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Biomolecules & Therapeutics Jun 2024Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it need for analgesics during oncology treatment, particularly in the context...
Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it need for analgesics during oncology treatment, particularly in the context ofthe coronavirus disease, where patients are more susceptible to contract high fever and sore throat. This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression. Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.
PubMed: 38871446
DOI: 10.4062/biomolther.2023.209 -
Clinical and Applied... 2024Aspirin is a widely used antiplatelet medication to prevent blood clots, reducing the risk of cardiovascular event. Healthcare providers need to be mindful of the risk...
BACKGROUND
Aspirin is a widely used antiplatelet medication to prevent blood clots, reducing the risk of cardiovascular event. Healthcare providers need to be mindful of the risk of aspirin-induced bleeding and carefully balancing its benefits against potential risks. The objective of this study was to create a practical nomogram for predicting bleeding risk in patients with a history of myocardial infarction treating with aspirin.
METHODS
A total of 2099 myocardial infarction patients with aspirin were enrolled. The patients were randomly divided into two groups, with a 7:3 ratio, for model development and internal validation. Boruta analysis was utilized to identify clinically significant features associated with bleeding. Logistic regression model based on independent bleeding risk factors was constructed and presented as a nomogram. Model performance was assessed from three aspects: identification, calibration, and clinical utility.
RESULTS
Boruta analysis identified eight clinical features from 25, and further multivariate logistic regression analysis selected four independent risk factors: hemoglobin, platelet count, previous bleeding, and sex. A visual nomogram was created based on these variables. The model achieved an area under the curve of 0.888 (95% CI: 0.845-0.931) in the training dataset and 0.888 (95% CI: 0.808-0.968) in the test dataset. Calibration curve analysis showed close approximation to the ideal curve. Decision curve analysis demonstrated favorable clinical net benefit for the model.
CONCLUSIONS
Our study focused on creating and validating a model to evaluate bleeding risk in patients with a history of myocardial infarction treated with aspirin, which demonstrated outstanding performance in discrimination, calibration, and net clinical benefit.
Topics: Humans; Nomograms; Myocardial Infarction; Aspirin; Hemorrhage; Female; Male; Middle Aged; Aged; Risk Factors; Platelet Aggregation Inhibitors; Risk Assessment
PubMed: 38870349
DOI: 10.1177/10760296241262789 -
Scientific Reports Jun 2024Although aspirin can reduce the incidence of colorectal cancer (CRC), there is still uncertainty about its significance as a treatment for CRC, and the mechanism of...
Although aspirin can reduce the incidence of colorectal cancer (CRC), there is still uncertainty about its significance as a treatment for CRC, and the mechanism of aspirin in CRC is not well understood. In this study, we used aspirin to prevent AOM/DSS-induced CRC in mice, and the anti-CRC efficacy of aspirin was assessed using haematoxylin and eosin (H&E) staining and by determining the mouse survival rate and tumour size. 16S rDNA sequencing, flow cytometry (FCM), and Western blotting were also conducted to investigate the changes in the gut microbiota, tumour immune microenvironment, and apoptotic proteins, respectively. The results demonstrated that aspirin significantly exerted anti-CRC effects in mice. According to 16S rDNA sequencing, aspirin regulated the composition of the gut microbiota and dramatically reduced the abundance of Enterococcus cecorum. FCM demonstrated that there were more CD155 tumour cells and CD4 + CD25 + Treg cells showed increased TIGIT levels. Moreover, increased TIGIT expression on Treg cells is associated with reduced Treg cell functionality. Importantly, the inhibition of Treg cells is accompanied by the promotion of CD19 + GL-7 + B cells, CD8 + T cells, CD4 + CCR4 + Th2 cells, and CD4 + CCR6 + Th17 cells. Overall, aspirin prevents colorectal cancer by regulating the abundance of Enterococcus cecorum and TIGIT + Treg cells.
Topics: Aspirin; Animals; Colorectal Neoplasms; T-Lymphocytes, Regulatory; Mice; Receptors, Immunologic; Gastrointestinal Microbiome; Enterococcus; Tumor Microenvironment; Male; Mice, Inbred C57BL
PubMed: 38867002
DOI: 10.1038/s41598-024-64447-0 -
[Nihon Koshu Eisei Zasshi] Japanese... Jun 2024Objectives Although self-reported questionnaires are widely used to collect information on medication use in epidemiological studies, their validity for studies...
Objectives Although self-reported questionnaires are widely used to collect information on medication use in epidemiological studies, their validity for studies involving older adults has not been sufficiently assessed. This study evaluated the validity of self-reported medication use using questionnaires in comparison with drug notebooks.Methods The study enrolled 370 older community dwellers who participated in an aging sub-study survey of the Tsuruoka Metabolomics Cohort Study between April 2019 and March 2021. Medication use was assessed by comparing self-reported questionnaire data with drug notebook records. We analyzed medications used for hypertension, dyslipidemia, myocardial infarction, angina, diabetes, rheumatism, osteoporosis/metabolic bone disease, constipation, anxiety/depression, dementia, asthma, allergy, thrombosis, and thyroid disease. Moreover, gastrointestinal (GI) medications, steroids, and antipyretic analgesics were assessed, and data on injectable medications for osteoporosis/metabolic bone disease was collected. Using drug notebook records, we identified regular medication users by assessing whether they had received oral medication prescriptions covering over 28 days and took the medication within the 90 days preceding the day of their survey. To define medication categories, we used Anatomical Therapeutic Chemical (ATC) classification codes. Sensitivity, specificity, and kappa statistics were calculated for each medication using drug notebooks as standards. Those who did not bring their drug notebooks on the day of the survey were defined as non-medication users.Results The mean age (standard deviation) of the 370 participants (146 men and 224 women) was 73.3 (4.0) years. The sensitivity and specificity for each medication were as follows: hypertension (0.97, 0.97), dyslipidemia (0.93, 0.98), myocardial infarction (0.24, 0.99), diabetes (0.94, 1.00), rheumatism (1.00, 1.00), osteoporosis/metabolic bone disease (0.82, 0.99), constipation (0.71, 0.98), GI conditions (0.63, 0.97), anxiety/depression (0.36, 1.00), dementia (0.67, 1.00), asthma (0.67, 0.98), allergy (0.57, 0.99), thrombosis (0.88, 0.98), steroids (0.80, 0.99), thyroid disease (1.00, 1.00) and antipyretic analgesics (0.75, 0.96).Conclusions Although sensitivity and specificity differed by medication categories, the results of our population-based cohort study suggested that self-reported questionnaires on medication use among older adults are valid, especially for medications with high sensitivity (≥ 0.8).
PubMed: 38866534
DOI: 10.11236/jph.23-110 -
Cureus May 2024We present an atypical case of risedronate-induced chronic fever in an 85-year-old woman with Parkinson's disease, with a dosage regimen of 17.5 mg/week. Our patient had...
We present an atypical case of risedronate-induced chronic fever in an 85-year-old woman with Parkinson's disease, with a dosage regimen of 17.5 mg/week. Our patient had been administered an analgesic/antipyretic drug, acetaminophen, at a rate of 600 mg/day for treatment of a vertebral fracture that occurred relatively frequently, which might have masked the fever caused by risedronate. We noted two clinically significant indications. Firstly, blood test results do not necessarily show the cause of risedronate-induced fever, as white blood cell counts and C-reactive protein levels vary. A simple way to diagnose risedronate-induced fever is to suspend risedronate for a certain period and observe if the patient's fever lowers. Secondly, in general, cases receiving polypharmacy tend to include an analgesic antipyretic agent, which may mask the drug-induced fever. Even in patients with Parkinson's disease whose body temperature is generally unstable due to autonomic nerve system disorder, if they are administered risedronate and experience chronic fever of unknown cause, the possibility of drug fever may be considered. This study concludes that risedronate-induced chronic fever, as observed in our case, represents a rare phenomenon, and it may be necessary to reconsider treatment methods for osteoporosis.
PubMed: 38864058
DOI: 10.7759/cureus.60117 -
Upsala Journal of Medical Sciences 2024Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses...
BACKGROUND
Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated.
METHODS
A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS).
RESULTS
Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations.
CONCLUSION
Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.
Topics: Humans; Hypnotics and Sedatives; Analgesics; Male; Female; Middle Aged; Aged; Intensive Care Units; Prospective Studies; Adult; Midazolam; Critical Care; Dexmedetomidine; Fentanyl; Critical Illness; Propofol; Clonidine; Ketamine; Morphine; Aged, 80 and over; Dose-Response Relationship, Drug; Thiopental; Acetaminophen
PubMed: 38863729
DOI: 10.48101/ujms.v129.10560 -
BMC Infectious Diseases Jun 2024Sepsis is a life-threatening disease accompanied by disorders of the coagulation and immune systems. P2Y12 inhibitors, widely used for arterial thrombosis prevention and...
BACKGROUND
Sepsis is a life-threatening disease accompanied by disorders of the coagulation and immune systems. P2Y12 inhibitors, widely used for arterial thrombosis prevention and treatment, possess recently discovered anti-inflammatory properties, raising potential for improved sepsis prognosis.
METHOD
We conducted a retrospective analysis using the data from Medical Information Mart for Intensive Care-IV database. Patients were divided into an aspirin-alone group versus a combination group based on the use of a P2Y12 inhibitor or not. Differences in 30-day mortality, length of stay (LOS) in intensive care unit (ICU), LOS in hospital, bleeding events and thrombotic events were compared between the two groups.
RESULT
A total of 1701 pairs of matched patients were obtained by propensity score matching. We found that no statistically significant difference in 30-day mortality in aspirin-alone group and combination group (15.3% vs. 13.7%, log-rank p = 0.154). In addition, patients received P2Y12 inhibitors had a higher incidence of gastrointestinal bleeding (0.5% vs. 1.6%, p = 0.004) and ischemic stroke (1.7% vs. 2.9%, p = 0.023), despite having a shorter LOS in hospital (11.1 vs. 10.3, days, p = 0.043). Cox regression showed that P2Y12 inhibitor was not associated with 30-day mortality (HR = 1.14, 95% CI 0.95-1.36, p = 0.154).
CONCLUSION
P2Y12 inhibitors did not provide a survival benefit for patients with sepsis 3 and even led to additional adverse clinical outcomes.
Topics: Humans; Male; Female; Sepsis; Aspirin; Retrospective Studies; Propensity Score; Aged; Middle Aged; Purinergic P2Y Receptor Antagonists; Length of Stay; Intensive Care Units; Treatment Outcome; Aged, 80 and over; Platelet Aggregation Inhibitors
PubMed: 38862910
DOI: 10.1186/s12879-024-09421-x -
BMJ (Clinical Research Ed.) Jun 2024To assess the effect of different antiplatelet strategies on clinical outcomes after coronary artery bypass grafting. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To assess the effect of different antiplatelet strategies on clinical outcomes after coronary artery bypass grafting.
DESIGN
Five year follow-up of randomised Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Grafting (DACAB) trial.
SETTING
Six tertiary hospitals in China; enrolment between July 2014 and November 2015; completion of five year follow-up from August 2019 to June 2021.
PARTICIPANTS
500 patients aged 18-80 years (including 91 (18.2%) women) who had elective coronary artery bypass grafting surgery and completed the DACAB trial.
INTERVENTIONS
Patients were randomised 1:1:1 to ticagrelor 90 mg twice daily plus aspirin 100 mg once daily (dual antiplatelet therapy; n=168), ticagrelor monotherapy 90 mg twice daily (n=166), or aspirin monotherapy 100 mg once daily (n=166) for one year after surgery. After the first year, antiplatelet therapy was prescribed according to standard of care by treating physicians.
MAIN OUTCOME MEASURES
The primary outcome was major adverse cardiovascular events (a composite of all cause death, myocardial infarction, stroke, and coronary revascularisation), analysed using the intention-to-treat principle. Time-to-event analysis was used to compare the risk between treatment groups. Multiple post hoc sensitivity analyses examined the robustness of the findings.
RESULTS
Follow-up at five years for major adverse cardiovascular events was completed for 477 (95.4%) of 500 patients; 148 patients had major adverse cardiovascular events, including 39 in the dual antiplatelet therapy group, 54 in the ticagrelor monotherapy group, and 55 in the aspirin monotherapy group. Risk of major adverse cardiovascular events at five years was significantly lower with dual antiplatelet therapy versus aspirin monotherapy (22.6% 29.9%; hazard ratio 0.65, 95% confidence interval 0.43 to 0.99; P=0.04) and versus ticagrelor monotherapy (22.6% 32.9%; 0.66, 0.44 to 1.00; P=0.05). Results were consistent in all sensitivity analyses.
CONCLUSIONS
Treatment with ticagrelor dual antiplatelet therapy for one year after surgery reduced the risk of major adverse cardiovascular events at five years after coronary artery bypass grafting compared with aspirin monotherapy or ticagrelor monotherapy.
TRIAL REGISTRATION
NCT03987373ClinicalTrials.gov NCT03987373.
Topics: Humans; Coronary Artery Bypass; Platelet Aggregation Inhibitors; Female; Male; Middle Aged; Ticagrelor; Aspirin; Aged; Follow-Up Studies; Adult; Aged, 80 and over; Drug Therapy, Combination; Adolescent; Postoperative Complications; Treatment Outcome; Young Adult; China; Dual Anti-Platelet Therapy
PubMed: 38862179
DOI: 10.1136/bmj-2023-075707 -
Drug Metabolism and Disposition: the... Jun 2024Acetaminophen (APAP) is the most used non-prescription drug throughout the world. At therapeutic doses, APAP has potent analgesic and antipyretic effects. The efficacy...
Acetaminophen (APAP) is the most used non-prescription drug throughout the world. At therapeutic doses, APAP has potent analgesic and antipyretic effects. The efficacy and safety of APAP are influenced by multi-factorial processes that are dependent upon dosing, namely frequency and total dose. APAP poisoning by repeated ingestion of supratherapeutic doses, depletes glutathione (GSH) stores in liver and other organs capable of metabolic bioactivation, leading to hepatocellular death due to exhausted antioxidant defenses. Numerous genes, encompassing transcription factors and signaling pathways, have been identified as playing pivotal roles in APAP toxicity, with the liver being the primary organ studied due to its central role in APAP metabolism and injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) and its array of downstream responsive genes are crucial in counteracting acetaminophen APAP toxicity. Nrf2, along with its negative regulator Kelch-like ECH-associated protein 1 (Keap1), plays a vital role in regulating intracellular redox homeostasis. This regulation is significant in modulating the oxidative stress, inflammation, and hepatocellular death induced by APAP. In this review, we provide an updated overview of the mechanisms through which Nrf2 activation and signaling critically influence the threshold for developing APAP toxicity. We also describe how genetically modified rodent models for Nrf2 and related genes have been pivotal in underscoring the significance of this antioxidant response pathway. While Nrf2 is a primary focus, the article comprehensively explores other genetic factors and related pathways that contribute to APAP toxicity, thereby providing a holistic understanding of the genetic landscape influencing susceptibility to this condition. This review scrutinizes the genetic elements and signaling pathways underlying acetaminophen (APAP)-induced liver toxicity, with a focus on the crucial protective role of the transcription factor NRF2. This review also delves into the genetic intricacies influencing APAP safety and potential liver harm and it emphasizes the need for deeper insight into the molecular mechanisms of hepatotoxicity, especially the interplay of NRF2 with other pathways.
PubMed: 38857948
DOI: 10.1124/dmd.124.001282 -
Theranostics 2024Acetaminophen (APAP) overdosing is a major cause of acute liver failure worldwide and an established model for drug-induced acute liver injury (ALI). While studying gene...
Acetaminophen (APAP) overdosing is a major cause of acute liver failure worldwide and an established model for drug-induced acute liver injury (ALI). While studying gene expression during murine APAP-induced ALI by 3'mRNA sequencing (massive analysis of cDNA ends, MACE), we observed splenic mRNA accumulation encoding for the neutrophil serine proteases cathepsin G, neutrophil elastase, and proteinase-3 - all are hierarchically activated by cathepsin C (CtsC). This, along with increased serum levels of these proteases in diseased mice, concurs with the established phenomenon of myeloid cell mobilization during APAP intoxication. In order to functionally characterize CtsC in murine APAP-induced ALI, effects of its genetic or pharmacological inhibition were investigated. We report on substantially reduced APAP toxicity in CtsC deficient mice. Alleviation of disease was likewise observed by treating mice with the CtsC inhibitor AZD7986, both in short-term prophylactic and therapeutic protocols. This latter observation indicates a mode of action beyond inhibition of granule-associated serine proteases. Protection in CtsC knockout or AZD7986-treated wildtype mice was unrelated to APAP metabolization but, as revealed by MACE, realtime PCR, or ELISA, associated with impaired expression of inflammatory genes with proven pathogenic roles in ALI. Genes consistently downregulated in protocols tested herein included , , and . Moreover, , a positive regulator of the toll-like receptor/interferon-axis, was reduced by targeting CtsC. This work suggests CtsC as promising therapeutic target for the treatment of ALI, among others paradigmatic APAP-induced ALI. Being also currently evaluated in phase III clinical trials for bronchiectasis, successful application of AZD7986 in experimental APAP intoxication emphasizes the translational potential of this latter therapeutic approach.
Topics: Animals; Acetaminophen; Cathepsin C; Mice; Chemical and Drug Induced Liver Injury; Mice, Inbred C57BL; Mice, Knockout; Male; Disease Models, Animal
PubMed: 38855187
DOI: 10.7150/thno.96092