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AbstractObjectiveTo conduct a randomised, open label comparison of the effectiveness and safety of intravenous vernakalant and intravenous procainamide for the management of acute atrial fibrillation in the emergency department.DesignRandomised clinical trial (RAFF4 trial).Setting12 tertiary care emergency departments in Canada.ParticipantsPatients with acute atrial fibrillation for whom acute rhythm control was a safe option.InterventionsPatients were randomised (1:1) to an intravenous infusion of vernakalant or procainamide; when rapid conversion did not occur, patients were offered electrical cardioversion.Main outcomes and measuresThe primary outcome was conversion to sinus rhythm within 30 minutes of drug infusion completion. Secondary outcomes included time to conversion to sinus rhythm and whether the patient required electrical cardioversion.ResultsOf the 350 enrolled eligible patients, baseline characteristics were similar in the procainamide (n=172) and vernakalant (n=178) groups. For the primary outcome of conversion success, vernakalant was more effective (62.4% v 48.3%; adjusted absolute difference 15.0%, 95% confidence interval 4.6% to 25.0%, P=0.005; adjusted odds ratio 1.87, 95% confidence interval 1.2 to 2.9, P=0.006). With vernakalant, time to conversion was faster (21.8 v 44.7 minutes; mean difference −22.9, 95% confidence interval −29.9 to −16.0, P<0.001), and fewer patients underwent attempted electrical cardioversion (33.7% v 44.2%; odds ratio 0.62, 95% confidence interval 0.39 to 0.96, P=0.033). Adverse events were similar in both groups, were generally mild and brief, and most patients were discharged home. Subgroup analysis strongly favoured vernakalant for conversion in patients younger than 70 years (73.3% v 47.2%; adjusted odds ratio 3.1, 95% confidence interval 1.7 to 5.5, P=0.001, interaction P=0.005).ConclusionsIn this head-to-head comparison, vernakalant was superior to procainamide for patients with higher conversion rates and faster times to conversion. Therefore, vernakalant is a safe and highly effective intravenous alternative for the rapid cardioversion and discharge home of patients with acute atrial fibrillation.Trial registrationClinicalTrials.gov NCT04485195

The efficacy and safety of vernakalant, a relatively atrial-selective antiarrhythmic agent, in converting atrial fibrillation (AF) to sinus rhythm (SR) were evaluated in this multicenter, open-label study of patients with AF lasting >3 hours and ≤45 days (RCT no. NCT00281554). Adult patients with AF and an indication for conversion to SR received a 10-minute intravenous infusion of vernakalant (3 mg/kg). If after a 15-minute observation period AF was present, a second 10-minute infusion of intravenous vernakalant (2 mg/kg) was given. The primary efficacy end point was the proportion of patients with recent-onset AF (AF lasting >3 hours to ≤7 days) who converted to SR within 90 minutes of the start of the first infusion. Safety evaluations included vital signs, telemetry and Holter monitoring, 12-lead electrocardiography, clinical laboratory tests, physical examinations, and adverse events (AEs). A total of 236 hemodynamically stable patients with AF received intravenous vernakalant. Among them, 167 (71%) had recent-onset AF and were eligible for the primary efficacy end point. Vernakalant rapidly converted recent-onset AF to SR in 50.9% of patients, with a median time to conversion of 14 minutes among responders. The most common AEs were dysgeusia, sneezing, and paresthesia. These occurred at the time of vernakalant infusion, were transient, and resolved spontaneously. Ten patients (4.2%) discontinued vernakalant treatment because of AEs, most commonly (in 4 of 10) hypotension. There were no episodes of torsades de pointes, ventricular fibrillation, or sustained ventricular tachycardia. Vernakalant rapidly converted recent-onset AF to SR, was well tolerated, and may be a valuable therapeutic alternative for reestablishing SR in patients with recent-onset AF.

Leishmaniasis is a neglected disease that affects more than 12 million people, with a limited therapy. Plant-derived natural products represent a useful source of anti-protozoan prototypes. In this work, four derivatives were prepared from neolignans isolated from the Brazilian plant Nectandra leucantha , and their effects against intracellular amastigotes of Leishmania ( L .) infantum evaluated in vitro . IC 50 values between 6 and 35 µM were observed and in silico predictions suggested good oral bioavailability, no PAINS similarities, and ADMET risks typical of lipophilic compounds. The most selective (SI > 32) compound was chosen for lethal action and immunomodulatory studies. This compound caused a transient depolarization of the plasma membrane potential and induced an imbalance of intracellular Ca 2+ , possibly resulting in a mitochondrial impairment and leading to a strong depolarization of the membrane potential and decrease of ATP levels. The derivative also interfered with the cell cycle of Leishmania , inducing a programmed cell death-like mechanism and affecting DNA replication. Further immunomodulatory studies demonstrated that the compound eliminates amastigotes via an independent activation of the host cell, with decrease levels of IL-10, TNF and MCP-1. Additionally, this derivative caused no hemolytic effects in murine erythrocytes and could be considered promising for future lead studies.

Summary Aberrant neural progenitor cell (NPC) proliferation and self-renewal have been linked to age-related neurodegeneration and neurodegenerative disorders including Alzheimer's disease (AD). Rhizoma Acori tatarinowii is a traditional Chinese herbal medicine against cognitive decline. In this study, we found that the extract of Rhizoma Acori tatarinowii (AT) and its active constituents, asarones, promote NPC proliferation. Oral administration of AT enhanced NPC proliferation and neurogenesis in the hippocampi of adult and aged mice as well as that of transgenic AD model mice. AT and its fractions also enhanced the proliferation of NPCs cultured in vitro. Further analysis identified [alpha]-asarone and [beta]-asarone as the two active constituents of AT in promoting neurogenesis. Our mechanistic study revealed that AT and asarones activated extracellular signal-regulated kinase (ERK) but not Akt, two critical kinase cascades for neurogenesis. Consistently, the inhibition of ERK activities effectively blocked the enhancement of NPC proliferation by AT or asarones. Our findings suggest that AT and asarones, which can be orally administrated, could serve as preventive and regenerative therapeutic agents to promote neurogenesis against age-related neurodegeneration and neurodegenerative disorders.

Alkenylbenzenes occur as natural constituents in a variety of edible plants, in particular those herbs and spices used to give a distinctive flavor to a range of food and feed items. Some alkenylbenzenes with relevance for food, such as estragole and methyleugenol, are known to be genotoxic and carcinogenic in rodents. However, the genotoxic and carcinogenic potential of other structurally related alkenylbenzenes, such as myristicin and elemicin, is still under scientific discussion. Here, we investigated the potential of myristicin and elemicin to induce micronuclei (MN) in V79 cells in comparison to that of estragole and methyleugenol. In addition, we determined the impact of these alkenylbenzenes on cell viability and on the induction of apoptosis and necrosis. All tested alkenylbenzenes affected cell viability in a concentration-dependent manner, albeit to varying degrees. Regarding MN formation, elemicin induced a weak but statistically significant response at 100 µM and 500 µM in the absence of an exogenous metabolizing system (S9 mix). Negative results were obtained for estragole and myristicin at the highest tested non-cytotoxic concentration of 10 µM and 100 µM, respectively. For methyleugenol, the MN assay results were considered equivocal, since the observed change in MN induction was rather small and not supported by a concentration-related trend. These findings indicate that traditional in vitro test systems utilizing exogenous metabolizing systems have limited explanatory power with regard to the genotoxic potential of alkenylbenzenes.

Non-alcoholic fatty liver disease is caused by excessive lipid accumulation in hepatocytes. Although trans-anethole (TAO) affects hypoglycemia and has anti-immune activity and anti-obesity effects, its role in non-alcoholic fatty liver disease remains unknown. This study aimed to evaluate the effects of TAO on cellular senescence, lipid metabolism, and reinforcement of microenvironments in HepG2 cells. To analyze the lipid metabolic activity of TAO, PCR analysis, flow-cytometry, and Oil Red O staining were performed, and mitochondrial membrane potential (MMP) and cellular senescence kits were used for assessing the suppression of cellular senescence. At 2000 μg/mL TAO, the cellular viability was approximately 99%, and cell senescence decreased dose-dependently. In the results for MMP, activity increased with concentration. The levels of lipolytic genes, CPT2, ACADS, and HSL, strongly increased over 3 days and the levels of lipogenic genes, ACC1 and GPAT, were downregulated on the first day at 1000 μg/mL TAO. Consequently, it was found that TAO affects the suppression of cellular senescence, activation of lipid metabolism, and reinforcement of the microenvironment in HepG2 cells, and can be added as a useful component to functional foods to prevent fatty liver disease and cellular senescence, as well as increase the immunoactivity of the liver.

Identification of new psychoactive substances (NPS) is challenging. Developing targeted methods for their analysis can be difficult and costly due to their impermanence on the drug scene. Accurate-mass mass spectrometry (AMMS) using a quadrupole time-of-flight (QTOF) analyzer can be useful for wide-scope screening since it provides sensitive, full-spectrum MS data. Our article presents a qualitative screening workflow based on data-independent acquisition mode (all-ions MS/MS) on liquid chromatography (LC) coupled to QTOFMS for the detection and identification of NPS in biological matrices. The workflow combines and structures fundamentals of target and suspect screening data processing techniques in a structured algorithm. This allows the detection and tentative identification of NPS and their metabolites. We have applied the workflow to two actual case studies involving drug intoxications where we detected and confirmed the parent compounds ketamine, 25B-NBOMe, 25C-NBOMe, and several predicted phase I and II metabolites not previously reported in urine and serum samples. The screening workflow demonstrates the added value for the detection and identification of NPS in biological matrices.

The study aimed to analyze morphological and functional changes of Staphylococcus aureus cells due to trans-anethole (a terpenoid and the major constituent of fennel, anise, or star anise essential oils) exposition, and their consequences for human neutrophils phagocytic activity as well as IL-8 production (recognized as the major chemoattractant). The investigation included the evaluation of changes occurring in S. aureus cultures, i.e., staphyloxanthin production, antioxidant activities, cell size distribution, and cells composition as a result of incubation with trans-anethole. It was found that the presence of trans-anethole in the culture medium reduced the level of staphyloxanthin production, as well as decreased antioxidant activities. Furthermore, trans-anethole-treated cells were characterized by larger size and a tendency to diffuse in comparison to the non-treated cells. Several cell components, such as phospholipids and peptidoglycan, were found remarkably elevated in the cultures treated with trans-anethole. As a result of the aforementioned cellular changes, the bacteria were phagocytized by neutrophils more efficiently (ingestion and parameters associated with killing activity were at a higher level as compared to the control system). Additionally, IL-8 production was at a higher level for trans-anethole modified bacteria. Our results suggest that trans-anethole represents a promising measure in combating severe staphylococcal infections, which has an important translational potential for clinical applications.

Natural products, known for their medicinal properties since antiquity, are continuously being studied for their biological properties. In the present study, we analyzed the composition of the volatile preparations of essential oils of the Greek plants Ocimum basilicum (sweet basil), Mentha spicata (spearmint), Pimpinella anisum (anise) and Fortunella margarita (kumquat). GC/MS analyses revealed that the major components in the essential oil fractions, were carvone (85.4%) in spearmint, methyl chavicol (74.9%) in sweet basil, trans-anethole (88.1%) in anise, and limonene (93.8%) in kumquat. We further explored their biological potential by studying their antimicrobial, antioxidant and antiproliferative activities. Only the essential oils from spearmint and sweet basil demonstrated cytotoxicity against common foodborne bacteria, while all preparations were active against the fungi Saccharomyces cerevisiae and Aspergillus niger. Antioxidant evaluation by DPPH and ABTS radical scavenging activity assays revealed a variable degree of antioxidant potency. Finally, their antiproliferative potential was tested against a panel of human cancer cell lines and evaluated by using the sulforhodamine B (SRB) assay. All essential oil preparations exhibited a variable degree of antiproliferative activity, depending on the cancer model used, with the most potent one being sweet basil against an in vitro model of human colon carcinoma.

The threat of antibiotic resistance is escalating, diminishing the effectiveness of numerous antibiotics due to the rapid development of resistant bacteria. In response, the use of green-synthesized nanoparticle, alone or combined with antimicrobial agents, appears promising. This study explores the effectiveness of zinc oxide nanoparticles (ZnONPs) synthesized using Loranthus cordifolius leaf extracts and subsequently coated with anethole. The fabrication of these nanoparticles was confirmed via UV-Vis, FTIR and TEM analyses, ensuring the nanoparticles were produced as intended. Utilizing a nanoprecipitation process that excludes evaporation and drying, a high drug loading capacity of 16.59% was accomplished. The encapsulation efficiency for anethole was recorded at 88.23 ± 4.98%. Antibacterial efficacy was assessed by com paring the green-synthesized ZnONPs (average size: 14.47 nm), anethole-loaded ZnONPs (average size: 14,75 nm), and commercially sourced ZnONPs. The ZnONPs with anethole demonstrated superior inhibition against all tested bacterial strains, including Gram-negative species like Pseudomonas aeruginosa and Escherichia coli , and Gram-positive species like Bacillus subtilis and Staphylococcus aureus , outperforming the commercially available ZnONPs. Additionally, anethole-coated ZnONPs showed the greatest inhibition of Gyr-B activity (IC50 = 0.78 ± 0.2 M), better than both green-synthesized and commercially available ZnONPs. These findings emphasize the enhanced antimicrobial properties of ZnONPs, particularly when combined with green synthesis and anethole loading, highlighting their potential in various biomedical applications.