Comparative Efficacy and Safety of Potassium-Competitive Acid Blockers vs. Proton Pump Inhibitors for Peptic Ulcer with or without Helicobacter pylori Infection: A Systematic Review and Network Meta-Analysis.

Novel potassium-competitive acid blockers (P-CABs) have emerged as effective acid-suppressive drugs in recent years, replacing proton pump inhibitors (PPIs). We aim to compare the efficacy and safety of P-CABs versus PPIs in the treatment of peptic ulcers with or without Helicobacter pylori (H. pylori) infection. We searched in PubMed, Embase, WOS, Cochrane Library, ClinicalTrials.gov, CNKI, and Wanfang databases (all years up to January 2024). Efficacy and safety outcomes were evaluated using odds ratio (OR) and 95% confidence intervals (CI). The Surface Under the Cumulative Ranking (SUCRA) probabilities were used to rank each intervention. Among 14,056 studies screened, 56 studies involving 9792 participants were analyzed. Vonoprazan demonstrated the best efficacy in ulcer healing rate and H. pylori eradication rate (SUCRA = 86.4% and 90.7%, respectively). Keverprazan ranked second in ulcer healing rates (SUCRA = 76.0%) and was more effective in pain remission rates (SUCRA = 91.7%). The risk of adverse events was low for keverprazan (SUCRA = 11.8%) and tegoprazan (SUCRA = 12.9%), and moderate risk for vonoprazan (SUCRA = 44.3%) was demonstrated. Compared to lansoprazole, vonoprazan exhibited a higher risk of drug-related adverse events (OR: 2.15; 95% CI: 1.60-2.89) and serious adverse events (OR: 2.22; 95% CI: 1.11-4.42). Subgroup analysis on patients with H. pylori-positive peptic ulcers showed that vonoprazan was at the top of the SUCRA rankings, followed by keverprazan. Vonoprazan showed superior performance in peptic ulcers, especially for patients with H. pylori-positive peptic ulcers. However, the risk of adverse events associated with vonoprazan should be noted. Keverprazan has also shown good therapeutic outcomes and has performed better in terms of safety.

Post-marketing safety concerns with palbociclib: a disproportionality analysis of the FDA adverse event reporting system.

OBJECTIVES: To explore the association between palbociclib and related adverse events (AEs) in the real world through U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: The signal strength of palbociclib-related AEs was done by disproportionality analysis. Clinical priority of palbociclib-related AEs was scored and ranked by assessing five different features. Outcome analysis, time to onset analysis, dose-report /AEs number analysis, and stratification analysis were all performed. RESULTS: There were 61,821 'primary suspected (PS)' reports of palbociclib and 195,616 AEs associated with palbociclib. The four algorithms simultaneously detected 18 positive signals at the SOC level, and 65 positive signals at the PT level. Bone marrow failure, neuropathy, peripheral, pleural effusion, myelosuppression, pulmonary edema, and pulmonary thrombosis were also found to have positive signals. Gender (female vs male, χ2 = 5.287, p = 0.022) and age showed significant differences in serious and non-serious reports. Palbociclib-related AEs had a median onset time of 79 days (interquartile range [IQR] 20-264 days). CONCLUSIONS: The study identified potential Palbociclib-related AEs and offered warnings for special AEs, providing further data for palbociclib safety studies in breast cancer patients. Nonetheless, prospective clinical trials are needed to validate these results and explain their relationship.

Post-marketing safety of anti-IL-5 monoclonal antibodies (mAbs): an analysis of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Anti-IL-5 monoclonal antibodies (mAbs) targeting IL-5 or IL-5 R α (including mepolizumab, benralizumab, and reslizumab) are widely used for inflammatory diseases such as asthma, eosinophilia, and polyangiitis. However, real-world data regarding its safety in a large sample population are incomplete. So, we evaluated the safety of anti-IL-5 mAbs by pharmacovigilance analyzes based on related adverse events (AEs) from the FDA Adverse Event Reporting System (FAERS). METHODS: In disproportionality analysis, four algorithms were employed to detect the signals of anti-IL-5 mAbs from the FAERS between 2016 and 2022. In addition, we also used MYSQL 8.0, Navicat Premium 15, and Microsoft EXCEL 2019 to analyze the signals of anti-IL-5 mAbs systematically. RESULTS: There are 9,476,351 reports collected from the FAERS database, of which 22,174 reports listed anti-IL-5 mAbs as the 'primary suspected (PS)' drug. A total of 59 (20 new signals, mepolizumab) and 62 (19 new signals, benralizumab) significant disproportionality preferred terms (PTs) conforming to the four algorithms were retained synchronously. Finally, we detected that the anti-IL-5 mAbs-induced AEs occurred in 31 organ systems (mepolizumab) and 30 organ systems (benralizumab). For mepolizumab and reslizumab, unexpected and new significant PTs of AEs were found, such as asthmatic crisis, chronic obstructive pulmonary disease (COPD), pneumonia, COVID-19, pneumothorax, adrenal insufficiency and so on. Notably, the risk signal of asthmatic crisis for mepolizumab was stronger than benralizumab (ROR 108.04 [95%CI, 96.09-121.47] vs 26.83 [95%CI, 18.91-38.06]). Comparing with mepolizumab and benralizumab, we found the proportion of serious adverse events in mepolizumab was both greater than benralizumab in each age group (≤20, 20-65, and ≥ 65). The median onset time of mepolizumab was 280 days (interquartile range [IQR] 1-367 days). CONCLUSION: Analysis of FAERS data identified anti-IL-5 mAbs-associated AEs, and our findings supported continuous clinical monitoring, pharmacovigilance, and further studies of anti-IL-5 mAbs. In addition, clinicians may be more aware of the limitations of use in package inserts of anti-IL-5 mAbs: Not for relief of acute bronchospasm or status asthmaticus. Because of some limitations in the FAERS such as self-reports from patients and other confounding factors, the safety of anti-IL-5 mAbs needed more studies in different dimensions, especially the risk of cancer.

Acid-suppressive drugs: A systematic review and network meta-analysis of their nocturnal acid-inhibitory effect.

BACKGROUND AND AIMS: Acid-suppressive drugs (ASDs) are widely used in many gastric acid-associated diseases. Nocturnal acid breakthrough has been a common problem of many ASDs, such as proton-pump inhibitors (PPIs) and H2 -receptor antagonists (H2RAs). Potassium-competitive acid blockers (P-CABs) are expected to solve this continuing conundrum. This article examined major ASDs and compared them with placebo in terms of nocturnal acid-inhibitory effects, using a network meta-analysis of randomized controlled trials (RCTs). METHODS: To compare the effectiveness of major ASDs, a Bayesian network meta-analysis (NMA) was applied to process data extracted from RCTs. The plausible ranking for each regimen and some subgroups were assessed by surface under the cumulative ranking curves (SUCRA). RESULTS: Fifty-five RCTs were conducted with 2015 participants. In terms of nocturnal acid-inhibitory effects, the overall results showed that tegoprazan (SUCRA 91.8%) and vonoprazan (SUCRA 91.0%) had the best performance, followed by new PPIs (including tenatoprazole and ilaprazole) (SUCRA 76.6%), additional H2RAs once at bedtime (AHB) (SUCRA 61.3%), isomer PPIs (including esomeprazole and dexlansoprazole) (SUCRA 38.6%), revaprazan (SUCRA 34.7%), traditional PPIs (including omeprazole, rabeprazole, pantoprazole, lansoprazole) (SUCRA 32.6%), H2RAs (SUCRA 23.1%), and placebo (SUCRA 0.3%). In some subgroups, the nocturnal acid-inhibitory effect of vonoprazan or tegoprazan was better than most of the other regimens, even new PPIs and AHB. CONCLUSIONS: This is the first study to compare the effect of ASDs on inhibiting nocturnal acid breakthrough. Overall, in terms of nocturnal acid-inhibitory effect, vonoprazan and tegoprazan had an advantage against other regimens including H2RAs, isomer PPIs, traditional PPIs, AHB, and new PPIs. Even in some subgroups, such as language classification (English), types of study design (crossover-RCT), age (≤40 years), BMI (18.5-24.9 kg/m2 ), continent (Asia and North America), disease status (health), the duration of therapy (2 weeks), and time of administration (at daytime or at night-time), the nocturnal acid-inhibitory effect of vonoprazan or tegoprazan were better than most regimens, even AHB and new PPIs.

A disproportionality analysis of adverse events associated to pertuzumab in the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Pertuzumab is widely used for the treatment of HER2 + breast cancer. But its safety in the real world should be continuously monitored. So, we evaluated the safety of pertuzumab by pharmacovigilance analyze based on related adverse events (AEs) from the FDA Adverse Event Reporting System (FAERS) and find whether potential or uncertain adverse events were present. METHODS: In disproportionality analysis, four algorithms were employed to detect the signals of pertuzumab from the FAERS between 2012 and 2022. In addition, we also used MYSQL 8.0, Navicat Premium 15, and Microsoft EXCEL 2019 to analyze the potential and high-ROR (reporting odds ratio) signals of pertuzumab. We also collected the onset times of pertuzumab-associated AEs. RESULTS: From January 2012 to December 2022, there are 39,190,598 AEs reported from the FAERS database, of which 14,707 AEs listed pertuzumab as the 'primary suspected (PS)' drug. A total of 115 (46 potential) significant disproportionality preferred terms (PTs) conforming to the four algorithms were retained. Finally, we detected that the pertuzumab-induced AEs occurred in 12 organ systems. For pertuzumab, unexpected and significant PTs of AEs were found, including but not limited to below PTs: haematotoxicity, cardiotoxicity, cardiomyopathy, mitral valve incompetence, tachycardia, intestinal perforation, hemorrhoids, erysipelas, dehydration, pneumonitis, skin toxicity, onychomadesis, cyanosis, and circulatory collapse. We found there were 9 strong signals (5 potential safety signals) and 68 medium intensity signals (21 potential safety signals) according to IC025 (information component). The potential strong signals (IC025 > 3.0) were myelosuppression, cardiotoxicity, cardiac dysfunction, ejection fraction decreased, interstitial lung disease, and onychomadesis. Excluding unreported or unreasonable onset time reports, a total of 2016 AEs reported onset time and the median onset time was 117 days (4, 96), as median (Q1, Q3). Notably, most of the all AEs (n = 1133, 56%) and cardiac-related events (n = 405, 53%) all occurred within one month after pertuzumab therapy. CONCLUSION: Analysis of FAERS data identified pertuzumab-associated AEs, and our findings supported continuous clinical monitoring, pharmacovigilance, and further studies of pertuzumab. A significant association was detected between pertuzumab and some potential adverse events which should be regarded with some care. We have to pay attention to the first month after pertuzumab therapy and prepare emergency measures, especially for the elderly and patients with cardiovascular diseases.

CRO infection and the Use of MRSA-active Medication for Prophylaxis affect the Prognosis of Patients with Hematological Malignancies after CAR-T Infusion.

Carbapenem-resistant organisms (CRO) are a high priority issue because there are limited medications available to treat CRO infections, and these pathogens replicate rapidly in immunosuppressed patients, including those with hematological malignancy. Risk factors and prognosis of CRO infections after chimeric antigen receptor-modified T cells (CAR-T) therapy are unclear. This study was conducted to analyse the risk factors for CRO infection in patients with hematological malignancies following CAR-T therapy, and prognosis 1 year after CAR-T infusion. Patients who were diagnosed with hematological malignancies and treated with CAR-T therapy between June 2018 and December 2020 at our center were included. The case group consisted of 35 patients who developed CRO infections within 1 year of CAR-T infusion, and the control group comprised 280 patients who did not develop CRO infections. Shockingly, therapy failure occurred in 62.82% of CRO patients vs. 13.21% of the control group (P=0.000). Patients with CRO colonization (odds ratio [OR]=15.48, confidence interval [CI] (6.43-37.25), P=0.000) and hypoproteinemia (OR=2.84, CI (1.20-6.73), P=0.018) were susceptible to CRO infections. CRO infections (hazard ratio [HR]=4.40, CI (2.32-8.37), P=0.000), prophylaxis with combination regimens containing methicillin-resistant Staphylococcus aureus (MRSA)-active agents (HR=5.42, CI (2.65-11.11), P=0.000), and bacterial infections occurring within 30 days of CAR-T infusion (HR=1.97, CI (1.08-3.59), P=0.028) were risk factors for poor outcomes within 1 year. This study shows that prophylaxis of CRO infection should be a top priority in CAR-T therapy, the serum albumin level of patients should be dynamically monitored and interventions put in place if necessary, and caution is required in prophylaxis with anti-MRSA activity agents.

Effect of ertugliflozin on renal function and cardiovascular outcomes in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: The global prevalence of type 2 diabetes mellitus (T2DM) is growing yearly. The efficacy of ertugliflozin (ERT), a recently licensed anti-diabetic drug, has been widely reported. However, additional evidence-based data is required to ensure its safety. In particular, convincing evidence on the effects of ERT on renal function and cardiovascular outcomes is needed. METHODS: We searched PubMed, Cochrane Library, Embase, and Web of Science for randomized placebo-controlled trials of ERT for T2DM published up to August 11, 2022. Cardiovascular events here mainly refer to acute myocardial infarction and angina pectoris (AP) (including stable AP and unstable AP). The estimated glomerular filtration rate (eGFR) was used to measure renal function. The pooled results are risk ratios (RRs) and 95% confidence intervals (CIs). Two participants worked independently to extract data. RESULTS: We searched 1516 documents and filtered the titles, abstracts, and full text, 45 papers were left. Seven trials met the inclusion criteria and were ultimately included in the meta-analysis. The meta-analysis found that ERT reduced eGFR by 0.60 mL·min-1·1.733 m-2 (95% CI: -1.02--0.17, P = .006) in patients with T2DM when used for no more than 52 weeks and these differences were statistically significant. Compared with placebo, ERT did not increase the risk of acute myocardial infarction (RR 1.00, 95% CI: 0.83-1.20, P = .333) and AP (RR 0.85, 95% CI: 0.69-1.05, P = .497). However, the fact that these differences were not statistically significant. CONCLUSION: This meta-analysis shows that ERT reduces eGFR over time in people with T2DM but is safe in the incidence of specific cardiovascular events.

Effect of potassium-competitive acid blockers on human gut microbiota: a systematic review and meta-analysis.

Background: Vonoprazan has been reported to exert more potent and long-lasting gastric acid inhibition than proton pump inhibitors, potentially leading to a greater impact on the gut microbiota. This study aimed to clarify changes in microbial diversity and bacterial composition after VPZ treatments. Methods: We searched from PubMed, Embase, WOS, Scopus, Cochrane Library, and ClinicalTrials.gov (all years up to May 2023). The primary outcomes were alpha and beta diversity, as well as differences in gut microbiota composition between before and after VPZ treatments. We performed a meta-analysis to uncover the potential changes in human gut microbiota among VPZ users by pooled mean difference (MD) with a 95% confidence interval (CI). The risk of bias was assessed using the ROBINS-I tool. Results: A total of 12 studies were included to compare differences before and after VPZ treatments. Compared with baseline, alpha diversity was significantly reduced after VPZ treatments and gradually returned to baseline with longer follow-up. At the phylum level, there was a decrease in the relative abundance of Firmicutes and Actinobacteria, while Bacteroidetes increased compared with baseline. At the genus level, we found a significant decrease in the relative abundance of Coprococcus and Bifidobacterium and a significant increase in the relative abundance of Bacteroides compared with those before treatment. In subgroup analyses according to country and participants, we found differences in microbial changes after VPZ treatments. Conclusion: Vonoprazan can affect the changes of gut microbiota, which may be potentially associated with its strong ability of acid inhibition. However, due to the large heterogeneity, further studies are required to validate these findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023412265.

Comparative effectiveness of first-line therapies for eradication of antibiotic-resistant Helicobacter pylori strains: A network meta-analysis.

BACKGROUND: As a first-line treatment regimen for Helicobacter pylori (H. pylori) infection, antibiotic therapy is widely used worldwide. However, the question of increasing antibiotic resistance must be considered. Given this issue, we need to find ways to reduce drug resistance. This study examined all currently available first-line regimens and compared them with standard triple treatment through a network meta-analysis of randomized controlled trials (RCTs). AIM: To compare first-line treatment regimens for eradication of antibiotic-resistant H. pylori strains. METHODS: To compare the effectiveness of the first-line regimens for treating H. pylori infection, a Bayesian network meta-analysis was applied to process data extracted from RCTs. The plausible ranking for each regimen was assessed by the surface under the cumulative ranking curve (SUCRA). In addition, we conducted a relevant search by reference citation analysis. RESULTS: Twenty-five RCTs involving 12029 participants [including 1602 infected with clarithromycin (CAM)-resistant strains and 1716 infected with metronidazole (MNZ)-resistant strains] were included, in which a total of seven regimens were used for H. pylori eradication. The results showed that dual therapy containing a high-dose proton pump inhibitor (HDDT) [odds ratio (OR): 4.20, 95% confidence interval (CI): 2.29-8.13] was superior to other therapies for all patients, including those with CAM/MNZ-resistant H. pylori infection. In the comparative effectiveness ranking, for CAM-resistant H. pylori, HDDT (OR: 96.80, 95%CI: 22.46-521.9) had the best results, whereas standard triple therapy ranked last (SUCRA: 98.7% vs 0.3%). In the subgroup of high cure rates (≥ 90%), HDDT was also generally better than other therapies. CONCLUSION: For the eradication of CAM- and MNZ-resistant H. pylori strains, HDDT exhibited considerable advantages. The studies of CAM-resistant H. pylori were based on small samples due to a lack of antibiotic sensitivity tests in many RCTs, but the results showed that all patients, including those with CAM-resistant H. pylori infection, had a concordant trend. Overall, HDDT may be a reference for RCTs and other studies of H. pylori eradication.

Protective effect of kinsenoside on acute alcohol-induced liver injury in mice

Abstract Anoectochilus roxburghii (Wall.) Lindl., Orchidaceae, is a Chinese medicinal plant which can be effective for some diseases such as hepatitis, nephritis, pneumonia. Its active ingredient is kinsenoside. The mechanisms of kinsenoside on the liver-protective effect have not been fully explored until today. The present study was aimed to investigate the protective effect and mechanism of kinsenoside on acute alcoholic liver injury. The protected activity of kinsenoside (10, 20 and 40 mg/kg) were investigated on acute alcoholic liver injury in mice. Male C57BL/6 J mice were fed with non-fat feed for 30 days and oral administrated 14 ml/kg bw of ethanol (50%) on the 31st day. The activities of serum aspartate aminotransferase, serum alanine aminotransferase, triacylglyceride and very low density lipoprotein were determined in serum. The hepatic levels of oxidative stress as glutathione, malondialdehyde were measured in liver homogenates. The levels of cytochrome P450 2E1 (CYP2E1) were measured by immunohistochemistry. Furthermore, histopathological observations were carried out on the separated livers of mice. It was suggested that the trends of acute hepatic injury and fatty degeneration induced by alcohol were reduced in the ethanol group after kinsenoside treatment. Compared to ethanol groups, triacylglyceride, malondialdehyde, very low density lipoprotein, reduced glutathione, serum alanine aminotransferase and serum aspartate aminotransferase levels of kinsenoside (20, 40 mg/kg) groups were decreased (p < 0.05). Meanwhile kinsenoside significantly decreased the level of protein CYP2E1. In conclusion, kinsenoside enhances antioxidant capacity of mice and antagonizes alcohol-induced lipid metabolism disorders. Besides, kinsenoside inhibits alcohol-caused hepatocyte apoptosis, reduces oxidative stress, and relieves hepatocyte death, which may be a mechanism of kinsenoside in the treatment of alcoholic liver.

Azacoccones A-E, five new aza-epicoccone derivatives from Aspergillus flavipes.

Azacoccones A-E (1-5), five new aza-epicoccone derivatives, were isolated from the culture of Aspergillus flavipes. Their structures were determined by extensive NMR spectroscopic analyses and the absolute configuration of 5 was determined by electronic circular dichroism (ECD) calculation. Compounds 1-5 are proposed to be generated via a Pictet-Spengler reaction-based biosynthetic route starting from the precursor flavipin. Pictet-Spengler reaction is rarely found in the fungal kingdom, which indicated the distinctive nature of 1-5. Compounds 3 and 5 exhibit significant free radical scavenging activities with IC50 values of 4.0 and 2.4µg/mL, respectively, which are better than the positive control trolox (4.55µg/mL).