Journal of Clinical Pharmacy and Therapeutics最新文献

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.

Introduction: Dental anxiety is a critical issue in dentistry. Buccal patches, a noninvasive drug delivery method, can potentially alleviate anxiety and pain during dental procedures. This study aimed to develop a three-layered buccal drug delivery system containing lidocaine or lidocaine–dexmedetomidine for improved pain management in dentistry.

Methods: Three-layered patches were made using ethyl cellulose, eudragit, and Carbopol, incorporating either lidocaine or a combination of lidocaine–dexmedetomidine. Forty participants were included: Both groups received placebo patches on one side of jaw and received their relevant drug patch of lidocaine or lidocaine–dexmedetomidine on the other side. Pain levels were assessed.

Results: The patches were 2-3 mm thick with a pH of 3.5–4.5. Lidocaine release efficiency was 41.69 ± 13.10%, and the combination patches showed 47.17 ± 5.10% for lidocaine and 74.71 ± 6.41% for dexmedetomidine. Release time for lidocaine and the combination patch was 25 and 15 min, respectively, with dexmedetomidine fully released within 3 min. The lidocaine–dexmedetomidine group reported significantly lower pain scores (2.1 ± 0.3) compared to the lidocaine group (4.3 ± 0.4) and placebo (6.8 ± 0.5). The onset and duration of analgesia was faster in the combination group versus the lidocaine group (5.2 ± 0.5 vs. 8.7 ± 0.6 min and 45 ± 5 vs. 30 ± 4 min, respectively).

Conclusion: Buccal patches, especially lidocaine–dexmedetomidine patches, significantly reduce pain and improve patient comfort. These patches offer a promising noninvasive alternative for pain management with enhanced efficacy and patient compliance. Further research is needed to optimize these patches for broader clinical applications.

Trial Registration: Iranian Clinical Trials Registration Center: IRCT20210118050067N2

Objective: The orally bioavailable glucokinase activator, globalagliatin, is used to improve glucose homeostasis. Its metabolism is primarily dependent on cytochrome P450 (CYP) 3A4. Here, the influence of rifampicin, a potent inducer of CYP3A4 and CYP2C19 inducer, moderate inducer of CYP1A2, CYP2B6, CYP2C8, and CYP2C9, and inhibitor of P-gp, on the pharmacokinetics of globalagliatin, were investigated in healthy Chinese subjects.

Methods: This single-center, open-label, one-sequence investigation was performed over 22 days in 24 healthy Chinese volunteers. The volunteers were given single oral doses of 80 mg of globalagliatin on Days 1 and 15 on an empty stomach, while rifampicin 600 mg was given orally once a day from Days 8–21 before breakfast. Blood samples were collected at 0 h (1 h before globalagliatin administration on Days 1 and 15) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 h after dosing to monitor the globalagliatin pharmacokinetic parameters. Blood samples on Day 8 were collected before rifampicin administration. The plasma levels of globalagliatin were assessed using LC-MS/MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin Version 8.3.3 and analyzed with SAS Version 9.4. Continuous monitoring was performed to assess drug safety and tolerance.

Results: Analysis of the effect of rifampicin on globalagliatin pharmacokinetics in 24 healthy participants showed that with rifampicin, the C_max of globalagliatin decreased by 88.9%, while the AUC_0–t and AUC_0–∞ values were reduced by 97.0% and 96.4%, respectively. The geometric mean ratios of globalagliatin C_max, AUC_0–t, and AUC_0–∞ and their 90% CI values were 11.09% (90% CI:9.40–13.10%), 2.96% (90% CI:2.59–3.39%), and 3.60% (90% CI:3.20–4.04%), respectively. The mean elimination half-life was reduced by 27.91 h, while T_max was prolonged by 3.52 h. Six treatment-related adverse events were reported by five subjects (20.8%), with all being of Grade 1 severity.

Conclusions: Cotreatment with rifampicin significantly reduces the plasma levels of globalagliatin. The safety and tolerability of globalagliatin, both as monotherapy and in combination with rifampicin, were good in healthy Chinese volunteers.

Trial Registration: Chinese Clinical Trial Register: CTR20210959

Background: The optimal strategy for dosing and monitoring vancomycin continues to evolve. A vancomycin 24-h steady-state area under the concentration–time curve/minimum inhibitory concentration (AUC/MIC) of ≥ 400 has been associated with positive clinical outcomes, while an AUC/MIC > 600–700 has been associated with increased risk of nephrotoxicity. The 2009 vancomycin dosing guidelines recommended target trough concentrations between 10–20 mcg/mL depending on infection; however, recent pharmacokinetic data suggest that most patients can achieve target AUC/MIC with trough concentrations < 15 mcg/mL. While existing literature has demonstrated reduced nephrotoxicity with AUC-guided dosing (AGD), there are limited data evaluating efficacy and other clinical outcomes. Therefore, this study compared the clinical efficacy of vancomycin using trough-guided dosing (TGD) versus AGD in patients with confirmed methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.

Methods: This was a retrospective, observational, quasiexperimental study of adult patients who received vancomycin for treatment of MRSA bacteremia. Patients with central nervous system infections, weighing > 200 kg, with acute kidney injury, or receiving hemodialysis/continuous renal replacement therapy were excluded. The primary outcome was microbiological success defined as negative blood cultures within 7 days of vancomycin initiation. Secondary outcomes included achievement of therapeutic target concentrations and incidence of nephrotoxicity.

Results: Microbiological success was achieved in 52/55 (95%) patients with TGD versus 50/51 (98%) patients with AGD (p = 0.619). In the TGD group, 24/55 (44%) patients achieved therapeutic target concentrations within 48 h of initiation of vancomycin compared to 24/51 (47%) patients in the AGD group (p = 0.723). The median hospital length of stay was longer in the TGD group compared to the AGD group (16 days, IQR 11–27 days versus 13 days, IQR 9–24 days, respectively, p = 0.260). Nephrotoxicity occurred in 7/55 (13%) TGD patients versus 5/51 (10%) AGD patients during vancomycin therapy (p = 0.763).

Conclusions: AGD was similar to TGD at achieving microbiological success in patients with MRSA bacteremia and may lead to shorter lengths of hospital stay and lower rates of nephrotoxicity.

What is Known and Objective: The use of multiple medications, or polypharmacy, is associated with an elevated risk of potential drug–drug interactions (pDDIs), consequently heightening the probability of adverse drug reactions. Currently, there is a dearth of data regarding pDDIs in Chinese patients with atrial fibrillation (AF) within real-world scenarios. This study is designed to investigate the existing state of polypharmacy and pDDIs in Chinese AF patients and to analyze the factors influencing pDDIs.

Methods: This was a single-center retrospective investigation conducted at a tertiary hospital in China. Polypharmacy and pDDIs were examined based on the medications prescribed at the time of discharge. The pDDIs were assessed using the Lexi-Interact database and classified into Types A, B, C, D, and X.

Results and Discussion: The study encompassed 802 AF patients. The median age was 73 years (ranging from 64 to 80). The most (72.7%) were 65 years or older, and 53.9% were male. The incidence rates of polypharmacy and excessive polypharmacy were 74.8% and 29.8%, respectively. At discharge, 69.0% of patients had at least one clinically relevant pDDI. There were 1820 (84.2%), 261 (12.1%), and 81 (3.7%) interactions categorized as Types C, D, and X, respectively. The most prevalent Type C interaction was the combined use of antihypertensive medications. Among Type D interactions, the most common was the combination of anticoagulants and antiplatelet drugs. The most frequent Type X interaction involved drugs that augmented the hyperkalemic effect. Through multivariate analysis, advanced age (p = 0.008) and a greater number of medications (p < 0.001) were significant predictors of pDDIs.

What is New and Conclusions: Polypharmacy and pDDIs are widespread among AF patients. Advanced age and an increased number of drugs were determined to be predictive factors for pDDIs. The risk of DDIs can be reduced by decreasing the number of medications or opting for alternative drugs.