Journal of Clinical Pharmacy and Therapeutics最新文献

Purpose: Inappropriate use of antibiotics contributes to the increase in antimicrobial resistance with negative health safety implications. Global health organizations have promoted projects to improve proper and rational use of antibiotics. Recent studies show how antibiotics can also influence the efficacy of immune checkpoint inhibitors (ICIs) treatment in cancer patients. This work analyzes the impact of concomitant antibiotic therapy in patients affected by skin, lung, and kidney cancer, who started immunotherapy in 2020-2021 at Veneto Institute of Oncology IRCCS. The aim of this study is to evaluate clinical outcomes, treatment efficacy, discontinuation causes, and occurrence of adverse drug reactions in cancer patients treated with ICIs.

Methods: Data from the real-world retrospective study were extracted from Territorial Pharmaceutical Care databases, medical records, and the AIFA registry. A descriptive analysis of the study population was performed, as well as of patient outcomes in terms of progression-free survival (PFS) and overall survival (OS).

Results: A total of 239 subjects affected by kidney (8%), lung (48%), and skin (44%) cancer were enrolled; of these, 50%, 32%, 9%, and 9% were treated with single-agent nivolumab, pembrolizumab, atezolizumab, and cemiplimab, respectively. A total of 119 patients received concomitant antibiotic therapy. Median OS was 8.8 months (95% CI: 5.02–11.8) and 31.05 months (95% CI: 24.81–NA) in subjects with high and low antibiotic exposure, respectively. Multivariate subgroup analysis confirmed that high antibiotic exposure is an unfavorable factor also for median PFS.

Conclusion: A prolonged exposure to antibiotics correlates with unfavorable outcomes in cancer patients undergoing concomitant immunotherapy. Thus, managing antibiotic exposure is fundamental for optimizing ICI treatment.

Aim: This study aimed to investigate post-marketing adverse events (AEs) of interleukin-6 (IL-6) inhibitors, and to explore risk factors for death.

Method: Disproportionality analyses were conducted on adverse event cases of IL-6 inhibitors reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS) from the time of drug launch until the fourth quarter of 2023. Univariate and multivariate logistic regression analyses were carried out utilizing patient-related clinical information, and prediction models for IL-6 inhibitor-related mortality risk were developed by incorporating patient age and weight factors.

Results: A total of 63,445 reports were retrieved, with the majority of known age groups falling between 18 and 64 years. Most reports were submitted by consumers and physicians, predominantly from the United States. Tocilizumab was associated with AEs such as drug intolerance and infection, while sarilumab showed symptoms of pain and condition aggravated. Siltuximab was linked to disease progression and thrombocytopenia. The median time to AEs with IL-6 inhibitors was 74 days (interquartile range [IQR] 10-311), mostly occurring within 1 month. Factors such as age, propionic acid derivative, infections and infestations, nervous system disorders, and immune system disorders were independent risk factors for deaths related to IL-6 inhibitor use (p < 0.05). The mortality risk prediction model demonstrated good discriminatory power and clinical applicability in both the training set (AUC 0.6968) and the validation set (AUC 0.7502).

Conclusion: Our postmarketing pharmacovigilance analysis revealed the types and incidence of AEs related to IL-6 inhibitors. Column line diagrams may be useful for clinical assessment of the occurrence of death and have high clinical utility.

Renal clear cell carcinoma (ccRCC) presents a unique landscape of genetic and epigenetic modifications, the understanding of which is crucial for the development of targeted therapies and improved prognostication. This study explores the differential expression of histone-related genes (HRGs) in ccRCC and correlates these findings with patient clinical outcomes. By leveraging the Cancer Genome Atlas (TCGA) data, we performed a robust multidimensional analysis of HRG expression profiles in ccRCC versus adjacent normal tissues. Our results demonstrate a significant upregulation of several key epigenetic regulators, including UHRF1, KDM5A, EZH2, PRDM6, and TWIST1, in tumor samples, with statistical significance suggesting their involvement in tumorigenesis and progression. Paired expression analysis within patient-matched samples confirmed the consistency of overexpression in tumors. The prognostic relevance of these genes was underscored through survival analyses, which revealed a clear stratification of patients into distinct risk categories based on their expression profiles. The integration of these genetic markers with clinical parameters facilitated the development of a predictive nomogram, yielding a quantifiable tool for survival prediction. Our comprehensive analysis elucidates the profound impact of epigenetic dysregulation in ccRCC and proposes a novel set of biomarkers for disease diagnosis, prognostic stratification, and potential therapeutic targeting, marking a significant stride toward precision oncology in renal cancer.

In recent years, the release of substantial amounts of synthetic endocrine-disrupting chemicals (EDCs) into the environment has posed significant threats to human health. Among these EDCs, bisphenol A (BPA) and its substitutes, such as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF), are widely used and have been implicated in disrupting various biological processes. This research aimed to evaluate the potential link between bisphenol-related gene expression and lung cancer prognosis. Using the Comparative Toxicogenomics Database (CTD), we identified genes involved in bisphenol metabolism and their significant associations with key oncogenes and hormone-disrupting pathways, including INS, ESR1, ESR2, AR, MAPK1, MAPK3, PPARG, and CYP19A1. Our Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicate that bisphenol-related genes may be associated with a variety of cancers, particularly lung cancer. To develop a risk model, we employed Cox regression and LASSO regression analyses, constructing a prognostic prediction model for lung cancer based on bisphenol-related gene expression (BBPPM). This model demonstrated prognostic significance, with lung cancer patients categorized into high-risk and low-risk groups, revealing significant differences in survival rates and highlighting the model’s accuracy in predicting lung cancer outcomes. In addition to bioinformatics analyses, experimental studies were conducted to evaluate the effect of BPA on lung cancer cell behavior. BPA exposure significantly promoted the proliferation of A549 lung cancer cells, as assessed by the CCK-8 assay, and increased the clonogenic potential of the cells in a colony formation assay.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with its pathogenesis intricately linked to metabolic and immune dysregulation. This study aims to elucidate the molecular mechanisms underpinning HCC by analyzing metabolic and immune-related pathways and constructing a prognostic risk model.

Methods: We utilized data from The Cancer Genome Atlas (TCGA) to analyze genomic and clinical characteristics of HCC. Techniques such as single-sample gene set enrichment analysis (ssGSEA), weighted gene coexpression network analysis (WGCNA), and gene set variation analysis (GSVA) were employed to explore the interplay between metabolic pathways, immune responses, and HCC progression. In addition, a prognostic risk model was developed using univariate Cox regression and LASSO regression analysis based on PPAR signaling and immune-related genes.

Results: Our ssGSEA results indicated a significant involvement of metabolism-related pathways in HCC. The WGCNA identified key immune-related genes, with particular modules correlating with macrophage activity. The prognostic model, comprising five key genes, effectively stratified patients into low- and high-risk groups, with implications for overall survival (OS). Further analyses revealed the model’s correlation with clinical characteristics and immune-related indexes, suggesting its utility in predicting HCC progression.

Conclusion: This study provides a comprehensive molecular portrait of HCC, emphasizing the role of metabolic reprogramming and immune responses. The prognostic model offers potential for personalized therapeutic strategies and improved clinical outcomes. Future research should focus on validating these findings and exploring the therapeutic potential of targeting metabolic and immune pathways in HCC.

Objective: The study assessed the following medication error indicators: drug education by pharmacists, the clarity of physician prescription forms, patients’ and students’ drug package insert (PI) reading habits, and the adequacy of information on drug PIs.

Design: A cross-sectional study was carried out. One-on-one interviews were conducted with the pharmacists alongside the use of structured questionnaires to assess their involvement in drug education and experience with the clarity of physician prescription forms. A structured questionnaire was used to investigate patients’ and students’ PI reading habits. Drug PIs were collected from pharmacies, and their components were examined based on the World Health Organization’s (WHO) criteria for labeling pharmaceutical products.

Setting: The study was conducted at four selected hospital pharmacies, four community pharmacies, and the University of Cape Coast, in the Cape Coast Metropolis, Ghana.

Participants: The study included pharmacists working at the pharmacies, patients, and students of the University of Cape Coast, who visited any of these pharmacies.

Results: Fifty-three percent of pharmacists educate their patients on drug dosage, storage, and precautions during each patient visit, 17.6% hardly do, and 29.4% do not educate their patients. A majority of the sampled prescription forms submitted by patients to the pharmacists had illegible handwriting (63.7%) and unconventional prescription notations (78.0%). Of the 138 visiting patients, only a few (41.0%) read the PIs before drug use as compared to students (72.9%). Out of the 88 PIs collected, 90.2% had component deficiencies.

Conclusion: Pharmacists’ drug education to visiting patients was poor, just as patients’ PI reading habits. Most PIs had component deficiencies, and the majority of prescription forms had some medication error-provoking features. Going forward, pharmacists, physicians, drug manufacturers, and patients must perform their responsibilities toward the collective effort of minimizing medication errors associated with drug use.

Cisplatin (CDDP) can combat various types of cancers, employing a multifaceted approach against these malignant diseases. Despite its efficacy, resistance to CDDP remains a significant clinical challenge, often resulting in treatment failure and disease progression. Currently, efforts are underway to unravel the mechanisms of CDDP drug resistance in cancer treatment. The elevated presence of glutathione S-transferase pi-1 (GSTP1-1) within tumor cells plays a pivotal role in the development of resistance toward the effects of CDDP. GSTP1-1 contributes to detoxification by conjugating glutathione (GSH) to CDDP, reducing its accumulation and effectiveness in the tumor cells. In this study, the efficacy of gliquidone, an antidiabetic drug, demonstrated its capacity to impede tumor cell proliferation in both lung cancer A549 cell lines and A549/CDDP cell lines. This was achieved by suppressing the expression of GSTP1-1 within tumor cells (IC₅₀: 16.8 ± 0.8 μM). Furthermore, through the establishment of a nude mouse model featuring lung adenocarcinoma A549/CDDP cell transplantation tumors, gliquidone demonstrated a significant therapeutic effect on the mice tumors, while avoiding discernible side effects. These findings suggest that gliquidone could potentially be repurposed as an adjunct therapy in CDDP-resistant lung cancer.

Introduction: Poly (ADP-ribose) polymerase (PARP) inhibitor has been widely used in ovarian cancer patients carrying BRCA mutations. However, resistance to PARP inhibitor is present in some patients, and no effective treatment is available for these patients. TH-302 is a hypoxia-activated prodrug, which releases the bis-DNA alkylator bromo-isophosphoramide mustard (Br-IPM) under hypoxic condition. The present study aims to determine whether TH-302 is effective in treating PARP inhibitor resistance.

Methods: The in vitro cytotoxicity of TH-302 was assessed by short-term proliferation assay (50% inhibitory concentration, IC₅₀) or long-term clonogenic assay (90% inhibitory concentration, IC₉₀) under various oxygen concentrations. In vivo efficacy of TH-302 was assessed in PARP inhibitor resistance, partially responsive and sensitive patient-derived xenograft (PDX) or cell line–derived xenograft (CDX) models. Antitumor activity via homologous recombination (HR) pathway for TH-302 was evaluated using DLD1 BRCA2 knockout cell line and BRCA/RAD51D deleterious mutant PDX/CDX models. Breaks of double-strand DNA and hypoxia fraction in tumors were determined by gamma histone 2AX (γH2AX) and pimonidazole immunohistochemistry in H460 CDX model following treatment.

Results: Cytotoxicity was significantly enhanced under hypoxia in 12 human cancer cell lines including four ovarian cancer cell lines. The cytotoxicity was 70 times higher in human colon cancer cell line with BRCA2 knock out compared to wild type under hypoxia following TH-302 treatment. γH2AX staining revealed that the cytotoxicity of TH-302 was associated with DNA damage. In addition, administration of TH-302 with olaparib led to better antitumor activities than either single drug/prodrug in olaparib-resistant PDX models.

Conclusion: TH-302 exhibits hypoxia-dependent cytotoxicity across a wide range of human cancer cell lines, and may be a drug candidate to treat ovarian cancer, bladder cancer, and pancreatic cancer with HR deficiencies with or without resistance to PARP inhibitor. TH-302 may be effective in recurrent epithelial ovarian cancer (EOC) with homologous recombination deficiency (HRD) or in EOC patients resistant to PARP inhibitors.

Background: Adenomatous polyposis coli (APC) gene, an oncogene, has been implicated in stomach adenocarcinoma (STAD), which is a common type of gastric cancer (GC). Although the relationship between APC gene mutations and gastric adenocarcinoma has been comprehensively studied, the potential role of these mutations in the prognosis and targeted therapy remains known.

Methods: We utilized The Cancer Genome Atlas (TCGA) database to obtain gene expression matrices, clinical information, and mutation data from patients with STAD. The mutation status of the APC gene was analyzed, and its correlation with tumor mutational burden (TMB), microsatellite instability (MSI), and clinical prognosis in STAD was investigated. Gene set enrichment analysis (GSEA) was conducted to explore the pathological role of APC gene mutations in STAD metabolic pathways. Drug sensitivity analysis was conducted to identify potential targeted antitumor drugs for patients with APC gene mutations in gastric adenocarcinoma.

Results: The results revealed that 88% (46/52) of STAD samples had nonsynonymous mutations. The mutation group exhibited a significantly higher TMB than the wild-type group (p < 0.001), and the percentage of high MSI (MSI-H) was significantly higher in the mutation group than in the wild-type group (p < 0.001). Patients with APC mutations had a worse prognosis than those with APC wild-type (p = 0.009). The APC gene mutation group displayed significant enrichment in amino acids, RNA, and several pathways (|NES| > 1 and nominal p value < 0.01). Compared to the wild-type group, the mutation group exhibited a higher infiltration proportion of natural killer (NK) cells resting and eosinophils, whereas a lower infiltration proportion of monocytes and resting mast cells (p value < 0.05). AZD5991 exhibited significant sensitivity in patients with STAD carrying APC mutations (p = 0.028).

Conclusion: APC gene mutations play a crucial role in the prognosis, molecular characteristics, and potential therapeutic strategies for gastric adenocarcinoma.

Programmed death receptor-1 monoclonal antibodies (PD-1 mAbs) have been applied in the treatment of different kinds of malignant tumors. However, a streamlined and expedited evaluation method for certain tumor types without approved indications is currently lacking in terms of their expandable applications. In this study, a novel evaluation method for the expandability of PD-1 mAb was established for the first time. Clinical trial data of PD-1 mAb in first-line treatment for advanced gastric cancer were collected for comparison. For the first time, the clinical trial outcomes were analyzed through the entropy weight method and the technique for order preference by similarity to ideal solution (TOPSIS) method to evaluate the effectiveness and safety. The accessibility was assessed using the World Health Organization/Health Action International (WHO/HAI) standard survey method. Combining the results of effectiveness, safety, and accessibility, the recommendation for expandability of PD-1 mAb was provided. Tislelizumab ranks seventh in effectiveness, higher than the chemotherapy group and the pembrolizumab group, and ranks fourth in safety evaluation and first in the combination chemotherapy groups. The annual drug cost of tislelizumab is 0.497 times the annual household income for urban residents of Shaanxi Province. 56.67% of medical institutions are equipped with tislelizumab in Shaanxi Province. These results indicate the promising efficacy and safety profile of tislelizumab in combination with chemotherapy as a first-line treatment option for advanced gastric cancer. Notably, tislelizumab emerges as a more accessible alternative to sintilimab and boasts greater affordability compared to nivolumab and pembrolizumab. Consequently, tislelizumab should be considered a viable option for expandable application in first-line treatment of advanced gastric cancer, contingent upon clinical necessity.