Journal of Clinical Pharmacy and Therapeutics最新文献

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.

Aims: When entering a mountain plateau, people are at risk of developing acute mountain sickness (AMS), for which there are limited prophylactic medicines available. This study aimed at exploring the effectiveness of ibuprofen, acetazolamide, and methazolamide in preventing AMS and at providing valuable insights for the future development of related drugs.

Methods: A total of 137 mountaineers were recruited for this study and divided into six groups: a control group, an ibuprofen group, an acetazolamide group, a methazolamide group, an ibuprofen/methazolamide combination group, and a high-dose ibuprofen/methazolamide combination group. After the assigned drug was taken for three days at a lower elevation (300 m), the participants ascended to a plateau environment at 5050 m. The Lake Louise AMS Score (LLS) system was used to diagnose and evaluate the AMS rates of the mountaineers in each group, and the results were compared through statistical analysis.

Results: The results show that all the medications tested herein were effective in preventing AMS, but their level of effectiveness varied. The prevalence of AMS was 50.00% in the control group, 14.29% in the ibuprofen group, 5.56% in the acetazolamide group, 27.27% in the methazolamide group, 44.8% in the ibuprofen and methazolamide group, and 22.50% in the high-dose ibuprofen and methazolamide group. Acetazolamide demonstrated a significant prophylactic effect on symptoms related to AMS diagnosis, and ibuprofen showed the best efficacy for preventing headache.

Conclusion: Acetazolamide remains an effective medicine for preventing AMS. Ibuprofen combined with methazolamide is less effective than ibuprofen alone to prevent AMS.

Trial Registration: ClinicalTrials.gov identifier: ChiCTR-TRC-12002219

WhatIs Known and Objective. Anti-EGFR (epidermal growth factor receptor) drugs are indicated for non-small-cell lung cancer (NSCLC). This review summarises the information available to date on the first anti-EGFRs granted market authorisation: erlotinib TARCEVA®, gefitinib IRESSA®, afatinib GIOTRIF®, dacomitinib VIZIMPRO®, and osimertinib TAGRISSO®. Methods. A literature search was conducted in the PubMed database including studies published in English using the terms gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib. Furthermore, bibliographies of selected references were also studied for relevant articles. Clinical trial (CT) data were extracted from clinicaltrials.gov (ongoing trials and adverse events (AEs)). Assessment of AEs for these drugs was conducted using global pharmacovigilance data from VigiBase®. Results and Discussion. Erlotinib and gefitinib are first-generation anti-EGFR drugs, able to bind competitively and reversibly to the ATP- (adenosine triphosphate-) binding site of the EGFR exon 19 and exon 21 mutations. Afatinib and dacomitinib are second-generation anti-EGFRs able to bind covalently and irreversibly to the ATP site and inhibit EGFR and HER (human epidermal growth factor receptor) such as HER2 and HER4 enzyme activity. Osimertinib is a third-generation PKI and overcomes the EGFR T790M gatekeeper mutation through covalent binding at the ATP site. Medical interactions with these drugs are reported, notably with cytochrome P450 inducers or inhibitors. The most reported AEs in CTs are cutaneous reactions and gastrointestinal disorders. The occurrence of cutaneous reactions is less reported with third generation than with first- and second-generation anti-EGFR drugs. These results are consistent with the results from the VigiBase® global pharmacovigilance database. What Is New and Conclusion. This review summarises current knowledge regarding five anti-EGFRs in the literature. The third-generation anti-EGFR appears to be more effective than the first and second generations and is indicated as first-line therapy. This trial is registered with NCT01523587, NCT01466660, NCT01774721, NCT01360554, and NCT02296125.

What Is Known and Objective. Given that autoantibodies are relatively abundant and easily measured, the detection of antibody biomarkers would be ideal for predicting therapeutic responses. Although anti-Ro60/SSA (anti-TROVE2) antibody has been identified as a useful predictor for the development of immunogenicity and therapeutic failure to adalimumab in RA patients, autoantibodies with similar predictive potentials are not yet sufficiently validated. Methods. We aimed to investigate the baseline autoantibodies, including rheumatoid factor (RF)-IgM, anti-citrullinated peptide antibodies (ACPA), antinuclear antibody (ANA), anti-Ro60/SSA antibody, and anti-La/SSB antibody, for their relationships with drug immunogenicity and therapeutic responses in RA patients assessed at week 48 of adalimumab therapy. We also compared adalimumab drug survival between participants with or without these autoantibodies. Results and Discussion. Our results showed that poor EULAR responders had significantly higher positive rates of baseline ANA, anti-Ro60/SSA antibody, and anti-La/SSB antibody than moderate or good responders. However, no significant differences in circulating levels of RF-IgM or ACPA were observed among groups with different responses. The multivariate logistic regression analysis revealed that ANA and anti-Ro60/SSA antibodies were significant predictors of developing immunogenicity to adalimumab (both p < 0.001). The presence of ANA, anti-Ro60/SSA, and anti-SSB antibodies could significantly predict poor EULAR response in adalimumab-treated RA patients (odds ratio, 4.98, 5.60, and 8.08, respectively, all p < 0.01). In Kaplan–Meier analysis, the adalimumab drug survival rate was significantly lower in RA patients with positivity for ANA, anti-Ro60/SSA, anti-SSB, and anti-drug antibodies than in the seronegative group. What Is New and Conclusion. Our results suggest that baseline ANA and anti-Ro60/SSA antibodies are potential predictive markers of drug immunogenicity and poor EULAR response in adalimumab-treated RA patients.

Background. Induction or augmentation of labor may cause more painful contractions compared to spontaneous labor and pose a challenge to the efficacy of analgesia provided by spinal opioids alone in the early phase of labor. Therefore, we studied the analgesic efficacy and maternal satisfaction during spontaneous and artificially induced or augmented delivery in parturients receiving neuraxial analgesia with intrathecal opioids. Methods. A forty-parturient cohort that received intrathecal opioid (sufentanil 5 µg or fentanyl 20 µg) by the combined spinal-epidural method at an early phase of labor (cervical dilatation ≤5 cm) was used for this post hoc study. Maternal satisfaction and pain during contractions were measured on 0–100 visual analog scale at 30 minutes after the initiation of labor analgesia. Obstetric parameters (methods used to advance labor, cervical dilatation, use of oxytocin, effective time of spinal opioids, and labor outcome) were also measured. Results. Of the 40 parturients, 18 had spontaneous labor and 22 had induced or augmented labor (prior cervical dilatation, artificial rupture of membranes, or oxytocin infusion at the time of neuraxial analgesia initiation). Spontaneous labor associated with lower mean pain scores (6.4 (±12.8) vs 29.6 (±30.6) mm, P = 0.005) and higher satisfaction scores (96.9 (±5.3) vs 81.1 (±28.0) mm, P = 0.024) compared to induced or oxytocin augmented labor at 30 minutes after the initiation of analgesia. The parturients were at a similar stage of labor, and their labor progressed at a similar rate. Conclusions. In parturients undergoing nonspontaneous labor, the initiation of labor analgesia by intrathecal opioids alone may not be sufficient for adequate analgesia and either intrathecal or epidural analgesia with a mixture of opioid and local anesthetic should be considered in this population. This trial is registered with NCT02885350.

Background. Succinylcholine and rocuronium are the predominant neuromuscular blocking agents (NMBAs) used for rapid sequence intubation (RSI) in the emergency department (ED). Prior studies have found reduced first-attempt intubation success (FAIS) with rocuronium compared to succinylcholine. Recent large registry data have shown no difference in intubating conditions or FAIS. Objectives. The objective of this study was to compare FAIS rates for rocuronium and succinylcholine when used for RSI in a high-acuity academic ED. Methods. This was a single-center retrospective study. Patients were included if they received either succinylcholine or rocuronium for RSI in the ED from January 2016 to August 2020. The primary endpoint was FAIS. Subgroup analyses were performed evaluating the impact of weight-based dosing on FAIS for each agent, and multivariate analysis was conducted to evaluate the impact of baseline characteristics on the primary outcome. Results. There were 448 patients who received rocuronium and 183 patients who received succinylcholine. No difference was observed in unadjusted FAIS between patients receiving rocuronium (median weight-based dose: 1.22 mg/kg) or succinylcholine (median weight-based dose: 1.43 mg/kg) (361 (80.6%) vs. 150 (82.0%), p = 0.69). There were no differences in FAIS between the weight-based dose categories for rocuronium and for succinylcholine. Conclusions. These findings were consistent with those from recent studies indicating no difference in FAIS between rocuronium and succinylcholine, although the median dose of rocuronium used in this study was higher than traditionally recommended. Larger prospective studies are warranted to further evaluate the effect of weight-based paralytic dosing on FAIS.

What is Known and Objective. Omalizumab is a humanized anti-IgE antibody, which is used in the treatment of chronic spontaneous urticaria (CSU). This study aims to investigate the trends in the efficacy of omalizumab for CSU, focusing on temporal aspects, drug dosages, and sample sizes. Methods. Cochrane, OVID MEDLINE, Embase, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) from 1900 to January 2023. The primary outcome was the percentage of complete responders (defined as the weekly urticaria activity score as 0, UAS7 = 0). Secondary outcomes included the percentage of patients with UAS7 ≤ 6, the percentage of patients achieving a minimally necessary difference in weekly itch severity score (defined as a reduction from baseline in ISS7 of ≥5 points, ISS7 MID), and adverse events (AEs). A cumulative meta-analysis was performed with pooled risk ratio (RR) and 95% confidence intervals (CI). Publication bias was assessed by the contour-enhanced funnel plots with the trim-and-fill method, alongside Begg’s and Egger’s tests. Results and Discussion. Twelve randomized, placebo-controlled studies encompassing 2166 patients were analyzed. Compared with the placebo group, the omalizumab group exhibited significant increases in the proportion of patients achieving UAS7 = 0 [RR 5.18, 95% CI (3.97, 6.75), I² = 14%], UAS7 ≤ 6 [RR 3.21, 95% CI (2.69, 3.83), I² = 30%], and ISS7 MID responders [RR 1.50, 95% CI (1.39, 1.63), I² = 33%]. AEs were similar between the omalizumab group and placebo group [RR 0.96, 95% CI (0.89, 1.03), I² = 4%]. What is New and Conclusion. The cumulative meta-analysis confirmed that the efficacy outcomes for omalizumab have remained consistent over time, across different drug doses and sample sizes, with improved precision from newer studies. Omalizumab is confirmed to be safe and effective for CSU. It is also suggested to minimize redundant RCTs to conserve scientific and medical resources efficiently.

Background. This study aims to assess and explore the different effects of national centralized drug procurement (NCDP) on three targeted antitumor drugs’ use in clinical practice. Materials and Methods. Clinical drug volume data were collected covering 18 months before, during, and after the seventh round of the NCDP in Inner Mongolia. The interrupted time-series method was employed to estimate the net effect of policy impact. Results. The volume of generic afatinib (30 mg) increased by 25.78 DDDs, the expenditures decreased by 3641.14 yuan (p = 0.001), and the DDDc decreased by 124.35 yuan (p < 0.001). The volume of generic afatinib (40 mg) increased by 65.19 DDDs (p < 0.001), the expenditures increased by 1304.93 yuan (p < 0.001), and the DDDc decreased by 120.2 yuan (p < 0.001). The volume of generic sunitinib increased by 75.79 DDDs (p < 0.001), the expenditures decreased by 15869.78 yuan (p < 0.001), and the DDDc decreased by 243.28 yuan. There was no significant change trend in volume, expenditures, and DDDc of the three original-targeted drugs after NCDP intervention. Conclusions. After the policy intervention, generic afatinib (40 mg) successfully aligned with the objectives of NCDP by reducing drug costs and enhancing patient affordability; however, the desired outcomes were not achieved for generic afatinib (30 mg) and generic sunitinib. This discrepancy may be attributed to the inherent clinical efficacy and safety profiles of these drugs. Therefore, in implementing NCDP, it is necessary to enhance the clinical efficacy and safety of generic-targeted antitumor drugs while considering economic efficiency.