Biological & pharmaceutical bulletin最新文献

Maintaining medication adherence remains a major clinical challenge, as higher daily dosing frequencies are often associated with decreased adherence. Although once-daily regimens are generally preferred, specific patient preferences regarding dosing frequency are unclear, despite implications for improving patient satisfaction and optimizing pharmacotherapy. Here, we evaluated the frequency at which patients begin to perceive dosing as excessive. A web-based questionnaire survey using the personal health record infrastructure of electronic medication notebooks was administered between July 20 and 26, 2023. Eligible participants were aged ≥20 years and had received oral tablets or capsules within 90 d of the survey. The questionnaire consisted of 6 items, including whether participants felt that the daily medication frequency was excessive. A multivariate logistic regression analysis was performed to identify the frequency beyond which patients perceive dosing as excessive, adjusting for confounders, such as medication formulation, number of medications, and patient characteristics. Of 1478 respondents, 1236 were included in the analysis. In total, 28.9% of participants reported that their medication frequency felt excessive. In the multivariate logistic regression analysis, twice-daily or more frequent dosing was significantly associated with the perception of excessiveness, using once-daily dosing as the reference. Twice-daily dosing is the frequency beyond which patients are significantly more likely to perceive medication as excessive. Our findings emphasize the importance of simplifying dosing regimens.

Diabetic nephropathy (DN) is among the most serious diabetes-related microvascular complications, a disease with risks leading to end-stage kidney disease (ESKD). However, only limited DN treatment options are currently available. DN development and progression involve different pathological mechanisms, including inflammation and oxidative stress. Stachybotrys microspora is a fungus producing the triphenyl phenol SMTP-44D, which exhibits anti-inflammatory and antioxidant properties in several disease models. In this study, we aimed to evaluate the effects of SMTP-44D in a DN mouse model, which was created by removing the right kidney of 6-week-old db/db mice. We administered SMTP-44D for 10 weeks between weeks 6 and 16 of age to observe blood glucose levels, renal function parameters, inflammatory factors, oxidative stress markers, and histopathological characteristics. SMTP-44D treatment did not reduce blood glucose level but significantly decreased serum creatinine and urinary albumin as renal function parameters, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and nicotinamide adenine dinucleotide phosphate oxidase-1 as inflammation and oxidative stress in the kidney. In addition, histopathological assessment revealed its preventive effect against glomerulosclerosis and local regenerative tubule. Therefore, we discovered that SMTP-44D might protect renal function without affecting blood glucose level in DN possibly via suppression of inflammation and oxidative stress. In conclusion, SMTP-44D could be a potential DN treatment agent, even in patients with poor glycemic control.

Idiosyncratic drug-induced liver injury (iDILI) is an unpredictable and potentially severe adverse drug reaction, in which immune-mediated mechanisms are suspected to play a central role. Although eosinophilia is often considered a marker of hypersensitivity reactions, the role of eosinophils in iDILI, including drug-specific risks, remains poorly understood. We conducted a case-control study using electronic medical records to evaluate drug-specific risks associated with drug-induced liver injury with eosinophilia (DILI-Eos). Among 17129 Japanese adult patients who underwent serial liver function tests and eosinophil counts, we extracted 631 DILI-Eos cases and 16498 non-DILI-Eos controls. Multivariable logistic regression analysis was performed for 38 drugs that were newly prescribed in more than 50 DILI-Eos cases within 60 d prior to liver injury onset. Sulbactam/cefoperazone showed the strongest association with DILI-Eos (adjusted odds ratio (OR) 14.51; 95% confidence interval (CI) 10.09-20.85), followed by meropenem (OR 5.68; 95% CI 4.10-7.82) and tazobactam/piperacillin (OR 3.55; 95% CI 2.63-4.75). Several commonly used drugs, such as mosapride, lansoprazole, furosemide, and ambroxol, were also significantly associated with increased risk. These findings suggest that DILI-Eos can be triggered by a wide range of drugs across various therapeutic classes potentially via immune-mediated pathways. Notably, substantial variability in risk was observed even within the same drug classes, such as β-lactam antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), underscoring the importance of drug-specific evaluation. Further studies are needed to clarify the causality and mechanisms underlying eosinophilic responses in DILI.

Fruquintinib is a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR) used in patients with metastatic colorectal cancer. Fruquintinib reportedly inhibits the phosphorylation of VEGFR-2 by >80% at plasma trough concentrations >176 ng/mL. Therefore, maintaining a stable trough concentration of fruquintinib is clinically necessary. To date, the only reported method for quantifying fruquintinib concentrations in human plasma is LC-MS/MS, which is challenging to use routinely in clinical settings given its high cost and technical demands. Therefore, in this study, we aimed to develop a method for determining fruquintinib levels in human plasma and validate it for therapeutic drug monitoring (TDM). For the analysis, a 50-μL human plasma sample was obtained, and protein precipitation was performed using acetonitrile extraction. Fruquintinib and acetanilide (internal standard) were separated on a reversed-phase column using a mobile phase consisting of 0.5% KH₂PO₄ (pH 2.6) and acetonitrile (69/31, v/v), pumped at a flow rate of 1.0 mL/min. The detection wavelength was set at 237 nm. The calibration curves for fruquintinib were linear (r² = 0.999) in the range of 50-2000 ng/mL. The accuracy and precision in all validation experiments adhered to the guidelines of the U.S. Food and Drug Administration. Using the validated method, we successfully measured fruquintinib concentrations in the plasma of a patient. This article presents a simple, novel, and sensitive HPLC-UV-based method for determining the plasma concentration of fruquintinib and confirms its applicability in the TDM of fruquintinib in the clinical setting.

Hepatocyte growth factor (HGF) exhibits mitogenic, motogenic, and morphogenic activities. Enhancing HGF production could serve as a therapeutic approach for organ regeneration, wound healing, and embryogenesis. Notably, HGF demonstrates therapeutic potential in the treatment of neurodegenerative diseases. In this study, we found that quercetin promotes HGF production in normal human dermal fibroblasts (NHDF) at low concentrations. cAMP response element binding protein (CREB), a transcription factor, is phosphorylated. Additionally, this activity may result from quercetin's interaction with the β2 adrenaline receptor (β2AR). Further pharmacological analysis suggested that HGF production is promoted via PKA pathway. In conclusion, quercetin shows potential as a drug for treating organ-related diseases, including neurodegenerative disorders, by enhancing HGF production.

In the development of pharmaceuticals and other chemical substances, it is important to evaluate their efficacy and safety. There is a growing trend toward reducing reliance on traditional in vivo testing using animals for safety assessments and utilizing new evaluation methods, such as in vitro and in silico testing, to refine human safety assessments. Furthermore, in medical and environmental fields, there is a growing demand for the utilization of vast amounts of information. This has led to the development of data-driven approaches that utilize large-scale medical information and artificial intelligence (AI). Machine learning enables computers to learn from known data, discover new patterns, and predict unknown data. This technology is also useful for in silico prediction of chemical toxicity and adverse reactions in humans. Recently, explainable AI, which presents the basis for forecasts obtained from machine learning models in a user-understandable manner, has attracted attention and is a useful technology for decision-making support. We have developed machine learning models focusing on a quantitative structure-activity relationship approach to predict toxicity and adverse reactions based on the structural information of chemical substances. Furthermore, we have begun to develop a model to predict package insert revisions based on post-marketing adverse reaction information. These efforts will contribute to solving regulatory science issues regarding the appropriate use of chemical substances such as pharmaceuticals.

Neisseria gonorrhoeae and its increasing antimicrobial resistance have raised global health concerns, creating an urgent need for more advanced diagnostics to contain the spread. We conducted a preclinical trial using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) with Thio-nicotinamide-adenine dinucleotide (NAD) cycling for the detection of N. gonorrhoeae. Three independent researchers conducted the initial experiments to obtain calibration curves. The inter-assay reproducibility across the 3 investigators yielded coefficients of variation of 11% when measuring 500000 CFU/mL, confirming the consistent performance of the ultrasensitive ELISA. Specificity against common clinical microorganisms was also assessed. Performance was first evaluated in simulated urine, vaginal fluid, and saliva. A comparative evaluation of 90 clinical isolates was then performed using a conventional ELISA method. The ultrasensitive ELISA produced consistent calibration curves (R² = 0.99) with limits of detection of 1.1 × 10⁴ to 1.8 × 10⁴ CFU/mL. No cross-reactivity to common pathogens was observed. The assay results revealed linearity in simulated fluids, with a modestly reduced sensitivity in urine and vaginal fluid. At 50000 CFU/mL, the ultrasensitive ELISA generated signals >50-fold stronger than the p-nitrophenyl phosphate (pNPP) ELISA. For clinical isolates, the ultrasensitive ELISA identified 78.9% as positive compared with 30.0% by pNPP ELISA (p = 0.0005). The ultrasensitive ELISA detected N. gonorrhoea with high sensitivity and specificity across sample types, consistently outperforming the conventional ELISA, and demonstrating the potential of this approach as a cost-effective diagnostic alternative.

Treatments to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) are urgently needed. Tanshinone VI (TanVI) is a compound extracted from the roots of Salvia miltiorrhiza Bunge (Lamiaceae) that exerts inhibitory effects on the development of cardiac remodeling under experimental conditions. However, the therapeutic effects of TanVI on HFpEF remain unclear. The present study aims to investigate the therapeutic effects of TanVI in a mouse model of HFpEF. HFpEF mice were prepared by feeding C57BL/6N mice a high-fat diet and providing water containing N^[ω]-nitro-L-arginine methyl ester hydrochloride (L-NAME) for 15 weeks, and TanVI (3 mg/kg/d) or vehicle was administered intraperitoneally using an osmotic pump for 5 weeks until the end of the experiment. The administration of a high-fat diet and L-NAME resulted in cardiac diastolic dysfunction with cardiac hypertrophy and fibrosis. In contrast, treatment with TanVI markedly attenuated cardiac hypertrophy and fibrosis and prevented cardiac diastolic dysfunction. In HFpEF mouse hearts, the phosphorylation levels of mitogen-activated protein (MAP) kinases such as c-Raf, MEK1/2, and extracellular signal-regulated kinase 1/2 (ERK1/2), which regulate cardiac hypertrophy and fibrosis, were elevated. In contrast, treatment with TanVI reversed the phosphorylation levels of c-Raf, MEK1/2, and ERK1/2. The present study showed that TanVI prevented the development of HFpEF by reducing cardiac remodeling. Furthermore, our findings suggest, at least in part, that TanVI attenuates the development of HFpEF by inhibiting the MAP kinase signaling pathway.

Chronic liver disease (CLD) poses a significant global health challenge, and liver fibrosis is a crucial process in the pathogenesis of CLD. However, effective interventions to halt and reverse the progression of liver fibrosis remain elusive. This study investigated the potential of the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 in treating diethylnitrosamine (DEN)-induced liver fibrosis in mice. We first demonstrated that DEN-induced hepatic fibrosis in mice was accompanied by upregulation of hepatic NAMPT and poly (ADP-ribose) polymerase 1 (PARP1) expression. Administration of FK866 inhibited the increase in alanine aminotransferase and aspartate aminotransferase levels and reversed the histopathological changes associated with DEN-induced liver fibrosis. It also suppressed the elevated expression of fibrotic markers, such as fibronectin, collagen IV, laminin, and α-smooth muscle actin. Further studies revealed that this therapeutic effect was achieved by inhibiting the NAD⁺ level, as well as the protein expression of NAMPT, PARP1, and inflammatory factors, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α, and P65. In conclusion, FK866 exhibits therapeutic potential for the treatment of liver fibrosis.

Disruption of osteoblast differentiation can lead to severe bone diseases, such as osteoporosis and osteosclerosis. Our previous study showed that a reduced 4S/6S ratio promotes osteoblast differentiation, linking this specific chondroitin sulfate (CS) modification to bone pathology. This study investigated the effect of forced elevation of the 4S/6S ratio on differentiation. C4ST-1 was found to exhibit overexpression, increasing the 4S/6S ratio, significantly suppressing osteoblast differentiation, as evidenced by reduced Akp2 gene expression and ALP activity. This inhibition was far more potent than that caused by the enzymatic removal of CS. Notably, treating C4ST-1-overexpressing cells with chondroitinase reduced differentiation inhibition to a level similar to that in mock cells treated with chondroitinase. These results suggest that the strong inhibition was due to the excessive 4-sulfated CS produced by C4ST-1, implying a mechanism distinct from the inhibition caused by a lack of CS. To elucidate this mechanism, we investigated the potential feedback loop. The increase in 4-sulfated CS from C4ST-1 overexpression enhanced Wnt3a expression, which upregulated p53 expression. Pharmacological inhibition of β-catenin and p53 partially restored Akp2 expression, confirming their roles as key mediators. We propose that a high 4S/6S ratio activates a Wnt/β-catenin-p53 axis, where p53 acts as a brake on differentiation. Our findings highlight the critical role of CS sulfation patterns in fine-tuning the osteoblast fate.