Pharmacology Research & Perspectives最新文献

This study aimed to evaluate the safety of colistin therapy by monitoring renal function and electrolyte levels in critically ill neonates with late-onset sepsis (LOS) hospitalized in the neonatal intensive care unit (NICU) between 2015 and 2021. This retrospective case-control study included 58 critically ill neonates treated with colistin for late-onset sepsis and 22 control neonates with late-onset sepsis who did not receive colistin. Data were analyzed to compare patient outcomes, microbiological profiles, and side effects of treatment. Statistical analyses were performed using repeated-measures ANOVA and Bayesian calculations to evaluate serum creatinine levels and biochemical parameters over time. Serum creatinine levels showed similar alterations within the first 7 days of colistin treatment with moderate evidence. However, serum magnesium and sodium levels were lower on the 7th day in the colistin-treated group compared with the control group. Colistin therapy in critically ill neonates with late-onset sepsis appears to be a viable treatment option with an acceptable short-term safety profile. These findings emphasize the importance of routine monitoring of renal function and electrolyte levels during colistin use in neonatal intensive care to minimize potential complications.

Baxdrostat is a novel, highly potent, selective, competitive inhibitor of human aldosterone synthase currently under development for the treatment of uncontrolled and resistant hypertension and chronic kidney disease. We assessed the risk of QTc-interval prolongation with baxdrostat using concentration-QTc (C-QTc) modeling in healthy adult participants using data from two placebo-controlled Phase 1 studies: a multiple-ascending dose (MAD) study of baxdrostat 0.5-5 mg (N = 56; NCT05500820) and a Phase 1 four-way crossover thorough QT/QTc (TQT) study assessing the pharmacokinetics, pharmacodynamics, safety and tolerability of baxdrostat at supratherapeutic doses of 16 and 32 mg (N = 28; NCT06194032). In the TQT study, 28 participants were randomized to one of four treatment sequences (each n = 7) of baxdrostat 16 mg, baxdrostat 32 mg, placebo and open-label moxifloxacin 400 mg. Digital electrocardiogram and pharmacokinetic data were collected at baseline and up to 48 h post dose. Dependent and independent variables of the pre-specified linear mixed-effect model were placebo-corrected baseline-adjusted ΔΔQTcF and baxdrostat plasma concentrations, respectively. Results were consistent between the two C-QTc modeling analyses. Baxdrostat treatment did not produce QT-interval prolongation, both at concentrations of interest and geometric mean of the maximum observed plasma concentration. Upper bounds of the two-sided 90% confidence interval for the ΔΔQTcF mean estimates were < 10 ms. Pharmacokinetic data for the 16 and 32 mg doses in the TQT study were as expected, and both doses were well tolerated. These data illustrate that baxdrostat is not associated with the risk of QT-interval prolongation at therapeutic and supra-therapeutic concentrations.

This study investigates the sex-dependent effects of therapeutic hypothermia and a neuroprotectant (CHF6467) on long-term neurobehavioral recovery in neonatal rats subjected to hypoxic-ischemic encephalopathy. Using the Rice-Vannucci model, rats were divided into five groups: sham lesion, hypoxic-ischemic insult, hypoxic-ischemic insult with CHF6467, hypoxic-ischemic insult with hypothermia, and hypoxic-ischemic insult with CHF6467 combined with hypothermia. Behavioral tests at postnatal day 30 (P30) and 60 (P60) revealed significant improvements in motor coordination and spatial memory in treated groups compared to the vehicle-treated group, associated with reductions in infarct size at P60. Notably, female rats exhibited superior motor coordination recovery compared to males, despite similar neuroprotection levels. This suggests that motor coordination recovery is not solely dependent on the extent of neuronal damage. Conversely, spatial memory impairment was sex-independent and closely associated with the degree of neuroprotection. These findings highlight the importance of considering sex differences in neuroprotective treatment efficacy and suggest potential variations in responses between males and females in clinical settings.

Drug repurposing offers a cost-effective and time-efficient strategy for identifying new cancer therapies. Sertraline, a widely prescribed selective serotonin reuptake inhibitor (SSRI), has shown promising anticancer properties through modulation of key pathways involved in tumor survival, stress adaptation, and therapeutic resistance. This scoping review systematically evaluates the current evidence on sertraline's anticancer mechanisms, efficacy, and translational potential. A systematic search of PubMed, EMBASE, Scopus, and Web of Science was conducted in accordance with PRISMA-ScR guidelines. Eligible studies included in vitro, in vivo, and clinical investigations. Data on cancer types, mechanisms, assays, and outcomes were extracted and synthesized. Of 97 screened articles, 67 met inclusion criteria, comprising 56 preclinical studies, nine population-based studies, and two mixed-methods reports. Sertraline induces apoptosis via mitochondrial dysfunction, caspase activation, and Bcl-2 downregulation, disrupts autophagy and the unfolded protein response, and impairs serine/glycine metabolism through SHMT inhibition. It also suppresses oncogenic signaling via mTOR and TCTP modulation. In vivo studies confirmed tumor growth inhibition in various cancer models, including breast, lung, glioblastoma, and liver. Sertraline enhances the efficacy of chemotherapy, radiotherapy, and targeted therapies by sensitizing resistant cells, modulating immune responses, and impairing metabolic recovery. Retrospective studies suggest no increased cancer risk with SSRI use and hint at protective associations in select malignancies. While current evidence is predominantly preclinical, sertraline's multi-targeted action and established safety profile support its candidacy for repurposing. Further translational research and biomarker-driven clinical trials are warranted to validate its therapeutic niche and optimize its integration into oncology.

Postoperative central nervous system (CNS) infections are associated with high mortality and present a therapeutic challenge due to limited antibiotic penetration into the brain extracellular fluid (ECF). Vancomycin, frequently used in this setting, requires therapeutic drug monitoring; however, its quantification in brain ECF via microdialysis is limited by the need for accurate calibration of relative recovery (RR). This study aimed to determine the in vitro RR of vancomycin under conditions simulating clinical neuromonitoring to support application in clinical practice. Vancomycin RR was assessed using forward dialysis and retrodialysis techniques at a fixed perfusion rate of 0.3 μL/min, consistent with standard neuromonitoring protocols. Vancomycin concentrations were measured using a homogeneous enzyme immunoassay across subtherapeutic, therapeutic, and supratherapeutic levels. RR was calculated as the ratio of microdialysate to reference solution concentrations. Mean RR was 86.5% (SD 3.6%) for forward dialysis and 86.4% (SD 2.1%) for retrodialysis, with no significant difference between techniques (p = 0.957). RR remained consistent across all tested concentration levels (p = 0.051). A strong correlation was observed between vancomycin concentrations in the microdialysate and the study solution (r = 0.997, p < 0.001). The high and stable RR achieved under clinically relevant conditions supports the use of this in vitro microdialysis model as a reliable calibration tool. This model may aid in estimating vancomycin concentrations in brain fluid, facilitating dose optimization in patients undergoing microdialysis-based monitoring for postoperative CNS infections.

Alzheimer's disease (AD) is the most prevalent cause of dementia, characterized by progressive cognitive decline and cerebral metabolic impairment. Yet, the therapeutic options for addressing the disease pathogenesis are limited. Here, we report an approach by targeting brain nucleoside homeostasis and energy metabolism to alleviate AD-associated cognitive deficits. A compound, J4, was designed to modulate nucleoside homeostasis by interacting with the equilibrative nucleoside transporter-1 (ENT1). The effects of J4 on brain nucleoside homeostasis and energy metabolism were examined in mice. Two AD animal models, THY-Tau22 and APP/PS1 mice, were used to evaluate the translational potential of J4 for the treatment of AD. Cognitive function and functional ability were assessed using the Morris water maze, Y-maze, and nesting behavior tests. The pharmacodynamic marker was explored, and the pharmacokinetic and safety properties of J4 were evaluated. As a result, being administered after disease onset, oral J4 administration rescued memory and cognitive dysfunction in both tau and amyloid AD mouse models. Metabolomic analysis showed that J4 increased brain nucleoside levels and facilitated brain primary metabolism, including glucose metabolism and the pentose phosphate pathway. The [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging further demonstrated that glucose metabolism can be used as a pharmacodynamic biomarker for the target engagement of J4 on ENT1. The nonclinical studies also demonstrated the ideal pharmacokinetic and safety profiles of J4, supporting that targeting nucleoside homeostasis can improve brain energy metabolism and is a promising approach for AD treatment.

Respiratory diseases are associated with high mortality worldwide. Respiratory infections can lead to the emergence of chronic respiratory diseases. Scientists are constantly striving to identify new therapies with reduced side effects. The rise of antibiotic resistance and the scarcity of effective treatments further necessitate the development of novel therapeutics specific to respiratory diseases. Extensive research has been conducted on natural products that could be effective against respiratory diseases. Mangiferin, a polyphenol with a C-glycosyl xanthone structure, is a bioactive phytochemical that has potential applications in the treatment of respiratory tract infections. Mangiferin could be a therapeutic option against respiratory diseases because of its ability to target a variety of pharmacological pathways implicated in the development of these infections. It has been shown to limit infections, lower inflammation, control immune responses, and enhance host defense mechanisms. This review provides comprehensive insight into mangiferin's potential against various respiratory disorders, focusing on its pharmacological activity and therapeutic prospects. Despite the potential of mangiferin against respiratory problems-related pathobiology, additional scientific validation through clinical trials is required before the clinical application of mangiferin in the management of respiratory diseases.

Drug repurposing is an authentic, emerging, and growing aspect of drug development when the demand for new therapeutic solutions is high. Many repurposed drugs have been discovered by serendipity or a non-ordered process driven by chance and sharp observation. These discoveries provide strong evidence for the existence of pharmacological pleiotropy, a highly ordered process well described by thermodynamics. Pleiotropy is an efficient way of propagating information and maintaining the specificity of a biological message and has been a cornerstone in genetics research over decades. While the definition, scale, diversity, and complexity associated with drug repurposing are well documented, pharmaceutical pleiotropy that is fundamental to our understanding of drug repurposing remains less explored. In this review, we examine pharmacological pleiotropy and its underpinning thermodynamics in drug repurposing. Additionally, we have drawn upon the universality of thermodynamics to provide insights into pharmaceutical pleiotropy. We suggest that, in serendipitous drug discovery, information in the repurposed drug often exceeds what was thought available with the rational design of the drug. Our interest in repurposing is on leveraging this information and knowledge generally once a therapeutic benefit from a new chemical entity (NCE) has been demonstrated. This requires a different process from standard drug discovery, and this repurposed pathway is the focus of our manuscript. In this review, we propose that drug repurposing can be defined using Information theory (Shannon entropy), Boltzmann statistical entropy, and the thermodynamic principles for spontaneity described by Gibbs free energy of binding. We conclude that therapeutics including repurposed drugs are facilitators of information and instructional transfer and that the distinguishing features of pharmacology, Information theory, and statistical mechanics are intimately linked. With advances in artificial intelligence and machine learning, with their strong links to Information theory and statistical mechanics, now is an appropriate time to further explore these relationships.

Pharmacology education at medical schools in the UK aims to give newly qualified doctors the ability to apply foundational knowledge of pharmacology and to be able to prescribe drugs safely. This study aimed to assess a current pharmacology curriculum and understand the perspectives of both students and educators around pharmacology teaching. Employing a mixed-methods approach, the research utilized documentation analysis, focus groups, semi-structured interviews, and online questionnaires with students, educators and senior academic tutors. The analysis of the current curriculum revealed that 1069 drugs or drug classes were introduced to students in their first 2 years of study of drugs and drug classes. Students reported feeling overwhelmed with the number of drugs they were expected to learn. They suggested increasing contextual learning experiences and more practical prescribing experience. Students emphasized the need for greater visibility of pharmacology teaching. Students and educators identified challenges in integrating pharmacology effectively, which contributed to knowledge gaps. Disparities between students' perceptions of pharmacology education and educators' confidence in its delivery were found. These findings suggest the need to address the number of drugs introduced to students in their first 2 years of study. Recommendations include reducing the number of drugs or drug classes introduced to students, highlighting important drugs or classes, enhancing the visibility of pharmacology in the curriculum, and educating and supporting staff when preparing teaching sessions that involve pharmacology. These measures may address students' feelings of being overwhelmed by pharmacology, aligning with the aim of developing medical students into safe prescribers following graduation.

Dyslipidemia, characterized by abnormal serum cholesterol or triglyceride (TG) concentrations, is prevalent among middle-aged and older adults and contributes to atherosclerosis and increased cardiovascular risk. Although oral statins effectively decrease low-density lipoprotein cholesterol, patients with high-TG concentrations remain at significant risk for atherosclerotic cardiovascular disease. Weibull analysis, a statistical method widely applied in reliability engineering and medicine, is suitable for assessing arterial stiffness, which reflects vascular aging or deterioration. This study explored the relationship between TG concentrations and arterial stiffness via Weibull analysis in patients treated with statins (STG) and patients without statin treatment (No-STG). The mode of the Weibull distribution was greater for STG (97.8 mg/dL) than for No-STG (80.7 mg/dL). Notably, compared with No-STG patients, STG patients presented lower hazard functions for TG concentrations up to 170 mg/dL. However, above 170 mg/dL, the hazard function for STG was equal to or slightly greater than that for No-STG. These findings suggest that without statin therapy, atherosclerosis may develop at lower TG concentrations, whereas statins effectively delay its onset. However, the data also highlight the limitations of statins in significantly reducing TG concentrations. This information underscores the importance of patient education in preventing the progression of atherosclerosis. Encouraging lifestyle changes, including improved exercise and dietary habits, can complement statin therapy to optimize cardiovascular health. These findings provide a basis for promoting patient awareness and fostering the proactive management of cardiovascular risk factors.