Drug Discoveries and Therapeutics最新文献

During an earlier multicenter, open-label, randomized controlled trial designed to evaluate the effectiveness of high-dose inhaled ciclesonide in patients with asymptomatic or mild coronavirus disease 2019 (COVID-19), we observed that worsening of shadows on CT without worsening of clinical symptoms was more common with ciclesonide. The present study sought to determine if an association exists between worsening CT shadows and impaired antibody production in patients treated with inhaled ciclesonide. Eighty-nine of the 90 patients in the original study were prospectively enrolled. After exclusions, there were 36 patients each in the ciclesonide and control groups. We analyzed antibody titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein at various time points. Changes in viral load during treatment were compared. There was no significant difference in age, sex, body mass index, background clinical characteristics, or symptoms between the two groups. Although evaluation on day 8 suggested a greater tendency for worsening shadows on CT in the ciclesonide group (p = 0.072), there was no significant difference between them in the ability to produce antibodies (p = 0.379) or the maximum antibody titer during the clinical course. In both groups, worsening CT shadows and higher viral loads were observed on days 1-8, suggesting ciclesonide does not affect clearance of the virus (p = 0.134). High-dose inhaled ciclesonide did not impair production of antibodies against SARS-CoV-2 or affect elimination of the virus, suggesting that this treatment can be used safely in patients with COVID-19 patients who use inhaled steroids for asthma and other diseases.

Structure-based virtual screening plays a critical role in drug discovery. However, numerous docking programs, such as AutoDock Vina and Glide, are time-consuming due to the necessity of generating numerous molecular conformations and executing steps like scoring, ranking, and refinement for the ligand-receptor complexes. Consequently, achieving rapid and reliable virtual screening remains a noteworthy challenge. Recently, a team of researchers from Massachusetts Institute of Technology, led by Stärk et al., developed an SE(3)-equivariant geometric deep learning based protein-ligand binding prediction approach, EQUIBIND. In comparison to conventional docking methods, EQUIBIND has the capacity to predict the binding modes of small molecules with target proteins rapidly and precisely. It presents an innovative resolution for high-throughput screening of drug-like compounds.

Acute viral pharyngitis is a self-limited disease but the symptoms, a sore throat in particular, can affect one's quality of life. Medicine for symptom relief is the main treatment. Recently, many studies have shown that Andrographis paniculata was efficacious in treating many diseases, including upper respiratory infections. However, adverse reactions to systemic intake are a concern. Therefore, A. paniculata spray is intended to reduce systemic adverse reactions and provide patients with more comfort as its local use. This randomized, double-blind study enrolled 60 adult patients with acute viral pharyngitis. All patients were asked to score the severity of symptoms including a sore throat, difficulty swallowing, and coughing using an 11-point numeric rating scale from 0 to 10. A physical examination was performed to score the severity of erythematous and swollen mucosa using a 0-3 score (0 = no, 1 = mild, 2 = moderate, and 3 = severe). The patients were randomized to receive treatment with either an A. paniculata spray or a positive control chamomile spray. Results revealed a significant reduction in the severity of all signs and symptoms in both groups (p < 0.05). The duration of treatment response in the A. paniculata spray group was 1.9 ± 0.7 days compared to 2.5 ± 1.2 days in the chamomile spray group (p = 0.049). No adverse events were noted in either group. A. paniculata spray is safe and highly efficacious in treating acute viral pharyngitis and can reduce symptoms more rapidly than a positive control spray.

Ciprofloxacin (CIP) is frequently detected in the environment and causes the emergence of drug-resistant bacteria. High levels of CIP in the environment are also harmful to humans and animals. Therefore, effective elimination of CIP is required. In this study, plant-based copper nanoparticles (CuNPs) have been fabricated for the purpose of eliminating CIP. Aqueous extracts of 6 plants were compared for their phytochemicals and reducing activity. Among all the extracts, Garcinia mangostana extract (GM) was the most potent with the highest total phenolic compounds, flavonoids, tannins, terpenoids, and reducing activity. CuNPs synthesized using GM (GM-CuNPs) were characterized using UV-VIS spectroscopy and dynamic light scattering. The results showed that the maximum absorption of GM-CuNPs was at 340 nm. The average size of GM-CuNPs is in the nanoscale range of 159.2 ± 61 nm, with a narrow size distribution and a negative zeta potential of - 4.13 ± 6.97 mV. The stability of GM-CuNPs is not solely due to their zeta potential but also phytochemicals in the extract. GM-CuNPs at 25 mM showed the highest efficiency of 95% in removing CIP from aqueous medium pH 6-7 at 25-35°C within 20 min. The results indicated that the electrostatic attraction between the negative charge of GM-CuNPs and the positive charge of CIP controlled the drug adsorption on the nanoparticles. In conclusion, the developed GM-CuNPs have excellent CIP removal efficiency. These synthesized GM-CuNPs are expected to be environmentally friendly for the removal of antibiotics and other drugs.

The precise role of indoleamine 2,3-dioxygenase (IDO) in cardiovascular diseases (CVD) among people living with HIV (PLWH) is still under debate, despite recognized links. This study aimed to investigate the impact of elevated IDO activity on endothelial dysfunction in PLWH. A total of 38 PLWH, who had not previously received anti-retroviral therapy (ART), were enrolled in the study. These participants were monitored for 36 months following the initiation of ART. Measurements including plasma levels of IDO activity, markers of endothelial dysfunction, inflammatory factors, and lipids. In vitro, human aortic endothelial cells (HAEC) were exposed to interferon-γ, an IDO inhibitor, a kynurenine 3-hydroxylase (KMO) inhibitor, as well as different concentrations of kynurenine. Pre-ART, PLWH demonstrated notably elevated plasma concentrations of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1(sVCAM-1), and IDO activity in comparison to healthy controls. Post-ART, both IDO activity and sICAM-1 levels experienced a significant decrease, with IDO activity reaching levels comparable to those observed in healthy controls. Furthermore, a positive correlation was observed between IDO activity and sICAM-1 (p = 0.0002), as well as sVCAM-1 (p < 0.0001) before ART. In vitro, the augmentation of kynurenine concentration in the medium and the induction of IDO expression in HAEC resulted in increased production of reactive oxygen species (ROS), with minimal impact on endothelial dysfunction. From these findings, it can be concluded that long-term ART has the potential to restore the heightened IDO activity observed in PLWH. The overexpression of IDO primarily influences the expression of ROS in HAEC.

This work describes a novel artificial intelligence-based training and monitoring system (AITMS) that was used to control and prevent nosocomial infections (NIs) by improving the skills of donning/removing personal protective equipment (PPE). The AITMS has two working modes, namely an AI-based protective equipment surveillance mode and an AI-based training mode, that were used for routine surveillance and training, respectively. Data revealed that the accuracy rate of donning/removing PPE improved as a result of the AITMS. Interestingly, the frequency of NIs decreased with the use of the AITMS. This study suggested the key role of using PPE in controlling and preventing NIs. Data preliminarily proved that appropriate donning/removing PPE may help to reduce the risk of NIs. In addition, the newest computerized technologies, such as AI, have proven to be useful in controlling and preventing NIs. These findings should helpful to formulate a better strategy against NIs in the future.

Disinfection of dental unit waterlines (DUWLs) plays a key role in control and prevention of nosocomial infection in a dental clinic. The most conventional disinfectant is hydrogen peroxide (H₂O₂), while chlorine dioxide (ClO₂) has been considered however was limited by the "activation" procedures. With the availability of commercialized stable ClO₂ solution (free of activation), direct application of ClO₂ in the dental practice became possible. This study was designed to compare the disinfecting effects of stable 5 ppm of ClO₂ solution with conventional 0.24% of H₂O₂ on DUWLs in dental practice. Studies of colony-forming units (CFUs), confocal laser scanning microscopy (CLSM) and scanning electron microscope (SEM) were employed for evaluation. In CFUs studies, we found that the efficiency of ClO₂ was no less than those of H₂O_2. In the morphological studies, the stronger disinfecting effects of ClO₂ was verified by both CLSM and SEM studies for removal and prevention of biofilm. Importantly, ClO₂ solution achieved a better disinfecting efficiency not only at the surface of bacterial biofilm, but also, it has penetrating effects, presented disinfecting effects from the surface to the bottom of the biofilm. This pilot study provided evidence regarding the efficiency of stable ClO₂ solution on disinfection of DUWLs in the dental practice setting. Application of stable ClO₂ solution in dental practice is therefore become possible.

Sotorasib, an oral small-molecule inhibitor, reportedly exerts promising activity against Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors. However, the currently administered dose may fail to represent the optimal dose based on the therapeutic efficacy. Herein, we developed a simple and sensitive method using high-performance liquid chromatography with ultraviolet (HPLC-UV) to measure the sotorasib concentration in human plasma. The sotorasib calibration curve exhibited linearity across the concentration range of 0.10-20.0 μg/mL (r² = 0.9999). The coefficients of intra- and inter-day validation ranged between 0.79-9.75% and 3.01-6.13%, respectively. The assay accuracy ranged between -3.14 and 5.18%, with > 98.5% recovery. Subsequently, we applied the developed method to estimate sotorasib concentrations in a patient with KRAS G12C-mutated non-small cell lung cancer. We anticipate that our HPLC-UV method will be valuable for assessing the safety and efficacy of sotorasib in larger patient cohorts.

The supraclavicular block (SCB) and the infraclavicular block (ICB) are introduced to meet upper extremity surgery, where the transducer or the insertion point is placed superiorly and inferiorly at the approximate midpoint of the clavicle, respectively. These two approaches are highly appealing since they clearly exhibited each cord and its associated anatomy. In addition, it directed the needle accurately with real-time imaging by ultrasound guidance. Therefore, it brought higher success rates and fewer complications. Numerous trials have recently been conducted to examine the SCB and ICB regarding the new approach, injection techniques, block dynamics, and complication of hemidiaphragmatic paresis. It was found that both approaches could improve block effectiveness and postoperative analgesia for upper extremity surgery, according to recent studies at the level of the clavicular brachial plexus block. However, there is still a lack of work comparing the clinical performance and effectiveness of both approaches with ultrasonography. This review aims to outline the current available data from clinical trials along with case reports about these two approaches and to describe the findings published in the literature during the previous 5 years. Based on these findings, we attempt to determine whether there exists a one-size-fits-all approach that has the potential to meet upper extremity surgery.

Gallbladder cancer (GBC) is a highly aggressive malignancy, which poses significant challenges for timely diagnosis, resulting in a dismal prognosis. Chemotherapy serves as a primary treatment option in cases where surgery is not feasible. However, the emergence of chemoresistance poses a significant challenge to the effectiveness of chemotherapy, ultimately resulting in a poor prognosis. Despite extensive research on mechanisms of chemotherapeutic resistance in oncology, the underlying mechanisms of chemoresistance in GBC remain poorly understood. In this review, we present the findings from the last decade on the molecular mechanisms of chemotherapeutic resistance in GBC. We hope that these insights may provide novel therapeutic and experimental targets for further investigations into this lethal disease.