ABSTRACTRare adverse drug reactions (ADRs) are underrecognized and underreported in the electronic medical record (EMR). These events often require clinical review, making systematic identification challenging. The study aim was to develop an approach to prioritize identification and validation of a rare ADR to trimethoprim‐sulfamethoxazole causing acute respiratory distress syndrome (TMP‐SMX ARDS) across medical institutions. We developed a clinical phenotype based on 2 local TMP‐SMX ARDS cases mapped to standardized elements of a national comparative healthcare database (PHIS). We validated identification of TMP‐SMX ARDS at scale across medical institutions. A set of scoring criteria was created to prioritize cases and generate a center‐specific top 10 list of candidate encounters. External validation at 3 PHIS contributing hospitals with a known TMP‐SMX ARDS case was performed by reviewing the top 10 candidate list for the known case. The review period was January 1, 2012–January 1, 2025. EMR data extracted from 2 TMP‐SMX ARDS cases included patients that both required extracorporeal membrane oxygenation for > 100 days, experienced air leak early in hospital presentation, required tracheostomy placement, and were hospitalized for > 440 days. Based on the TMP‐SMX ARDS phenotype, the local cases ranked 1st and 3rd on the PHIS generated top 10 candidate list for internal validation. For external validation, known cases were identified on their respective hospital top 10 lists, ranking 3rd, 3rd, and 5th. Applying a TMP‐SMX ARDS phenotype to a national health care database paired with clinical review of candidate cases may be an effective approach to identify underrecognized ADRs.

ABSTRACTInterindividual variability (IIV) in drug response complicates both fixed‐dose design and individualized therapy. Understanding how pharmacokinetic (PK) and pharmacodynamic (PD) processes jointly shape this variability is essential, particularly in combination therapy, where multiple interacting pathways influence outcomes. This study employed a unified PK–Signal–Reaction–Stimulus–Response (PK–SRSR) modeling framework to quantify and compare the impact of IIV in PK and PD parameters under monotherapy and combination therapy. Monte Carlo simulations were used to generate response distributions across hypothetical physiological conditions, while Sobol variance‐based sensitivity analysis decomposed total response variability into contributions from individual parameters (FOI) and their interactions (TOI). Results showed that PD variability, especially that related to system‐level modulatory processes (S0A, S0B, βA, βB, and βiA), exerted a greater influence on overall response than drug effect level PD (SmaxA, SmaxB, KA, and KB) variability and PK (CLA/F and CLB/F) variability. Variability in response was most sensitive to S0B, βB (FOI > 34%, TOI > 32%) during monotherapy and SmaxA (FOI > 25%, TOI > 27%), SmaxB (FOI > 17%, TOI > 24%), and βB (FOI > 32%, TOI > 34%) during combination therapy. At 45% CV in all parameters, variability in response was lower during combination therapy (CV = 44%, 42%, and 33%) than during monotherapy (CV = 59%, 52%, and 53%) for additive, antagonistic, and synergistic PD interactions, respectively. Introducing a second drug targeting a modulatory pathway reduced response variability by stabilizing regulatory mechanisms, explaining previous observations in which patients achieve therapeutic response despite suboptimal plasma concentrations during combination therapy. Coordinated dose optimization of all agents, supported by response‐guided, system‐aware strategies, may yield more robust, consistent, and individualized treatment outcomes than traditional PK‐guided dosing approaches.

ABSTRACTColorectal carcinoma (CRC) ranks among the top five most common malignancies globally, characterized by a high incidence and poor prognosis. Hepatocyte growth factor receptor (HGFR), a tyrosine kinase oncoprotein, plays a critical role in tumor progression. This study aimed to investigate the effects of stylosin (STL), a natural monoterpene, on human CRC cells, with focus on its potential interactions with HGFR. For computational analysis, the expression of HGFR was assessed in CRC tissues, pharmacokinetics of STL were predicted, and the interaction between STL and HGFR was determined by molecular docking. For experimental studies, STL was isolated from Ferula ovina roots via thin layer chromatography, and its structure was confirmed by 1H NMR spectroscopy. LoVo cells were treated with STL at concentrations of 25, 50, and 100 μM for 24, 48, 72, 96, and 120 h. Cell viability was assessed by alamarBlue, while apoptosis was evaluated by annexin V‐FITC/PI staining followed by flow cytometry analysis. Results demonstrated significant overexpression of HGFR in CRC tissues relative to normal samples. The pharmacokinetic analysis of STL predicted high bioavailability, favorable distribution, and low toxicity risks. Molecular docking predicted a favorable binding affinity of STL to the active site of HGFR. Treatment with STL led to a dose‐dependent decrease in cell viability, with the most pronounced cytotoxic effect observed at 100 μM. This was supported by notable morphological changes and increased apoptosis in treated cells. Collectively, the present findings show anticancer activity of STL in CRC cells, with computational predictions suggesting possible HGFR involvement and favorable pharmacokinetic properties. These results provide initial evidence supporting further investigation and position STL as a potent agent against CRC.

ABSTRACTThe absolute number of spontaneous adverse drug reaction (ADR) reports increased in the past in several national and international ADR databases. However, in most studies drug exposure was not considered. Our study aimed to evaluate the number of ADR reports from Germany in relation to the number of patients with outpatient drug prescriptions stratified by sex, age groups, seriousness, and reporter types (physician versus consumer). Therefore, 407 882 spontaneous ADR reports from Germany, after exclusion of ADR reports related to vaccines, intentional misuses and accidental exposure, submitted between 01.01.2012 and 31.12.2021 were analyzed. The annual numbers of patients with at least one outpatient drug prescription were provided by the Central Research Institute for Ambulatory Health Care in Germany. Reporting rates per year were calculated by dividing the annual number of spontaneous ADR reports by the annual number of patients with at least one outpatient drug prescription. Between 2012 and 2021 (2.4‐fold), and strikingly between 2017 and 2018 (2.2‐fold), the annual reporting rate increased. This increase appears to be primarily driven by non‐serious ADR reports submitted by consumers (32.5‐fold increase), whereas reporting rates for serious ADRs and for reports submitted by physicians remained stable. Furthermore, the rise of non‐serious ADR reports from consumers was particularly apparent for females aged 12–17 and 18–64 years. Overall, the observed increase of non‐serious ADR reports is most likely related to changes in reporting obligations for pharmaceutical companies. Our study suggests that females might report ADRs more frequently.

ABSTRACTSyntaxin‐binding protein 1 (STXBP1) mutations lead to severe epilepsy, intellectual disability, developmental delay, and movement disorder. Effective treatments for these conditions do not exist. Recent studies in Munc18‐1 (STXBP1) C. elegans models demonstrate that 4‐phenylbutyrate (4‐PBA) or related pharmacological chaperones stabilize Munc18‐1 protein levels and rescue locomotion deficits. These studies suggest a novel treatment strategy for these patients. Here, we used a stxbp1a zebrafish model with a profound movement disorder to screen 4‐PBA and alternative structural analogs identified using artificial intelligence (AI)‐based screening. Automated locomotion assays conducted on larval stxbp1a mutant zebrafish at 5 days post‐fertilization (dpf) confirm and extend the movement disorder endophenotype. Drug treatment (4‐PBA or 16 identified candidates) failed to rescue the stxbp1a mutant zebrafish locomotion deficit. Electrophysiology studies in a stxbp1b zebrafish model characterized by spontaneous seizure activity (i.e., epilepsy) failed to detect a reduction in ictal‐like events with 4‐PBA treatment. Taken together, our results suggest caution in repurposing 4‐PBA or related compounds for the treatment of STXBP1 disorders.

ABSTRACTThe teaching of pharmacology includes a fundamental understanding of ligand binding; how it is measured and how it is calculated. We sought to modernize the techniques by which ligand affinity is determined by undergraduate students and introduce them to parameter estimation through curve fitting. We taught a NanoBRET ligand binding assay to student cohorts completing their second year of undergraduate study in Natural Sciences (71 and 61 students in 2024 and 2025 respectively). The aim was to measure the affinity of fluorescent and unlabeled ligands for the β2‐adrenoceptor in live cells. Affinities were then calculated from their data using a custom Microsoft Excel spreadsheet. This series of practical classes was well received by students, with most students able to follow the protocol and successfully determine ligand affinities. Furthermore, students recognized the benefit of the practical class for their education, confirming they felt it improved their understanding of how ligand affinity is calculated. We also demonstrated that this protocol could be scaled up to accommodate larger class sizes (class of 367 students studying medicine and veterinary sciences).

ABSTRACTSynthetic cannabinoids remain one of the most prominent classes of New Psychoactive Substances (NPS). The introduction of “blanket bans” has only invigorated the development and emergence of novel compounds. Recently, a putative synthetic cannabinoid, AB‐MDMSBA, was identified in Australia and New Zealand, with little to no pharmacological data on this compound. This current study, therefore, aimed to determine the potential activity of AB‐MDMSBA at the human cannabinoid CB1 receptor. Results revealed AB‐MDMSBA failed to activate cAMP and β‐arrestin 2 pathways, or to induce a conformational change in a CB1 biosensor, unlike the known synthetic agonist AMB‐FUBINACA, suggesting the compound is not a synthetic cannabinoid. These findings may aid in drug classification and the identification of structurally similar compounds.

ABSTRACTStatins, widely prescribed for cardiovascular prevention, have emerged as potential disease‐modifying agents in neurodegenerative disorders due to their pleiotropic effects on cholesterol metabolism, neuroinflammation, oxidative stress, and protein aggregation. Over the past decade, growing interest has focused on the potential repurposing of statins for Parkinson's disease (PD) and Alzheimer's disease (AD); however, clinical evidence remains heterogeneous and, in some cases, contradictory. This state‐of‐the‐art review synthesizes clinical and preclinical studies published between 2021 and 2025 to critically evaluate the therapeutic potential and limitations of statins in PD and AD. Recent observational studies and large‐scale cohort analyses suggest that long‐term statin use may be associated with a reduced risk of incident PD and AD, as well as slower cognitive decline in selected patients' subgroups. However, these associations appear to depend on factors such as statin lipophilicity, treatment duration, and genetic background. Preclinical models provide mechanistic support, showing that statins can attenuate neuroinflammation, modulate microglial activation, reduce α‐synuclein aggregation in PD models, and interfere with amyloid‐β production and tau phosphorylation in AD models. Nevertheless, randomized controlled trials remain limited in number and often underpowered, and some reports indicate neutral or even adverse neurological outcomes, underscoring the complexity of cholesterol‐dependent and cholesterol‐independent mechanisms in the central nervous system (CNS). Collectively, the evidence from 2021 to 2025 highlights both the therapeutic promise and the unresolved challenges of statin repurposing in neurodegenerative diseases. Future research should prioritize well‐designed clinical trials and biomarker‐driven patient stratification to determine whether statins can be effectively leveraged as adjunctive disease‐modifying therapies in PD and AD.

ABSTRACTThis prospective observational study investigated the acute effects of a single 10 mg dose of methylphenidate (MPH) on hemodynamic and electrocardiographic parameters in 60 children aged 6–16 years newly diagnosed with Attention Deficit Hyperactivity Disorder (ADHD). All participants received 10 mg short‐acting MPH, and systolic and diastolic blood pressure, heart rate, and electrocardiographic measurements (QTc, PR, QRS intervals, and rhythm) were obtained both before and 30–45 min after administration under standardized conditions and interpreted by a pediatric cardiologist. Following MPH intake, significant increases were observed in systolic blood pressure (105.0 ± 7.7 to 110.1 ± 8.9 mmHg, p < 0.001), diastolic blood pressure (69.3 ± 9.2 to 73.4 ± 9.8 mmHg, p < 0.001), and heart rate (79.8 ± 9.0 to 84.9 ± 9.8 bpm, p < 0.001). QTc (395.9 ± 11.6 to 401.0 ± 12.5 ms), PR (135.8 ± 16.8 to 140.9 ± 16.7 ms), and QRS durations (91.1 ± 9.5 to 93.6 ± 9.5 ms) also showed significant prolongation (all p < 0.001). Post‐treatment ECG rhythm abnormalities were observed in 15.0% of participants (p = 0.002), including sinus tachycardia, sinus arrhythmia, and isolated premature atrial or ventricular beats, with markedly higher prevalence among those below the 5th BMI percentile (75.0%, p < 0.001), whereas no rhythm disturbances were detected in the 5th–85th percentile group. These findings indicate that MPH induces acute but measurable cardiovascular changes in children with ADHD, particularly in underweight children, underscoring the need for ECG and blood pressure monitoring during treatment initiation.

ABSTRACTPodocarpus neriifolius, a widely distributed medicinal plant in South and Southeast Asia, has traditionally been used to treat rheumatism and joint pain. This study aimed to investigate the phytochemical profile and therapeutic potential of the ethanolic leaf extract of P. neriifolius (EEPN) using integrated in vitro, in vivo, and in silico approaches. Phytochemical analysis via FT‐IR and GC–MS revealed the presence of steroidal glycosides, flavonoids, alkenes, aliphatic compounds, steroids, saponins, and other glycosides. In a COX inhibition assay, EEPN demonstrated notable in vitro anti‐inflammatory effects, further validated in a mouse paw edema test. In Swiss albino mice, EEPN (200 and 400 mg/kg) showed increased head dipping in HBT (43.4 ± 1.14 and 69.2 ± 1.22), where the standard showed (57.5 ± 1.01), and improved open‐arm entries and time in EPM (260.3 and 280.6 s) compared to the standard (245.2 s). EEPN produced a dose‐dependent sedative effect both in HCT and OFT. Furthermore, EEPN significantly lowered immobility time in the tail suspension and forced swimming tests, demonstrating its antidepressant effects. According to molecular docking studies, the phytochemicals in EEPN showed a strong affinity for binding to important drug target proteins linked to inflammation, anxiety, and depression. The EEPN had binding affinities of −6.6, −5.4, and −10 kcal/mol with COX2, GABAA, and the serotonin transporter, respectively. Protein‐ligand complex stability was validated through molecular dynamics simulations analysis. The pharmacokinetic and safety profile of the compounds in ADMET analysis showed druggable qualities within acceptable ranges, implying the possibility as potential medications in the future. However, further research is necessary to ascertain whether P. neriifolius leaves can be utilized as a therapeutic agent.