Adverse event profiles of drug-induced liver injury caused by antidepressant drugs: a disproportionality analysis.

Background: Antidepressants are widely used to manage depression and other psychiatric diseases. A previous study revealed that hepatotoxicity was the main adverse event related to antidepressants. Therefore, drug-induced liver injury (DILI) caused by antidepressants deserves more attention. Objectives: To investigate DILI adverse events reported due to antidepressant use in the United States Food and Drug Administration Adverse Events Reporting System (FAERS) database. Research design: A disproportionality analysis of spontaneously reported adverse events was conducted to assess the association between antidepressant drugs and DILI. Methods: FAERS data from 1 January 2004 to 31 December 2021 were compiled and analyzed using the reporting odds ratio (ROR) and information component (IC). Results: As per the FAERS database, of the 324,588 cases that were administered antidepressants, 10,355 were identified as cases with DILI. Among the identified 42 antidepressants, nefazodone (n = 47, ROR = 7.79, IC = 2.91), fluvoxamine (n = 29, ROR = 4.69, IC = 2.20), and clomipramine (n = 24, ROR = 3.97, IC = 1.96) had the highest ROR for cholestatic injury; mianserin (n = 3, ROR = 21.46, IC = 3.99), nefazodone (n = 264, ROR = 18.67, IC = 3.84), and maprotiline (n = 15, ROR = 5.65, IC = 2.39) for hepatocellular injury; and nefazodone (n = 187, ROR = 12.71, IC = 0.48), clomipramine (n = 35, ROR = 2.07, IC = 0.26), and mirtazapine (n = 483, ROR = 1.96, IC = 0.94) for severe drug-related hepatic disorders. Only nefazodone elicited hepatic failure signals (n = 48, ROR = 18.64, IC = 4.16). There are limited reports on the adverse reactions of relatively new antidepressant drugs, such as milnacipran, viloxazine, esketamine, and tianeptine, and those not approved by the Food and Drugs Administration, such as reboxetine and agomelatine. Conclusion: A significant association was observed between DILI and nefazodone. Duloxetine and clomipramine were associated with three DILI categories, except hepatic failure. The disproportionality analysis cannot conclude on a definite causal link between antidepressants and DILI. Additional research is required to assess new-generation antidepressants for their propensity to cause DILI.

Adverse events reported on drug-induced liver injury caused by antidepressants Introduction: Adverse drug events (ADEs) refer to all harmful events related to medications, including adverse drug reactions (ADRs) and other unexpected events. ADEs encompass a wider range and are very important for the post-market surveillance of drugs. This study investigated the voluntary reporting of drug-induced liver injury (DILI) adverse events associated with antidepressant drugs. Methods: We retrieved data on DILI and related terms submitted between 2004 and 2021 from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) database. We analyzed the data for the detection of DILI signals associated with antidepressants. Results: We retrieved and analyzed 324,588 reports on antidepressant drugs. A total of 10,355 reports were associated with DILI. The three drugs with the highest reporting odds ratio (ROR) in each DILI category were as follows: cholestatic injury (nefazodone, fluvoxamine, and clomipramine)hepatocellular injury (mianserin, nefazodone, and maprotiline)hepatic failure (nefazodone)drug related hepatic disorders-severe events (nefazodone, clomipramine, and mirtazapine) The absence of signals from some drugs may be due to: non-association with DILInovelty of the drug in the marketnon-approval from the Food and Drugs Administration (FDA)lack of voluntary reporting of adverse events due to other reasons Conclusion: Drug safety studies utilizing publicly available large databases allowed the evaluation of the safety profile of widely used antidepressant drugs in clinical practice. Nefazodone, duloxetine, and clomipramine were associated with significant DILI signals. Further research is needed to determine the safety concerns of new-generation antidepressants.

Statin-related neurocognitive disorder: a real-world pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND: Concerns regarding statin-related neurocognitive disorders have emerged in recent years. However, previous studies have reported inconsistent results. We evaluated the association between statins and neurocognitive disorders using the FDA Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS: Data from 2004 to 2022 were obtained from the FAERS database. After deduplication and standardization of drug names, we extracted neurocognitive disorder event (NCDE) cases reported with statins as the suspected drugs. The significant association between statins and NCDE was evaluated using the reporting odds ratio (ROR) and information component. RESULTS: In total, 6,959 NCDE cases with statins as the primary suspected drugs were identified. Signals were detected in pravastatin (ROR, 1.49; 95% CI: 1.32-1.67), atorvastatin (ROR, 1.39; 95% CI: 1.34-1.44), and simvastatin (ROR, 1.31; 95% CI: 1.25-1.38). Age-stratified analysis showed that (1) in the population aged 65 years and older, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, and pitavastatin; and (2) in populations under 65 years of age, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, and lovastatin. CONCLUSIONS: This study suggests a significant association between the NCDE and statins, including atorvastatin, simvastatin, and pravastatin. The intensity of the association increased with age.

With the extensive use of statins worldwide in recent years, some patients have reported that statins lead to cognitive impairment. Researchers have conducted studies on this issue; however, the results have been inconsistent. Some believe that statins have no impact on cognitive function, while others believe they are beneficial, and others believe they have negative effects.To further investigate this issue, we analyzed data from the FDA adverse event reporting system, which collects adverse drug reactions reported by people worldwide, to evaluate the association between statins and cognitive impairment. Our findings suggest that some statins are associated with cognitive impairment. Therefore, when cognitive changes occur in patients taking statins, they should be taken seriously.

Mechanisms of PANoptosis and relevant small-molecule compounds for fighting diseases.

Pyroptosis, apoptosis, and necroptosis are mainly programmed cell death (PCD) pathways for host defense and homeostasis. PANoptosis is a newly distinct inflammatory PCD pathway that is uniquely regulated by multifaceted PANoptosome complexes and highlights significant crosstalk and coordination among pyroptosis (P), apoptosis (A), and/or necroptosis(N). Although some studies have focused on the possible role of PANpoptosis in diseases, the pathogenesis of PANoptosis is complex and underestimated. Furthermore, the progress of PANoptosis and related agonists or inhibitors in disorders has not yet been thoroughly discussed. In this perspective, we provide perspectives on PANoptosome and PANoptosis in the context of diverse pathological conditions and human diseases. The treatment targeting on PANoptosis is also summarized. In conclusion, PANoptosis is involved in plenty of disorders including but not limited to microbial infections, cancers, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), ischemia-reperfusion, and organic failure. PANoptosis seems to be a double-edged sword in diverse conditions, as PANoptosis induces a negative impact on treatment and prognosis in disorders like COVID-19 and ALI/ARDS, while PANoptosis provides host protection from HSV1 or Francisella novicida infection, and kills cancer cells and suppresses tumor growth in colorectal cancer, adrenocortical carcinoma, and other cancers. Compounds and endogenous molecules focused on PANoptosis are promising therapeutic strategies, which can act on PANoptosomes-associated members to regulate PANoptosis. More researches on PANoptosis are needed to better understand the pathology of human conditions and develop better treatment.

Analysis of the association between Janus kinase inhibitors and malignant skin tumors using the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Malignant skin tumors are adverse events of concern regarding Janus kinase (JAK) inhibitors. AIM: This study aimed to evaluate the association between JAK inhibitors and adverse events of malignant skin tumors, and to characterize the main features. METHOD: Data (2012-2021) were collected using the US Food and Drug Administration Adverse Event Reporting System (FAERS). Adverse event cases of JAK inhibitors as the primary suspected drug were extracted for further analysis. Disproportionality analysis evaluated the association between JAK inhibitors and malignant skin tumor events by estimating the reporting odds ratio (ROR) and the information component (IC) with 95% confidence intervals (95% CI). RESULTS: A total of 142,673 cases with JAK inhibitors as a primary suspected drug were collected, including 1400 malignant skin tumor events. Ruxolitinib, upadacitinib, tofacitinib, and baricitinib were included in the disproportionality analysis. Three JAK inhibitors were associated with malignant skin tumor events, namely ruxolitinib (ROR 5.40, 95% CI 5.03-5.81; IC 2.39, 95% CI 2.14-2.62), upadacitinib (ROR 4.79, 95% CI 4.03-5.71; IC 2.24, 95% CI 1.62-2.77), and tofacitinib (ROR 1.67, 95% CI 1.53-1.83; IC 0.73, 95% CI 0.43-1.02). The median time to onset time was 378.5 days. CONCLUSION: We found association between malignant skin tumors and ruxolitinib, upadacitinib, and tofacitinib. More attention should be paid to these events when prescribing JAK inhibitors in clinical practice.

Risk of diabetic ketoacidosis of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). However, the risk of diabetic ketoacidosis (DKA) in patients remains unclear. The purpose of this study is to conduct this systematic review and network meta-analysis for the risk of DKA of SGLT2 inhibitors in patients with T2DM. Methods: We searched for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T2DM in PubMed, EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov from inception to January 2022. The primary outcomes were the risk of DKA. We assessed the sparse network with a fixed-effect model and consistency model in a frequentist framework with a graph-theoretical method by the netmeta package in R. We assessed the evidence quality of evidence of outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: In total, 36 studies involving 52,264 patients were included. The network showed that there was no significant difference observed among SGLT2 inhibitors, other active antidiabetic drugs, and placebo in the risk of DKA. There was no significant difference in the DKA risk between different doses of SGLT2 inhibitors. The certainty of the evidence ranged from very low to moderate. The probabilities of rankings and P-score showed that compared to placebo, SGLT2 inhibitors might increase the risk of DKA (P-score = 0.5298). Canagliflozin might have a higher DKA risk than other SGLT2 inhibitors (P-score = 0.7388). Conclusion: Neither SGLT2 inhibitors nor other active antidiabetic drugs were associated with an increased risk of DKA compared to placebo, and the risk of DKA with SGLT2 inhibitors was not found to be dose-dependent. In addition, the use of canagliflozin was less advisable than other SGLT2 inhibitors according to the rankings and P-score. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier PROSPERO, CRD42021297081.

Biomimetic Cell-Derived Nanoparticles: Emerging Platforms for Cancer Immunotherapy.

Cancer immunotherapy can significantly prevent tumor growth and metastasis by activating the autoimmune system without destroying normal cells. Although cancer immunotherapy has made some achievements in clinical cancer treatment, it is still restricted by systemic immunotoxicity, immune cell dysfunction, cancer heterogeneity, and the immunosuppressive tumor microenvironment (ITME). Biomimetic cell-derived nanoparticles are attracting considerable interest due to their better biocompatibility and lower immunogenicity. Moreover, biomimetic cell-derived nanoparticles can achieve different preferred biological effects due to their inherent abundant source cell-relevant functions. This review summarizes the latest developments in biomimetic cell-derived nanoparticles for cancer immunotherapy, discusses the applications of each biomimetic system in cancer immunotherapy, and analyzes the challenges for clinical transformation.

Cost-effectiveness analysis of trastuzumab deruxtecan in patients with HER2-low advanced breast cancer based on DESTINY-Breast04.

Background and purpose: Breast cancer is a rapidly raising healthcare problem worldwide. DESTINY-Breast04 demonstrated that trastuzumab deruxtecan (T-Dxd) had a survival advantage comparing to the physician's choice of chemotherapy for patients with HER2-low metastatic breast cancer. But at the same time, this expensive novel treatment also brought an economic burden. This study assessed the cost-effectiveness of T-Dxd based on results of DESTINY-Breast04 from the perspective of Chinese healthcare system. Materials and methods: A three-state partitioned-survival model [progression-free survival (PFS), progressive disease (PD) and death] based on data from DESTINY-Breast04 and Chinese healthcare system was used to estimate the incremental cost-effectiveness ratio (ICER) of T-Dxd vs. the physician's choice of chemotherapy for HER2-low metastatic breast cancer. Costs, quality-adjusted life-years (QALYs) and the ICER in terms of 2022 US$ per QALY gained were calculated for both hormone receptor-positive cohort and all patients. One-way and probabilistic sensitivity analyses were performed to assess the model robustness. Results: Compared with the physician's choice of chemotherapy, T-Dxd increased costs by $104,168.30, while gaining 0.31 QALYs, resulting in an ICER of $336,026.77 per QALY in all patients. The costs of T-Dxd and the utility of PFS were the crucial factors in determining the ICER. In the hormone receptor-positive cohort, the ICER was lower than that in all patients, with the ICER of $274,905.72 per QALY. The ICER was much higher than the commonly accepted willingness-to-pay threshold ($357,96.83 per QALY). Conclusion: T-Dxd as second- or subsequent-line treatment is not a cost-effective treatment option for HER2-low metastatic breast cancer from the perspective of the Chinese healthcare system.

Long-term sciatic nerve block led by a supramolecular arrangement of self-delivery local anesthetic nano systems.

Classical local anesthetics are unsuitable to treat regional pain lasting several days due to their limited duration and systemic toxicity. Self-delivery nano systems without excipients were designed for long-term sensory blocks. 1a self-assembled into different vehicles with different fractions of intermolecular π-π stacking, transported itself into nerve cells, and released single molecules slowly to achieve long-term duration for rats' sciatic nerve block for 11.6 h in water, 12.1 h in water with CO2 and 3.4 h in NS (normal saline). After the counter ions were changed to SO42-, 1e can self-assemble into vesicles and prolong the duration to 43.2 h, which was much longer than the 3.8 h led by (s)-bupivacaine hydrocloride (0.75%). This was mainly caused by the enhancement of self-release and counter ion exchange inside nerve cells, which were affected by the gemini surfactant structure, pKa of the counter ions and π-π stacking interactions.

Efficacy and safety of inclisiran in stroke or cerebrovascular disease prevention: a systematic review and meta-analysis of randomized controlled trials.

Aims: As the impact of inclisiran in stroke prevention in atherosclerotic cardiovascular disease (ASCVD) patients or those at high risk of ASCVD is still unclear, we conducted a systematic review and meta-analysis of randomized controlled trials (RCT) to quantify the effectiveness of inclisiran in stroke prevention in these patients. Methods: Literature research was conducted in four electronic databases (PubMed, EMBASE, Web of Science, CENTRAL) and two clinical trials registers (ClinicalTrials.gov, WHO ICTRP) from the inception of the study to 17 October 2022, and was updated by the end of the study on 5 January 2023. Two authors independently screened the studies, extracted the data, and assessed the bias. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB 2). The intervention effect was estimated by calculating risk ratio (RR), weighted mean difference (WMD), and 95% confidence interval (CI) with R 4.0.5. Sensitivity analysis by changing meta-analysis model was also performed to test the robustness of the pooled results. If this was not possible, a descriptive analysis was conducted. Results: Four RCTs (n = 3,713 patients) were rated as high-risk bias. Meta-analysis of three RCTs (ORION-9, ORION-10, and ORION-11) showed that inclisiran reduced myocardial infarction (MI) risk by 32% (RR = 0.68, 95%CI = 0.48-0.96) but did not reduce stroke (RR = 0.92, 95%CI = 0.54-1.58) and major cardiovascular events (MACE) (RR = 0.81, 95%CI = 0.65-1.02) risk. Sensitivity analysis results were stable. Safety was similar to the placebo group but had frequent injection-site reactions (RR = 6.56, 95%CI = 3.83-11.25), which were predominantly mild or moderate. A descriptive analysis of one RCT (ORION-5) was conducted due to different study designs, and suggested that inclisiran might be given semiannually from the beginning. Conclusion: Inclisiran is not beneficial for stroke or MACE prevention in ASCVD or patients at high risk of ASCVD but is associated with the reduction of MI. Given the limited number and quality of the available studies and the lack of a standardized definition for cardiovascular events, further studies are essential for confirming the results.

Targeting glutaminase 1 (GLS1) by small molecules for anticancer therapeutics.

Glutaminase-1 (GLS1) is a critical enzyme involved in several cellular processes, and its overexpression has been linked to the development and progression of cancer. Based on existing research, GLS1 plays a crucial role in the metabolic activities of cancer cells, promoting rapid proliferation, cell survival, and immune evasion. Therefore, targeting GLS1 has been proposed as a promising cancer therapy strategy, with several GLS1 inhibitors currently under development. To date, several GLS1 inhibitors have been identified, which can be broadly classified into two types: active site and allosteric inhibitors. Despite their pre-clinical effectiveness, only a few number of these inhibitors have advanced to initial clinical trials. Hence, the present medical research emphasizes the need for developing small molecule inhibitors of GLS1 possessing significantly high potency and selectivity. In this manuscript, we aim to summarize the regulatory role of GLS1 in physiological and pathophysiological processes. We also provide a comprehensive overview of the development of GLS1 inhibitors, focusing on multiple aspects such as target selectivity, in vitro and in vivo potency and structure-activity relationships.

Recent Advances on Small-Molecule Bromodomain-Containing Histone Acetyltransferase Inhibitors.

In recent years, substantial research has been conducted on molecular mechanisms and inhibitors targeting bromodomains (BRDs) and extra-terminal (BET) family proteins. On this basis, non-BET BRD is gradually becoming a research hot spot. BRDs are abundant in histone acetyltransferase (HAT)-associated activating transcription factors, and BRD-containing HATs have been linked to cancer, inflammation, and viral replication. Therefore, the development of BRD-containing HATs as chemical probes is useful for understanding the specific biological roles of BRDs in diseases and drug discovery. Several types of BRD-containing HATs, including CBP/P300, PCAF/GCN5, and TAF1, are discussed in this context in terms of their structures, functions, and small-molecule inhibitors. Additionally, progress in BRD inhibitors/chemical probes and proteolysis targeting chimeras in terms of drug design, biological activity, and disease application are summarized. These findings provide insights into the development of BRD inhibitors as potential drug candidates for various diseases.

Behaviors of self-delivery lidocaine nano systems affected by intermolecular interaction.

Lidocaine salts self-assembled into different nano systems in water at a clinical dosage (2%, 0.2 mL) without excipient addition, and led to different sensory block durations and acute systemic toxicities, which were affected by the self-delivery and self-release behaviors of the salts in vivo. These differences were mainly caused by intermolecular π-π stacking under different conditions, which was proved by the unique supramolecular arrangement of gourd-shaped Janus particles. π-π stacking in lidocaine nano systems can be enhanced by carbon dioxide addition or the exchange of counter ions from Br- to Cl-. Without π-π stacking, nano systems self-assembled by lidocaine hydrobromide achieved 7.8 h sensory block by intradermal administration on rats, which is much longer than the efficacy of classical local anesthetics and more suitable for postoperative treatment.

Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System.

AIMS: To investigate interstitial lung disease (ILD) in men with prostate cancer receiving hormone therapy. METHODS: We gathered cases diagnosed with prostate cancer based on the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database from 2004 to 2020. We divided the included cases into 3 groups based on the primary suspected drugs: a hormone therapy group, a positive control group (taxanes), and a negative control group. We employed reporting odds ratio, a disproportionality method, to detect the association between ILD events and target drugs. RESULTS: We finally included a total of 85 403 cases, 69 894 cases (628 ILD event cases) in the hormone therapy group, 2302 cases (158 ILD event cases) in the positive control group and 13 207 cases (72 ILD event cases) in the negative control group. There were 394 ILD event cases (62.74%) in the hormone therapy group in Japan; 78.68% of the ILD events occurred within the first year after hormone treatment. Disproportionality analysis indicated that ILD events were significantly associated with nilutamide, flutamide, bicalutamide, goserelin, degarelix and apalutamide; the reporting odds ratios (95% confidence interval) were 32.14 (11.03-93.63), 9.93 (3.62-27.21), 8.19 (6.01-11.16), 3.74 (2.61-5.37), 2.41 (1.55-3.75) and 1.94 (1.01-3.75), respectively. CONCLUSION: Based on this FAERS pharmacovigilance analysis, the association between ILD events and hormone therapy drugs, including bicalutamide, flutamide, nilutamide, goserelin, degarelix and apalutamide, should not be ignored, especially in the Japanese population. Lung function of prostate cancer patients should be monitored when receiving the hormone therapy drugs mentioned above, especially for the first year post medication.

Impact of the expert consensus on polypharmacy and potentially inappropriate medication use in elderly lung cancer outpatients with multimorbidity: An interrupted time series analysis, 2016-2021.

Objectives: Elderly lung cancer patients often have chronic diseases other than lung cancer. Therefore, this kind of population is often accompanied by polypharmacy. This situation and the resulting potentially inappropriate medication (PIM) use are an increasing global concern. In this context, the Chinese Association of Geriatric Research issued an expert consensus on the safety management of polypharmacy. However, the long- and short-term effects of the expert consensus on polypharmacy and PIM use are not clear. Methods: The study was conducted in Chengdu, a city in southwestern China, consisting of prescriptions for elderly lung cancer outpatients with multimorbidity (cancer with other diseases) from January 2016 to December 2021. The 2019 Beers criteria were used to evaluate PIM use, and interrupted time series analysis was used to evaluate the longitudinal effectiveness of expert consensus by measuring the prevalence of polypharmacy and PIM use. We used R software version 4.2.0 for data analysis. Results: A total of 7,238 elderly lung cancer outpatient prescriptions were included in the study. After the publication of the expert consensus, the level (ß = -10.273, P < 0.001) of the prevalence of polypharmacy decreased, but the trend (ß = 0.158, p = 0.855) of polypharmacy increased. The prevalence of PIM use decreased abruptly (ß = -22.828, p < 0.001) after the intervention, but the long-term trend was still upward (ß = 0.907, p = 0.916). Conclusion: The long-term effects of the publication of the expert consensus on the prevalence of polypharmacy and PIM use in hospitals in Chengdu were not optimal. Future research on interventions rationing polypharmacy and PIM use is needed.

Cardiovascular safety of febuxostat and allopurinol in patients with gout: A meta-analysis.

Background: Gout is a common disease and is usually treated with uric acid-lowering drugs (the most commonly used of which are febuxostat and allopurinol). However, the cardiovascular safety of febuxostat and allopurinol is still controversial. The purpose of our study is to evaluate the cardiovascular safety of the two drugs in patients with gout using one-stage and two-stage meta-analysis. Methods: PubMed, Embase, CBM, CNKI, WanFang, Central, and VIP were searched from inception to 30 January 2022. Randomized controlled trials which evaluated the cardiovascular safety of febuxostat or allopurinol for treating patients with gout were included. Based on the Kaplan-Meier curves of the two studies, individual patient data (IPD) were extracted and reconstructed. We used time-varying risk ratios (RRs) to summarize time-to-event outcomes, and the RRs of MACE incidence, cardiovascular mortality, and all-cause mortality were calculated by a multi-level flexible hazard regression model in 1-stage meta-analyses. p values were calculated using a log-rank test. At the same time, using the reconstructed IPD, we performed 2-stage meta-analyses to inform the quantitative estimates of time-specific relative risks at the six time points (1 , 2, 3, 4, 5, and 6 years) based on a random-effects model. Results: Two RCTs with 12,318 participants were included. In the incidence of major adverse cardiovascular events between the two regimens, there was no significant difference [RR = 0.99 (95% CI, 0.89-1.11), p = 0.87]; at the same time, there was no significant difference in cardiovascular mortality [RR = 1.17 (95% CI, 0.98-1.40),p = 0.08] or all-cause mortality [RR = 1.03 (95% CI, 0.91-1.17),p = 0.62]. In terms of 2-stage meta-analyses, there was no significant difference in any outcomes at any time point (moderate-to low-certainty evidence). Conclusion: In patients without atherosclerotic disease, febuxostat likely has a similar cardiovascular profile to allopurinol. However, in patients with a history of cardiovascular disease, allopurinol treatment is associated with less cardiovascular mortality as compared with febuxostat. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/#loginpage, identifier PROSPERO, CRD42022325656.

Nanomedicines for Overcoming Cancer Drug Resistance.

Clinically, cancer drug resistance to chemotherapy, targeted therapy or immunotherapy remains the main impediment towards curative cancer therapy, which leads directly to treatment failure along with extended hospital stays, increased medical costs and high mortality. Therefore, increasing attention has been paid to nanotechnology-based delivery systems for overcoming drug resistance in cancer. In this respect, novel tumor-targeting nanomedicines offer fairly effective therapeutic strategies for surmounting the various limitations of chemotherapy, targeted therapy and immunotherapy, enabling more precise cancer treatment, more convenient monitoring of treatment agents, as well as surmounting cancer drug resistance, including multidrug resistance (MDR). Nanotechnology-based delivery systems, including liposomes, polymer micelles, nanoparticles (NPs), and DNA nanostructures, enable a large number of properly designed therapeutic nanomedicines. In this paper, we review the different mechanisms of cancer drug resistance to chemotherapy, targeted therapy and immunotherapy, and discuss the latest developments in nanomedicines for overcoming cancer drug resistance.

Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy.

Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor protein tyrosine kinases that play an important role in the regulation of tumor-induced angiogenesis. Currently, VEGFR inhibitors have been widely used in the treatment of various tumors. However, current VEGFR inhibitors are limited to a certain extent due to limited clinical efficacy and potential toxicity, which hinder their clinical application. Thus, the development of new strategies to improve the clinical outcomes and minimize the toxic effects of VEGFR inhibitors is required. Given the synergistic effect of VEGFR and other therapies in tumor development and progression, VEGFR dual-target inhibitors are becoming an attractive approach due to their favorable pharmacodynamics, low toxicity, and anti-resistant effects. This perspective provides an overview of the development of VEGFR dual-target inhibitors from multiple aspects, including rational target combinations, drug discovery strategies, structure-activity relationships and future directions.

An observational, retrospective, comprehensive pharmacovigilance analysis of hydroxychloroquine-associated cardiovascular adverse events in patients with and without COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic. Hydroxychloroquine (HCQ)-associated cardiovascular adverse events (CVAEs) have been increasingly reported. AIM: This study aimed to present an observational, retrospective, and comprehensive pharmacovigilance analysis of CVAE associated with HCQ in patients with and without COVID-19 using the US Food and Drug Administration Adverse Events Reporting System (FAERS) data from January 2020 to December 2020. METHOD: We identified 3302 adverse event reports from the FAERS database in the year 2020 and divided them into COVID-19 and non-COVID-19 groups, respectively. Then we analyzed whether there were differences in CVAEs between the two groups. RESULTS: We found that CVAE was higher in cases with COVID-19 compared to those without COVID-19, odds ratio (OR) of 1.26 and a 95% confidence interval (95% CI) of 1.02-1.54. Cases with COVID-19 treated with HCQ exhibited relatively higher proportions of torsade de points (TdP) and QT prolongation (OR 3.10, 95% CI 2.24-4.30), shock-associated TdP (OR 2.93, 95% CI 2.13-4.04), cardiac arrhythmias (OR 2.07, 95% CI 1.60-2.69), cardiac arrhythmia terms (including bradyarrhythmias and tachyarrhythmias) (OR 2.15, 95% CI 1.65-2.80), bradyarrhythmias (including conduction defects and disorders of sinus node function) (OR 2.56, 95% CI 1.86-3.54), and conduction defects (OR 2.56, 95% CI 1.86-3.54). CONCLUSION: Our retrospective observational analysis suggested that the proportion of CVAE associated with HCQ, especially TdP and QT prolongation, was higher in patients with COVID-19. Understanding the effects of COVID-19 on the cardiovascular system is essential to providing comprehensive medical care to patients receiving HCQ treatment.

Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS.

Acute kidney injury (AKI) is a common complication among patients with the novel coronavirus (COVID-19). COVID-19 along with AKI usually resulted in a poor prognosis for those affected. Remdesivir is a novel antiviral drug that was urgently approved for the treatment of COVID-19. In the current study, safety data of remdesivir were limited. We gathered information on COVID-19 cases in patients with adverse events that were reported to the U.S. Food and Drug Administration (US FDA) Adverse Event Reporting System (FAERS) database. We employed the reporting odds ratio (ROR) method to perform disproportionality analysis. Finally, we identified 12,869 COVID-19 cases. A total of 3,991 of these cases reported remdesivir as a primary suspected drug, while 8,878 cases were treated with other drugs. More AKI events occurred in cases of male patients and those above the age of 65 years. We detected a significant association between remdesivir and AKI: ROR = 2.81, 95% CI (2.48, 3.18). The association was stronger after the propensity score matching ROR = 3.85, 95% CI (3.11, 4.78). The mean time to AKI event onset was 4.91 ± 7.25 days in COVID-19 cases with remdesivir therapy. The fatality proportion was 36.45% in AKI cases with remdesivir treatment. This pharmacovigilance study identified a significant association between AKI events and remdesivir treatment in COVID-19 patients by mining FAERS real-world big data. Although causality was not confirmed, the association between remdesivir and AKI should not be ignored, especially in the older, male COVID-19 inpatients.

ProNGF/NGF Modulates Autophagy and Apoptosis through PI3K/Akt/mTOR and ERK Signaling Pathways following Cerebral Ischemia-Reperfusion in Rats.

NGF is involved in the process of autophagy; however, the underlying mechanisms of proNGF/NGF on autophagy in cerebral ischemia-reperfusion (CIR) remain unclear. This study explored the potential pathway of proNGF/NGF in mediating autophagy and apoptosis and thereby contributed to poststroke neurological rehabilitation. In this study, PC12 cell lines and male SD rats were used to simulate CIR; it was found that within 24 h reperfusion, proNGF was the predominant form of Ngf while after 24 h NGF was produced by proNGF transformation. The mature NGF was found to protect neurons against autophagic and apoptotic damage caused by CIR, but proNGF can cause both autophagic and apoptotic neuronal damage. The protective effect of NGF is associated with the activation of the PI3K/Akt/mTOR and ERK pathway and, as well as the change of autophagy-related proteins. On the other hand, proNGF promoted the ERK pathway increasing autophagy and affected the apoptosis-related proteins in vivo and in vitro. These results were also verified in male SD rats with CIR that neurological deficit caused by CIR can be rescued by recombinant and wild-type NGF, and vice-versa by proNGF.