Journal of Clinical Pharmacy and Therapeutics最新文献

Background: Cold atmospheric plasma (CAP) therapy has emerged as a novel nonthermal modality for managing chronic wounds. However, its clinical efficacy relative to standard wound care remains uncertain. This systematic review and meta-analysis aimed to evaluate the effectiveness of CAP in promoting complete wound healing.

Method: An extensive literature search was performed across major databases for randomized controlled trials (RCTs) published between January 2005 and January 2025. Eligible studies included adult patients with chronic wounds treated with CAP compared to standard care or placebo. The primary outcome was complete wound healing. Risk ratios (RRs) with 95% confidence intervals (CIs) were synthesized using a random-effects model in RStudio with the metafor package.

Results: Three RCTs comprising 149 participants (CAP group: 76; control group: 73) were included. The fixed-effects meta-analysis demonstrated that CAP therapy radically improved wound healing outcomes compared to standard care, with a pooled RR of 3.53 (95% CI: 2.12–5.89; p < 0.001). However, the random-effects model yielded a nonsignificant result (RR = 3.31; 95% CI: 0.35–31.59; p = 0.150) and revealed substantial heterogeneity (I² = 68.9%, Q = 6.44, p = 0.040). Random-effects analysis was nonsignificant; findings are suggestive and require confirmation through larger, rigorous randomized trials.

Conclusions: CAP therapy significantly enhances complete wound healing in patients with chronic wounds and demonstrates a favorable safety and efficacy profile. These findings support CAP as a promising adjunct to standard wound care.

Background: Melanoma is an aggressive skin cancer with a high potential for developing resistance to targeted therapies. One such therapy, vemurafenib, specifically inhibits the B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation, a key driver of melanoma progression. However, acquired resistance to vemurafenib remains a major challenge, necessitating alternative treatment strategies. Quercetin, a natural flavonoid with well-documented anticancer properties, has demonstrated potential in overcoming drug resistance, making it a promising candidate for melanoma therapy.

Materials and Methods: This study evaluated the effects of quercetin on both melanoma A375.S2 and vemurafenib-resistant A375.S2/VR cells. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while apoptosis was measured through caspase-3/-7 activity and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Ribonucleic acid (RNA) sequencing and Ingenuity Pathway Analysis (IPA) were employed to identify the mechanisms underlying quercetin’s effects.

Results: Quercetin significantly reduced cell viability in a dose-dependent manner in both cell lines, with A375.S2/VR cells requiring higher concentrations, while HaCaT cells, a normal keratinocyte cell line, remained unaffected, accompanied by an increase in apoptotic cell numbers and caspase-3/-7 activity. RNA sequencing revealed 379 differentially expressed genes, with IPA indicating significant involvement of the p53 signaling pathway. Increased caspase-3/-7 activity and apoptotic cell numbers confirmed apoptosis induction. Key regulators and pathways involved in apoptosis and inflammation were identified.

Conclusions: Quercetin effectively induces apoptosis in vemurafenib-resistant melanoma cells by modulating the p53 signaling pathway, presenting a promising therapeutic strategy for overcoming drug resistance. Furthermore, in vivo studies are needed to validate these findings and explore clinical applications.

Oncolytic viruses (OVs) are naturally occurring or genetically engineered viruses that selectively target and destroy cancer cells. They act through multiple mechanisms, including direct tumor cell lysis, stimulation of immune-mediated cytotoxicity, and modulation of the tumor microenvironment (TME). Recent studies have shown that, beyond their direct oncolytic activity, OVs also influence the immune landscape by modulating the expression of PD-1/PD-L1 axis. In many cases, OVs trigger the release of proinflammatory cytokines, leading to increased PD-L1 levels on immune cells. This upregulation plays a key role in modulating the TME and shaping immune checkpoint signaling. While there is also evidence that OVs can directly reduce PD-L1 expression on tumor cells, the most prominent effect appears to be the boost in PD-L1 expression. This shift is thought to be crucial in influencing how the immune system responds to tumors. These changes could modulate PD-L1-mediated immune suppression and alter the exhaustion and anergy rate of the effector tumor-specific T cells infiltrated into the TME. This review discusses how OVs influence PD-1 and PD-L1 expression, with a focus on innate and adaptive immune activation, interferon signaling pathways, and engineered OVs designed to express immunomodulatory cytokines and chemokines. We explore how these mechanisms can be leveraged to enhance antitumor immunity, particularly in combination with ICIs. Furthermore, we discuss the potential of OVs to remodel the TME, modulate PD-L1 expression, and promote immune-mediated tumor clearance. Overall, this review highlights the evolving role of OVs in cancer therapy and their potential to augment the effectiveness of current immunotherapeutic strategies.

Background: Retinoblastoma (RB) is the most common primary intraocular malignancy in children, primarily caused by inactivation of the RB1 tumor suppressor gene. Despite advancements in multimodal therapies, the molecular mechanisms underlying RB progression and its tumor microenvironment (TME) remain poorly understood, limiting the development of effective targeted treatments.

Methods: This study integrates bulk and single-cell RNA sequencing data to characterize the molecular landscape of RB. Differential gene expression analysis, pathway enrichment analysis, and single-sample gene set enrichment analysis (ssGSEA) were performed to uncover key pathways and immune cell populations. Immune checkpoint molecules, m6A RNA modification-related genes, and ferroptosis-associated genes were analyzed to identify potential therapeutic targets. Protein-protein interaction (PPI) networks and cell-cell communication analyses were conducted to explore intercellular signaling within the TME. Additionally, functional validation was performed for CDKN1A, a candidate gene identified from transcriptomic analysis, using shRNA-mediated knockdown and in vitro assays.

Results: Transcriptomic profiling revealed distinct gene expression signatures between RB and normal retinal tissues, including upregulation of oncogenic pathways (e.g., MYC targets and G2/M checkpoint regulation) and downregulation of tumor suppressor pathways (e.g., p53 signaling). Chemotherapy-induced gene expression changes were observed, notably the activation of immune-related pathways such as antigen presentation and NK cell-mediated cytotoxicity. Immune checkpoint molecules (PDCD1, CD274, HAVCR2) exhibited cell-type-specific expression, indicating potential for immunotherapy. Elevated expression of m6A regulators (METTL3, WTAP) and ferroptosis-associated genes (ACSL4, SLC7A11) pointed to novel therapeutic vulnerabilities. Among key regulatory genes, CDKN1A was identified as significantly downregulated in RB. Functional experiments demonstrated that knockdown of CDKN1A inhibited cell proliferation and induced G1 phase arrest in RB cell lines, supporting its potential tumor-promoting role in this context.

Conclusion: This study provides a comprehensive molecular and cellular overview of RB progression and reveals novel therapeutic targets, including immune checkpoints, m6A modification enzymes, ferroptosis regulators, and CDKN1A. Our findings emphasize the need to address tumor heterogeneity and cell-type-specific gene expression in designing effective personalized therapies for RB patients.

Background: Lifestyle modifications are the cornerstone of prediabetes management, aiming to prevent or delay progression to diabetes. In addition to lifestyle interventions, pharmacologic treatment with oral hypoglycemic agents (OHAs), particularly metformin, is frequently considered.

Objectives: The objective of this study was to identify optimal strategies for the management of prediabetes in low- and middle-income countries (LMICs) like Nepal.

Methods: A comparative experimental study was conducted to assess the effects of lifestyle modification and treatment with OHA separately in prediabetic patients (16 per group). The lifestyle modification group (Group A) received structured counseling on dietary modifications and physical activity, and the OHA group (Group B) was prescribed metformin. Baseline parameters were recorded for all participants, and blood pressure and HbA1c levels were reassessed at 90 days to determine changes from the baseline.

Results: Significant reduction in HbA1c was observed for both the OHA group (p = 0.0034) and the lifestyle modification group (p < 0.001). The lifestyle modification group achieved significantly greater reductions in HbA1c compared with the OHA group (p = 0.0002).

Conclusions: Lifestyle modification and pharmacological therapy with metformin can lead to a significant decrease in HbA1c levels in the prediabetic population as a sole intervention. Lifestyle modification resulting in greater reduction could be a sustainable and cost-effective alternative, particularly in LMICs like Nepal.

Objective: This prospective cohort study aimed to systematically evaluate the clinical outcomes associated with off-label rivaroxaban regimens (10 mg vs. 15 mg daily) in elderly Chinese patients with nonvalvular atrial fibrillation (NVAF).

Methods: A hospital-based observational cohort was established at Pudong Hospital, Shanghai, in 2021, enrolling 247 consecutive NVAF patients receiving rivaroxaban therapy after obtaining institutional ethics approval and informed consent. Multivariable logistic regression analyses were performed to identify independent predictors of clinical outcomes.

Results: The cohort comprised 155 patients in 10 mg daily group and 92 patients in 15 mg daily group, with a mean age of 79 years. During 12-month follow-up, the 15 mg daily group demonstrated superior antithrombotic efficacy with significantly lower incidence of thrombotic events (15 mg: 1.50% vs. 10 mg: 5.90%, p = 0.017). Both regimens showed comparable safety profiles regarding bleeding events (15 mg: 10.90% vs. 10 mg: 13.90%, p = 0.302). Multivariate analysis identified CHA2DS2-VASc score as the primary predictor of thrombosis, while lower BMI, elevated HAS-BLED score, and diabetes mellitus emerged as independent bleeding predictors (all p < 0.05).

Conclusion: Rivaroxaban 15 mg daily showed better thromboembolic protection than 10 mg without increasing bleeding risk, supporting its use in selected high-risk elderly NVAF patients.

Objectives: This study aimed to characterize ceftazidime/avibactam trough concentrations (C_min) in patients infected with resistant Gram-negative bacteria. Additionally, we assessed the risk factor associated with clinical cure, including joint optimal pharmacokinetic/pharmacodynamic (PK/PD) target.

Methods: We conducted a single-center observational retrospective study involving patients receiving ceftazidime/avibactam therapy for Gram-negative infections and undergoing therapeutic drug monitoring of ceftazidime and avibactam. Analysis was performed on the C_min of ceftazidime and avibactam. The joint PK/PD target of ceftazidime/avibactam was considered as optimal when both the PK/PD targets of ceftazidime (100%fT > 4 × MIC) and avibactam (100%fT > C_T) were simultaneously achieved; quasi-optimal if only one was achieved; and suboptimal if neither was achieved. Finally, logistic regression analysis was utilized to detect potential variables associated with clinical cure.

Results: This study analyzed a total of 39 infected patients, with results showing that the C_min of ceftazidime and avibactam was 24.1 ± 14.3 mg/L (coefficients of variation 59.5%), and 6.0 ± 4.4 mg/L (coefficients of variation 73.5%), respectively. Patients with renal insufficiency exhibited significantly higher C_min of ceftazidime and avibactam compared to those with normal renal function (p < 0.05). Similarly, C_min were elevated in patients receiving continuous renal replacement therapy (CRRT) versus non-CRRT recipients (p < 0.05). No significant difference in C_min of ceftazidime and avibactam was observed between elderly and nonelderly patients. Clinically cured patients accounted for 76.9% (30/39) of the total. For 23 infected patients with minimum inhibitory concentration results, optimal joint PK/PD target was observed in 16 patients (69.6%) and quasi-optimal in 7 patients (30.4%). Independent predictors of clinical cure were found to be optimal joint PK/PD target and co-administered with aztreonam.

Conclusions: The findings indicated that the C_min of ceftazidime and avibactam exhibit significant variability. With the current regimen of ceftazidime/avibactam, the majority of patients can achieve clinical cure and optimal PK/PD target.

Purpose:​ Direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) such as sofosbuvir/velpatasvir (SOF/VEL) and glecaprevir/pibrentasvir (GLE/PIB) are effective in treating recipients of organs infected with HCV. The objective of this project is to identify changes in tacrolimus pharmacokinetics throughout DAA therapy in recipients of abdominal transplants from nucleic acid testing-positive (NAT+) donors.

Methods: Adult kidney or liver transplant recipients transplanted between 4/22/2019 and 6/23/2022 were included. Recipients of HCV NAT+ organs were treated with DAAs based on institutional protocol and insurance preference. Recipients of HCV NAT− organs from donors who fit Public Health Service (PHS) risk criteria for HCV transmission were included in the comparator group. Tacrolimus doses and concentrations were collected at DAA initiation and cessation and at the time of sustained virologic response assessment at 12 weeks after treatment completion (SVR12); these time points were matched in the NAT− control group. The primary outcome was difference in concentration-to-dose ratio (C/D) change (ΔC/D) over time between NAT+ and NAT− organ recipients.

Results: At DAA initiation, NAT+ organ recipients required a lower tacrolimus dose to reach goal than NAT− organ recipients (ΔC/D NAT+ = −0.41, ΔC/D NAT− 0.60, p = 0.01); however, a known tacrolimus interaction with fluconazole—administered to liver transplant recipients at high risk for invasive fungal infection (IFI)—represents a significant confounding factor. No differences in average C/D ratio between NAT+ and NAT− organ recipients were identified at any time point.

Conclusion: These results do not support empiric dose adjustments based on donor HCV NAT status or antiviral therapy.