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Background: Gilteritinib and midostaurin are FLT3 inhibitors that have made significant progress in the treatment of acute myeloid leukemia. However, their real-world safety profile in a large sample population is incomplete. Objectives: We aimed to provide a pharmacovigilance study of the adverse events (AEs) associated with gilteritinib and midostaurin through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Design: A retrospective analysis of the FAERS database was conducted by disproportionality analyses. Methods: We conducted disproportionality analyses to identify drug-AE associations, including the reporting odds ratio and the Bayesian confidence propagation neural network. A signal was detected if both methods achieved statistical significance. Results: There were 1887 and 2091 case reports for gilteritinib and midostaurin, respectively. We have separately retained significant disproportionality AEs across two algorithms, with a total of 53 AEs for gilteritinib and 46 for midostaurin. The common AEs observed with gilteritinib included febrile neutropenia, pyrexia, anemia, and thrombocytopenia. Similarly, the prevalent AEs associated with midostaurin were nausea, vomiting, diarrhea, pyrexia, and febrile neutropenia. The common AEs of both drugs are consistent with previous clinical trials. Notably, we also revealed unexpected significant AEs for both drugs. For gilteritinib, 29 positive signals for AEs not mentioned in its instructions were identified, such as cerebral hemorrhage, tumor lysis syndrome, and interstitial lung disease. Midostaurin exhibited 24 positive signals for AEs not listed in its instructions, including neutropenic colitis, neutropenic sepsis, and septic shock. Conclusion: This study highlights the need for continued monitoring and evaluation of these drugs in clinical practice, as it first reveals their AEs in a large real-world sample population. Some AEs are generally consistent with the instructions and previous studies, but some unexpected AEs are detected for each drug. Due to the limitations of the spontaneous report database, such as including potential underreporting, overreporting, lack of causal relationship, unable to calculate incidence, and other confounding factors, more pharmacoepidemiology studies are needed to validate our findings.

Background: Hepatocellular carcinoma poses a significant public health burden in China, necessitating the economic evaluation of new therapeutic strategies for policy-makers and clinicians. The international, randomized phase 3 trial CARES-310 revealed that camrelizumab plus rivoceranib provided a substantial clinical benefit in patients with advanced hepatocellular carcinoma, but the economic outcome remains unclear. This study aimed to evaluate the cost-effectiveness of camrelizumab plus rivoceranib versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CARES-310) from the perspective of the Chinese health care system. Methods: A partitioned survival model was developed to estimate the lifetime cost and clinical outcomes of camrelizumab plus rivoceranib versus sorafenib in first-line treatment of advanced hepatocellular carcinoma. Survival data from the CARES-310 trial were used to create a hypothetical cohort of 543 patients with advanced hepatocellular carcinoma for modeling disease progression. The life-year, quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER) was used to measure the model’s outcome, with the willingness-to-pay threshold set at 3 times China’s gross domestic product (GDP) per capita (US$36 780). Univariate, multivariable probabilistic sensitivity analyses, and subgroup analysis were performed to assess parameter uncertainty, complemented by a scenario analysis using health utilities reported in literature. Results: The camrelizumab group yielded an additional 0.239 QALYs at an added cost of US$8340 compared with sorafenib, resulting in an ICER of US$34 897/QALY. Univariate sensitivity analysis indicated that the model results were most sensitive to the utility of progression-free survival in the camrelizumab group, sorafenib cost, and camrelizumab cost. Probabilistic sensitivity analysis revealed a 56% probability of cost-effectiveness of camrelizumab plus rivoceranib among all patients. The results of the subgroup analysis demonstrated camrelizumab plus rivoceranib was the most cost-effective in the subgroup with albumin-bilirubin grade 2. Conclusions: At a willingness-to-pay threshold of US$36 780/QALY, camrelizumab plus rivoceranib is likely to be a cost-effective option compared with sorafenib as first-line treatment for advanced hepatocellular carcinoma in China.

ObjectiveNivolumab, recently proven in a phase 3 clinical trial (CheckMate 901) to enhance survival when combined with gemcitabine-cisplatin for advanced urothelial carcinoma. This study aimed to assess its cost-effectiveness against gemcitabine-cisplatin alone, from US and Chinese payers’ perspectives.MethodsA partitioned survival model was established to assess the life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) of nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone as first-line treatment for advanced urothelial carcinoma. Univariate, two-way, and probabilistic sensitivity analyses were conducted to assess the model’s robustness. Additionally, subgroup analyses were performed.ResultsNivolumab plus gemcitabine-cisplatin and gemcitabine-cisplatin achieved survival benefits of 4.238 life-years and 2.979 life-years for patients with advanced urothelial carcinoma, respectively. Compared with gemcitabine-cisplatin, nivolumab plus gemcitabine-cisplatin resulted in ICERs of $116,856/QALY in the US and $51,997/QALY in China. The probabilities of achieving cost-effectiveness at the current willingness-to-pay thresholds were 77.5% in the US and 16.5% in China. Cost-effectiveness could be reached if the price of nivolumab were reduced to $920.87/100mg in China. Subgroup analyses indicated that the combination had the highest probability of cost-effectiveness in patients under 65 or with an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 in the US and China.ConclusionNivolumab plus gemcitabine-cisplatin first-line treatment for advanced urothelial carcinoma results in longer life expectancy than gemcitabine-cisplatin, but is not cost-effective in China at current price. However, cost-effectiveness is likely to be achieved in most patient subgroups in the US.

Abstract Background Circular RNAs (circRNAs) play critical roles in the tumorigenesis and radiosensitivity of multiple cancers. Nevertheless, the biological functions of circRNA periostin (circ‐POSTN) in esophageal cancer (EC) progression and radiosensitivity have not been well elucidated. Methods The expression of circ‐POSTN, microRNA‐876‐5p (miR‐876‐5p), and proto‐oncogene tyrosine‐protein kinase (FYN) was analyzed by quantitative reverse transcription PCR (RT‐qPCR). Cell proliferation was assessed by MTT, colony formation, and 5‐ethynyl‐2′‐deoxyuridine (EDU) assays. All protein levels were detected by western blot assay. Cell apoptosis and invasion were assessed by flow cytometry analysis and transwell assay, respectively. Dual‐luciferase reporter and RNA immunoprecipitation (RIP) assays were used to validate the interaction between miR‐876‐5p and circ‐POSTN or FYN. The role of circ‐POSTN in vivo was explored by establishing mice xenograft model. Results Circ‐POSTN was overexpressed in EC tissues and cells. Knockdown of circ‐POSTN inhibited cell proliferation and invasion and elevated apoptosis and radiosensitivity in EC cells. MiR‐876‐5p was a direct target of circ‐POSTN, and its knockdown reversed the role of sh‐circ‐POSTN in EC cells. FYN was a direct target of miR‐876‐5p, and FYN elevation weakened the effects of miR‐876‐5p overexpression on the progression and radiosensitivity of EC cells. Moreover, circ‐POSTN acted as a miR‐876‐5p sponge to regulate FYN expression. Circ‐POSTN interference also suppressed tumor growth and enhanced radiosensitivity in vivo. Conclusion Circ‐POSTN knockdown inhibited proliferation and invasion, but increased apoptosis and enhanced radiosensitivity in EC cells via modulating miR‐876‐5p/FYN axis, which might be a potential diagnostic and therapeutic target for EC.

Objective: Cholinesterase inhibitor (ChEIs) is the first-line drug for Alzheimer’s disease (AD). Understanding torsade de pointes (TdP)/QT prolongation with different ChEIs is essential for its safe and rational administration. This study aimed to evaluate the correlation between different ChEIs and TdP/QT prolongation.Methods: All ChEIs related TdP/QT prolongation cases were retrieved from the FAERS database using standard MedDRA query (SMQ) from the first quarter of 2004 to the third quarter of 2022. Disproportionality and sensitivity analysis were used to determine the signal of TdP/QT prolongation related to ChEIs.Results: 557 cases of TdP/QT prolongation related to 3 ChEIs were searched by SMQ. The patients were mostly elderly people, with markedly more female than male. The signals of TdP/QT prolongation for ChEIs were detected by disproportionality analysis, and the signal of Donepezil was the strongest. The sensitivity analysis results indicate a robust and stable correlation between these signals with ChEIs. TdP/QT prolongation usually occurs within 1 month after taking ChEIs. The drug with the highest frequency of combination with donepezil and galantamine is citalopram, and the drug with the highest frequency of combination with rivastigmine is atorvastatin.Conclusion: The signals of TdP/QT prolongation related to ChEIs were strong and stable. It is necessary to be vigilant about the TdP/QT prolongation of various ChEIs, especially in elderly women, the initial stage after taking ChEIs, and when ChEIs combining with drugs that could prolong the QT interval.

The relatively new discipline of pharmacovigilance (PV) aims to monitor the safety of drugs throughout their evolution and is essential to discovering new drug risks. Due to their specific and complex physiology, children, pregnant women, and elderly adults are more prone to adverse drug reactions (ADRs). Additionally, the lack of clinical trial data exacerbates the challenges faced with pharmacotherapy in these populations. Elderly patients tend to have multiple comorbidities often requiring more extensive medication, which adds additional challenges for healthcare professionals (HCPs) in delivering safe and effective pharmacotherapy. Clinical trials often have inherent limitations, including insufficient sample size and limited duration of research; as some ADRs are attributed to long-term use of a drug, these may go undetected during the course of the trial. Therefore, the implementation of PV is key to insuring the safe and effective use of drugs in special populations. We conducted a thorough review of the scientific literature on PV systems across the European Union, the United States, and China. Our review focused on basic physiological characteristics, drug use, and PV for specific populations (children, pregnant women, and the elderly). This article aims to provide a reference for the development of follow-up policies and improvement of existing policies as well as provide insight into drug safety with respect to patients of special populations.

ObjectiveThe ASTRUM-005 trial demonstrated that adding serplulimab to chemotherapy significantly prolonged the survival of patients with extensive-stage small cell lung cancer (SCLC), but also increased the risk of adverse events. Given the high cost of serplulimab compared to chemotherapy, this study aimed to evaluate the cost-effectiveness of serplulimab plus chemotherapy as a first-line treatment for extensive-stage SCLC from the perspective of China’s healthcare system.MethodsA Markov model was developed to simulate the disease process of extensive-stage SCLC and estimate the health outcomes and direct medical costs of patients. Scenario analyses, univariate sensitivity analyses, and probabilistic sensitivity analyses were conducted to explore the impact of different parameters on model uncertainty. The primary model outcomes included costs, life-years (LYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER).ResultsCompared to placebo plus chemotherapy, serplulimab plus chemotherapy resulted in an additional 0.25 life-years and 0.15 QALYs, but also increased costs by $26,402, resulting in an ICER of 179,161 USD/QALY. Sensitivity analysis showed that the ICER was most sensitive to the cost of serplulimab, and the probability that serplulimab was cost-effective when added to chemotherapy was only 0 at the willingness-to-pay threshold of 37,423 USD/QALY. Scenario analysis revealed that price discounts on serplulimab could increase its probability of being cost-effective.ConclusionSerplulimab plus chemotherapy is not a cost-effective strategy for first-line treatment of extensive-stage SCLC in China. Price discounts on serplulimab can enhance its cost-effectiveness.

[Objectives] The analgesic and hemostatic effects of Paris polyphylla, Scutellaria baicalensis, and their compatibility were studied. [Methods]（i） In the experiment on the writhing of mice induced by acetic acid, 60 Kunming SPF mice were randomly selected, and were randomly divided into 6 groups according to the male-to-female ratio of 1∶1, including blank control group, P. polyphylla group, S. baicalensis group, and three P. polyphylla and S. baicalensis compatibility groups（with the ratio of 1∶2, 1∶1 and 1∶2）. There were 10 mice in each group. In the experimental groups, the mice were given 1 g/mL Chinese medicine extract according to a dose of 20 mL/kg. In the control group, the mice were given 0.9% normal saline in equal volumes. Gavage was performed one time every 24 h and lasted for 14 d. 1 h after the gavage on the 14 th day, they were given 0.5% glacial acetic acid solution via intraperitoneal injection.（ii） In the hot plate experiment, 60 Kunming SPF mice were selected, and the ratio of male to female, grouping, administration and gavage were the same as those of the glacial acetic acid-induced writhing experiment. Gavage was lasted for 14 d. 1 h after the gavage on the 14 th day, the mice were placed on a hot plate apparatus at（55±0.5） ℃, and the time of licking hindfoot was measured.（iii） The hemostatic effect was explored through three experimental methods of tail hemostasis, femoral artery hemostasis and liver hemostasis. 60 Kunming SPF mice were taken in each of the three experiments, and the male-female ratio and grouping were the same as above. The powder was covered on the surface of the wound sites, and the bleeding was observed. The hemostatic time was recorded, and the hemostatic time was recorded as 3 min if it exceeded 3 min. [Results]（i） In the acetic acid-induced writhing experiment, compared with the blank control group, the pain of mice in the experimental groups was inhibited. Among them, P. polyphylla group, S. baicalensis group, compatibility 1∶2 group, compatibility 1∶1 group, and compatibility 2∶1 group had significant effects（P<0.05）, and the inhibition rate of writhing was 20.43%, 28.32%, 52.30%, 32.79 %, and 39.02%, respectively. The analgesic effect of the compatibility 1∶2 group was the most obvious.（ii） In the hot plate experiment, compared with the blank control group, the experimental groups had analgesic effect. Among them, P. polyphylla group, S. baicalensis group, compatibility 1∶2 group, compatibility 1∶1 group, and compatibility 2∶1 group had significant effects（P<0.05）, and the increase rate of pain threshold was 29.17%, 47.83%, 61.54%, and 50.61%, and 53.83%, respectively. The analgesic effect of the compatibility 2∶1 group was the most significant.（iii） In the hemostatic experiment, there was a significant difference in hemostatic time between the compatibility 1∶2 group and the blank control group, P. polyphylla group, and S. baicalensis group（P<0.05）. The hemostatic effect of the compatibility 1∶2 group was the best. [Conclusions] P. polyphylla, S. baicalensis, and its compatibility had good analgesic and hemostatic effects, and the best compatibility ratio was 1∶2. [ABSTRACT FROM AUTHOR]