Cerebral vasospasm following aneurysmal subarachnoid hemorrhage remains a leading cause of morbidity and mortality. Endovascular treatment with intra-arterial vasodilators is established for medically refractory vasospasm, yet medication delivery relies on manual hand-syringe injection with limited control over infusion rate and volume. In this proof-of-concept technical note, we describe a workflow innovation repurposing a dual-head programmable power injector (Nemoto PRESS DUO elite, Nemoto Kyorindo) for simultaneous contrast administration and controlled vasodilator infusion during endovascular vasospasm treatment. One chamber delivers contrast for angiographic runs, while the other contains a triple vasodilator cocktail of verapamil, nicardipine, and nitroglycerin, delivered via the injector's programmable Infusion Mode at operator-defined flow rates and volumes. This closed-system, dual-chamber architecture eliminates tableside syringe exchanges, reduces the risk of air entrainment, and enables precise, reproducible multi-agent delivery. In our experience with 9 patients (12 treatment sessions), the injector-based workflow facilitated routine use of the triple vasodilator cocktail with angiographic improvement observed in all sessions. Fluoroscopy time, radiation dose, contrast volume, and total procedural duration did not differ significantly from those of a historical manual-injection cohort, which served as a procedural workflow reference. Because the manual cohort received a different vasodilator regimen without nicardipine, the two cohorts are pharmacologically unmatched and angiographic outcomes were not compared between groups. No procedural complications related to the delivery method occurred. These preliminary findings suggest the dual-head programmable injector provides a feasible, ergonomic, and reproducible closed-system workflow for intra-arterial vasodilator delivery during cerebral vasospasm treatment, with broader applicability to other intra-arterial drug delivery settings.

This historical review provides a short biographical overview of the British pharmacologist Edward Miles Vaughan Williams (1918-2016) and summarises the experimental findings which form the basis for his original definition of three classes of antiarrhythmic drug (AAD) action, i.e. class I action: Na[+] channel block; class II action: suppression of sympathetic activity; class III action: prolongation of action potential duration. As a putative class IV action, central nervous system modulation was discussed. The development and approval of novel antiarrhythmic compounds subsequently required more refined subdivision of class I action and a fourth class of action, i.e. 'Ca[2+] antagonism' as exemplified by verapamil. For half a century, this simple and easy to remember classification has served as an orientation for students and clinicians alike. Nevertheless, it has also been criticised for not being sufficiently systematic and for failing to predict the increased mortality when applied post-myocardial infarction for prevention of sudden cardiac death as published in the Cardiac Arrhythmia Suppression Trial. To overcome this seeming shortcoming, the consensus of the European task force led to a more extensive classification ('The Sicilian Gambit'), with complete listing of multiple actions of the individual antiarrhythmic drugs known at that time. The resulting classification was never widely embraced by cardiologists, most likely due to its inherent complexity. Recently, the original Vaughan Williams classification of AAD action has been expanded in order to reflect today's improved knowledge about arrhythmia mechanisms and to include novel targets for AAD actions, but at the same time, the basic concept that proved so useful in the clinical management remained conserved.

ATP-binding cassette (ABC) transporters play important roles in insecticide resistance, but their functional contributions and structural basis of substrate recognition remain poorly understood. Here, we demonstrate that ABCG9 is an important determinant of chlorpyrifos resistance in Nilaparvata lugens, a destructive rice pest throughout Asia. Verapamil synergism suggested the involvement of active efflux, and expression profiling identified ABCB7, ABCC5, and ABCG9 as constitutively upregulated in the resistant strain and inducible by chlorpyrifos. However, only RNAi-mediated knockdown of ABCG9 significantly increased chlorpyrifos susceptibility, suggesting that this transporter plays a critical role in chlorpyrifos resistance in N. lugens. Structural analysis revealed that ABCG9 adopts a canonical ABCG half-transporter architecture with a conserved N-terminal nucleotide-binding domain (NBD) and a C-terminal transmembrane domain (TMD) containing six helices. Molecular docking and dynamics simulations showed that chlorpyrifos binds within a hydrophobic pocket at the TMD cavity entrance, stabilized primarily by van der Waals interactions (ΔGvdW = -39.04 kcal/mol), with a total binding free energy of -33.46 kcal/mol. Notably, the predicted hydrogen bond was transient, whereas hydrophobic contacts persisted throughout the 100 ns simulation, highlighting the importance of dynamic approaches over static docking alone. These findings identify ABCG9 as a phase III efflux transporter completing the chlorpyrifos detoxification cascade and provide structural insights into substrate recognition by insect ABCG transporters.

Overcoming multidrug resistance (MDR) remains a formidable obstacle in cancer chemotherapy, largely attributable to drug efflux mediated by the P-glycoprotein (P-gp) pump. To address this challenge, we designed and synthesized 27 novel phenylindole derivatives and systematically assessed their MDR-reversal activity in MCF-7/ADR cells. Among these compounds, Ina4 demonstrated potent reversal activity (RF = 229.4), exceeding that of the reference P-gp inhibitors verapamil (RF = 51.0) and cyclosporine A (RF = 103.3), while exhibiting low intrinsic cytotoxicity. Mechanistic investigations, including western blot and Rhodamine 123 (Rh123) accumulation assays, revealed that Ina4 effectively inhibits the efflux function of P-gp without altering its protein expression levels. Furthermore, molecular docking analysis indicated that Ina4 may bind to the active pocket of P-gp, primarily via π-π stacking interactions. Notably, in a 3D tumor spheroid model, co-administration of Ina4 with doxorubicin (DOX) resulted in significant suppression of spheroid growth. Collectively, these findings indicate that Ina4 is a promising P-gp inhibitor.

Although laser-assisted drug delivery (LADD) technology is well established, its clinical application has now expanded to include a broader range of energy-based devices (EBDs). This review aims to evaluate the use of energy-based device-assisted drug delivery (EADD) in the treatment of hypertrophic scars (HTS) and keloids. Following a comprehensive search of English and Chinese databases, 30 relevant studies were included. These studies evaluated the combined application of various EBDs-including ablative and non-ablative fractional lasers, micro-plasma radiofrequency (MPR), ultrasound, and thermomechanical fractional injury-with pharmacological agents such as corticosteroids, 5-fluorouracil (5-FU), verapamil, botulinum toxin type A (BTXA), and photosensitizers (5-aminolevulinic acid). The results indicate that for corticosteroids, EADD achieves efficacy comparable to that of intralesional injection while significantly reducing pain and lowering the risk of skin atrophy and telangiectasia, offering particular benefits for pediatric patients. The combination of EADD with 5-FU effectively improves scar thickness, whereas CO2 AFL-assisted photosensitizers delivery shows an exceptionally low recurrence rate in the treatment of acne-induced HTS. In contrast, for keloids, intralesional BTXA injections remain superior to CO2 AFL-assisted BTXA delivery. Furthermore, emerging strategies such as the triple-modality "light-light-sound" therapy, which combines intense pulsed light, CO2 ablative fractional laser, and ultrasound, provide promising prospects for recalcitrant cases. In summary, EBDs enhance drug delivery through micropore formation or acoustic effects, establishing it as a key therapeutic strategy that balances efficacy with improved safety and patient compliance compared to monotherapy. However, standardized treatment protocols still require further validation through future research.

Cantilever-based biosensors provide a powerful approach for monitoring cardiomyocyte contractility, but conventional designs often exhibit baseline bending that compromises sensitivity and limits predictive accuracy in drug screening. Here, we present a tri-layer polymer cantilever biosensing platform integrated with a full-bridge piezoresistive strain sensor for the quantitative measurement of cardiomyocyte contractility. The hybrid KMSF-SU-8-KMSF structure minimizes residual stress and reduces baseline deformation by more than 85% compared to SU-8-only cantilevers. This architecture improves strain transfer to the embedded sensors and achieves a limit of detection of approximately 1.2 kPa, which is lower than that of previously reported cantilever systems. The top KMSF layer functions as both an encapsulation barrier and a tissue-guiding interface, promoting alignment, enhancing sarcomere organization, and increasing connexin-43 expression to support cardiomyocyte maturation. Drug screening further confirms the platform's predictive accuracy, as the device successfully detects the expected pharmacological effects: verapamil decreases contractile force, isoproterenol increases both force and beat rate, blebbistatin suppresses myofilament activity, and astemizole induces arrhythmic beating consistent with hERG channel blockade. By providing stable, label-free, and high-sensitivity electronic readouts of cardiomyocyte contractility, this platform establishes a robust and scalable solution for preclinical cardiotoxicity testing, disease modeling, and personalized medicine.

Many drugs that block voltage-gated K+ channels encoded by the human ether-à-go-go-related gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically approved hERG blockers, including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism underpins facilitation. We focus on nifekalant, a class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblocking of these open-yet-blocked channels results in supranormal hERG current. We developed rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generated atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements revealed that agonism-while-blocking can result in nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.

Background and Objectives: Vitamin D deficiency has been implicated in muscle weakness and functional decline among older adults. However, its association with sarcopenia-related impairment, particularly when evaluated using readily available nutritional and functional indicators in routine clinical practice, remains incompletely understood. Materials and Methods: This retrospective cross-sectional study included 148 adults aged ≥65 years who attended a Physical Medicine and Rehabilitation outpatient clinic. Sarcopenia-related risk was classified using an EWGSOP2-informed operational framework based on handgrip strength together with nutritional and functional indicators available in the retrospective dataset. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured using a chemiluminescent microparticle immunoassay. Group comparisons, correlation analyses, and multivariable logistic regression analyses were performed. Results: The prevalence of probable sarcopenia and probable sarcopenia with nutritional/functional risk indicators was significantly higher among participants with vitamin D deficiency. Serum 25(OH)D levels differed significantly across the three study groups (p < 0.001). Post-hoc Tukey analysis demonstrated significantly lower serum 25(OH)D concentrations in the probable sarcopenia with nutritional/functional risk indicators group than in both the no sarcopenia and probable sarcopenia groups (both p < 0.001). Serum 25(OH)D levels were moderately and inversely correlated with sarcopenia-related risk severity (r = -0.48, p < 0.001). Lower vitamin D levels were also associated with reduced serum albumin levels and a higher prevalence of falls and assistive walking device use. In multivariable logistic regression analysis, vitamin D deficiency remained independently associated with sarcopenia-related risk after adjustment for age and sex. Conclusions: Vitamin D deficiency was significantly associated with greater sarcopenia-related risk severity and poorer functional status in older adults. Assessment of vitamin D status may therefore represent a simple, inexpensive, and readily available tool for identifying individuals at increased risk of sarcopenia-related impairment in routine geriatric practice. Prospective studies incorporating direct measures of muscle quantity and standardized physical performance assessments are needed to confirm these findings.

Background: The Biopharmaceutics Classification System (BCS) classifies drug substances according to their aqueous solubility and intestinal permeability; however, its application to veterinary drugs should account for species-specific gastrointestinal physiology. Grapiprant is a selective prostaglandin E2 receptor subtype 4 (EP4) antagonist approved as an oral tablet to control pain and inflammation associated with osteoarthritis in dogs, but its properties within the BCS framework remain unclear. Methods: This study evaluated the equilibrium solubility of grapiprant across pH conditions relevant to the canine gastrointestinal tract and calculated the dose number (D0) based on different gastric fluid volumes. A Caco-2 cell monolayer model was used to assess grapiprant intestinal permeability and the effects of time, concentration, pH, and efflux transporter inhibitors on its transepithelial transport. Results: Grapiprant showed relatively small changes in solubility across the tested pH range. D0 varied with pH and gastric fluid volume and approached or fell below 1 at larger fluid volumes. In the Caco-2 model, grapiprant showed generally limited apparent absorptive permeability, with permeability varying with pH. Efflux ratios were greater than 1, and verapamil reduced the efflux ratio, suggesting possible P-glycoprotein (P-gp) involvement. Conclusions: These findings suggest that both solubility and apparent intestinal permeability may limit the oral absorption of grapiprant under certain canine-relevant conditions. Accordingly, this study provides a biopharmaceutical characterization of grapiprant within the BCS framework rather than a definitive canine BCS classification, highlighting the importance of considering canine gastrointestinal conditions when interpreting its solubility and permeability. The results may support future optimization of dosing conditions and oral formulations.