J Med Internet Res. 2025 Feb 5;27:e65546. doi: 10.2196/65546.

ABSTRACT

BACKGROUND: Medication-related harm, including adverse drug events (ADEs) and medication errors, represents a significant iatrogenic burden in clinical care. Digital health technology (DHT) interventions can significantly enhance medication safety outcomes. Although the clinical effectiveness of DHT for medication safety has been relatively well studied, much less is known about the cost-effectiveness of these interventions.

OBJECTIVE: This study aimed to systematically review the economic impact of DHT interventions on medication safety and examine methodological challenges to inform future research directions.

METHODS: A systematic search was conducted across 3 major electronic databases (ie, PubMed, Scopus, and EBSCOhost). The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for this systematic review. Two independent investigators conducted a full-text review after screening preliminary titles and abstracts. We adopted recommendations from the Panel on Cost-Effectiveness in Health and Medicine for data extraction. A narrative analysis was conducted to synthesize clinical and economic outcomes. The quality of reporting for the included studies was assessed using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines.

RESULTS: We included 13 studies that assessed the cost-effectiveness (n=9, 69.2%), cost-benefit (n=3, 23.1%), and cost-utility (n=1, 7.7%) of DHT for medication safety. Of the included studies, more than half (n=7, 53.9%) evaluated a clinical decision support system (CDSS)/computerized provider order entry (CPOE), 4 (30.8%) examined automated medication-dispensing systems, and 2 (15.4%) focused on pharmacist-led outreach programs targeting health care professionals. In 12 (92.3% ) studies, DHT was either cost-effective or cost beneficial compared to standard care. On average, DHT interventions reduced ADEs by 37.12% (range 8.2%-66.5%) and medication errors by 54.38% (range 24%-83%). The key drivers of cost-effectiveness included reductions in outcomes, the proportion of errors resulting in ADEs, and implementation costs. Despite a significant upfront cost, DHT showed a return on investment within 3-4.25 years due to lower cost related with ADE treatment and improved workflow efficiency. In terms of reporting quality, the studies were classified as good (n=10, 76.9%) and moderate (n=3, 23.1%). Key methodological challenges included short follow-up periods, the absence of alert compliance tracking, the lack of ADE and error severity categorization, and omission of indirect costs.

CONCLUSIONS: DHT interventions are economically viable to improve medication safety, with a substantial reduction in ADEs and medication errors. Future studies should prioritize incorporating alert compliance tracking, ADE and error severity classification, and evaluation of indirect costs, thereby increasing clinical benefits and economic viability.

PMID:39909404 | DOI:10.2196/65546

Front Immunol. 2025 Jan 21;15:1508129. doi: 10.3389/fimmu.2024.1508129. eCollection 2024.

ABSTRACT

QUESTION: Can previously reported, largely anecdotal associations between exposure to any of a comprehensive list of putative trigger drugs and the development of pemphigus be reproduced using population level data?

FINDINGS: In this series of observational, retrospective, case-control, pharmacovigilance analyses of the FDA Adverse Event Reporting System, the odds of reporting the adverse event pemphigus were significantly elevated among individuals exposed to 11/36 previously reported trigger drugs namely, gold sodium thiomalate, penicillamine, piroxicam, rifampin, hydroxychloroquine, imiquimod, hydrochlorothiazide, irbesartan, lisinopril, nivolumab, and nifedipine.

MEANING: Environmental exposures such as drugs are relevant players in the pathogenesis of autoimmune diseases and clinicians who treat patients with autoimmune blistering diseases such as pemphigus should consider performing a detailed medication history leveraging this information regarding deleterious drug-disease interactions at initial evaluation as well as longitudinal monitoring of patients to better inform clinical care decisions.

IMPORTANCE: Pemphigus vulgaris (PV) is a rare, potentially fatal autoimmune disease with pathogenic contributions from both genetic as well as environmental factors, notably drug exposures. Despite anecdotal reports linking multiple drugs to PV, corroborating evidence from large datasets is missing.

OBJECTIVE: To examine the extent to which previously reported associations between a comprehensive list of 36 drugs implicated in PV pathogenesis could be replicated using population-level pharmacovigilance data.

DESIGN: Series of observational, retrospective, case-control, pharmacovigilance analyses (one analysis/drug, 36 total).

SETTING: Population based.

PARTICIPANTS: Individuals who submitted a report of a drug-related adverse event to the FDA from Q4 of 2003 to Q2 of 2023.

EXPOSURE: Cases were identified by the presence of adverse events described by the MedDRA preferred term "pemphigus" (10034280) and then sorted based on exposure to each of the drugs of interest.

MAIN OUTCOMES AND MEASURES: Reporting Odds Ratios (RORs) quantifying the association between a given drug exposure and reports of pemphigus adverse events.

RESULTS: The analyses revealed statistically significant associations between reports of pemphigus and exposure to 11/36 previously reported drugs, two of which had particularly high RORs (>200) [gold sodium thiomalate (ROR, 266.0; 95% CI, 202.6-349.3) and hydroxychloroquine (ROR, 282.6; 95% CI, 261.0-306.1)], three had very strong RORs (14-45) [penicillamine (ROR, 30.5; 95% CI, 11.4-81.7), piroxicam (ROR, 14.8; 95% CI, 8.2-26.7), and imiquimod (ROR, 42.3; 95% CI, 26.2-68.3)], and six had modestly strong RORs (2-5) [rifampin (ROR, 2.8; 95% CI, 1.4-5.6), hydrochlorothiazide (ROR, 1.6; 95% CI, 1.2-2.1), irbesartan (ROR, 2.7; 95% CI, 1.6-4.4), lisinopril (ROR, 5.3; 95% CI, 4.5-6.2), nivolumab (ROR, 2.7; 95% CI, 1.8-4.1), and nifedipine (ROR, 3.0; 95% CI, 1.9-5.0)]. Associations for other previously reported drugs (25/36) were not detected.

CONCLUSIONS AND RELEVANCE: This study represents a comprehensive evaluation of suspected drug triggers of pemphigus using real-world data. The significant associations reported here provide empirical support for the hypothesis that certain drugs act as triggers for PV. Moreover, all of the drugs found to be associated with PV in this study harbor immunomodulatory capacity, suggesting that the ability to induce such perturbations, directly or indirectly, may be a critical factor connecting drug exposure to pemphigus pathogenesis. However, the absence of signals for other previously reported putative trigger drugs does not preclude their potential role in PV pathogenesis. Our findings reinforce the need for larger, more definitive studies to confirm these associations and to explore the mechanisms by which these drugs may contribute to PV development. Finally, these findings underscore the importance of considering environmental factors in the development and course of PV in genetically susceptible individuals.

PMID:39906745 | PMC:PMC11790476 | DOI:10.3389/fimmu.2024.1508129

Clin Transl Sci. 2025 Feb;18(2):e70133. doi: 10.1111/cts.70133.

ABSTRACT

Piperaquine tetraphosphate (PQP), a long-acting antimalarial, is being considered in a combination for chemoprevention. Dihydroartemisinin-piperaquine tablets (hard and dispersible) approved for the treatment of acute uncomplicated malaria should be administered in a fasted state, as PQP bioavailability increases with food. A new taste-masked dispersible granules PQP formulation aims to minimize the impact of food on drug exposure. This randomized, open label, parallel group, Phase I pilot study was conducted between 24th July 2023, and 3rd January 2024, at the Ifakara Health Institute, Bagamoyo, Tanzania in 60 healthy African adults (five cohorts of 12). Single-dose pharmacokinetics and relative systemic exposure of the oral PQP dispersible granules formulation prototype (320 mg) was compared to the hard tablet when fasted and PQP granules in three different fed conditions. In the fasted state, the relative exposure of PQP granules versus the tablet was 73.9% (90% CI 48.3, 113.0) for Cmax and 86.5% (68.2, 109.6) for AUC0-t. Following a typical East African low-fat meal, a standard high-fat meal, or 250 mL whole milk, the relative exposure of PQP granules versus the fasted state was 202% (90% CI 132, 311), 275% (193, 391), and 294% (203, 425) for Cmax and 164% (124, 217), 184% (148, 228), and 195% (147, 259) for AUC0-t, respectively. Both formulations were well tolerated with one drug-related adverse event (moderate migraine). No severe or serious adverse events or clinically relevant laboratory or electrocardiograph changes were observed. PQP dispersible granules had lower systemic exposures versus the tablet when fasted, whereas various meals increased drug exposure.

PMID:39905737 | DOI:10.1111/cts.70133

Sci Rep. 2025 Feb 4;15(1):4157. doi: 10.1038/s41598-025-87724-y.

ABSTRACT

Adverse Drug Reactions (ADRs) stand out as a pressing challenge in public health and a critical aspect of drug discovery. The dilemma arises from the inherent impossibility of conducting a comprehensive evaluation of a drug before its market release, constrained by the limitations in scale and duration of clinical trials. Therefore, the post-marketing detection of ADRs in a timely and accurate manner becomes imperative. Adding to the complexity, a multitude of tweets harbor concealed information about adverse drug reactions, creating difficulties due to their concise, sporadic, and noisy content. To solve the problem, we regard ADR detection as a question-answer problem and introduces an innovative neural network framework with multiple GRU layers designed for extracting ADR-related information from tweets. The Von Mises-Fisher distribution is applied to derive keyword vectors through tweet sampling. An attention mechanism is employed to enhance the interaction between these keyword vectors and the word sequences within tweets. The credibility of word sequences is systematically evaluated based on the reliability of answer factors. To address concerns related to background information and training speed, we propose a quality assurance mechanism utilizing a GRU network due to its straightforward structure and efficient training capabilities. As a result of the training process, word sequences are mapped to a low-latitude vector space, generating corresponding answers. Experimental results obtained from two Twitter ADR datasets affirm that our Question-Answer Mechanism, leveraging multi-GRU architecture, significantly improves the accuracy of ADR detection in tweets. Our method achieved F1-scores of 81.3% and 73.3% on the two datasets, respectively, while consistently maintaining a higher recall.

PMID:39905141 | DOI:10.1038/s41598-025-87724-y

Eur J Hosp Pharm. 2025 Feb 4:ejhpharm-2024-004414. doi: 10.1136/ejhpharm-2024-004414. Online ahead of print.

ABSTRACT

OBJECTIVE: Drug-related problems (DRPs) are a frequent reason for visits to the emergency department (ED). However, data about the characteristics associated with early revisits are limited. We aimed to identify clinical phenotype clusters of patients admitted to emergency rooms due DRPs to identify those patients with the highest risk of new visits.

METHODS: We included consecutive patients admitted to EDs due DRPs (February 2021 to December 2022), including DRP admissions in 2023 as validation cohort. We employed K-means clustering to group patients according to adjusted morbidity groups (GMA), age, and number of drugs at admission. To determine the optimal number of cluster centres, we used the elbow method. The impact of 30-day revisits in each cluster was assessed.

RESULTS: 1611 patients (mean (SD) age 75.0 (15.1) years) were included. We identified six clusters, with 30-day revisits rates ranging from 14.8% to 24.5%. The main groups of drugs implicated in the DRP episodes were diuretics (190 patients; 11.8%). The most common DRP diagnoses were constipation (191; 11.9%) and gastrointestinal bleeding (158; 9.8%). Six clusters of patients were identified. Significantly higher 30-day revisits in patients identified in cluster 4 (24.5% vs 17.5%; p=0.007). The highest revisit rate was observed in the cluster including patients with a higher number of drugs and GMA status.

CONCLUSIONS: Patients admitted to the ED due DRPs exhibit varying revisit rates across different clinical phenotypes. K-means clustering aids in identifying patients who derive the greatest rates of readmission, and is a useful tool to prioritise interventions in these units.

PMID:39904593 | DOI:10.1136/ejhpharm-2024-004414

Eur J Hosp Pharm. 2025 Feb 4:ejhpharm-2024-004463. doi: 10.1136/ejhpharm-2024-004463. Online ahead of print.

NO ABSTRACT

PMID:39904591 | DOI:10.1136/ejhpharm-2024-004463

Drug Ther Bull. 2025 Feb 4:dtb-2023-000059. doi: 10.1136/dtb.2023.000059. Online ahead of print.

ABSTRACT

Cancer treatment is rapidly evolving and this review provides healthcare professionals who are not specialists in cancer therapeutics with a broad overview of the role of cancer systemic therapy, with a particular focus on chemotherapy.Historically, the majority of cytotoxic chemotherapy was used in patients with incurable or metastatic disease with the goal of disease control and symptom palliation. Now, with the advent of more effective, targeted systemic therapies (incorporating both cytotoxic and non-cytotoxic agents), systemic therapies are being used in more diverse treatment settings, both to increase the likelihood of cure and to induce prolonged disease remission.Chemotherapy (henceforth referring specifically to cytotoxic chemotherapy) remains important for the treatment of many cancer types. This article will review the principles of chemotherapy and the first-line systemic treatment paradigm of different cancer types. The potential toxicities of chemotherapy will also be described.

PMID:39904574 | DOI:10.1136/dtb.2023.000059

PLoS One. 2025 Feb 4;20(2):e0317660. doi: 10.1371/journal.pone.0317660. eCollection 2025.

ABSTRACT

BACKGROUND: Identification of real-time adverse drug reactions [ADRs] (as opposed to the risk of ADRs) in older poly-medicated people in primary care is a challenging task, often undertaken without an explicit strategy. This systematic review aims to evaluate replicable instruments and methods for identifying and addressing ADRs.

METHODS: A systematic search was conducted in Medline, CINAHL, Scopus, Web of Science and Cochrane library, using controlled vocabulary (MeSH) and free-text terms. Randomised controlled trials (RCTs) implementing strategies to identify or resolve ADRs experienced by patients in primary care were included. Two reviewers independently screened studies, extracted data, and assessed the risk of bias using the Cochrane Risk of Bias tool. Discrepancies were resolved by discussion.

RESULTS: From 2,182 unique records, 49 studies were identified for full review. Eight papers reporting results from 6 RCTs were included. All six trials utilised a list of medicine-related unwanted symptoms to identify ADRs. Two of three studies using adverse drug reaction questionnaires reported statistically significant increased rates of ADR reporting. Two of three studies that combined symptom questionnaires with prescriber consultations reported reductions in the number of health problems. Overall, results suggest that the three studies that described multidisciplinary collaborations using lists of ADRs plus prescriber reviews enhanced patient safety. However, the RCTs were unblinded and reported suboptimal retention. When considered as a whole, findings are equivocal and the data are too heterogenous to warrant any firm conclusions, beyond the need for more research to optimise strategies to safeguard patient wellbeing.

IMPLICATIONS: Adaptable and scalable instruments with decision support are needed in primary care to identify and mitigate medicine-related harm in older poly-medicated people. The effectiveness of adverse drug reaction identification instruments, the value of comprehensive instruments, and the optimum method of delivery should be explored in multicentre trials.

PMID:39903764 | DOI:10.1371/journal.pone.0317660

Clin Cancer Res. 2025 Feb 4. doi: 10.1158/1078-0432.CCR-24-1525. Online ahead of print.

ABSTRACT

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is currently approved to treat metastatic triple-negative breast cancer and HR+/HER2- breast cancer, and is under clinical investigation for a range of other tumor types. This review describes its mode of action, development, and clinical outcomes. SG is composed of SN-38 (a topoisomerase I inhibitor derived from irinotecan) covalently linked to an anti-Trop-2 monoclonal antibody (sacituzumab; hRS7) via a hydrolysable CL2A linker. SN-38 was chosen due to its potent antitumor activity; CL2A occupies the most effective position on SN-38 for maintaining stability during transport, with pH-sensitive payload release in the tumor, and the antigen target (Trop-2) is highly expressed on many solid tumors. SG has an ~8:1 drug-to-antibody ratio and delivers therapeutic SN-38 concentration to Trop-2+ expressing tumor cells via rapid internalization and efficient payload release. Free SN-38 can subsequently enter the tumor microenvironment and kill adjacent tumor cells with or without Trop-2 expression (bystander effect). SN-38 induces DNA breakage and inhibits nucleic acid synthesis via a drug-induced topoisomerase 1:DNA complex that interferes with cell proliferation, causing apoptosis. Dose-finding studies support SG 10 mg/kg on days 1 and 8 of a 21-day cycle as the monotherapy dose for clinical use; this was determined by therapeutic index improvement based on efficacy and safety. Payload-linker dynamics and SG potency ensure continued tissue penetration. Neutropenia and diarrhea are the most common grade ≥ 3 treatment-emergent adverse events with SG, but they are manageable. Efficacy of SG has been demonstrated across a broad spectrum of solid tumors.

PMID:39903492 | DOI:10.1158/1078-0432.CCR-24-1525

Thorac Cancer. 2025 Feb;16(3):e70006. doi: 10.1111/1759-7714.70006.

ABSTRACT

BACKGROUND: Recently, the treatment needs of elderly lung cancer patients have become comparable with those of younger patients. This study evaluated the efficacy and safety of first-line immune checkpoint inhibitors (ICI) in elderly patients with nonsmall-cell lung cancer (NSCLC), stratified by immune-related adverse events (irAEs) severity, and identified key prognostic factors.

METHODS: This retrospective study targeted patients with advanced or recurrent NSCLC who received ICI therapy as first-line treatment between April 2017 and March 2023.

RESULT: Of the 138 patients enrolled in this study, 81 and 57 patients were classified into the elderly (aged 70 and above) and nonelderly (under 70 years old) groups, respectively. Severe irAEs were significantly associated with shorter overall survival (OS) in the elderly group (severe irAEs vs. others, 9.9 vs. 24.7 months; p = 0.043) and favorable OS in nonelderly group (severe irAEs vs. others, NR [not reached] vs. 21.0 months, p = 0.026). The OS of patients with severe irAEs was significantly worse in the elderly group than in the nonelderly group (elderly group vs. nonelderly group, 9.9 vs. NR months, p = 0.001). In the multivariate analysis, mild irAEs were associated with a favorable prognosis in elderly patients (hazard ratio, 0.446; p = 0.032).

CONCLUSION: Severe irAEs demonstrated different outcomes in elderly and nonelderly patients. Contrastingly, mild irAEs were associated with a favorable prognosis in elderly patients, emphasizing the need for appropriate patient selection, early intervention for irAEs and new tools to accurately predict irAE severity in elderly patients.

PMID:39901355 | DOI:10.1111/1759-7714.70006

Sci Rep. 2025 Feb 3;15(1):4104. doi: 10.1038/s41598-025-88838-z.

ABSTRACT

This study aims to monitor and identify adverse events (AEs) associated with cetuximab, a drug used to treat various late-stage (metastatic) tumors, to improve patient safety and guide drug use. This study retrospectively analyzed the cases reported in the FDA adverse event reporting system (FAERS) related to the application of cetuximab from 2013 Q1 to 2022 Q4. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the empirical Bayesian geometric mean (EBGM) algorithms, were employed to quantify the signals of cetuximab-associated AEs. A total of 8364225 reports were contained in the FAERS database, of which 5186 reports of cetuximab were identified as 'primary suspected (PS)' AEs. The application of cetuximab resulted in AEs in 22 system organ classes (SOCs), which preserved 176 significant disproportionality preferred terms (PTs) through the computation of four algorithms. The main SOCs (Skin and subcutaneous tissue disorders, investigations, metabolism and nutrition disorders, and blood and lymphatic system disorders) accounted for 58.63%. Some AEs were not on the drug label: speech disorder, intervertebral discitis, glomerulonephritis rapidly progressive and disseminated intravascular coagulation. This study identified new signals of adverse drug reactions (ADRs) other than those mentioned in the specification associated with cetuximab, providing valuable insights into the relationship between ADRs and cetuximab use. The findings highlight the importance of continuous surveillance to detect and manage AEs effectively, ultimately improving patient safety during treatment with cetuximab.

PMID:39901061 | DOI:10.1038/s41598-025-88838-z

Drug Ther Bull. 2025 Feb 3:dtb-2024-000073. doi: 10.1136/dtb.2024.000073. Online ahead of print.

NO ABSTRACT

PMID:39900487 | DOI:10.1136/dtb.2024.000073

PLoS One. 2025 Feb 3;20(2):e0317907. doi: 10.1371/journal.pone.0317907. eCollection 2025.

ABSTRACT

OBJECTIVES: To estimate the prevalence of polypharmacy among community-dwelling adults in the UK and determine its association with mortality, hospitalization, adverse drug reactions and falls at one and five years. To also determine the effect of polypharmacy on the outcomes in different patient groups.

METHODS: A retrospective cohort study was carried out using 1000 patients aged 75 years and above from the Clinical Practice Research Datalink. The study periods for the one- and five-years analysis were January 2010-December 2010 and January 2010-December 2014 respectively. Sociodemographic and clinical variables were retrieved using medical and product codes. Polypharmacy was defined as the use of five or more medicines. The association between polypharmacy and mortality, falls, adverse drug reactions, or hospitalization was determined using cox regression analysis while confounding for age, sex, Charlson's comorbidity index, potentially inappropriate medicines, hospitalization prior to study, and falls prior to study. Subgroup analysis was used to determine the effect of polypharmacy on the outcomes for different patient groups.

KEY FINDINGS: 977 people were reviewed. 36% were male and the mean age was 83 years. The prevalence of polypharmacy was 47%. Adjusted hazard ratios with their 95% confidence intervals for association between polypharmacy and outcomes at five years were: mortality 1.60 (1.30-2.00), hospitalization 1.49 (1.30-1.70), falls 1.49 (0.90-2.40) and adverse drug reactions 0.97 (0.50-1.80). The results for the one-year analysis were mortality 2.37 (1.40-3.90), hospitalization 2.47 (1.40-4.30), and falls 0.37 (0.03-4.00).

CONCLUSION: Polypharmacy was found to be a risk factor for mortality and hospitalization. The risk increased with an increase in age, potentially inappropriate medicines and comorbidities.

PMID:39899651 | DOI:10.1371/journal.pone.0317907

PLoS One. 2025 Feb 3;20(2):e0317734. doi: 10.1371/journal.pone.0317734. eCollection 2025.

ABSTRACT

INTRODUCTION: Chronic kidney disease (CKD) patients suffer from different comorbid conditions and are prone toward drug-related problems (DRPs) which affect their clinical parameters as well as quality of life (QoL). This study was aimed to evaluate the impact of clinical pharmacist-led interventions on the mean number of DRPs and the mean QoL score difference per patient DRPs in CKD patients.

METHOD: An open-labeled, randomized control trial performed from April 2023 to July 2023 in the nephrology unit of a tertiary care setting in Peshawar Pakistan. Those patients who met the inclusion criteria were randomized into two groups 1:1, i.e., control and intervention group. Clinical pharmacists identified the DRPs at baseline using Pharmaceutical Care Network Europe (PCNE) 9.1 guidelines. The QoL of patients were assessed at baseline and endpoint by using the Functional Assessment of Non-Life-Threatening Conditions (FANLTC) questionnaire.

RESULTS: A total of 100 patients were recruited having 50 in each group. The pharmacist identified a total of n = 230 DRPs in the intervention group, majority of the DRPs were attributed to inappropriate drug selection according to guidelines/formulary"; "inappropriate combinations of drugs or with herbal medications or dietary supplements"; and situations where "too many different drugs or active ingredients were prescribed". There was 46.52% reduction in the DRPs while comparing baseline and endpoint interventions suggested by pharmacist in the intervention group. The clinical pharmacist provided interventions in order to resolve the DRPs, and 37.40% interventions were accepted and fully implemented; 31.30% of the interventions were accepted and partially implemented. The clinical pharmacist identification and proposed intervention for DRPs contributed to a statistically significant improvement in QoL, from mean ± SD scored 58.64 ± 9.10 at the baseline to 74.48 ± 10.11 at the endpoint, with a p-value of < 0.001.

CONCLUSION: A significant improvement in the QoL and laboratory parameters for patients with CKD following clinical pharmacist-led interventions having proposed interventions were implemented successfully from baseline to endpoint; however, a considerable number of proposed interventions were not accepted and implemented.

PMID:39899613 | DOI:10.1371/journal.pone.0317734

Naunyn Schmiedebergs Arch Pharmacol. 2025 Feb 3. doi: 10.1007/s00210-025-03838-0. Online ahead of print.

ABSTRACT

PURPOSE: In chronic kidney disease (CKD), raised plasma aldosterone levels are strongly associated with adverse cardiorenal outcomes. Current standard of care may improve outcomes; however, elevated aldosterone levels often persist. We report safety results for BI 690517 (vicadrostat), a potent, selective aldosterone synthase inhibitor under investigation for CKD.

METHODS: Four phase 1 studies of BI 690517 conducted in healthy European/Chinese/Japanese men: two single rising dose (SRD) and two multiple rising dose (MRD) studies.

PRIMARY ENDPOINT: proportion of participants with investigator-defined drug-related adverse events (AEs).

RESULTS: Single and multiple doses of BI 690517 ≤ 80 mg (0.7-80 mg [European SRD]; 3-80 mg [Chinese/Japanese SRD and MRD]) were well tolerated. Proportions of participants with drug-related AEs: European SRD, 8.3% (4/48); Chinese/Japanese SRD, 21.4% (12/56); European MRD, 13.9% (10/72); Japanese MRD, 2.8% (1/36). No serious AEs, deaths, or AEs leading to treatment discontinuation were reported; one AE of severe orthostatic hypotension occurred (European SRD). Plasma exposure to BI 690517 increased dose dependently; median time to maximum concentration was 0.50-1.75 h and mean half-life was 4.4-6.3 h. Exposure was slightly higher in Asians versus Europeans and may relate to lower body weight in Asian participants. A standardized high-fat/high-calorie meal reduced the rate, but not extent, of BI 690517 absorption. Plasma aldosterone concentrations decreased markedly 1-2 h after BI 690517 administration; decreases were more pronounced with increasing BI 690517 doses.

CONCLUSION: BI 690517 was well tolerated and demonstrated dose-dependent inhibition of aldosterone synthesis. Larger studies are warranted to confirm these findings.

PMID:39899058 | DOI:10.1007/s00210-025-03838-0

Int J Med Sci. 2025 Jan 13;22(3):732-744. doi: 10.7150/ijms.103270. eCollection 2025.

ABSTRACT

Aminoglycosides and cisplatin drugs are extensively utilized for their high efficacy in treating various conditions in the clinic, however, their ototoxic side effects warrant significant attention. These drugs could penetrate the inner ear via specific channels or transporters, which not only affect the survival of hair cells but also induce the overproduction of reactive oxygen species. Currently, scientific research mainly addresses this issue through the downstream intervention of reactive oxygen species. However, recent studies have revealed that directly reducing the uptake of these drugs by hair cells can effectively avoid initial damage. In particular, the interactions between drugs and hair cells, as well as the specific functions of relevant channels and transporters, can be explored in detail through the use of molecular dynamics simulations. The swift advancement in the field of structural biology has shed light on the structural functions of various channels and transporters closely related to drug absorption, such as electromechanical transduction channels (MET) and organic cation transporter-2, etc., providing theoretical basis and potential targets for novel ear protection strategies. It is, therefore, imperative to investigate the regulatory role of the MET channel in the up-taking of ototoxic drugs, serving as a pivotal point for the development of preventative and therapeutic approaches. This review aims to highlight the mechanism of inhibition of ototoxic substances absorption by auditory hair cells, explore how to develop novel ear protection methods by targeting these channels and transporters, and provide a new perspective and strategy for addressing drug-induced ototoxicity. The approach to protecting hair cells by targeting these channels and transporters not only broadens our understanding of the underlying mechanisms of ototoxicity, but could also spur further research and progress in the field of auditory protection.

PMID:39898250 | PMC:PMC11783074 | DOI:10.7150/ijms.103270

Cureus. 2024 Dec 31;16(12):e76694. doi: 10.7759/cureus.76694. eCollection 2024 Dec.

ABSTRACT

Most herbal medicines contain licorice, which may inhibit 11-beta-hydroxysteroid dehydrogenase type 2 (11βHSD2). When licorice inhibits 11βHSD2, accumulated cortisol binds excessively to the mineralocorticoid receptor (MR) instead of aldosterone, promoting sodium absorption and potassium excretion. This condition has been called pseudoaldosteronism due to its clinical manifestations resembling those of primary aldosteronism, producing excessive aldosterone. Primary aldosteronism and pseudoaldosteronism usually present with increased urine potassium excretion in the face of hypokalemia due to excessive MR activation by aldosterone and cortisol, respectively, the so-called renal potassium loss. Here, we report an atypical case of licorice-induced pseudoaldosteronism, which unexpectedly presented with decreased urine potassium excretion in the presence of severe hypokalemia in an elderly patient. A spot potassium-to-creatinine ratio was decreased to 4.5 mmol/g creatinine. A 24-hour urine collection also revealed decreased urine potassium excretion of 7.5 mmol/day in the presence of severe hypokalemia. These results on urine potassium were atypical for pseudoaldosteronism. Urine sodium excretion was also significantly reduced to 27.5 mmol/day, suggesting low sodium intake due to anorexia. Low sodium intake followed by low sodium delivery to the collecting duct was the crucial cause of decreased urine potassium excretion in pseudoaldosteronism. Clinicians need to understand the side effects of licorice and assess the risks and benefits associated with the use of licorice-containing drugs, especially in patients with risk factors for pseudoaldosteronism, such as advanced age or low body weight. Careful follow-up of blood pressure or serum potassium concentration is required to prevent the development of pseudoaldosteronism.

PMID:39898153 | PMC:PMC11781896 | DOI:10.7759/cureus.76694

Mol Genet Metab Rep. 2025 Jan 15;42:101189. doi: 10.1016/j.ymgmr.2025.101189. eCollection 2025 Mar.

ABSTRACT

Mucopolysaccharidosis (MPS) IVA (Morquio A syndrome) is an autosomal recessive lysosomal storage disorder caused by a mutation affecting the enzyme N-acetylgalactosamine-6-sulfatase (EC 3.1.6.4, GALNS). Enzyme replacement therapy (ERT) has been shown to improve physical performance, quality of life, and respiratory function in patients with MPS IVA; however, owing to the rarity of MPS IVA, data on Korean patient characteristics are limited. This retrospective study reports clinical, radiographic, biochemical, and molecular findings, and analyzes long-term clinical outcomes, from the largest cohort of Korean patients with MPS IVA in a single center. The analysis included 17 patients from 14 families (58.8 % females; median [range] age at diagnosis 5.2 [1.8-33.7] years). The majority of patients (64.7 %) were classified as having a severe phenotype, 23 % had an intermediate phenotype, and 11.8 % had an attenuated phenotype. Skeletal manifestations and radiologic abnormalities at initial diagnosis included gait abnormality (35.3 %), short stature (23.5 %), chest deformity (23.5 %), scoliosis (17.6 %), kyphosis (11.8 %), dysmorphic face (6 %), hip pain (6 %), and leg deformity (6 %). Twelve different GALNS mutations were identified. Patients received ERT for a median (range) 7.4 years (3.0-12.1). Twelve patients reached final adult height, and all patients with the severe/intermediate phenotype had short stature (<3rd percentile). Hemiepiphysiodesis was the most common surgical intervention among patients with the severe/intermediate phenotype. Drug-related adverse events (urticaria, rash, and anaphylaxis) were reported in four patients but were managed with antihistamines or desensitization. At follow-up, patients experienced improvements in functional independence measure score, ejection fraction, and the 6-min walk test compared with the pre-treatment baseline. This study provides real-world evidence for long-term stabilization of functional independence, endurance, and respiratory function among patients with MPS IVA treated with ERT, with no new safety concerns identified.

PMID:39897469 | PMC:PMC11783393 | DOI:10.1016/j.ymgmr.2025.101189

Cureus. 2025 Jan 2;17(1):e76780. doi: 10.7759/cureus.76780. eCollection 2025 Jan.

ABSTRACT

Angioedema involves fluid accumulation into the interstitial spaces of the dermis, subcutaneous tissue, and mucosal surfaces. While usually benign and self-limited, angioedema can lead to laryngeal edema, a life-threatening condition. The most common causes are histamine-mediated allergic reactions. However, angioedema can also be mediated by bradykinin. Bradykinin-mediated angioedema can occur in the setting of hereditary deficiency of C1q esterase and after exposure to several medications. Drug-induced angioedema is most commonly a secondary complication of non-steroidal anti-inflammatory drug (NSAID) or sulfa drug use. All providers must be aware of the potential side effects of the medications they use or prescribe. We present a case of angioedema resulting from the use of technetium-99m sestamibi tracer injection during an adenosine nuclear stress test.

PMID:39897283 | PMC:PMC11787052 | DOI:10.7759/cureus.76780

Lancet Reg Health West Pac. 2025 Jan 18;55:101464. doi: 10.1016/j.lanwpc.2025.101464. eCollection 2025 Feb.

ABSTRACT

BACKGROUND: Teprotumumab significantly improved proptosis and diplopia in patients with active, moderate-to-severe thyroid eye disease (TED) in previous North American and European studies. This is the first evaluation of efficacy and safety of teprotumumab for active, moderate-to-severe TED in Japanese patients.

METHODS: This randomised, double-masked, placebo-controlled trial was conducted in 16 centres in Japan. Main inclusion criteria were as follows: age 20-80 years; Graves' disease, in a euthyroid or mild hypo/hyperthyroid state; clinical activity score (CAS) ≥3; moderate-to-severe TED; ≥3-mm increase in proptosis before TED onset and/or proptosis ≥18 mm at baseline; and TED duration ≤9 months. Patients were randomised (1:1, stratified by smoking status) to either teprotumumab or placebo. Patients received eight intravenous infusions, one every three weeks for 24 weeks. Patients, investigators, site personnel (except formulating pharmacists) were masked. Primary endpoint was proptosis responder rate (percentage of patients with ≥2-mm proptosis reduction from baseline) at week 24 in the intent-to-treat population. Adverse events were assessed in all patients. This trial was registered at Japan Registry for Clinical Trials (jRCT2031210453).

FINDINGS: Fifty-four patients were randomised (teprotumumab, 27; placebo, 27) between February and November 2022. All patients completed the randomised period, although one teprotumumab patient and two placebo patients missed ≥2 doses. At week 24, the proportion of patients with proptosis response was higher in the teprotumumab group (89%, 24/27) compared with the placebo group (11%, 3/27), 95% confidence interval, 61-95; P<0.0001. Study drug-related adverse events (AEs) occurred in 14 patients (52%) in the teprotumumab group and two patients (7%) in the placebo group; hyperglycaemia-related events were reported in six (22%) and one patient (4%), and hearing impairment in four (15%) and one (4%) patient, respectively. Study drug-related serious AEs and deaths were not reported.

INTERPRETATION: Teprotumumab significantly improved proptosis compared with placebo in Japanese patients with active TED. No study drug-related serious AEs were observed.

FUNDING: Horizon Therapeutics plc (now Amgen).

PMID:39896230 | PMC:PMC11787687 | DOI:10.1016/j.lanwpc.2025.101464