Drug Discoveries and Therapeutics最新文献

Opioids are commonly prescribed for the management of moderate to severe pain, but their use is associated with dependency and other adverse effects. For decades, the development of safe and effective non-addictive alternatives for treating moderate to severe pain has seen limited progress. On January 30, 2025, the U.S. Food and Drug Administration approved suzetrigine, the first Nav1.8 inhibitor, for the treatment of moderate to severe acute pain. Nav1.8 is a voltage-gated sodium channel that is selectively expressed in peripheral nociceptive neurons, which are responsible for transmitting pain signals. By highly selectively inhibiting the Nav1.8 channel, suzetrigine can effectively alleviate pain. Unlike opioids, this drug does not induce euphoria or excitement in the brain, thereby eliminating concerns about addiction. Suzetrigine offers a novel therapeutic option and a potential combination for multimodal analgesia, with the promise of transforming acute pain management and establishing new treatment standards.

This article was to summarize the treatment course and prognosis of immunocompetent and immunocompromised patients with pulmonary cryptococcal infections and to analyse the relevant factors. The chisquared test was used to test for differences in categorical variables, and the independent samples t test was used to compare continuous variables. Multivariable analyses using the Cox proportional hazards model were used to estimate the effect of prognostic factors on treatment time and improvement time. A total of 243 patients were included in the analysis. Immunocompetent patients with diffuse imaging infiltrates had an extension of the treatment course within six months (P = 0.048) and an extension of the improvement days within four weeks (P = 0.008). In immunocompromised patients, an antigen assay ≥ 40 (P = 0.013) is an unfavourable factor leading to an extension of treatment by nine months. The serum antigen assay in 26/98 (26.53%) immunocompetent patients who did not turn negative when the treatment had finished was significantly lower than that in 14/29 (48.28%) immunocompromised patients (P = 0.027). All patients who underwent surgical resection had a good prognosis. Diffuse imaging infiltrates suggest longer treatment days and a longer improvement time in immunocompetent patients. Higher serum antigen levels in immunocompromised patients indicate longer treatment. Serum antigen assays in immunocompromised patients are difficult to negative.

Fosfomycin, with its unique mechanism of action, has emerged as a promising option for clinicians to combat antimicrobial resistance and the limited availability of effective drugs, which has led to an increase in associated adverse events (AEs). This study aims to explore the AEs caused by fosfomycin through data mining of the US FDA Adverse Event Reporting System (FAERS) to inform clinical safety. As revealed by FAERS, the 796 fosfomycin-associated AEs occurred more commonly in females (61.90%), with Italy reporting the highest incidence (32.40%), and have a significant rise with peak years in 2018 and 2019. The analysis revealed that gastrointestinal disorders, injury, poisoning and procedural complications, and skin and subcutaneous tissue disorders were among the most commonly reported system organ classes (SOCs), accounting for 16.29%, 13.50%, and 11.26% of cases, respectively. The median time to onset (TTO) for fosfomycin associated AEs was 2 days, indicating an early failure type distribution. Off-label use, diarrhoea, and nausea were among the top 50 most frequent AEs, with reporting odds ratios (RORs) of 3.39, 3.87, and 1.79, respectively. These findings emphasize the need for careful monitoring of fosfomycin use, particularly among female patients and in high-reporting regions. The unique profile of fosfomycin associated AEs identified in this analysis calls for a reevaluation of existing safety profiles, as it may differ from previous studies and product labeling. Our findings offer important insights for medical and public health fields, and are essential for enhancing pharmacovigilance and refining clinical management.

Excessive free radicals in the skin cause oxidative stress, damaging cells and leading to aging, melasma, and inflammation. This study developed a liposome system for co-delivering antioxidants to enhance their efficacy in deeper skin layers. Four phenolic compounds were screened for antioxidant activity using DPPH, nitric oxide scavenging, and lipid peroxidation assays. Gallic acid and curcumin, showing the strongest activity, were selected for liposome encapsulation via an emulsification method, with particle size reduction by probe sonication. High-performance liquid chromatography (HPLC) was used for chemical analysis, and particle morphology was examined with transmission electron microscopy. Studies on skin penetration, retention, and release were conducted. The optimized liposome (LP4) had a small particle size (< 150 nm), an unilamellar structure, and high entrapment efficiency (99% gallic acid and 92% curcumin). LP4 promoted effective skin retention of curcumin with slow penetration, while the release of gallic acid and curcumin from LP4 followed a Higuchi kinetic model and Zero-order kinetic model, respectively. This delivery system demonstrates potential for targeted antioxidant delivery, offering enhanced protection against oxidative damage in the skin.

This study sought to investigate the temporal variations in serum calcium concentrations among patients with acute type B aortic dissection (ATBAD) following initial diagnosis, document the incidence of severe complications, and evaluate their potential associations. In this retrospective analysis, we examined 42 consecutive patients diagnosed with ATBAD at Zhejiang Hospital between April 2019 and April 2024. Serum-ionized calcium levels were measured at admission and 24 hours post-admission. Based on changes in calcium levels, patients were categorized into either the elevated or decreased groups. Univariate and multivariate logistic regression analyses were performed to compare clinical characteristics and assess the incidence of severe complications following the initial diagnosis. The study further explored the association between 24-hour serum calcium levels, their dynamic changes, and the occurrence of severe complications in patients with ATBAD. The results showed that the decreased group had a significantly higher frequency of severe complications, including mortality, cardiac complications, acute renal failure, and organ hypoperfusion (P < 0.05), while no significant differences were observed for neurological or pulmonary complications (P > 0.05). Logistic regression revealed that a decline in serum calcium levels within 24 hours was an independent risk factor for severe complications (OR = 16.722, P = 0.03). The receiver operating characteristic (ROC) curve showed an area under the curve (AUC) of 0.864. Decreased serum calcium concentration is an independent predictor of severe complications in ATBAD patients, significantly associated with mortality, cardiac complications, acute kidney injury, and inadequate organ perfusion. No significant correlation with neurological and pulmonary complications was observed.

Bighead carp (Aristichthys nobilis) has garnered significant attention due to its potential health benefits, yet its bioactive protein components remain largely unexplored. In this study, two proteins S3 and Z1 were isolated from Aristichthys nobilis using ammonium sulfate precipitation and serial column chromatography guided by their in vitro antitumor activity. Both proteins were found to be homogeneous in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with a purity exceeding 95% as confirmed by reverse-phase high performance liquid chromatography (RP-HPLC). Electrospray ionization tandem mass spectrometry (ESI-MS/MS) analysis revealed their precise molecular weights to be 44.335 kDa for S3 and 43.028 kDa for Z1. Their amino acid sequences were elucidated through tandem mass spectroscopy and transcriptome unigene analysis, identifying S3 as phosphoglycerate kinase and Z1 as creatine kinase. Furthermore, secondary structure was measured by circular dichroism and three-dimensional structure was predicted by modeling software. The antitumor potential of S3 was evaluated by an in vitro assay, yielding an IC₅₀ value of 26.3 ± 2.9 μM against the HT-29 cell line. Z1 demonstrated antiproliferative activity in vitro with IC₅₀ values of 21.8 ± 1.4, 22.3 ± 2.1, and 22.3 ± 2.5 μM against HT-29, HeLa, and HepG2 cell lines, respectively. Notably, Z1 was found to enhance glucose metabolism and significantly increase the production of lactic acid and CO₂ in tumor cells. These findings suggest that bighead carp (A. nobilis) could serve as a promising source for both antitumor agents and functional food ingredients.

Recently, increased attention has been paid to the consideration of individual characteristics, including sex and age, in the context of medication use and adverse events. However, the characteristics and patterns of adverse events reported in the Japanese Adverse Drug Event Report (JADER) database stratified by sex and age have not yet been clarified. This study aimed to clarify the characteristics and patterns of adverse event reports in the JADER database over a 20-year period (April 2004-March 2024). Data were stratified into 20 groups based on sex and age (aged 0-9 years, 10-19 years, 20-29 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, 70-79 years, 80-89 years, and ≥90 years). The female/male ratio of adverse event reports in JADER was 0.95. The largest group comprised males in their 70s. Adjusting for the proportion of adverse event reports in each group according to the demographic composition in 2015 highlighted that the reporting rates of adverse events were higher in people aged ≥70 years and that females aged 20-49 years reported more adverse events than males. Medical history, causative drugs, and adverse events reported to JADER were characterized by combinations of sex and age. Our results provide additional insights into the interpretation of previous studies using JADER. In addition, the results of this study will help understand the characteristics of adverse event reports contained in JADER and conduct appropriate subgroup and sensitivity analyses.

This study aimed to investigate in detail the efficacy of switching from etanercept reference product (RP) to etanercept biosimilar in patients with rheumatoid arthritis (RA) under real-world clinical conditions using clinical indices and musculoskeletal ultrasound (MSUS). This interventional, multicenter, open-label, single-arm clinical trial involved 24- or 52-week follow-up. This study enrolled patients with RA who had been treated with etanercept-RP for ≥ 24 weeks, achieved clinical low disease activity (LDA) or remission, and switched from etanercept-RP to etanercept biosimilar. This study included 20 patients. Of the 17 patients, 16 (94.1%; 95% confidence interval [CI]: 71.3-99.9) remained in LDA/remission on DAS28-ESR at 24 weeks. The dose of 50 mg/week was reduced to 25 mg/week at 24 weeks, and LDA/remission was sustained until 52 weeks in 9 (81.8%, 95% CI: 48.2-97.7] of 11 participants. DAS28-ESR, DAS28-CRP, SDAI, and CDAI scores showed no apparent worsening. The median total PD score remained 0. The switch from etanercept-RP to etanercept biosimilar and subsequent dose reduction demonstrated favorable outcomes, including MSUS evaluation.

Numerous medications have been associated with an increased risk of vaginal hemorrhage in women. In this study, we analyzed data from the FDA Adverse Event Reporting System (FAERS), focusing on reports of drug-induced vaginal bleeding in women. Risk signals were assessed using disproportionality analyses, specifically the reporting odds ratio (ROR) and the proportional reporting ratio (PRR), to identify significant associations between drugs and adverse events. We found that anticoagulants, hormonal drugs, psychotropic drugs, hypoglycemic agents, antineoplastic agents, anti-inflammatory drugs, immunological agents, and some drugs for osteoporosis were significantly associated with the risk of vaginal hemorrhage. Hormonal drugs, anticoagulants, and particularly antifungal agents were attributed to a notably high proportion of vaginal hemorrhage cases, necessitating further investigation into the underlying mechanisms. Therefore, precise clinical management of medications and optimization of treatment regimens are necessary to reduce the risk of vaginal hemorrhage and improve safety.