Adverse event signal mining and serious adverse event influencing factor analysis of fulvestrant based on FAERS database.

Fulvestrant, as the first selective estrogen receptor degrader, is widely used in the endocrine treatment of breast cancer. However, in the real world, there is a lack of relevant reports on adverse reaction data mining for fulvestrant. To perform data mining on adverse events (AEs) associated with fulvestrant and explore the risk factors contributing to severe AEs, providing a reference for the rational use of fulvestrant in clinical practice. Retrieved adverse event report information associated with fulvestrant from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, covering the period from market introduction to September 30, 2023. Suspicious AEs were screened using the reporting odds ratio (ROR) and proportional reporting ratio methods based on disproportionality analysis. Univariate and multivariate logistic regression analyses were conducted on severe AEs to explore the risk factors associated with fulvestrant-induced severe AEs. A total of 6947 reports related to AEs associated with fulvestrant were obtained, including 5924 reports of severe AEs and 1023 reports of non-severe AEs. Using the disproportionality analysis method, a total of 210 valid AEs were identified for fulvestrant, with 45 AEs (21.43%) not listed in the product labeling, involving 11 systems and organs. The AEs associated with fulvestrant were sorted by frequency of occurrence, with neutropenia (325 cases) having the highest number of reports. By signal strength, injection site pruritus showed the strongest signal (ROR = 658.43). The results of the logistic regression analysis showed that concurrent use of medications with extremely high protein binding (≥ 98%) is an independent risk factor for severe AEs associated with fulvestrant. Age served as a protective factor for fulvestrant-related AEs. The co-administration of fulvestrant with CYP3A4 enzyme inhibitors did not show statistically significant correlation with the occurrence of severe AEs. Co-administration of drugs with extremely high protein binding (≥ 98%) may increase the risk of severe adverse reactions of fulvestrant. Meanwhile, age (60-74 years) may reduce the risk of severe AEs of fulvestrant. However, further clinical research is still needed to explore and verify whether there is interaction between fulvestrant and drugs with high protein binding through more clinical studies.

Adverse Event Profile Differences between Trastuzumab Emtansine and Trastuzumab Deruxtecan: A Real-world, Pharmacovigilance Study.

Introduction: Trastuzumab emtansine(T-DM1) and trastuzumab deruxtecan (T-DXd, formerly DS-8201a), the human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC), are commonly used in metastatic breast cancer. However, their real-world safety profile has not been adequately compared. Objective: We aimed to investigate the adverse event (AE) profile of T-DM1 and T-DXd reported by the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: All indications were searched for T-DM1 and T-DXd, as primary suspected drugs, from FAERS data (January 2004 to June 2023). Disproportionality analyses were performed by reporting odds ratios (ROR) and proportional reporting ratio (PRR). The odds ratio (OR) of fatal AEs associated with T-DM1 and T-DXd under different exposure factors were performed by univariate and multivariate logistical regression analysis. Results: 3723 and 2045 reports of T-DM1 and T-DXd were submitted to FAERS. Finally, 94 and 61 significant signals for T-DM1 and T-DXd were systematically analyzed. The valid AEs with the highest frequency and the strongest signal intensity for T-DM1 were platelet count decreased (n=108) and hepatopulmonary syndrome (ROR=680.42), respectively. Interstitial lung disease (n=262, ROR=82.55) and pneumonitis (n=89, ROR = 48.34) showed both high frequency and strong signal intensity for T-DXd. The proportion of AEs in each SOC system was different. T-DM1 had a greater proportion of valid AEs in the nervous system, musculoskeletal system, hepatobiliary system, ocular system, cardiac system and hematologic system(p<0.05). T-DXd had a greater proportion of valid AEs in the skin disorders, respiratory system, infestations, general system and gastrointestinal system(p<0.05). Furthermore, the analysis of fatal AEs in four systems revealed that T-DXd exhibited a significantly higher proportion of fatal outcomes in the hematologic and respiratory system compared to T-DM1. Conversely, T-DM1 had a significantly higher proportion of fatal outcomes in the hepatobiliary system. Neither T-DM1 nor T-DXd exhibited a high mortality ratio in the cardiac system. Logistic regression analysis indicated that advanced age (≥65 years) and male gender were identified as independent risk factors of fatal AEs for both T-DM1 and T-DXd. Additionally, the drug combination therapy, particularly with a CYP3A4 inhibitor, was found to be a risk factor for fatal AEs specifically related to T-DXd. Conclusions: Hematological and respiratory toxicity of T-DXd and hepatobiliary toxicity of T-DM1 exhibited a high incidence of fatal outcomes. It is crucial to identify high-risk factors and enhance the monitoring of AEs during clinical application.

AB4 inhibits Notch signaling and promotes cancer cell apoptosis in liver cancer.

The etiology for liver cancer has been clearly defined. Unfortunately, therapeutic approaches for liver cancer are rather limited, and liver cancer is insensitive to chemotherapy and radiotherapy. Traditional Chinese medicine (TCM) has become a promising strategy for cancer treatment as TCM elicits broad spectrum anticancer activity. In the present study, we evaluated the anticancer efficacy of AB4, an extract from the medical herb Pulsatilla chinensis (Bunge) Regel, in liver cancer in vitro and in vivo. We found that AB4 readily dose­ and time­dependently inhibited liver cancer HepG2 and Huh­7 cell proliferation and colony formation. Western blot and flow cytometry analyses suggested that AB4 treatment induced liver cancer cell apoptosis. Moreover, these findings could be readily recaptured in vivo, in which the AB4 regimen resulted in tumor suppression and cancer cell apoptosis in xenograft tumor­bearing nude mice. Importantly, we noted that treatment with a Notch signaling inhibitor DAPT produced very similar anticancer efficacy in both HepG2 and Huh­7 cell lines, and administration of DAPT also efficiently suppressed HepG2 xenograft outgrowth. To this end, we anticipated that AB4 and DAPT may act on the same signaling pathway, probably through inhibition of the Notch pathway. Indeed, we found decreased expression of Notch1 protein, as well as downstream targets Hes1 and Hey1, after AB4 treatment. Immunohistochemistry analysis further confirmed the suppression of Notch signaling in HepG2 xenograft­bearing mice. Taken together, our study highlighted the anticancer efficacy of AB4 in liver cancer. We also provided preliminary data showing Notch as a therapeutic target of AB4. It would be interesting to investigate the anticancer efficacy of AB4 in other types of cancer with elevated Notch activity.

Anemoside B4 exerts anti-cancer effect by inducing apoptosis and autophagy through inhibiton of PI3K/Akt/mTOR pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and novel therapeutic approaches are urgently required. Anemoside B4 (AB4) is a compound extracted from Pulsatilla chinensis (P. chinensis). Previous studies have indicated that P. chinensis extract P. chinensis saponins has anti-cancer activity. However, the pharmacological effect of AB4 in cancer is largely unknown. In this study, we investigated the anti-cancer efficacy of AB4 in HCC. We used CCK-8 assay and colony formation assay to evaluate the cytotoxicity of AB4 and found that this agent markedly inhibited SMMC7721 cell proliferation. By using a panel of morphological and molecular experiments, we reported that AB4 induced HCC SMMC7721 cell apoptosis and autophagy. Notably, AB4 treatment acts on the Bcl-2-caspase-3 pathway and Beclin-1-LC3-p62 pathway, thereby regulates both apoptosis and autophagy. Finally, we showed that AB4-induced apoptosis and autophagy converges at the PI3K/Akt/mTOR signaling. AB4 treatment inhibits this signaling transduction pathway and leads to HCC cell death. Collectively, our study highlighted the anti-cancer efficacy of AB4 and suggested that AB4 might be a novel way to treat HCC.