Biomed Hub. 2024 May 22;9(1):83-88. doi: 10.1159/000539074. eCollection 2024 Jan-Dec.

ABSTRACT

INTRODUCTION: Older adults with dementia who are on multiple medications are more vulnerable to the use of potentially inappropriate medications (PIMs), which can significantly increase the risk of adverse events and drug-related problems. PIMs use is prevalent and varies among older adults with dementia or cognitive impairment (CI) attending memory clinics. However, the prevalence of PIMs, polypharmacy, and hyper-polypharmacy among older adults with dementia or CI who are attending memory clinics is not well understood. We will conduct a systematic review and meta-analyses to examine the overall estimate of the prevalence of the PIMs, polypharmacy, and hyper-polypharmacy use among older adults attending memory clinics, with dementia or CI. The secondary objective of this study will be to compile a list of commonly implicated PIMs and to investigate factors that may be associated with using PIMs in this population.

METHODS: Ovid MEDLINE, Ovid Embase, Scopus, Cochrane library, EBSCOhost CINAHL, and Ovid International Pharmaceutical Abstracts (IPA) will be systematically searched by a researcher (R.S.) with the help of a librarian (C.C.). All databases will be searched from inception to May 05, 2023. Cross-sectional, cohort, randomized clinical trials, quasi-experimental, and case-control studies will be included if they assess PIM's use among older adults with dementia and/or CI. A step-by-step guide by Pai et al. [Natl Med J India. 2004;17(2):86-95] will be followed when conducting this systematic review (S.R.). The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist will be followed for reporting this SR.

CONCLUSION: The findings from this SR/MA will identify the pooled prevalence of PIMs, providing a more precise estimate of the true prevalence of the PIMs, polypharmacy, hyper-polypharmacy in older adults with dementia or CI who are attending memory clinics at primary, secondary, or tertiary healthcare settings by considering the results of multiple studies.

PMID:39015200 | PMC:PMC11249799 | DOI:10.1159/000539074

PLoS One. 2024 Jul 16;19(7):e0305766. doi: 10.1371/journal.pone.0305766. eCollection 2024.

ABSTRACT

Invasive fungal infections (IFIs) are growing in importance in veterinary and human medicine. IFIs such as aspergillosis, blastomycosis, coccidioidomycosis and histoplasmosis remain challenging to treat in dogs. Isavuconazole is a novel antifungal medication that, when compared to currently used azoles, has an expanded spectrum of antifungal activity Rudramurthy (2011), Pfaller (2013), Spec (2018), has more predictable pharmacokinetics in humans Desai (2016), Cojutti (2021) and may cause fewer side effects such as liver and renal toxicity Maertens (2016), DiPippo (2018). The pharmacokinetic profile and safety of isavuconazole in dogs has not yet been characterized. The purpose of this study was to evaluate the pharmacokinetics of isavuconazole in healthy dogs that received a single dose of the prodrug isavuconazonium sulfate. Using full crossover design, six healthy beagle dogs received isavuconazonium sulfate at a mean (+/- SD) dose of 20.6 (+/- 2.8) mg/kg orally and 21.8 (+/- 4.2) mg/kg intravenously. Plasma was collected for batched pharmacokinetic analysis of prodrug and metabolite, isavuconazole, by ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The median (Q1-Q3) maximum isavuconazole peak plasma concentration was estimated at 3,876.5 (2,811.0-4,800.0) ng/mL following oral administration, with a median (Q1-Q3) peak level at 1.3 (1.0-2.0) hours. Following intravenous administration, the median (Q1-Q3) isavuconazole peak plasma concentration was estimated at 3,221.5 (2,241.5-3,609.0) ng/mL, with a median (Q1-Q3) peak level at 0.4 (0.3-0.6) hours. The median (Q1-Q3) half-life of isavuconazole was 9.4 (7.0-12.2) hours and 14.0 (8.1-21.7) hours for oral and intravenous routes, respectively. One dog received inadvertent subcutaneous drug administration without any apparent adverse effects. Another dog experienced an anaphylactic reaction following accidental rapid drug infusion. No other drug-related adverse events were observed. At dosages used in this study, healthy dogs achieved isavuconazole plasma levels comparable to human therapeutic targets, and when properly administered the drug was well-tolerated.

PMID:39012876 | DOI:10.1371/journal.pone.0305766

Future Oncol. 2024 Jul 16:1-11. doi: 10.1080/14796694.2024.2355724. Online ahead of print.

ABSTRACT

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the publication about the DESTINY-Lung01 study, which was published in the New England Journal of Medicine in September 2021. The DESTINY-Lung01 study includes 181 adults with metastatic non-small-cell lung cancer (NSCLC) that could not be treated with surgery and who have had previous standard anticancer treatment. The publication includes information and results about 91 of the 181 study participants. These 91 participants had HER2-mutant NSCLC. Researchers wanted to learn if the drug trastuzumab deruxtecan (T-DXd) could help treat participants with HER2-mutant NSCLC. At the time of this publication, this study is ongoing.

WHAT ARE THE KEY TAKEAWAYS?: Results from the study showed that 55% of participants responded to treatment with T-DXd. The median length of time participants continued to respond to T-DXd was 9.3 months.After receiving T-DXd, 92% of participants had disease control. After receiving T-DXd, half of the participants lived for at least 17.8 months. After receiving T-DXd, half of the participants lived for 8.2 months before their cancer got worse.During the study, 97% of participants had drug-related adverse events, with nausea being the most common. There were 20% of participants with serious drug-related adverse events.

WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Based on these results, T-DXd could be a treatment option for people with HER2-mutant NSCLC that has been previously treated.Clinical Trial Registration: NCT03505710 (DESTINY-Lung01) (ClinicalTrials.gov).

PMID:39012221 | DOI:10.1080/14796694.2024.2355724

Future Microbiol. 2024 Jul 16:1-5. doi: 10.1080/17460913.2024.2362128. Online ahead of print.

ABSTRACT

Conventional itraconazole (c-ITZ) can be used for a variety of fungal infections although variable absorption has been a significant limitation. Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation that overcomes absorption concerns by utilizing a polymer-matrix to disperse active drug and facilitate dissolution. The pH-driven matrix allows concurrent proton pump inhibitor administration without significant effects on drug concentrations. The enhanced bioavailability of SUBA-ITZ allows for lower dosing, while achieving similar serum concentrations as c-ITZ and SUBA-ITZ is now US FDA approved in the treatment of blastomycosis, histoplasmosis and aspergillosis. Common side effects of SUBA-ITZ include gastrointestinal disorders, peripheral edema and drug-induced hypertension. Given the significant differences in pharmacokinetics between the formulations, c-ITZ and SUBA-ITZ capsules are not considered interchangeable. It is important to note that drug errors may occur when transitioning a patient from one formulation to another.

PMID:39011995 | DOI:10.1080/17460913.2024.2362128

Indian J Hematol Blood Transfus. 2024 Jul;40(3):517-521. doi: 10.1007/s12288-023-01726-2. Epub 2024 Feb 24.

ABSTRACT

Increased bleeding tendency is a common and challenging complication of warfarin therapy which results in extensive pharmacogenomic studies in order to develop a personalized dosing approach and minimize the risk of related side effects. Here we aimed to explore the potential role of NQO1 gene expression in warfarin response in a group of Iranian patients. We also evaluated the NQO1 promoter methylation and its association with mRNA expression. A total of 87 patients on warfarin therapy including 34 cases with drug-induced bleeding events and 53 matched controls without bleedings were included in the study. The expression of NQO1 was examined by real-time q-PCR and the methylation status of its promoter region was analyzed using methyQESD technique. There was a significant association between the reduced NQO1 gene expression and susceptibility to bleeding before (OR = 1.92, 95% CI = 1.23-3.00, p = 0.004) and following adjustment for hypertriglyceridemia (OR = 2.22, 95% CI = 1.33-3.69, p = 0.002). Furthermore, a medium negative correlation was observed between NQO1 expression and its promoter methylation (r = - 0.382, p = 0.001). The lower expression of NQO1 which partly arises from increased methylation of promoter region, may predispose warfarin treated patients to bleeding events.

PMID:39011266 | PMC:PMC11246350 | DOI:10.1007/s12288-023-01726-2

Acute Med Surg. 2024 Jul 15;11(1):e981. doi: 10.1002/ams2.981. eCollection 2024 Jan-Dec.

ABSTRACT

BACKGROUND: Severe metformin intoxication can lead to lactic acidosis and vasoplegic shock, for which the optimal management strategy remains uncertain, especially in cases of severe circulatory collapse.

CASE PRESENTATION: A 45-year-old diabetic woman on metformin therapy presented with impaired consciousness and seizures. She had experienced a cardiac arrest and undergone extracorporeal cardiopulmonary resuscitation. Blood gas analysis showed severe lactic acidosis. A 71-g metformin packet was found at the patient's home, suggesting an overdose. Despite extracorporeal support and blood purification, severe lactic acidosis and hypotension persisted. Methylene blue was administered 32 h from the onset, which improved her metabolic and circulatory status. We examined her blood sample throughout the case to check the transition of metformin blood concentration.

CONCLUSION: Methylene blue may be beneficial for severe metformin toxicity, regardless of the blood concentration of metformin and the time since intoxication. However, further research is needed to establish its optimal use and effectiveness.

PMID:39010890 | PMC:PMC11247704 | DOI:10.1002/ams2.981

BMC Med Imaging. 2024 Jul 15;24(1):174. doi: 10.1186/s12880-024-01349-7.

ABSTRACT

Polypharmacy involves an individual using many medications at the same time and is a frequent healthcare technique used to treat complex medical disorders. Nevertheless, it also presents substantial risks of negative medication responses and interactions. Identifying and addressing adverse effects caused by polypharmacy is crucial to ensure patient safety and improve healthcare results. This paper introduces a new method using Graph Convolutional Networks (GCN) to identify polypharmacy side effects. Our strategy involves developing a medicine interaction graph in which edges signify drug-drug intuitive predicated on pharmacological properties and hubs symbolize drugs. GCN is a well-suited profound learning procedure for graph-based representations of social information. It can be used to anticipate the probability of medicate unfavorable impacts and to memorize important representations of sedate intuitive. Tests were conducted on a huge dataset of patients' pharmaceutical records commented on with watched medicate unfavorable impacts in arrange to approve our strategy. Execution of the GCN show, which was prepared on a subset of this dataset, was evaluated through a disarray framework. The perplexity network shows the precision with which the show categories occasions. Our discoveries demonstrate empowering advance within the recognizable proof of antagonistic responses related with polypharmaceuticals. For cardiovascular system target drugs, GCN technique achieved an accuracy of 94.12%, precision of 86.56%, F1-Score of 88.56%, AUC of 89.74% and recall of 87.92%. For respiratory system target drugs, GCN technique achieved an accuracy of 93.38%, precision of 85.64%, F1-Score of 89.79%, AUC of 91.85% and recall of 86.35%. And for nervous system target drugs, GCN technique achieved an accuracy of 95.27%, precision of 88.36%, F1-Score of 86.49%, AUC of 88.83% and recall of 84.73%. This research provides a significant contribution to pharmacovigilance by proposing a data-driven method to detect and reduce polypharmacy side effects, thereby increasing patient safety and healthcare decision-making.

PMID:39009978 | DOI:10.1186/s12880-024-01349-7

JMIR Public Health Surveill. 2024 Jul 15;10:e51007. doi: 10.2196/51007.

ABSTRACT

BACKGROUND: The COVID-19 pandemic, caused by SARS-CoV-2, has had a profound impact worldwide, leading to widespread morbidity and mortality. Vaccination against COVID-19 is a critical tool in controlling the spread of the virus and reducing the severity of the disease. However, the rapid development and deployment of COVID-19 vaccines have raised concerns about potential adverse events following immunization (AEFIs). Understanding the temporal and spatial patterns of these AEFIs is crucial for an effective public health response and vaccine safety monitoring.

OBJECTIVE: This study aimed to analyze the temporal and spatial characteristics of AEFIs associated with COVID-19 vaccines in the United States reported to the Vaccine Adverse Event Reporting System (VAERS), thereby providing insights into the patterns and distributions of the AEFIs, the safety profile of COVID-19 vaccines, and potential risk factors associated with the AEFIs.

METHODS: We conducted a retrospective analysis of administration data from the Centers for Disease Control and Prevention (n=663,822,575) and reports from the surveillance system VAERS (n=900,522) between 2020 and 2022. To gain a broader understanding of postvaccination AEFIs reported, we categorized them into system organ classes (SOCs) according to the Medical Dictionary for Regulatory Activities. Additionally, we performed temporal analysis to examine the trends of AEFIs in all VAERS reports, those related to Pfizer-BioNTech and Moderna, and the top 10 AEFI trends in serious reports. We also compared the similarity of symptoms across various regions within the United States.

RESULTS: Our findings revealed that the most frequently reported symptoms following COVID-19 vaccination were headache (n=141,186, 15.68%), pyrexia (n=122,120, 13.56%), and fatigue (n=121,910, 13.54%). The most common symptom combination was chills and pyrexia (n=56,954, 6.32%). Initially, general disorders and administration site conditions (SOC 22) were the most prevalent class reported. Moderna exhibited a higher reporting rate of AEFIs compared to Pfizer-BioNTech. Over time, we observed a decreasing reporting rate of AEFIs associated with COVID-19 vaccines. In addition, the overall rates of AEFIs between the Pfizer-BioNTech and Moderna vaccines were comparable. In terms of spatial analysis, the middle and north regions of the United States displayed a higher reporting rate of AEFIs associated with COVID-19 vaccines, while the southeast and south-central regions showed notable similarity in symptoms reported.

CONCLUSIONS: This study provides valuable insights into the temporal and spatial patterns of AEFIs associated with COVID-19 vaccines in the United States. The findings underscore the critical need for increasing vaccination coverage, as well as ongoing surveillance and monitoring of AEFIs. Implementing targeted monitoring programs can facilitate the effective and efficient management of AEFIs, enhancing public confidence in future COVID-19 vaccine campaigns.

PMID:39008362 | DOI:10.2196/51007

JMIR Public Health Surveill. 2024 Jul 15;10:e49811. doi: 10.2196/49811.

ABSTRACT

BACKGROUND: Adverse events associated with vaccination have been evaluated by epidemiological studies and more recently have gained additional attention with the emergency use authorization of several COVID-19 vaccines. As part of its responsibility to conduct postmarket surveillance, the US Food and Drug Administration continues to monitor several adverse events of special interest (AESIs) to ensure vaccine safety, including for COVID-19.

OBJECTIVE: This study is part of the Biologics Effectiveness and Safety Initiative, which aims to improve the Food and Drug Administration's postmarket surveillance capabilities while minimizing public burden. This study aimed to enhance active surveillance efforts through a rules-based, computable phenotype algorithm to identify 5 AESIs being monitored by the Center for Disease Control and Prevention for COVID-19 or other vaccines: anaphylaxis, Guillain-Barré syndrome, myocarditis/pericarditis, thrombosis with thrombocytopenia syndrome, and febrile seizure. This study examined whether these phenotypes have sufficiently high positive predictive value (PPV) to ensure that the cases selected for surveillance are reasonably likely to be a postbiologic adverse event. This allows patient privacy, and security concerns for the data sharing of patients who had nonadverse events can be properly accounted for when evaluating the cost-benefit aspect of our approach.

METHODS: AESI phenotype algorithms were developed to apply to electronic health record data at health provider organizations across the country by querying for standard and interoperable codes. The codes queried in the rules represent symptoms, diagnoses, or treatments of the AESI sourced from published case definitions and input from clinicians. To validate the performance of the algorithms, we applied them to electronic health record data from a US academic health system and provided a sample of cases for clinicians to evaluate. Performance was assessed using PPV.

RESULTS: With a PPV of 93.3%, our anaphylaxis algorithm performed the best. The PPVs for our febrile seizure, myocarditis/pericarditis, thrombocytopenia syndrome, and Guillain-Barré syndrome algorithms were 89%, 83.5%, 70.2%, and 47.2%, respectively.

CONCLUSIONS: Given our algorithm design and performance, our results support continued research into using interoperable algorithms for widespread AESI postmarket detection.

PMID:39008361 | DOI:10.2196/49811

Diabetes Ther. 2024 Jul 15. doi: 10.1007/s13300-024-01617-3. Online ahead of print.

ABSTRACT

INTRODUCTION: ISIS 449884, a 2'-O-methoxyethyl antisense oligonucleotide that targets the glucagon receptor (GCGR), has demonstrated an ability to reduce hepatic glucose output and lower the blood glucose level. The primary objective of this study was to investigate the safety and efficacy of ISIS 449884 as an add-on to metformin in a population of Chinese patients with type 2 diabetes mellitus (T2DM).

METHOD: This was a multicenter, placebo-controlled (2:1), randomized, double-blind, parallel-enrollment, multiple-dose phase II study in Chinese patients with T2DM. A total of 90 patients who were uncontrolled by stable metformin monotherapy were randomized into three cohorts. Thirty subjects were enrolled in each cohort and received injections of ISIS 449884 (50 mg or 60 mg weekly or 100 mg every other week) or a corresponding volume of placebo (0.25 mL and 0.3 mL weekly or 0.5 mL every other week) subcutaneously in a 2:1 ratio for 16 weeks.

RESULTS: The primary efficacy endpoint was analyzed in 88 subjects (ISIS 449884, n = 59; placebo, n = 29). The corrected LS mean change from baseline in glycated hemoglobin (HbA1c) at week 17 in the pooled ISIS 449884 treatment group was - 1.31% (95% CI - 1.66%, - 0.96%), and that in the pooled placebo group was 0.15% (95% CI - 0.37%, 0.66%). The LS mean difference between the two groups was - 1.46% (95% CI - 1.92%, - 1.00%, P < 0.001). Treatment-emergent adverse events (TEAEs) occurred in 53/60 subjects (88.3%) and 25/30 subjects (83.3%) in the pooled ISIS 449884 treatment group and the pooled placebo group, respectively, with similar incidences. Drug-related TEAEs occurred in 41/60 subjects (68.3%) and 9/30 subjects (30.0%), respectively. TEAEs of grade 3 or higher occurred in 5/60 (8.3%) subjects and 2/30 (6.7%) subjects, respectively, and none of them were drug related.

CONCLUSIONS: The ISIS 449884 injection add-on to metformin significantly reduced HbA1c in patients with T2DM uncontrolled by stable metformin monotherapy and showed an acceptable benefit/risk profile.

CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn , CTR20191096.

PMID:39008234 | DOI:10.1007/s13300-024-01617-3

Int J Clin Pharm. 2024 Jul 15. doi: 10.1007/s11096-024-01769-z. Online ahead of print.

ABSTRACT

BACKGROUND: Anticholinergic medications are now widely acknowledged for their unfavorable risk-to-benefit profile owing to their adverse effects. Health-related quality of life (HRQoL) is commonly regarded as a crucial person-centered outcome.

AIM: This study aimed to investigate the association between anticholinergic burden and HRQoL in hospitalized and ambulatory patients seen in Ethiopia.

METHOD: This cross-sectional study utilized a questionnaire and medical records to collect data from a convenience sample of adult patients attending both inpatient wards and ambulatory clinic of University of Gondar Comprehensive Specialized Hospital between April and September 2022. Anticholinergic burden was measured by anticholinergic cognitive burdens scale (ACBS), while HRQoL was measured using EQ5D-index (Euroqol-5 dimensions-5-Levels index) and EQ5D-VAS (visual analogue scale). Linear regression was used to assess the influence of high anticholinergic burden (ACBS score ≥ 3) on EQ5D-index and EQ5D-VAS, with adjustments made for sociodemographic and clinical confounders.

RESULTS: A total of 828 patients participated in this study (median (IQR) age was 45.0 (30, 60) and 55.9% were female). On multiple linear regression analysis, high anticholinergic burden was associated with a statistically significant decline in HRQoL, as evidenced by reductions in both EQ5D index (- 0.174 (- 0.250, - 0.098)) and EQ5D-VAS scores (- 9.4 (- 13.3, - 5.2)).

CONCLUSION: A significant association between high anticholinergic burden and diminished HRQoL was found among a relatively younger cohort in a resource-limited setting, even after adjustment for important confounding variables. Clinicians should be cognizant of the cumulative impact of anticholinergic burden on HRQoL outcomes and strive to minimize anticholinergic burden.

PMID:39007992 | DOI:10.1007/s11096-024-01769-z

Cureus. 2024 Jun 14;16(6):e62382. doi: 10.7759/cureus.62382. eCollection 2024 Jun.

ABSTRACT

Minoxidil is an effective and relatively safe topical drug that is used to treat androgenetic alopecia and other types of alopecia. This active ingredient is used in dermatology as a hair growth stimulant; however, the use of solutions containing minoxidil can be accompanied by a variety of cardiovascular systemic side effects. In this case report, we describe the case of a 23-year-old man who presented with complaints of dizziness, blurred vision, general malaise, fatigue, and feeling pre-syncopal while standing after applying large amounts of topical minoxidil solution for three days in a row. Other potential causes of the presenting condition were excluded. The symptoms quickly resolved after the discontinuation of minoxidil. No other treatment was used apart from minoxidil withdrawal.

PMID:39006707 | PMC:PMC11246695 | DOI:10.7759/cureus.62382

Cureus. 2024 Jun 13;16(6):e62293. doi: 10.7759/cureus.62293. eCollection 2024 Jun.

ABSTRACT

Cyclin-dependent kinase (CDK) 4 and 6 inhibitors, such as palbociclib, have emerged as essential in managing hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. While effective, these inhibitors can cause rare dermatologic side effects, including vitiligo-like depigmentation. We report a rare case of a 52-year-old female with HR+, HER2- metastatic breast cancer who developed vitiligo-like depigmentation following palbociclib treatment. The patient presented with asymptomatic depigmented lesions on the lower limbs and abdomen, appearing seven months after starting palbociclib. Examination and investigations confirmed the diagnosis after excluding other potential causes. Despite treatment with topical steroids and calcineurin inhibitors, there was no significant improvement, highlighting the need for more research into effective management strategies for drug-induced vitiligo. This case emphasizes the importance of recognizing rare dermatologic side effects of CDK4/6 inhibitors like palbociclib. Ongoing vigilance, reporting, and research are necessary to improve understanding and management of these side effects, ultimately enhancing patient care in oncology.

PMID:39006687 | PMC:PMC11245740 | DOI:10.7759/cureus.62293

Pharmaceut Med. 2024 Jul;38(4):321-329. doi: 10.1007/s40290-024-00530-1. Epub 2024 Jul 13.

ABSTRACT

INTRODUCTION: Several quantitative methods have been established, in pharmacovigilance, to detect signals of disproportionate reporting (SDRs) from databases containing reports of adverse drug reactions (ADRs). The signal detection algorithms (SDAs) and the source of the reporting per product vary, but it is unclear whether any algorithm can provide satisfactory performance using data with such large variance factors.

OBJECTIVE: Determine the appropriate SDA for Biogen's internal Global Safety Database (GSD) given the characteristics of the database including frequencies of events, data skewness, outliers, and missing information. Compare performance of standard approaches (EBGM, EB05, PRR, and ROR), well accepted by industry, to a Biogen-developed Machine Learning (ML) Regression Decision Tree (RDT) model, across several Biogen products, to determine a champion SDA.

METHODS: All data associated with seven marketed Biogen products were chosen and a historical subset of reported ADRs were considered. Six SDAs (five common industry disproportionality methods) and RDT were evaluated. The SDRs were calculated on training and test data composed of quarterly reporting intervals from 2004-2019. The performance measures used were sensitivity, precision, time to detect new events, and frequency of detected cases for each algorithm for each product. Outcomes in the test data are known a priori and easily compared to predicted outcomes. Validation was performed via rates of misclassification. This work solely represents Biogen's internal information, intentionally chosen to serve the performance review of its signal detection systems, and results will not necessarily be generalizable to other external sources.

RESULTS: Several algorithms performed differently among products, but no one method dominated any other. Performance was dependent on the thresholds used to define a signal according to different criteria. However, those different statistics subtly influenced the achievable performance. The relative performance of RDT and Medicines and Healthcare products Regulatory Agency (MHRA) algorithms were superior and paired across products. A reduction in precision for all methods spanning the products was present. Hence, companies evaluating signal detection approaches, search for innovative methods to minimize this effect.

CONCLUSIONS: In designing signal detection systems, careful consideration should be given to the criteria that are used to define SDRs. The choice of disproportionality statistics does not affect the achievable range of signal detection performance. These choices should consider mainly ease of implementation and interpretation. The implementation of a method is specific to its accuracy. The RDT attempted to take advantage of known methods and compare results on a per-product basis. Many factors influencing ADRs may improve RDT in future efforts. In this experiment, RDT demonstrated superiority in terms of quickest time to detect and capturing of the highest number of ADRs. Next steps include expansion of data for products representing other indications and testing models in external databases to investigate generalizability of estimates when comparing SDAs.

PMID:39003400 | DOI:10.1007/s40290-024-00530-1

Spectrochim Acta A Mol Biomol Spectrosc. 2024 Jun 12;322:124623. doi: 10.1016/j.saa.2024.124623. Online ahead of print.

ABSTRACT

Mitotic inhibitors are drugs commonly used in chemotherapy, but their nonspecific and indiscriminate distribution throughout the body after intravenous administration can lead to serious side effects, particularly on the cardiovascular system. In this context, our investigation into the mechanism of the cytotoxic effects on endothelial cells of mitotic inhibitors widely used in cancer treatment, such as paclitaxel (also known as Taxol) and Vinca alkaloids, holds significant practical implications. Understanding these mechanisms can lead to more targeted and less harmful cancer treatments. Human aorta endothelial cells (HAECs) were incubated with selected mitotic inhibitors in a wide range of concentrations close to those in human plasma during anticancer therapy. The analysis of single cells imaged by Raman spectroscopy allowed for visualization of the nuclear, cytoplasmic, and perinuclear areas to assess biochemical changes induced by the drug's action. The results showed significant changes in the morphology and molecular composition of the nucleus. Moreover, an effect of a given drug on the cytoplasm was observed, which can be related to its mechanism of action (MoA). Raman data supported by fluorescence microscopy measurements identified unique changes in DNA form and proteins and revealed drug-induced inflammation of endothelial cells. The primary goal of mitotic inhibitors is based on the impairment of tubulin formation and the inhibition of the mitosis process. While all three drugs affect microtubules and disrupt cell division, they do so through different MoA, i.e., Vinca alkaloids inhibit microtubule formation, whereas paclitaxel stabilizes microtubules. To sum up, the work shows how a specific drug can interact with endothelial cells.

PMID:39002470 | DOI:10.1016/j.saa.2024.124623

Sci Rep. 2024 Jul 12;14(1):16124. doi: 10.1038/s41598-024-67020-x.

ABSTRACT

This study aims to figure out the worldwide prevalence of anticancer therapy-associated acute kidney injury (AKI) and tubulointerstitial nephritis (TIN) and the relative risk of each cancer drug. We conducted an analysis of VigiBase, the World Health Organization pharmacovigilance database, 1967-2023 via disproportionate Bayesian reporting method. We further categorized the anticancer drugs into four groups: cytotoxic therapy, hormone therapy, immunotherapy, and targeted therapy. Reporting odds ratio (ROR) and information component (IC) compares observed and expected values to investigate the associations of each category of anticancer drugs with AKI and TIN. We identified 32,722 and 2056 reports (male, n = 17,829 and 1,293) of anticancer therapy-associated AKI and TIN, respectively, among 4,592,036 reports of all-drug caused AKI and TIN. There has been a significant increase in reports since 2010, primarily due to increased reports of targeted therapy and immunotherapy. Immunotherapy exhibited a significant association with both AKI (ROR: 8.92; IC0.25: 3.06) and TIN (21.74; 4.24), followed by cytotoxic therapy (7.14; 2.68), targeted therapy (5.83; 2.40), and hormone therapy (2.59; 1.24) for AKI, and by cytotoxic therapy (2.60; 1.21) and targeted therapy (1.54; 0.61) for TIN. AKI and TIN were more prevalent among individuals under 45 years of age, with a female preponderance for AKI and males for TIN. These events were reported in close temporal relationship after initiation of the respective drug (16.53 days for AKI and 27.97 days for TIN), and exhibited a high fatality rate, with 23.6% for AKI and 16.3% for TIN. These findings underscore that kidney-related adverse drug reactions are of prognostic significance and strategies to mitigate such side effects are required to optimize anticancer therapy.

PMID:38997405 | DOI:10.1038/s41598-024-67020-x

BMJ Evid Based Med. 2024 Jul 12:bmjebm-2024-112886. doi: 10.1136/bmjebm-2024-112886. Online ahead of print.

ABSTRACT

OBJECTIVES: To assess the efficacy and safety of pharmacological interventions for preventing upper gastrointestinal (GI) bleeding in people admitted to intensive care units (ICUs).

DESIGN AND SETTING: Systematic review and frequentist network meta-analysis using standard methodological procedures as recommended by Cochrane for screening of records, data extraction and analysis. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence.

PARTICIPANTS: Randomised controlled trials involving patients admitted to ICUs for longer than 24 hours were included.

SEARCH METHODS: The Cochrane Gut Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Latin American and Caribbean Health Science Information database (LILACS) databases were searched from August 2017 to March 2022. The search in MEDLINE was updated in April 2023. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP).

MAIN OUTCOME MEASURES: The primary outcome was the prevention of clinically important upper GI bleeding.

RESULTS: We included 123 studies with 46 996 participants. Cimetidine (relative risk (RR) 0.56, 95% CI 0.40 to 0.77, moderate certainty), ranitidine (RR 0.54, 95% CI 0.38 to 0.76, moderate certainty), antacids (RR 0.48, 95% CI 0.33 to 0.68, moderate certainty), sucralfate (RR 0.54, 95% CI 0.39 to 0.75, moderate certainty) and a combination of ranitidine and antacids (RR 0.13, 95% CI 0.03 to 0.62, moderate certainty) are likely effective in preventing upper GI bleeding.The effect of any intervention on the prevention of nosocomial pneumonia, all-cause mortality in the ICU or the hospital, duration of the stay in the ICU, duration of intubation and (serious) adverse events remains unclear.

CONCLUSIONS: Several interventions seem effective in preventing clinically important upper GI bleeding while there is limited evidence for other outcomes. Patient-relevant benefits and harms need to be assessed under consideration of the patients' underlying conditions.

PMID:38997152 | DOI:10.1136/bmjebm-2024-112886

Clin Cancer Res. 2024 Jul 12. doi: 10.1158/1078-0432.CCR-24-0103. Online ahead of print.

ABSTRACT

PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor.

PATIENTS AND METHODS: This first-in-human, multicenter, open-label, phase 1/2 study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase 2 dose (RP2D), and characterize the pharmacokinetics (PK); exploratory objectives included pharmacodynamics and efficacy.

RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were grade 1/2. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The RP2D was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7 to 46.9), and the objective response rate as assessed by independent radiological review using Response Evaluation Criteria in Solid Tumors version 1.1 was 72%.

CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT whose disease is not amenable to surgery.

PMID:38995311 | DOI:10.1158/1078-0432.CCR-24-0103

J Clin Endocrinol Metab. 2024 Jul 12:dgae472. doi: 10.1210/clinem/dgae472. Online ahead of print.

ABSTRACT

CONTEXT: Supplemental methotrexate (MTX) may affect the clinical course of Graves' disease (GD).

OBJECTIVE: Evaluate efficacy of add-on MTX on medical treatment in GD.

DESIGN: Prospective, open-label, randomized supplementation controlled trial.

SETTING: Academic endocrine outpatient clinic.

PATIENTS: One hundred and fifty-three untreated hyperthyroid patients with GD.

INTERVENTION: Patients received MTX 10 mg/d with methimazole (MMI) or MMI only. MTX and MMI were discontinued at months 12-18 in euthyroid patients.

MAIN OUTCOME MEASURES: Discontinuation rate at months 18 in each group.

RESULTS: In the MTX with MMI group, the discontinuation rate was higher than the MMI group at months 15-18 (50.0 vs. 33.3%, P=0.043, 95% CI 1.020 to 3.922; and 55.6 vs 38.9%, P=0.045, 95%CI 1.011 to 3.815, respectively). The decrease in TRAb levels in the MTX with MMI group was significant from baseline to months 6 compared to the MMI alone group [MTX+MMI 67.22% (43.12-80.32), MMI 54.85% (33.18-73.76), P= 0.039) and became more significant from months 9 [MTX+MMI 77.79% (62.27-88.18), MMI 69.55% (50.50-83.22), P= 0.035] to months 18 (P < 0.01 in 15-18 months). A statistically significant difference between the levels of TRAb in the MTX with MMI group and the MMI group at 9-18 months. There were no significant differences in the levels of FT3, FT4 and TSH between two groups. No serious drug-related adverse events were observed in both groups(P=0.771).

CONCLUSIONS: Supplemental MTX with MMI resulted in higher discontinuation rate and improvement in decreased TRAb levels to homeostatic levels faster than methimazole treatment alone at months 12-18.

PMID:38994582 | DOI:10.1210/clinem/dgae472

Mater Today Bio. 2024 Jun 15;27:101124. doi: 10.1016/j.mtbio.2024.101124. eCollection 2024 Aug.

ABSTRACT

Osteoarthritis (OA) is a prevalent chronic disease, characterized by chronic inflammation and cartilage degradation. This study aims to deepen the understanding of OA's pathophysiology and to develop novel therapeutic strategies. Our study underscores the pivotal role of Epiphycan (EPYC) and the IL-17 signaling pathway in OA. EPYC, an essential extracellular matrix constituent, has been found to exhibit a positive correlation with the severity of OA. We have discovered that EPYC modulates the activation of the IL-17 signaling pathway within chondrocytes by regulating the interaction between IL-17A and its receptor, IL-17RA. This regulatory mechanism underscores the intricate interplay between the extracellular matrix and immune signaling in the pathogenesis of OA Another finding of our study is the therapeutic effectiveness of protocatechualdehyde (PAH) in OA. PAH significantly reduces chondrocyte hypertrophy and supports cartilage tissue recovery.by targets EPYC. To reduce the side effects of orally administered PAH and maintain its effective drug concentration, we have developed a decellularized matrix hydrogel loaded with PAH for intra-articular injection. This novel drug delivery system is advantageous in minimizing drug-related side effects and ensuring sustained release PAH within the joint cavity.

PMID:38994469 | PMC:PMC11237976 | DOI:10.1016/j.mtbio.2024.101124