Minimum Effective Concentration Research Articles

Surfactant-Assisted Wet Granulation-Based Matrix Tablets without Exceptional Additives: Prolonging Systemic Exposure of Model BCS Class II Ketoprofen.

The present studywas aimed to ameliorate the issue of solubility and thereby, bioavailability of ketoprofen, a BCS Class II drug. The sustained release matrix tablets (MT) were prepared using surfactant-assisted wet granulation (SAWG) with 1-5% of different surfactants. The tablet characteristics were within the compendial limits. The selected sustained release-compliant matrix tablet formulation containing granules prepared using 3% Soluplus® (MT2) released the drug by swelling-erosion. In human volunteers, MT2 attained the maximum plasma concentration (Cmax) of 5.72µg /ml ± 0.30 h, time to Cmax (Tmax) of 5.56 ± 0.30 h and maintained the plasma concentration above its minimum effective concentration (MEC), 0.7 µg.ml-1 till 24h. A control formulation, prepared from granules without surfactant (MT16), promptly attained Cmax of 9.62 ± 0.76 µg/ml within 1h but rapidly declined to below MEC in 8h. Area under the curve from initial point to infinity (AUC0-∞) of MT2 (78.65 ± 7.64 µg.h.ml-1) was 2.29 folds higher than 34.39 ± 3.06 µg.h.ml-1 of MT16. With decreased Cmax, increased AUC0-∞, delayed Tmax and retained ketoprofen concentration above MEC for longer time, MT2 corresponded with the in-vitro sustained drug release characteristic. There is a likelihood of administration of once-a-day single dose of MT2 without plasma fluctuations, expected from two doses of MT16. SAWG helped developing a swellable-erodible sustained release matrix tablet formulation of ketoprofen with the desired biopharmaceutical and pharmacokinetics properties, merely by addition of Soluplus® in granules and without incorporation of any special ingredients or the major manipulation of the formulative ingredients in the formulation.

SPECIES IDENTIFICATION AND IN VITRO ANTIFUNGAL SUSCEPTIBILITY TESTING OF ASPERGILLUS ISOLATED FROM VARIOUS CLINICAL SAMPLES

Objectives: Aspergillus is ubiquitous mold species present in environment in the form of spores. Infection due to Aspergillus is uncommon in immunocompetent individuals unless they possess any abnormality or have undergone any treatment with corticosteroids. In immunocompromised individuals, infection by this fungus is common among people with prolonged neutropenia, transplants, and human immunodeficiency virus infection. The symptoms are diverse, ranging from allergic reactions to invasive aspergillosis and life-threatening complications. The aim of this study is to isolate and identify Aspergillus species obtained from various clinical specimens and perform antifungal susceptibility testing (AFST). Methods: A total of 200 isolates in which positive direct microscopic findings correlated well with culture growth for Aspergillus were included. Antifungal susceptibility was performed by micro broth dilution technique according to clinical laboratory standard institute M38-A2 guidelines. Results: Aspergillus flavus was found to be predominant species followed by Aspergillus fumigatus. AFST was performed, where all Aspergillus strains exhibited low minimum inhibitory concentration (MIC) and minimum effective concentration (MEC) values for most of antifungal drugs tested except for one strain of A. flavus, which exhibited high MIC for voriconazole and high MEC for caspofungin. Conclusion: Polyenes, azoles, and echinocandin resistance are emerging in many parts of the world. Therefore, continued application of AFST combined with morphological characterization for species identification is critical in detecting the emergence of resistance among various Aspergillus species to reduce mortality, morbidity, and overcome treatment failure.

Identification of Synergistic Interactions in Green Corrosion Inhibitor Mixtures by Molecular Modeling

ABSTRACT The composition of corrosion inhibitors used in the Oil and Gas industry are predominantly based on multiple components. It is highly desired that all the components present in a corrosion inhibitor will interact synergistically. Synergistic corrosion inhibitor mixtures will improve performance and reduce the minimum effective inhibitor concentration, which is key particularly for subsea applications. Additionally, subsea applications in the North Sea, the Norwegian shelf and other areas of the world require corrosion inhibitors to follow strict environmental regulations. In this work, the application of molecular modeling by using the frontiers orbitals matching principle for the screening and selection of prospective green multicomponent corrosion inhibitors is reported. The introduction of the HOMO/LUMO orbitals energies of the complex in addition to the HOMO/LUMO energies of the single components when using the frontier orbitals matching principle allowed for a consistent explanation of the synegistic effects found thus suggesting that the modified approach can be a useful tool for the prediction of synergistic effects.

In Vitro Synergistic Activity of Rifampicin Combined with Minimal Effective Antibiotic Concentration (MEAC) of Polymyxin B Against Extensively Drug-Resistant, Carbapenem-, and Polymyxin B-Resistant Klebsiella pneumoniae Clinical Isolates.

We investigated the in vitro antibacterial activity of the combination rifampicin (RIF) + polymyxin B (PB) against extensively drug-resistant (XDR) Klebsiella pneumoniae isolates. We evaluated clinical isolates co-resistant to PB (non-mcr carriers; eptB, mgrB, pmr operon, and ramA mutations) and to carbapenems (KPC, CTX-M, and SHV producers; including KPC + NDM co-producer), belonging to sequence types (ST) ST16, ST11, ST258, ST340, and ST437. We used the standard broth microdilution method to determine RIF and PB minimum inhibitory concentration (MIC) and the checkerboard assay to evaluate the fractional inhibitory concentration index (FICI) of RIF + PB as well as to investigate the lowest concentrations of RIF and PB that combined (RIF + PB) had antibacterial activity. Time-kill assays were performed to evaluate the synergistic effect of the combination against selected isolates. PB MIC (32-256µg/mL) and RIF MIC (32-1024µg/mL) were determined. FICI (<0.5) indicated a synergistic effect for all isolates evaluated for the combination RIF + PB. Our results showed that low concentrations of PB (PB minimal effective antibiotic concentration [MEAC], ≤0.25-1µg/mL) favor RIF (≤0.03-0.125µg/mL) to reach the bacterial target and exert antibacterial activity against PB-resistant isolates, and the synergistic effect was also observed in time-kill results. The combination of RIF + PB showed in vitro antibacterial activity against XDR, carbapenem-, and PB-resistant K. pneumoniae and could be further studied as a potential combination therapy, with cost-effectiveness and promising efficacy.

Pharmacokinetics of methadone after intravenous and subcutaneous administration in domestic ferrets (Mustela putorius furo)

ObjectiveTo determine the pharmacokinetic profile of methadone after intravenous (IV) and subcutaneous (SC) administration in domestic ferrets (Mustela putorius furo). Study designCrossover experimental study. AnimalsA group of eight healthy adult ferrets weighing 1.01 ± 0.23 kg (mean ± standard deviation). MethodsMethadone hydrochloride (0.3 mg kg–1) was injected IV or SC to each ferret with a 3 week washout period. Blood samples were collected via a jugular catheter before and 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360 and 480 minutes after drug administration. Liquid chromatography–tandem mass spectrometry was used to determine plasma methadone concentrations. A nonlinear mixed effects model was used to analyze the data. ResultsAfter IV injection, systemic clearance (Clss) and volume of distribution (Vdss) were 78.9 mL min–1 kg–1 and 9.8 L kg–1, respectively. Elimination half-life was 2.0 hours and SC bioavailability was fixed at 1. The maximum observed plasma concentration after SC injection was 92.1 ± 76.8 ng mL–1. Behavioral changes were observed after both routes. Conclusions and clinical relevanceThe pharmacokinetic profile of IV methadone was characterized by a high Clss and large Vdss, with high bioavailability and absorption rate after SC administration. Half-life was short and mean plasma methadone concentrations stayed above the minimum effective concentration (MEC) reported in humans only after SC administration for 5 minutes, but remained above that reported in dogs for 45 minutes following both routes. Further studies investigating the MEC and pharmacodynamics of methadone in ferrets are warranted.

Characterization and Antimicrobial Activity of Postbiotic from Lactobacillus Acidophilus LA5 on Staphylococcus Aureus in Food Model and In vitro

Background: Postbiotics, also called biogenics, metabiotics, or Cell-Free Supernatants (CFS), are soluble compounds produced by live probiotic microorganisms or released after the lysis of probiotics that could provide beneficial health effects to the host. Objective: This study was conducted with the aim of investigating the antimicrobial, antibiofilm, antioxidant, and cytotoxic effects of postbiotics derived from Lactobacillus acidophilus. Methods: In this study, the antimicrobial properties of the postbiotic of L. acidophilus on Staphylococcus aureus were investigated in different experimental settings, in-vitro, and pasteurized milk. The antioxidant effect of postbiotic was also evaluated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 20-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) method. Furthermore, the chemical composition of the postbiotics was identified via gas chromatography-mass spectrometry. The cytotoxic effects of the compounds were investigated using a human normal cell line. Results and Discussion: According to the results, postbiotics had aconcentration-dependent antimicrobial effect, and the inhibitory effect increased with increasing concentrations. The antimicrobial activity was mainly linked with lactic acid and laurostearic acid. The Minimum Inhibitory Concentration (MIC) of the prepared postbiotic was determined to be 100 mg/ml. The lowest Minimum Effective Concentration (MEC) of postbiotics significantly differed in the food matrix, and a low MEC (minimum effective concentration) index (150 mg/ml) was detected for postbiotic of L. acidophilus. Conclusion: Therefore, the prepared postbiotic should be subjected to more in-depth analysis to examine its suitability as a food additive.

Molecular characterization of histone gene in golden pompano (Trachinotus ovatus) and antimicrobial activity of its derived peptides

In addition to controlling gene expression, mediating DNA folding into chromatin, and responding to immunological stimuli, histones are also thought to have antimicrobial effects. This study identified the molecular characteristics of core Histone MacroH2A2 (TOMacroH2A2) and Histone H2B 1/2 (TOH2B) from Trachinotus ovatus, and the antimicrobial potential of their derived peptides (To.mh2a and To. h2b). The open reading frames (ORFs) of TOMacroH2A2 and TOH2B from T. ovatus were 1010 bp and 375 bp, encoding polypeptides of 369 and 124 amino acids, respectively. The TOMacroH2A2 included an H2A domain and an A1pp domain, while TOH2B included an H2B domain. The amino acid sequences of TOMacroH2A2 and TOH2B demonstrated high homology with other teleost's sequences of histone macroh2a2 and histone h2b, with homologies exceeding 90 %. Expression analysis showed high expression of TOMacroH2A2 in brain, stomach, heart, and skin tissues and TOH2B in gill, brain, and skin tissues. In addition, the histone-derived peptides To. mh2a and To. h2b, synthesized based on two histone sequences from T. ovatus, exhibited typical physical characteristics of antimicrobial peptides, including positive charges, amphipathicity, hydrophobicity, and rich α-helix structure. Crucially, the vitro antibacterial results demonstrated that To. mh2a and To. h2b can inhibit the growth of various aquatic pathogens including Streptococcus agalactiae, Staphylococcus aureus, Bacillus subtilis, Acinetobacter baumannii, Aeromonas hydrophila, and Escherichia coli to varying degrees. Specifically, To. mh2a and To. h2b were capable of disrupting the cell surface structures of S. aureus and penetrating the cell membrane, leading to the leakage of cellular contents, thereby exerting their antibacterial effects. Furthermore, gel electrophoresis migration assays showed that To. mh2a and To. h2b participated in antimicrobial activity by binding to bacterial genomic DNA and reducing the migration rate of gDNA in a dose-dependent manner. The minimum effective concentration for binding to DNA was approximately 50 μM. In conclusion, our study suggested that To. mh2a and To. h2b can act as antimicrobial peptides, providing a potential strategy for controlling bacterial diseases in T. ovatus.

Dissolvable microneedle-based wound dressing transdermally and continuously delivers anti-inflammatory and pro-angiogenic exosomes for diabetic wound treatment

Due to overactive inflammation and hindered angiogenesis, self-healing of diabetic wounds (DW) remains challenging in the clinic. Platelet-derived exosomes (PLT-Exos), a novel exosome capable of anti-inflammation and pro-angiogenesis, show great potential in DW treatment. However, previous administration of exosomes into skin wounds is topical daub or intradermal injection, which cannot intradermally deliver PLT-Exos into the dermis layer, thus impeding its long-term efficacy in anti-inflammation and pro-angiogenesis. Herein, a dissolvable microneedle-based wound dressing (PLT-Exos@ADMMA-MN) was developed for transdermal and long-term delivery of PLT-Exos. Firstly, a photo-crosslinking methacrylated acellular dermal matrix-based hydrogel (ADMMA-GEL), showing physiochemical tailorability, fast-gelling performance, excellent biocompatibility, and pro-angiogenic capacities, was synthesized as a base material of our dressing. For endowing the dressing with anti-inflammation and pro-angiogenesis, PLT-Exos were encapsulated into ADMMA-GEL with a minimum effective concentration determined by our in-vitro experiments. Then, in-vitro results show that this dressing exhibits excellent properties in anti-inflammation and pro-angiogenesis. Lastly, in-vivo experiments showed that this dressing could continuously and transdermally deliver PLT-Exos into skin wounds to switch local macrophage into M2 phenotype while stimulating neovascularization, thus proving a low-inflammatory and pro-angiogenic microenvironment for DW healing. Collectively, this study provides a novel wound dressing capable of suppressing inflammation and stimulating vascularization for DW treatment.

Comparative evaluation of Sensititre YeastOne and CLSI M38-Ed3 reference method for determining echinocandin minimum effective concentrations against Aspergillus isolates.

The minimum inhibitory concentration (MIC) of echinocandins against Aspergillus spp. does not represent the actual inhibition threshold of echinocandins. Therefore, the recommended method to evaluate their activity is determining the minimum effective concentration (MEC) in broth microdilution, a method that is less common in clinical settings. This study aimed to assess a user-friendly commercial method, Sensititre YeastOne (SYO), to determine the effectiveness of echinocandins (caspofungin, anidulafungin and micafungin) against Aspergillus spp. Echinocandins MEC was determined against 23 isolates of Aspergillus spp. using SYO and the reference Clinical and Laboratory Standards Institute (CLSI) method. MECs were read with an inverted microscope and a reading mirror. Essential agreement (EA) between the tested methods was defined as a ±twofold dilution difference. There was a high EA (91%-100%) between the reference method and SYO in determining echinocandins MEC against Aspergillus isolates using inverted microscopy. A high EA was also observed between SYO MEC determined by inverted microscopy and a reading mirror, but different incubation times were required. SYO is a reliable, simple method for determining the MEC of echinocandins against Aspergillus isolates, preferably with an inverted microscope, and can be easily used in clinical laboratories when echinocandin susceptibility testing is required.IMPORTANCEUsing a commercial method such as Sensititre YeastOne (SYO) to determine the minimum effective concentration (MEC) of echinocandins against Aspergillus spp. has been shown to be a reliable alternative to the Clinical and Laboratory Standards Institute (CLSI) reference method. This makes it more suitable for high-volume clinical laboratories. SYO provides accurate results comparable to the standard method and could potentially improve patient care by guiding more optimal antifungal treatment choices for patients with Aspergillus infections.

Oxidative Stress, Oxidative Damage, and Cell Apoptosis: Toxicity Induced by Arecoline in Caenorhabditis elegans and Screening of Mitigating Agents.

As the areca nut market is expanding, there is a growing concern regarding areca nut toxicity. Areca nut alkaloids are the major risky components in betel nuts, and their toxic effects are not fully understood. Here, we investigated the parental and transgenerational toxicity of varied doses of areca nut alkaloids in Caenorhabditis elegans. The results showed that the minimal effective concentration of arecoline is 0.2-0.4 mM. First, arecoline exhibited transgenerational toxicity on the worms' longevity, oviposition, and reproduction. Second, the redox homeostasis of C. elegans was markedly altered under exposure to 0.2-0.4 mM arecoline. The mitochondrial membrane potential was thereafter impaired, which was also associated with the induction of apoptosis. Moreover, antioxidant treatments such as lycopene could significantly ameliorate the toxic effects caused by arecoline. In conclusion, arecoline enhances the ROS levels, inducing neurotoxicity, developmental toxicity, and reproductive toxicity in C. elegans through dysregulated oxidative stress, cell apoptosis, and DNA damage-related gene expression. Therefore, the drug-induced production of reactive oxygen species (ROS) may be crucial for its toxic effects, which could be mitigated by antioxidants.

Exploration of the application of the sprayed γ-GGT fluorescent probe for visual imaging of epithelial ovarian cancer.

127 Background: To explore the feasibility, accuracy and related influencing factors of spraying γ -GGT fluorescent probe in visual imaging of epithelial ovarian cancer. Methods: This study employed a previously developed spray-type γ-GGT fluorescent probe in fresh ex vivo epithelial ovarian cancer tissues. The experimental group selected ovarian cancer lesions of varying sizes and observed fluorescence imaging after spraying different concentrations of the probe. The optimal imaging concentration and observation time were determined based on pathological results. The validation group then used the optimal parameters to image primary and metastatic lesions, normal tissue, and suspicious areas, confirming the probe's accuracy. Clinical data from patients, such as age and stage, were analyzed to identify factors affecting probe imaging. Results: A total of 16 cases of epithelial ovarian cancer were included in this study, 8 cases were in the experimental group and 8 cases were in the validation group, and the samples were collected from the primary ovarian lesions, omental metastases and peritoneal metastases. In the experimental group, 42 lesions of 3 different diameters were collected. The visible lesions were not found to have any changes in the imaging within 1min-1h after spraying the γ-GGT fluorescent probe, and the SBR value within 1min-1h was between 1.26-1.29, with no statistical difference ( P&gt;0.05), and the visible effect of 5 h was weaker or even invisible to the naked eye, and the best observation time was 1min-1h after spraying the γ-GGT fluorescent probe, and the SBR value of 1min-1h after spraying 10 μM of γ-GGT fluorescent probe was significantly higher than that of 1 μM and 5 μM ( P&lt;0.05), and the best visible effect was achieved by the naked eye, resulting in a minimum effective imaging concentration of 10 μM. A total of 27 points were collected from the lesion with a diameter of &lt;0.3 cm and its surrounding normal tissues with a distance of 1 cm or tissues with a diameter of 1-1.5 cm with a height of suspicion but normal to the naked eye, and 26 of the 27 tissues were confirmed by pathology to be cancerous and 1 was non-cancerous, with a true positive rate of 96.3% and a false positive rate of 3.7%. The overall true positive rate of fluorescence imaging was 98.6%. Univariate analysis showed that there were significant differences in the level of preoperative γ-GGT and the SBR value of preoperative treatment (all P&lt;0.05), and the results of multivariate analysis showed that preoperative treatment was an independent influencing factor for fluorescence imaging of γ-GGT fluorescent probe ( P&lt;0.05). Conclusions: This study tested the γ-GGT fluorescent probe for ovarian cancer imaging, finding 10 μM as the effective concentration and 1 minute to 1 hour as the optimal observation window. The probe's effectiveness is influenced by preoperative treatments.

Optimization of scale inhibitor and adsorption enhancer during squeeze process in offshore oilfields

To solve the problem that scale in oilfields can lead to a reduction of formation permeability and blockage of wellbore and production system pipelines, through the scale inhibitor-formation water compatibility experiment and the minimum effective scale inhibitor concentration experiment, three different types of surfactants are selected as adsorption promoters. Three different types of surfactants were selected as adsorption–desorption accelerators through dynamic core adsorption–desorption experiments. The results of the indoor experiment show that the three types of scale prevention agents selected can meet the environmental protection requirements of the sea area. The static scale prevention rate at high temperature (&amp;gt;120 °C) exceeds 80%, and the minimum effective concentration is less than 3.5 mg L−1. The preferred cation Gemini surfactant has a stable adsorption enhancement effect of the scale inhibitor under different water-bearing conditions and can effectively extend the squeezing life under complex formation conditions. The results improve the comprehensive economic benefits of the field and provide technical feasibility to significantly improve the scale prevention efficiency of the field.

MODL-14. TARGETING GL1/GL2-DNMT1-UHRF1 EPIGENETIC COMPLEX DISRUPTION VIA BET INHIBITION IMPAIRS SHH MB DEVELOPMENT

Abstract BACKGROUND Sonic Hedgehog Medulloblastoma (SHH MB) shares 30% among all molecular subtypes of medulloblastomas (MBs). Constitutive activation of SHH signaling in the cerebellum’s granular cell precursors (GCPs) is critical for this MB development. When SHH receptor PATCHED-1 (PTCH1) is mutated, stimulation of this receptor by SHH ligand binding leads to derepression of heterotrimeric GTP-binding protein–coupled receptor Smoothened (SMO) eventually altering the activity, location, and stability of the three downstream glioma associated oncogene (GLI) family members: GLI1, GLI2, and GLI3. GLI1 and GLI2 mostly function as transcriptional activators, while GLI3 mainly plays a repressor role. The bromodomain and extra-terminal domain (BET) family of proteins comprises four conserved members (Brd2, Brd3, Brd4, and Brdt), which are critical regulators of GLI1 and GLI2-mediated transcription. METHODS In the present study, we pharmacologically inhibited BETs with a previously described BET inhibitor, BMS986158, and a novel BET inhibitor, UM002, discovered by our lab. We treated human SHH MB cells (ONS76 cells) in vitro and ex vivo in mouse SHH MB cells (from Ptch1 conditional knockout mice) with minimum effective concentrations of these inhibitors. We screened for GLI1/GLI2-DNMT1-UHRF1 epigenetic complex components expressions by immunoblotting and assessed the effectiveness of inhibiting their interactions by performing PLA assays. RESULTS In this study, we show that pharmacological inhibition of BETs leads to attenuated GLI1 and GLI2 levels. This GLI1 and GLI2 inhibition eventually disrupts the previously reported GL1/GL2, DNMT1-UHRF1 epigenetic complex, which is crucial for SHH MB development. A previously described BET inhibitor, BMS986158, and a novel BET inhibitor, UM002, synthesized and characterized by our lab can inhibit BETs. This could be a potential therapeutic approach targeting GLI-associated epigenetic complexes to treat SHH medulloblastoma.

Investigation of antifungal susceptibility of Aspergillus species isolated from systemic clinical specimens by different methods

PurposeDue to the potential for Aspergillus species to cause lethal infections and the rising rates of antifungal resistance, the significance of antifungal susceptibility tests has increased. We aimed to assess the sensitivities of Aspergillus species to amphotericin B (AMB), voriconazole (VOR), itraconazole (ITZ), and caspofungin (CAS) using disk diffusion (DD) and gradient diffusion (GD) methods and compare them with broth microdilution (BMD) as the reference susceptibility method. MethodsThe study involved 62 Aspergillus fumigatus, 28 Aspergillus flavus, and 16 Aspergillus terreus isolates, totaling 106 Aspergillus isolates. BMD and DD methods were performed in accordance with CLSI M38-A2 and CLSI M51-A documents, respectively. The GD method utilized nonsupplemented Mueller Hinton agar (MHA) as the medium. ResultsIn the BMD method, the lowest minimal inhibitory concentration (MIC)90 or minimal effective concentration (MEC)90 values were observed for VOR and CAS (0.5 μg/mL and 0.06 μg/mL, respectively). AMB and ITZ MIC90 values were both 2 μg/mL. In our comparison of the GD method with the BMD method at ±2 dilution, we observed essential agreement rates of 91.6%, 99.1%, 100%, and 38.6% for AMB, VOR, ITZ, and CAS, respectively. When comparing DD and BMD methods, we found categorical agreement rates of 65.1%, 99.1%, 77.3%, and 100% for AMB, VOR, ITZ, and CAS, respectively. For GD and BMD methods, these rates were 79.2%, 99.1%, 87.8%, and 100%. ConclusionsGiven the high essential and categorical agreement rates, we posit that the GD method is a viable alternative to the BMD method for AMB, ITZ and VOR but not for CAS. In addition, the use of nonsupplemented MHA in the GD method proves advantageous due to its cost-effectiveness and widespread availability compared to other growth media.

In Vitro Activitiy of Rezafungin in Comparison with Anidulafungin and Caspofungin against Invasive Fungal Isolates (2017 to 2022) in China.

The efficacy of different echinocandins is assessed by evaluating the in vitro activity of a novel antifungal, rezafungin, against invasive fungal isolates in comparison with anidulafungin and caspofungin. Using the broth microdilution (BMD) method, the susceptibility of 1000 clinical Candida isolates (including 400 C. albicans, 200 C. glabrata, 200 C. parapsilosis, 150 C. tropicalis and 50 C. krusei) and 150 Aspergillus isolates (100 A. fumigatus and 50 A. flavus) from the Eastern China Invasive Fungi Infection Group (ECIFIG) was tested for the antifungals including anidulafungin, rezafungin, caspofungin and fluconazole. The echinocandins showed strong activity against C. albicans that was maintained against fluconazole-resistant isolates. The GM MIC (geometric mean minimum inhibitory concentration) value of rezafungin was found to be comparable to that of anidulafungin or caspofungin against the five tested common Candida species. C. tropicalis exhibited higher resistance rates (about 8.67-40.67% in different antifungals) than the other four Candida species. Through the sequencing of FKS genes, we searched for mutations in echinocandin-resistant C. tropicalis isolates and found that all displayed alterations in FKS1 S654P. The determined MEC (minimal effective concentration) values against A. fumigatus and A. flavus for rezafungin (0.116 μg/mL, 0.110 μg/mL) are comparable to those of caspofungin (0.122 μg/mL, 0.142 μg/mL) but higher than for anidulafungin (0.064 μg/mL, 0.059 μg/mL). Thus, the in vitro activity of rezafungin appears comparable to anidulafungin and caspofungin against most common Candida and Aspergillus species. Rezafungin showed higher susceptibility rates against C. glabrata. Rezafungin indicates its potent activity for potential clinical application.

Insectoacaricide activity of 5% D-cyphenothrin Emulsion against argasid ticks and biting lice

The purpose of the research is to evaluate the insectoacaricidal activity of the drug 5% D-cyphenothrin Emulsion against argasid ticks and biting lice in different concentrations.Materials and methods. We carried out a parasitological examination of an open-type cinderblock poultry building in peasant household BUGLEN-2 (the Republic of Dagestan) using the avian ectoparasite collecting methods of B. A. Frolov (1975). The studies were performed using procedures outlined in the studies by A. A. Nepoklonov and G. A. Talanov (1973), M. V. Arisov and I. A. Arkhipov (2018) as modified. In the Laboratory of Ectoparasitosis in the VNIIP – FSC VIEV, the acaricidal activity of 5% D-cyphenothrin Emulsion was evaluated against argasid ticks and LD50 and LD95 were determined. The insecticidal activity of the studied drug in different concentrations against the biting lice Menopon gallinae and Menacanthus stramineus was studied on naturally infected chickens that were kept on the farm. Parasitic arthropods were identified to species using identification guides by I. G. Galuzo (1957), N. A. Fillipova (1966) and D. I. Blagoveshchensky (1940).Results and discussion. In laboratory, we observed rapid death of argasid ticks within 30 minutes after their contact with absorbent paper impregnated with 0.005% and 0.05% concentrations of the studied drug. In the assessment of the 5% D-cyphenothrin Emulsion insecticidal activity against biting lice of two species Menopon gallinae and Menacanthus stramineus on naturally infected chickens, we observed the death of parasitic insects after 24 hours on the birds treated with a 0.005% emulsion. Thus, the minimum effective concentration of 0.005 % of the study drug, 5% D-cyphenothrin Emulsion, was determined for the above parasitic arthropods.

Identification of Xuanfei Baidu granule constituents by liquid chromatography-quadruple-time-of-flight-mass spectrometry and its anti-inflammatory active constituents using a lipopolysaccharide-induced RAW264.7 cell model.

The Xuanfei Baidu (XFBD) prescription, a traditional Chinese medicine prescription, has demonstrated significant anti-inflammatory activities; however, the number of its reported constituents is limited, and its anti-inflammatory constituents are unclear. In this study, the constituents of XFBD granule, a granule dosage of XFBD prescription, were thoroughly examined in vitro and in vivo using liquid chromatography-quadruple-time-of-flight-mass spectrometry, and the anti-inflammatory constituents were screened. A total of 214 constituents were identified from the XFBD granule, 62 of which were confirmed via comparison with reference standards. After intragastric administration of XFBD granule, 63 and 28 constituents were absorbed into the rat sera and lungs in prototype form, respectively. XFBD granule and XFBD-containing serum were found to significantly reduce nitric oxide (NO) and interleukin-6 (IL-6) secretion in lipopolysaccharide-induced RAW264.7 cells. Five anti-inflammatory constituents (verbasoside, scutellarin, luteolin, apigenin, and pogostone) were found to reduce the concentration of NO and IL-6 in a dose-dependent manner. Moreover, the combination of these five constituents could significantly reduce NO secretion even when the concentration of each constituent was two to three orders of magnitude lower than their individual minimum effective concentrations. Overall, this study provides a valuable reference for the discovery of effective constituents from the XFBD granule.

The 90% minimum effective concentration of ropivacaine for ultrasound‐guided interscalene brachial plexus block in children aged 1–10 years: A biased coin design up‐and‐down sequential allocation trial

AbstractRopivacaine is a commonly used local anesthetic for brachial plexus blocks in children, but the minimum effective dose of ropivacaine for interscalene brachial plexus blocks has not been reported. The aim of this study was to determine the 90% minimum effective concentration (MEC90) of ropivacaine for an ultrasound‐guided interscalene brachial plexus block (ISB). A total of 155 patients, aged from 1 to 10 years, underwent unilateral surgical procedures on areas of the upper extremity not innervated by the ulnar nerve. The biased coin design up‐and‐down sequential method (BCD‐UMD) was used to determine the MEC90 of ropivacaine for ultrasound‐guided ISB. In our study, the initial concentration of ropivacaine was 0.07% in the toddler group and 0.09% in the preschool and school‐age groups. During the trial, the concentration of ropivacaine for each subsequent patient was determined by the blocking effect of the previous patient. In case of failure, the concentration for the next patient was increased by 0.01%. Otherwise, the concentration was either decreased by 0.01%, with a probability of 0.11, or kept the same, with a probability of 0.89. Overall, the MEC90 of ropivacaine was 0.104% (95% confidence interval (CI), 0.070%–0.106%) in the toddler group, 0.114% (95% CI, 0.090%–0.117%) in the preschool group, and 0.133% (95% CI, 0.099%–0.136%) in the school‐age group. No adverse events occurred. Our study showed that lower concentrations of ropivacaine could provide effective nerve blocks and reduce the risk of local anesthetics.

Tenofovir, emtricitabine, lamivudine and dolutegravir concentrations in plasma and urine following drug intake cessation in a randomized controlled directly observed pharmacokinetic trial to aid point-of-care testing.

Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions. We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT. Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Plasma and spot urine were collected on Day 15 (0-336 h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90 = 64 ng/mL) and minimum effective concentration (MEC = 324 ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500 ng/mL]. Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0 h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4 ng/mL (22.1-32.7). Tenofovir in urine reached 1500 ng/mL by 101 h (58.6-205) with an equivalent plasma concentration of 6.20 ng/mL (4.21-8.18). These data support use of a urinary tenofovir threshold of <1500 ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).

Novel aurone-derived piperazine sulfonamides: Development and mechanisms of action as immunostimulants against plant bacterial diseases

Bacterial diseases pose a significant threat to the sustainable production of crops. Given the unsatisfactory performance and poor eco-compatibility of conventional bactericides, here we present a series of newly structured bactericides that are inspiringly designed by aurone found in plants of the Asteraceae family. These aurone-derived compounds contain piperazine sulfonamide motifs and have shown promising in vitro performance against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola and Xanthomonas axonopodis pv. citri, in particular, compound II23 achieved minimum half-maximal effective concentrations of 1.06, 0.89, and 1.78 μg/mL, respectively. In vivo experiments conducted in a greenhouse environment further revealed that II23 offers substantial protective and curative effects ranging between 68.93 and 70.29% for rice bacterial leaf streak and 53.17–64.43% for citrus bacterial canker, which stands in activity compared with lead compound aurone and commercial thiodiazole copper. Additional physiological and biochemical analyses, coupled with transcriptomics, have verified that II23 enhances defense enzyme activities and chlorophyll levels in rice. Significantly, it also stimulates the accumulation of abscisic acid (ABA) and upregulates the expression of key genes OsPYL/RCAR5, OsBIPP2C1, and OsABF1, thereby activating the ABA signaling pathway in rice plants under biological stress from bacterial infections.