screening of those samples. This study demonstrates the need for more comprehensive testing including representatives of marine species for a better detection of EEDCs. The DLES test appears as a pertinent tool to predict adverse effects and to widen the scope of screening and hazard assessment of EEDCs in the environment.

Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

Navacaprant, a novel and selective kappa opioid receptor antagonist, has no agonist properties implicated in opioid-related abuse

Kappa opioid receptors (KORs) are implicated in the pathophysiology of various psychiatric and neurological disorders creating interest in targeting the KOR system for therapeutic purposes. Accordingly, navacaprant (NMRA-140) is a potent, selective KOR antagonist being evaluated as a treatment for major depressive disorder. In the present report, we have extended the pharmacological characterization of navacaprant by further demonstrating its selective KOR antagonist properties and confirming its lack of agonist activity at KORs and related targets involved in opioid-related abuse. Using CHO–K1 cells expressing human KOR, mu (MOR), or delta (DOR) opioid receptors, navacaprant demonstrated selective antagonist properties at KOR (IC50 = 0.029 μM) versus MOR (IC50 = 3.3 μM) and DOR (IC50 > 10 μM) in vitro. In vivo, navacaprant (10–30 mg/kg, i.p.) dose-dependently abolished KOR-agonist induced analgesia in the mouse tail-flick assay. Additionally, navacaprant (10, 30 mg/kg, p.o.) significantly reduced KOR agonist–stimulated prolactin release in mice and rats, confirming KOR antagonism in vivo. Navacaprant showed no agonist activity at any opioid receptor subtype (EC50 > 10 μM) in vitro and exhibited no analgesic effect in the tail-flick assays at doses ≤100 mg/kg, p.o. thereby confirming a lack of opioid receptor agonist activity in vivo. Importantly, navacaprant did not alter extracellular dopamine concentrations in the nucleus accumbens shell of freely-moving rats following doses ≤100 mg/kg, p.o., whereas morphine (10, 20 mg/kg, i.p.) significantly increased dopamine levels. These results demonstrate that navacaprant is a KOR-selective antagonist with no pharmacological properties implicated in opioid-related abuse.

Structure of the Ion Channel Kir7.1 and Implications for its Function in Normal and Pathophysiologic States.

Hereditary defects in the function of the Kir7.1 in the retinal pigment epithelium are associated with the ocular diseases retinitis pigmentosa, Leber congenital amaurosis, and snowflake vitreal degeneration. Studies also suggest that Kir7.1 may be regulated by a GPCR, the melanocortin-4 receptor, in certain hypothalamic neurons. We present the first structures of human Kir7.1 and describe the conformational bias displayed by two pathogenic mutations, R162Q and E276A, to provide an explanation for the basis of disease and illuminate the gating pathway. We also demonstrate the structural basis for the blockade of the channel by a small molecule ML418 and demonstrate that channel blockade in vivo activates MC4R neurons in the paraventricular nucleus of the hypothalamus (PVH), inhibiting food intake and inducing weight loss. Preliminary purification, and structural and pharmacological characterization of an in tandem construct of MC4R and Kir7.1 suggests that the fusion protein forms a homotetrameric channel that retains regulation by liganded MC4R molecules.

Pharmacological characterization of sex differences in the effects of dopaminergic drugs on effort-based decision making in rats.

Motivational dysfunctions related to effort exertion are common in psychiatric disorders. Dopamine systems regulate exertion of effort and effort-based choice in humans and rodents. Previous rodent studies mainly employed male rats, and it is imperative to conduct studies in male and female rats. The present studies compared the effort-related effects of IP injections of the dopamine antagonists ecopipam and haloperidol, and the vesicular monoamine transport-2 inhibitor tetrabenazine (TBZ), in male and female rats using the fixed ratio 5/chow feeding choice task. Ecopipam (0.05-0.2mg/kg) and haloperidol (0.05-0.15mg/kg) induced a low-effort bias, decreasing lever pressing and increasing chow intake in males and females in the same dose range. With lever pressing, there was a modest but significant dose x sex interaction after ecopipam injection, but there was no significant interaction after administration of haloperidol. In the first study with TBZ (0.25-1.0mg/kg), there was a robust sex difference. TBZ shifted choice from lever pressing to chow intake in male rats, but was ineffective in females. In a second experiment, 2.0mg/kg affected choice behavior in both males and females. TBZ increased accumbens c-Fos immunoreactivity in a sex-dependent manner, with males significantly increasing at 1.0mg/kg, while females showed augmented immunoreactivity at 2.0mg/kg. The neural and behavioral effects of TBZ differed across sexes, emphasizing the importance of conducting studies in male and female rats. This research has implications for understanding the effort-related motivational dysfunctions seen in psychopathology.

A comprehensive review on pharmacognosy, phytochemistry and pharmacological activities of 8 potent species of southeast Asia.

Genus Prunus comprising around 430 species is a vast important genus of family Rosaceae, subfamily amygdalaoidae. Among all 430 species, around 19 important species are commonly found in Indian sub-continent due to their broad nutritional and economic importance. Some most common species of genus Prunus are Prunus amygdalus, Prunus persica, Prunus armeniaca, Prunus avium, Prunus cerasus, Prunus cerasoides, Prunus domestica, Prunus mahaleb, etc. A newly introduced species of Prunus i.e Prunus sunhangii is recently discovered which is morphologically very similar to Prunus cerasoides. Plants of Prunus species are short to medium-sized deciduous trees mainly found in the northern hemisphere. In India and its subcontinent, it extends from the Himalayas to Sikkim, Meghalaya, Bhutan, Myanmar etc. Different Prunus species have been extensively studied for their morphological, microscopic, pharmacological and phytoconstituents characteristics. Total phenolic content of Prunus species explains the presence of phenols in high quantity and pharmacological activity due to phenols. Phytochemical screening of species of genus Prunus shows the presence of wide phytoconstituents which contributes in their pharmacological significance and reveals the therapeutic potential and traditional medicinal significance of this genus. Genus Prunus showed a potent antioxidant activity analyzed by 1,1-diphenyl-2-picryl-hydrazyl radical assay. Plant species belonging to the genus Prunus is widely used traditionally for the treatment of various disorders. Some specific Prunus species possess potent anticancer, anti-inflammatory, hypoglycemic etc. activity which makes the genus more interesting for further research and findings. This review is an attempt to summarize the comprehensive study of Prunus.

New synthetic opioids: Advances of receptor assays as tools for pharmacological characterization and analytical screening

New synthetic opioids: Advances of receptor assays as tools for pharmacological characterization and analytical screening

The Application and Mechanism Exploration of N-Butylphthalide in the Treatment of Carbon Monoxide Poisoning

This study comprehensively explored the application and the mechanism of action of N-Butylphthalide (NBP) in the treatment of carbon monoxide (CO) poisoning. The article begins with an overview of the physiological impacts of CO poisoning, particularly highlighting its inhibition of blood oxygenation function and its extensive damage to the nervous system. Subsequently, the paper delves into the pharmacological characteristics of NBP, discussing its potential role in neuroprotection, and supports the application value of NBP in the treatment of CO poisoning with animal experiments and preliminary clinical data. Although current research results have preliminarily confirmed the neuroprotective effects of NBP, key parameters such as the specific dosage, therapeutic time window, and long-term safety in the treatment of CO poisoning still require further investigation and clarification. The paper concludes with a proposal for future studies to deepen the understanding of the mechanism of action of NBP, explore its synergistic effects with existing treatments, and validate its efficacy and safety in the treatment of CO poisoning through extensive clinical trials. In summary, as an emerging neuroprotective agent, NBP shows significant potential in the field of CO poisoning treatment, and it is hoped that future research will provide more effective and safe treatment options for patients with CO poisoning.

An in-depth review of thalidomide's basic moieties

Thalidomide, also referred to as N-phthalimido glutarimide, was initially made available as a sedative by Chemie Grunelthal GmbH in West Germany in 1957. Thalidomide's chemical structure primarily consists of two rings: the phthalimide ring and the glutarimide ring. Although small substitutions in one or both rings might be tolerated without a reduction in toxicity, both of these groups were necessary for embryopathic action. A cyclic chemical structure that is a component of thalidomide is the phthalimide ring. The phthalimide ring is thought to contribute to both the teratogenic (causes birth defects) and some therapeutic aspects of the medication. Another cyclic structure seen in the chemical makeup of thalidomide is the Glutarimide Ring. The pharmacological characteristics of thalidomide are also connected to this portion of the molecule. Based on their activities and structural connections, this review study gives an overview of the interaction between phalidimide and the glutarimide ring for teratogenicity of the thalidomide type. Understanding how thalidomide interacts with the human body, both for its intended therapeutic effects and its negative side effects, especially when taken during pregnancy, is important given the combination of these rings in the drug's chemical structure.

Exploring cocrystals and polymorphism in pharmaceutical science: A comprehensive review

The pharmaceutical industry has been working hard in recent years to find ways to control polymorphism, which involves many solid drug forms due to their various physical and chemical characteristics. Creating cocrystals and salts of active pharmaceutical ingredients (APIs) is one potential research direction. These substances have drawn a lot of attention because they can improve crucial pharmacological features without reducing therapeutic efficacy. It is significant to note that not all compounds having multiple hydrogen bond donor/acceptor groups and polymorphism properties will form cocrystals; this behavior varies. Pharmaceutical firms and researchers alter APIs, frequently by generating cocrystals, salts, or polymorphs. This review discusses analytical approaches for solids drug forms such as diffraction, spectroscopy, thermal analysis, and pharmaceutical characterization. These techniques enable us to investigate solid APIs thoroughly, from their bulk characteristics to their molecular composition. They offer vital details regarding the composition, attributes, purity, and probable changes of the substance. These technologies are also useful for continuous monitoring and analysis of drug development physical procedures.

Impact of different dose reduction criteria on dose assignment of current DOACs and related outcomes: an analysis from 4-year data of the ETNA-AF Europe programme

Abstract Background Direct oral anticoagulants (DOACs) are the standard treatment for stroke prevention in patients with atrial fibrillation (AF). Pharmacological characteristics and dose reduction criteria of the four currently available DOACs are different. Several studies have reported frequent use of non-recommended doses of DOACs associated with worse clinical outcomes. Data from real-world studies, such as the edoxaban Treatment in routiNe clinical prActice (ETNA)-AF, may help assessing the size of this phenomenon and its impact on clinical outcomes. Purpose To evaluate the distribution of dose reduction criteria and explore associated outcomes in a large, unselected, real-world population using 4-year data from the ETNA-AF EU study. Methods The ETNA-AF EU is a prospective, observational, study to evaluate safety and effectiveness of edoxaban in patients with AF from Europe. Patients with available data regarding the SmPC dose reduction criteria of the four currently available DOACs were included. Patients with a creatinine clearance &amp;lt;30 mL/min were excluded. Patients were classified by dose reduction criteria for the different DOACs (i.e., full dose for all [FULL], reduced dose for all [REDUCED], patients not included in previous groups [INTERMEDIATE]). Results We included 12,866 patients from the ETNA-AF EU study. According to the SmPC dose reduction criteria, the percentage of patients that would be eligible for a dose reduction in the ETNA population was highly heterogenous across different DOACS: 5.7% for apixaban, 16.8% for rivaroxaban, 23.8% for edoxaban and 52.9% for dabigatran. Moreover, differences in the dose reduction criteria included in each SmPC was reflected by the distribution of patients in the three pre-specified groups. Among the 11,003 assignable patients, 42.4% would receive a full dose, 5.1% would receive a reduced dose and the largest percentage, 52.5%, was in the INTERMEDIATE group, which would receive either a full or reduced dose of any DOAC depending on the selected agent. Of the patients included in the INTERMEDIATE group, 65.2% received a full dose of edoxaban due to its specific labelling. Interestingly, the INTERMEDIATE group included the vast majority of patients known to be at risk of adverse events: very elderly (i.e., ≥85 yrs; 76.5%), frail as per investigator (73.3%), history of previous stroke (60.4%) or history of bleeding (61.3%). Clinical outcomes at four years were significantly higher in both the INTERMEDIATE and the REDUCED groups compared to the FULL group, with the only exception of haemorrhagic stroke (Table). Conclusion(s): According to the different dose reduction criteria of currently available DOACs, notable percentage of patients could receive either a full or a reduced dose depending on the DOAC chosen by the physician. Considering that the chosen dose of the DOAC has an impact on clinical outcomes, patients in the INTERMEDIATE group need careful assessment, which warrants further analysis.

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel.

Gain-of-function (GoF) variants in KCNT1 channels cause severe, drug-resistant forms of epilepsy. Quinidine is a known KCNT1 blocker, but its clinical use is limited due to severe drawbacks. To identify novel KCNT1 blockers, a homology model of human KCNT1 was built and used to screen an in-house library of compounds. Among the 20 molecules selected, five (CPK4, 13, 16, 18, and 20) showed strong KCNT1-blocking ability in an in vitro fluorescence-based assay. Patch-clamp experiments confirmed a higher KCNT1-blocking potency of these compounds when compared to quinidine, and their selectivity for KCNT1 over hERG and Kv7.2 channels. Among identified molecules, CPK20 displayed the highest metabolic stability; this compound also blocked KCNT2 currents, although with a lower potency, and counteracted GoF effects prompted by 2 recurrent epilepsy-causing KCNT1 variants (G288S and A934T). The present results provide solid rational basis for future design of novel compounds to counteract KCNT1-related neurological disorders.

Neuroprotective and cognitive enhancing effects of herbecetin against thioacetamide induced hepatic encephalopathy in rats via upregulation of AMPK and SIRT1 signaling pathways

Acute liver injury, there is a risky neurological condition known as hepatic encephalopathy (HE). Herbacetin is a glycosylated flavonoid with many pharmacological characteristics. The purpose of this study was to assess the ability of herbacetin to protect against the cognitive deficits associated with thioacetamide (TAA) rat model and delineate the underlying behavioral and pharmacological mechanisms. Rats were pretreated with herbacetin (20 and 40 mg/kg) for 30days. On 30th day, the rats were injected with TAA (i.p. 350 mg/kg) in a single dose. In addition to a histpathological studies, ultra-structural architecture of the brain, liver functions, oxidative stress biomarkers, and behavioral tests were evaluated. Compared to the TAA-intoxicated group, herbacetin improved the locomotor and cognitive deficits, serum hepatotoxicity indices and ammonia levels. Herbacetin reduced brain levels of malodialdeyde, glutamine synthetase (GS), tumor necrosis factor- alpha (TNF-α), interleukin 1 B (IL-1β), annexin v, and increased brain GSH, Sirtuin 1 (SIRT1), and AMP-activated kinase (AMPK) expression levels. Also, herbacetin improve the histopathological changes and ultra- structure of brain tissue via attenuating the number of inflammatory and apoptotic cells. Herbacetin treatment significantly reduced the toxicity caused by TAA. These findings suggest that herbacetin might be taken into account as a possible neuroprotective and cognitive enhancing agent due to its ability to reduce oxidative stress, inflammation and apoptosis associated with TAA.