Pharmacology Research & Perspectives

BackgroundThe CXCR2 receptor pathway plays a major role in inflammatory and invasive angiogenesis in human disease. ObjectiveWe evaluated AZD5069, a selective CXCR2 antagonist, as an angiogenesis inhibitor in human cell culture. MethodsHuman Umbilical Venous Endothelial Cells (HUVECs), Human Aortic Endothelial Cells (HAECs), and Human Pulmonary Artery Endothelial Cells (HPAECs) were cultured with standard in vitro techniques. AZD5069 (0, 8, 16, 32, 64, 128, 256 M) was evaluated as an angiogenesis inhibitor with fluorescent-labeled 5-Ethynyl-2-deoxyuridine (EdU) uptake to quantify endothelial cell proliferation, scratch assay to quantify endothelial cell migration, and Geltrex assay to quantify endothelial cell tubule and hub formation. AZD5069 cytotoxicity was evaluated with in situ terminal deoxynucleotidyl transferase 2-Deoxyuridine triphosphate- 5 (dUTP) nick-end labeling (TUNEL) to quantify apoptosis and membrane-impermeable cyanine dye uptake to quantify necrotic cell death. ResultsAZD5069 significantly reduced HUVEC, HAEC, and HPAEC proliferation, migration, tubule count, total tubule length, and node count with a dose-response. AZD5069 did not cause apoptosis nor necrotic cell death. ConclusionsAZD5069 inhibited angiogenesis without cytotoxicity in human endothelial cell culture. The endothelial cell CXCR2 receptor pathway may be a novel target for anti-angiogenesis therapy. AZD5069 may have clinical utility in cardiovascular, oncologic, and inflammatory disease. Condensed AbstractThe CXCR2 receptor pathway plays a major role regulating angiogenesis in inflammation and cancer. The CXCR2 receptor pathway has been evaluated in humans as a target for therapy in inflammatory disease and cancer but not as a therapeutic approach to block pathologic angiogenesis. AZD5069 is a clinical stage, direct CXCR2 antagonist. In human endothelial cell culture, AZD5069 inhibited angiogenesis without causing apoptosis or necrotic cell death. The endothelial cell CXCR2 receptor pathway may be a novel target for anti-angiogenesis therapy. AZD5069 may have clinical utility as a novel angiogenesis blocker in human disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/731993v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1ac8fb4org.highwire.dtl.DTLVardef@ea89forg.highwire.dtl.DTLVardef@607f94org.highwire.dtl.DTLVardef@157cec4_HPS_FORMAT_FIGEXP M_FIG Visual Abstract: AZD5069, a selective CXCR2 antagonist, significantly reduced endothelial cell proliferation, migration, and vascular tubule formation without causing necrotic or apoptotic cell death. The endothelial cell CXCR2 receptor pathway may be a novel target for anti-angiogenesis therapy. AZD5069 may have clinical utility in human cardiovascular, oncologic, and inflammatory disease with pathologic, dysregulated, or excessive angiogenesis. C_FIG

ABSTRACT Background: Post-traumatic elbow stiffness is a recognised complication following orthopaedic trauma surgery, occurring in 10-15% of trauma patients sustaining injuries. Pain remains the primary barrier to physiotherapy compliance, with surgical arthrolysis carrying recurrence rates of up to 34%. The supraclavicular brachial plexus block, referred to as the 'spinal of the arm', provides anaesthesia and analgesia to the entire upper limb below the shoulder. A structured non-surgical approach combining continuous catheter analgesia with timed rehabilitation was identified as an unmet need in this patient group. Methods: A single-centre retrospective observational study was conducted on data of patients treated for post-surgical upper limb stiffness between January 2022 and April 2026. Of 30 patients identified, 28 with elbow involvement formed the primary analysis group following exclusion of 2 patients with isolated wrist stiffness and complex regional pain syndrome. Ultrasound- guided supraclavicular brachial plexus catheters were inserted using the Contiplex system. Patients received 0.5% Bupivacaine (10-15ml) for initial blockade, followed by daily top-up doses of 0.2% Ropivacaine(20ml) given 30 minutes prior to structured physiotherapy and CPM sessions for up to 5 days. The primary outcome was change in arc of elbow motion in degrees, measured by the attending orthopaedic consultant using standard goniometry. Results: Complete pre- and post- intervention data were available for all 28 patients. Mean pre-intervention arc of elbow motion was 39.1{degrees}(SD+/-23.2{degrees}), improving to 104.2{degrees}(SD+/- 30.0{degrees}) post-intervention. Mean improvement was 65.1{degrees}(SD+/- 30.6{degrees} ); 95% CI 53.8{degrees} to 76.4{degrees} ; range 10{degrees}-140{degrees} ; paired t-test t=-11.27, p<0.0001). Mean catheter duration was 5.2 days (SD+/- 1.3). Five patients (17.9%) experienced mechanical catheter complications- 3 dislodgements, 1 kinking and 1 block failure- with no episodes of Local Anaesthetic Systemic toxicity, infection or neurological deficit. Conclusion: Continuous supraclavicular brachial plexus catheter analgesia represents a promising, minimally invasive rehabilitation tool for post-surgical elbow stiffness - achieving statistically and clinically meaningful Range of Motion (ROM) improvement through targeted regional analgesia, without the need for surgical intervention. These findings support prospective evaluation of this protocol as a primary non-surgical rehabilitation strategy.

BACKGROUND. In patients with venous thromboembolism (VTE), renal impairment increases the risks for both recurrence and bleeding. Because these patients are underrepresented in clinical trials, we assessed whether standard direct factor Xa inhibitor (DXI) lead-in followed by early dose reduction was noninferior to standard anticoagulation in patients with acute VTE and moderate-to-severe renal impairment. METHODS. The VERDICT trial was a randomized, prospective, multicenter, open-label, blinded-endpoint, noninferiority trial. Consecutive patients with acute proximal deep-vein thrombosis or pulmonary embolism and chronic renal impairment (creatinine clearance 15?50 mL/min) were randomized 1:1 to an early DXI dose reduction strategy or standard therapy (heparin plus a vitamin K antagonist). Patients allocated to the DXI strategy underwent a second 1:1 randomization to apixaban or rivaroxaban, each administered at an initial standard lead-in dose followed by early dose reduction. The primary outcome was net clinical benefit at 3 months, defined as the composite of major bleeding and symptomatic recurrent VTE. RESULTS. Due to slow recruitment, the trial was prematurely terminated after enrolling 200 of the planned 800 patients (DXI: n=104; standard: n=96). The median age was 85.9 years, 31% were male, and 29.0% had severe renal impairment. The primary outcome occurred in 8 patients (7.7%) in the DXI group and 9 patients (9.3%) in the standard therapy group (adjusted subhazard ratio [sHR], 0.87; 95% CI, 0.26 to 2.87; P = 0.19 for noninferiority; noninferiority margin 1.30). Major bleeding occurred in 6.7% and 6.2% of patients and recurrent VTE occurred in 1.0% and 3.1% of patients, respectively. CONCLUSION. In patients with VTE and moderate-to-severe renal impairment, noninferiority of an early DXI dose-reduction strategy versus standard therapy could not be demonstrated for net clinical benefit. Although no major differences in efficacy or safety outcomes were observed between groups, the reduced sample size precludes definitive conclusions.

The platelet P2Y1 receptor (P2Y1R) is necessary for inflammation, signalling via Rho-GTPase pathways to elicit functions that are distinct from aggregation (PLC-dependent canonical signalling pathway). Whether these distinct platelet inflammatory functions can be selectively suppressed to preserve hemostasis through the rational design of P2Y1R antagonists has not been explored. In silico molecular docking analysis examined biased nucleotide interactions within the P2Y1R binding pocket. The identified possible key amino acid residues guided rational design to synthesize compounds for pathway selective inhibition, evolving from nucleotide to non-nucleotide structures. The nucleotide analogue KMR-82-13 was predicted to engage distinct regions of the binding pocket and selectively inhibited platelet chemotaxis while preserving aggregation. These findings informed the design of a non-nucleotide compound KSN-159-27, aiming to retain key KMR-82-13-like interactions while improving drug-like properties. Docking and molecular dynamics simulation supported a stable but dynamic binding mode for KSN-159-27 within the P2Y1R pocket, consistent with pathway-selective inhibition. KSN-159-27 displayed characteristics of a pathway selective inverse agonist at P2Y1R towards G12/13-mediated pathways, but not those associated by Gq activation in P2Y1R-transfected HEK293T cells. KSN-159-27 showed functionally selective inhibition for platelet P2Y1R-mediated functions. In vivo, KSN-159-27 suppressed inflammatory cell recruitment, whilst preserving bleeding time and ADP-induced thromboembolic responses, in contrast to the neutral P2Y1R antagonist MRS2500. This first demonstration for the rational design of a pathway selective inverse agonist at platelet P2Y1Rs has significant implications for novel therapeutic strategies developed to safely target platelet activation during inflammation, in contrast to current anti-platelet drugs used in the prevention of thrombosis. Key PointsO_LIBiased inverse platelet P2Y1R agonists selectively supress inflammation whilst preserving hemostasis and the ability of platelets to aggregate. C_LIO_LIBiased inverse agonism selectively inhibited P2Y1R G12/13 (Rho-GTPAse functions) but not Gq activities (PLC functions). C_LI

Background: Sphingosine 1-phosphate receptor (S1PR) modulators can cause transient, dose-related negative chronotropic effects. Mocravimod is an oral S1PR modulator that is developed as a maintenance therapy in allogenic haematopoietic cell transplantation (allo-HCT). This phase I study evaluated whether two dose-titration regimens attenuate early bradycardia when initiating mocravimod while preserving pharmacokinetic (PK) and pharmacodynamic (PD) activity. Patients and methods: In this randomized, double-blind, placebo-controlled, parallel-group study, healthy adults received once-daily oral mocravimod using either dose titration (DT) regimen DT1 (0.3-2.0 mg with 4-day stepwise escalation) or regimen DT2 (0.5 mg to Day 14, 1.2 mg Days 15-18, then 2 mg), a fixed 2 mg regimen, or placebo for 21 days. The primary endpoint was the number of bradycardia episodes on treatment initiation and dose-escalation days derived from 24-hour Holter monitoring; PK of mocravimod and mocravimod-phosphate (whole blood) and PD effects (absolute lymphocyte count [ALC]) were assessed. Results: Fifty-six participants were randomized and 53 completed the study. Both titration regimens resulted in fewer bradycardia episodes than fixed initiation at 2 mg during the first week of treatment. Differences between titration and fixed dosing were no longer evident after Day 9, consistent with tolerance development. PK profiles were consistent with prior phase I data. By Day 21, DT1 achieved exposures close to the fixed 2 mg regimen, whereas DT2 yielded lower exposures, reflecting slower escalation. Peripheral lymphopenia developed in all active treatment groups and was comparable between regimens by Day 21, returning toward baseline by study end. Safety was similar between titration regimens and placebo, with similar distribution and incidence of adverse events. No serious adverse events occurred. Conclusion: Two practical titration regimens mitigated the early negative chronotropic effect observed with fixed-dose initiation of mocravimod at 2 mg once daily. Importantly, titration preserved the expected PK and PD profile, supporting dose escalation as an effective initiation strategy to improve early cardiac tolerability.

Effective postoperative pain control is essential following laparoscopic cholecystectomy, yet the analgesic value of a standardised 150 mg preoperative dose of pregabalin has not been clearly established. This systematic review and meta-analysis synthesised evidence from seven randomised controlled trials published between 2008 and 2025 to evaluate the efficacy and safety of pregabalin when administered before surgery. Four trials reported 24-hour postoperative pain scores, and pooled analysis demonstrated that pregabalin significantly reduced pain compared with control (SMD = 0.80 lower; 95% CI, 1.42 to 0.18 lower; p = 0.01), although statistical heterogeneity was high (I-squared = 81%). Pregabalin also produced notable reductions in opioid consumption, including fentanyl (SMD = 1.24 lower; p = 0.002) and tramadol (SMD = 4.21 lower; p = 0.002), again with considerable variability across studies. Sedation was slightly increased but did not reach statistical significance, and there were no significant differences in postoperative nausea, vomiting, or headache. Sensitivity analyses supported the stability of these findings. Overall, the results indicate that a single 150 mg preoperative dose of pregabalin meaningfully reduces postoperative pain and opioid requirements following laparoscopic cholecystectomy while maintaining an acceptable safety profile, supporting its use as part of a multimodal analgesic strategy.

Background. Compounded tirzepatide is prescribed at scale as a cheaper substitute for branded Mounjaro and Zepbound, yet the cost case is almost always built by setting one compounded price against one branded list price. That framing ignores the question that actually decides the answer: cheaper than which branded price the patient can reach. Branded tirzepatide is now sold at sharply different tiers, namely insurance copay (often $25-$150/month), LillyDirect Self Pay ($299-$449/month), and retail cash price ($1,000-$1,200/month). Whether compounded saves money turns entirely on which of these a given patient faces. A second open question is whether the two formulations even produce comparable effectiveness, since observed differences may reflect selection on insurance, baseline characteristics, and adherence rather than the drug. Methods. We conducted a retrospective cohort study of tirzepatide users in the Mochi Health telehealth program, classified by formulation from their refills as branded-only (Mounjaro/Zepbound; 6,238), compounded-only (71,683), or switchers (4,996); switchers were excluded from the formulation contrast. Among single-formulation patients with a documented six-month weight observation, the analytic cohort was 7,271 (869 branded, 6,402 compounded). The primary outcome was six-month percent body weight loss; the secondary outcome was >=10% response. We used 1:1 nearest-neighbor propensity-score matching (0.25 SD caliper) on baseline covariates only - age, sex, baseline BMI, baseline weight, comorbid diabetes, hypertension, dyslipidemia, prior bariatric surgery, and self-reported insurance coverage - deliberately excluding post-treatment variables such as adherence and time in program, which are mediators of the formulation effect. We pre-specified an equivalence margin of +/-2 percentage points on mean loss and tested equivalence with two one-sided tests (TOST). A directed acyclic graph (DAG) makes the identifying assumptions explicit; metformin use could not be reliably ascertained and is treated as an unmeasured confounder. The cost comparison reports the savings or premium of compounded versus branded under five branded price scenarios: retail list, LillyDirect Self Pay (two dose tiers), and insurance copay (typical and low end). It is a cost comparison (cost-minimization under demonstrated similar effectiveness), not a formal cost-effectiveness analysis: we computed no ICER, QALY, or discounting. Results. Branded and compounded patients had similar outcomes even before adjustment (mean loss 11.7% vs 11.5%; >=10% response 60.9% vs 58.8%). The largest baseline difference between the groups was insurance coverage (branded patients far more likely insured; standardized mean difference 0.67), which matching balanced to 0.01. After 1:1 matching (718 pairs, all |SMD| < 0.04), mean loss was 11.4% vs 11.4% (difference +0.08 pp, 95% CI -0.70 to +0.80) and >=10% response 59.3% vs 57.2% (difference +2.1 pp, 95% CI -3.1 to +7.1). The two formulations were statistically equivalent within the pre-specified +/-2 pp margin (TOST p < 0.001). Cost depends on the branded scenario: compounded saves $6,000 over six months versus retail list price, $1,494 versus LillyDirect maintenance-dose (5-15 mg) Self Pay, and $594 over a low-dose (2.5 mg) LillyDirect prescription, while it costs $300 more than branded under a typical insurance copay ($150/month) and is more expensive still at lower copays (savings turn negative below $200/month). Conclusions. Branded and compounded tirzepatide were statistically equivalent in six-month effectiveness within a pre-specified +/-2 pp margin, so the choice between them is essentially a cost decision - and that cost advantage is real but conditional on the branded price the patient can access. It is large against retail list price and shrinks to zero or reverses against LillyDirect Self Pay or a low insurance copay. Whether compounded is the lower-cost choice for an individual patient is, therefore, a question about which price tier that patient faces.

Background & Aims: Activation of apoptosis signal-regulating kinase 1 (ASK1), a ubiquitous redox-sensitive kinase, results in inflammation, apoptosis, and fibrosis, key common pathways in human liver disease. SRT-015 is a novel, small molecule inhibitor of ASK1. This study evaluated the in vitro efficacy of SRT-015, compared it to other ASK1 inhibitors, and determined the in vivo efficacy of SRT-015 across multiple acute and chronic liver disease models. Methods: In vitro studies determined the kinase potency and selectivity of SRT-015, and cellular studies were used to demonstrate direct mechanisms of action. The cardiac hERG channel inhibition was assessed and PK determined in rodents and nonhuman primates. In vivo studies evaluated SRT-015 efficacy in rodent models of drug-induced hepatotoxicity (acetaminophen (APAP) overdose), alcohol-associated liver disease (ALD), metabolic-disease associated steatohepatitis (MASH) and cholestatic disease (bile duct ligation, BDL). Results: SRT-015, was demonstrated a selective ASK1 kinase, and SRT-015 treatment directly inhibited fibrosis, apoptosis and inflammation in activated human fibroblasts, hepatocytes and PBMCs, respectively without safety signals or hERG inhibition. Other ASK1 inhibitors had safety concerns or limited functional activity. Liver and kidney selective PK were observed for SRT-015 in all species evaluated. In vivo, SRT-015 treatment was efficacious in the acute mouse APAP overdose and ALD model significantly (P<0.05) decreasing serum ALT. Using a therapeutic diet-induced obesity (DIO)-MASH model with biopsy-verified fibrosis, SRT-015 treatment significantly (P<0.05) inhibited DIO-induced liver enzymes, hepatomegaly, fibrosis, inflammation, and apoptosis independent of body weight loss whereas treatment with selonsertib was ineffective. In a rat cholestatic model, SRT-015 treatment significantly (P<0.05) decreased fibrosis and stellate cell activation. Conclusions: These findings support SRT-015 as a potential therapeutic for human liver diseases of any etiology.

Background: Postoperative nausea and vomiting (PONV) is a common consequence of anaesthesia, affecting up to 30% of postoperative patients. Female sex is one of the strongest risk factors for PONV, yet no dedicated analysis has examined how this association varies across surgical settings and timepoints. This systematic review and meta-analysis aimed to quantify sex differences in PONV incidence across different surgical contexts. Methods: A systematic search was conducted using PRISMA guidelines across Medline and Embase from inception to September 1, 2025. Eligible studies were observational cohort studies (n[&ge;]500) of adult patients that conducted multivariate regression analyses including sex as a variable. Two reviewers independently screened, extracted data, and assessed risk of bias using ROBINS-E. A random-effects meta-analysis was performed. Subgroup analyses and multiple sensitivity analyses were completed. Results: From 4620 identified studies, 23 met the inclusion criteria, including 462,828 patients across various surgical settings and specialties (52% female). The pooled incidence of PONV was 21% (95% CI[16-27%]), with high heterogeneity (I2=99.9%). Meta-analysis confirmed females had a higher risk of developing PONV compared to males (pooled OR=2.40, 95% CI[2.06-2.79], I2=93.1%, p<0.0001). Sensitivity analyses confirmed robustness of pooled estimates. Subgroup analyses demonstrated consistently elevated risk of PONV for females at all three timepoints (PACU, 24-hour, 48-hour post-operative) and across studies including and excluding female-only surgeries. Studies were generally at high risk of bias. Discussion: Female sex is a strong risk factor for PONV across surgical settings. Further research into precise subgroups, underlying mechanisms of sex-differences, and the use of prophylaxis may help improve this inequity.

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are widely used for the treatment of renal anemia; however, their effects on intraocular vascular endothelial growth factor (VEGF) expression remain unclear. In this study, we examined the effects of all five HIF-PH inhibitors --roxadustat, daprodustat, vadadustat, enarodustat, and molidustat--on Vegfa expression in the retina in mice. C57BL/6J mice were orally administered each inhibitor. Six hours after administration, the kidney, retina, and liver were collected, and transcription levels were quantified by real-time quantitative reverse transcription PCR. Renal Epo transcription was significantly increased by molidustat (P < 0.01), roxadustat (P < 0.01), and enarodustat (P < 0.05). Retinal Vegfa transcription was significantly increased by four inhibitors (P < 0.01), with molidustat showing no significant effect. In the liver, Vegfa transcription was increased by daprodustat (P < 0.05) and vadadustat (P < 0.01). Furthermore, renal Epo and retinal Vegfa transcription levels showed a moderate positive correlation with a marginal trend toward statistical significance (r = 0.37, P = 0.08). These findings indicate that HIF-PH inhibitors differentially regulate hypoxia-responsive genes across tissues and suggest that retinal VEGF upregulation should be considered when evaluating the safety of these agents.

Background: Dietary supplements (DS) are extensively used in Pakistan, frequently in conjunction with prescription medicines. Pharmacists are well positioned for patient counsesling due to their accessibility. However, their ability to provide evidence-based counseling remains uncertain due to their varying knowledge and training, especially in low- and middle-income countries (LMICs), including Pakistan. The study assessed pharmacists' knowledge, attitudes, and practices (KAP) regarding DS counseling and identified gaps requiring intervention. Methods: A cross-sectional study was conducted among 256 registered pharmacists in Lahore, Pakistan. Data were collected using a validated, self-administered questionnaire assessing knowledge, attitudes, and counseling practices concerning dietary supplements over a period of six months i.e., July to December 2025. Statistical analyses were performed using SPSS version 27. A p-value of < 0.05 was considered statistically significant. Results: Mean age was 31.0 {+/-} 6.2 years, with male predominance (56.3%), Doctor of Pharmacy degree (75.0%), community pharmacy practice (62.5%), and 1-5 years of experience (48.4%). Mean knowledge score was 6.18 {+/-} 1.71, with most (76.6%) exhibiting moderate knowledge. Mean attitude score was 7.01 {+/-} 1.94, with 91.4% demonstrating positive attitudes. Mean practice score was 7.91 {+/-} 2.93, with 68% exhibiting good counseling practices. Knowledge scores were significantly higher among female pharmacists (6.96 {+/-} 1.52 vs. 5.57 {+/-} 1.61, p=0.001), urban residents (6.39 {+/-} 1.61 vs. 4.37 {+/-} 1.30, p<0.001), and clinical pharmacists (7.10 {+/-} 1.68, p=0.001). Conclusion: Pharmacists practicing in Lahore, Pakistan demonstrated positive attitudes but moderate knowledge and inconsistent counseling practices. Key gaps were identified in drug-supplement interaction knowledge and counseling practices. These findings underscore the need for organized education, continued training, and regulatory supervision to improve counseling practices of dietary supplements.

Introduction: Conventional substance-level disproportionality analysis may miss safety patterns specific to a dose form, route, or intended site. More granular analyses are hindered by incomplete, inconsistent reporting of product information. The Pharmaceutical Product Identifier (PhPID), representing products by substance, strength, and dose form, may support more granular analyses. Objective: To explore the use of PhPID-like dose form information for site-specific disproportionality analysis in dexamethasone. Methods: We evaluated VigiBase reports (January 1, 2001 - December 31, 2024) for completeness of dose form and route data. We standardized dexamethasone entries to PhPID Level 3 standards, representing substance and administrable dose form. Through disproportionality analysis (Information Component, IC) we compared substance-level and site-specific results. Results: Among 56.4 million suspected/interacting drugs, dose form was reported in 47.7%, route in 69.4%. Among 109,248 dexamethasone entries, 703 dose form and 80 route variations were mapped to 53 and 44 standard codes respectively; about half could be mapped unambiguously. Site-specific analyses revealed biologically plausible patterns not apparent in substance-level analyses. Ocular use showed higher ICs for glaucoma and cataract, while systemic use showed higher IC for psychiatric and endocrine events (e.g., depression, agitation, Cushing's syndrome). IC time-trends suggested that some signals (e.g., cataract with Ocular use) could emerge earlier in site-specific analyses. Conclusion: More granular product information, aligned with PhPID, may improve signal detection and characterization of site-specific safety issues. These findings support granular identifiers in pharmacovigilance while highlighting the need for better capture and standardization of dose form and route of administration data.

Background: Adverse drug withdrawal events (ADWEs) are a key safety concern during deprescribing but remain poorly explored in pharmacovigilance systems. Objectives: To identify and compare ADWE signals across drug classes, different drugs within drug classes, and across patient characteristics, countries, and over time. Methods: A case/non-case disproportionality analysis was conducted in FDA-FAERS and EMA-EudraVigilance pharmacovigilance databases, with stratification by age (adults: 18-64, older adults: [&ge;]65), sex (male/female), reporting time (2004-2023 in 5-year intervals), and country (for EMA data). Disproportionality analysis (quantitative signal detection) was used to detect signals between ADWEs and drugs using the proportional reporting rate (PRR[&ge;]2), reporting odds ratio (ROR>1), and information component (IC>0) with case count [&ge;]5. Results: Overall, 158,501 reports (FDA-FAERS 145,514; EMA-EudraVigilance 12,987) included drug-event pairs related to ADWEs. In FDA-FAERS, clobetasone (IC=5.58; PRR=79.18; ROR=176.90) showed the strongest ADWE signals, followed by hydromorphone (4.85; 29.94; 37.37), hydrocodone, and paroxetine. In EMA-EudraVigilance, ethyl loflazepate (IC=6.01; PRR=119.80; ROR=197.53), clobetasone (5.39; 102.73; 155.10), veralipride, and levomethadone had the strongest signals. Most drugs maintained positive ADWE signals in analysis stratified into adults and older adults. However, among the top 10 drugs (based on highest IC values), buprenorphine/naloxone, desvenlafaxine, and baclofen in FDA-FAERS (ICs 4.95-6.05) showed stronger signals in older adults. A sex-based difference was observed, with paroxetine, venlafaxine, and buprenorphine/naloxone showing a stronger positive signal in females in both databases, whereas several opioids had stronger signals in males versus females across both databases. Conclusion: This study suggests ADWE signals for some medications differ by age and sex, potentially indicating different risks for withdrawal effects.

Introduction: Adverse drug withdrawal events (ADWEs) are a key safety concern with deprescribing but are infrequently reported in trials. Although pharmacovigilance systems have advanced our understanding of medication-related harms, it is unclear how extensively these systems have been used for ADWEs. Objectives: To examine the reporting patterns of ADWEs for all drugs recorded in United States and European pharmacovigilance databases between 2004 and 2023. Methods: A retrospective study was conducted using two pharmacovigilance databases, the publicly available FDA-FAERS dataset and EMA-EV Level 2A (individual-level) dataset. ADWE cases were identified using relevant MedDRA preferred terms. Data on patient characteristics, reporter type, drugs, indication, ADWE outcomes, dechallenge/rechallenge, seriousness criteria, time to onset, duration, and causality were summarised. Results: A total of 158,505 ADWE reports were analysed (FDA-FAERS: 145,514; EMA-EV: 12,987), with mean ages of 46.1 (FDA; 55.3% female) and 45.5 years (EMA; 57.1% female). The frequently reported drug classes were opioids (FDA: oxycodone, 29.8%; EMA: buprenorphine, 19%), antidepressants (FDA: duloxetine, 32%; EMA: venlafaxine, 25.9%) and gabapentinoids (FDA: pregabalin, 6.7%; EMA: pregabalin, 6.0%). The most common adverse outcomes were other serious medical conditions (FDA=63.9%; EMA=46.0%), hospitalisation (FDA=15.9%; EMA=28.3%), and disability (FDA=13.3%; EMA=6.2%) and these outcomes varied significantly based on sex and age group (p<0.05). Conclusions: This study provides novel evidence of reporting patterns and characteristics of ADWEs across drugs in pharmacovigilance data. These findings emphasise that adverse drug reaction reporting systems need to accommodate ADWEs (i.e., clarity on terminologies, dechallenge/rechallenge, causality assessment) to effectively capture ADWE-related data to support evidence-based deprescribing practices for better patient safety

Immunosuppressive drugs, which are required to maintain graft function in transplant recipients, are associated with many unavoidable side effects including posttransplant diabetes mellitus (PTDM) that involves both peripheral insulin resistance and impairment of insulin secretion. To characterize in detail the concentration-dependency of the effect of well-known immunosuppressive drugs on glucose-stimulated insulin secretion (GSIS), we performed dynamic perifusion studies with human pancreatic islets. The effect on the time-profile of GSIS has been assessed over a wide concentration range for several clinically relevant immunomodulatory therapies, including small-molecule drugs (cyclosporine, sirolimus, tacrolimus, prednisolone acetate, and loteprednol etabonate) and biologics (abatacept and anti-CD40L), plus a prospective {beta}-cell proliferation-inducing agent (harmine). While biologics showed no significant detrimental effects after one-day treatment even at relatively high concentrations (5 {micro}M), all small-molecule drugs inhibited insulin secretion in a concentration-dependent manner, although glucocorticoids showed a distinct response pattern. Calcineurin and mTOR inhibitors preserved GSIS within their therapeutic ranges but progressively distorted its time-profile at higher concentrations and completely suppressed secretion at the highest levels. Cyclosporine exhibited the least, only about 35-fold, separation between its therapeutic target (Ctarg) and half-maximal GSIS inhibitory (IC50) concentrations. Glucocorticoids did not alter the shape of the time-profile but inhibited overall insulin secretion even at therapeutic levels. Their inhibitory effect only increased slowly with concentration and did not follow a classic sigmoid pattern that has unity Hill slope. These findings establish quantitative benchmarks for immunosuppressant-induced {beta}-cell toxicity and provide a framework for optimizing immunosuppressive regimens to reduce the risk of PTDM.

GLP-1 receptor agonists achieve weight loss but are associated with clinically significant reductions in lean mass. Activin type II receptors (ActRIIA and ActRIIB) mediate signaling of myostatin and activin A, both of which negatively regulate muscle growth, suggesting that dual blockade of these receptors may preserve or increase lean mass while promoting fat loss. In this study, we developed anti-ActRIIA/B antibodies using AI-driven platforms (AlfaDAX) and selected the lead candidate AB130-165 based on in vitro binding, functional blocking, and developability assessments. Compared with a laboratory-prepared bimagrumab analog, AB130-165 exhibited potent dual inhibition of ActRIIA/B signaling, with a 9.5-fold higher functional blocking activity against activin A-induced SMAD signaling and 1054-fold improvements in binding affinity for ActRIIA (KD = 0.204 pM), 10-fold for ActRIIB (KD = 0.243 pM), respectively. In diet-induced obese mice, combination therapy with AB130-165 and semaglutide resulted in a 33.4% body weight reduction, which was superior to semaglutide monotherapy (-24.3%) and the bimagrumab combination group (-25.5%). Moreover, the combination significantly improved body composition, reducing fat mass percentage by 77.8% (vs. 65.0% in the bimagrumab combination group) and increasing the lean-to-body weight ratio to 67.3% (vs. 62.3%), demonstrating superior fat loss with better preservation of lean mass. Collectively, these findings establish AB130-165 as a differentiated anti-ActRII antibody that enables high-quality weight loss, and its combination with semaglutide shows superior efficacy over bimagrumab-based regimens. With favorable developability and potential for long-acting subcutaneous administration, AB130-165 represents a promising next-generation therapeutic candidate for obesity and muscle-sparing weight management.

BACKGROUND: Caudal block is widely employed in pediatric lower abdominal surgeries and adult anorectal surgical by its simplicity of operation, reliable efficacy, and high safety. Previous studies have found that the dose of ropivacaine for Caudal block in adults exhibits gender differences. However, it remains unclear whether such differences in the median effective concentration (EC50) of ropivacaine also exist in the elderly population . METHODS: This is a double-blind, prospective study, We enrolled patients aged 60-80 years with ASA physical status I-? who were scheduled for anorectal surgery under caudal anesthesia, and allocated them to 2 study groups according to their gender. Each participant received a single injection of 20mL ropivacaine. Using Dixons up-and-down sequential allocation, the initial concentration of ropivacaine was set at 0.35% and the subsequent concentrations were determined by the analgesic response of the previous patients to the pinprick testing. The concentration change was 0.025%. The EC50 of ropivacaine in each group was determined using the the up-and-down method and probit regression. The primary outcome was the EC50 (95% confidence interval [CI]) of the 2 groups. Data on the surgical time, analgesic duration, and adverse events during surgery were also recorded. RESULTS: This study included a total of 40 elderly patients (20 male and 20 female). The EC50 of ropivacaine for caudal block in elderly male patients was 0.263% (95% CI: 0.179%-0.311%), while that in elderly female patients was 0.281% (95% CI: 0.161%-0.353%). The EC50 of ropivacaine for caudal block in elderly female patients was approximately 6.4% higher than that in elderly male patients. CONCLUSIONS: There is a significant gender difference in the EC50 of ropivacaine for caudal block among the elderly, with elderly female requiring a higher EC50 than male.

Background & AimsCurrent nucleos(t)ide analogs efficiently suppress hepatitis B virus (HBV) replication but have limited effects on viral transcription from covalently closed circular DNA (cccDNA) and integrated HBV DNA. We aimed to identify clinically applicable compounds that directly inhibit HBV transcription by screening FDA-approved drugs. Approach & ResultsScreening of 1,470 FDA-approved compounds using an HBV enhancer I/X promoter reporter system identified vorapaxar and aripiprazole as potent inhibitors of viral promoter activity. Both compounds suppressed HBV replication in HBV-producing cells, HBV-infected HepG2-hNTCP cells, and primary human hepatocytes. Aripiprazole reduced hepatocyte nuclear factor 4 (HNF4) protein levels through an ERK/JNK-dependent pathway and inhibited HBV core promoter activity, whereas vorapaxar acted independently of HNF4. Both compounds suppressed enhancer I/X promoter activity through inhibition of STAT3 signaling. Vorapaxar inhibited PAR-1-mediated SRC, EGFR, and STAT3 activation, while aripiprazole suppressed SRC-STAT3 signaling independently of EGFR. PAR-1 activation enhanced HBV transcription, whereas PAR-1 knockdown reduced promoter activity and viral RNA expression. Both compounds also reduced HBV replication in human liver chimeric mice at clinically relevant exposure levels without apparent severe toxicity. ConclusionsVorapaxar and aripiprazole suppress HBV transcription and replication through distinct host signaling pathways. These findings identify PAR-1-STAT3 signaling as a previously unrecognized regulator of HBV transcription and suggest that host-targeting approaches may complement current therapies by suppressing viral gene expression from both cccDNA and integrated HBV DNA. Impact and implicationsCurrent nucleos(t)ide analogues effectively suppress HBV reverse transcription but have limited effects on viral transcription from cccDNA and integrated HBV DNA, highlighting the need for therapies targeting viral gene expression. We identify PAR-1- STAT3 signaling as a previously unrecognized regulator of HBV transcription and demonstrate that two clinically approved drugs, vorapaxar and aripiprazole, suppress HBV replication through distinct host signaling pathways. These findings are relevant to researchers developing host-targeting antivirals and to clinicians seeking complementary therapeutic strategies beyond current nucleos(t)ide analogue therapy. Although further clinical validation and combination studies are required, our results provide a rationale for repurposing approved drugs and for developing transcription-targeting therapies that may complement existing treatments for chronic hepatitis B. HighlightsO_LIVorapaxar and aripiprazole suppress HBV through distinct host pathways. C_LIO_LIBoth drugs inhibit HBV replication in vitro and in humanized liver mice. C_LIO_LIPAR-1 inhibition reduces HBV transcription by blocking SRC/EGFR/STAT3 signaling. C_LIO_LIPAR-1-STAT3 signaling is a novel regulator of HBV transcription. C_LIO_LIHost-targeting antiviral therapy complements current HBV treatment. C_LI

Repeated low-dose psilocybin is being developed as a scalable outpatient treatment for mood and anxiety disorders, but chronic exposure raises concern because psilocin binds the cardiac serotonin 5-HT2B receptor, whose sustained agonism causes drug-induced valvular heart disease (VHD). We evaluated this risk using an exposure-response model that incorporates functional efficacy and exposure duration rather than binding affinity alone. Plasma psilocin concentrations were converted into the time-integrated increment in 5-HT2B Gq signaling above endogenous serotonergic tone ({Delta}TIA) and calibrated against drugs and conditions with known valvular outcomes. All modeled exposures known to cause human VHD scored {Delta}TIA [&ge;] +172 %{middle dot}h/day, whereas exposures not associated with VHD scored [&le;] +28. A candidate 3 mg daily psilocybin regimen scored {Delta}TIA +3, roughly two orders of magnitude below the weakest valvulopathic exposure. This safety margin arises from psilocins low-efficacy partial agonism at 5-HT2B (Emax {approx}51.8% of serotonin, compared with 96% for norfenfluramine) and its short half-life ({approx} 2.5 h), which prevents accumulation and produces brief daily receptor engagement. In support of the model, rats receiving continuous psilocin for 12 days at plasma concentrations {approx}2.4-fold above the projected human peak for 3 mg daily psilocybin showed no valvular lesions by blinded histopathology. This exposure duration however cannot exclude slowly developing fibrosis. Emerging human data, including serial echocardiography in repeated LSD microdosing and a large observational cohort, are also agreement with the model. Collectively, these findings suggest a favorable safety margin for daily, sub-hallucinogenic psilocybin use in clinical indications. Nevertheless, continued pharmacological and clinical investigations should include prospective echocardiographic monitoring to advance the clinical safety profile of sub-hallucinogenic psilocybin and support its evaluation across a broad array of therapeutic programs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=54 SRC="FIGDIR/small/739440v1_ufig1.gif" ALT="Figure 1"> View larger version (10K): org.highwire.dtl.DTLVardef@1ef0508org.highwire.dtl.DTLVardef@1337d52org.highwire.dtl.DTLVardef@1689943org.highwire.dtl.DTLVardef@261605_HPS_FORMAT_FIGEXP M_FIG C_FIG Three key determinants of cardiac safety margins for repeated low-dose psilocybin are shown. Psilocin is a low-efficacy partial agonist at 5-HT2B (ceiling {approx}52% vs 96% for norfenfluramine; left). Its short half-life yields a brief daily pulse of receptor engagement rather than a sustained plateau (center). The resulting integrated 5-HT2B signal ({Delta}TIA) at 3 mg daily lies roughly two orders of magnitude below valvulopathic exposures, and continuous in vivo exposure produced no valvulopathy (right).

Wallerian degeneration of anucleated axonal segments is driven by SARM1, which depletes axonal NAD+, disrupting energy metabolism and triggering self-destruction. SARM1 inhibition is an emerging therapeutic target for traumatic nerve injuries. Boldine, a natural aporphine alkaloid from Peumus boldus, modulates connexin hemichannels, oxidative stress, and inflammation. Building on our published work showing boldines neuroprotective effects in nerve injury models, we hypothesized that boldine also inhibits SARM1 directly. A fluorescence polarization assay revealed that boldine inhibits SARM1 NADase activity with an IC50 of approximately 7.5 uM. AI-assisted structural modeling (AlphaFold3-based Boltz-1 with GNINA docking) predicted two boldine binding sites on SARM1: the TIR catalytic site (Kd [~] 13.5 uM) and the ARM-TIR regulatory interface (Kd [~] 12 uM). In a sciatic nerve explant model, boldine preserved the integrity of anucleated axonal segments at 3 and 7 days post-transection relative to vehicle controls. These findings suggest boldine may act as a dual-site SARM1 inhibitor and support its development as a neuroprotective therapy after traumatic axonal injury.