Medicine and Pharmacology

Abstract: Palatability critically determines pediatric medication adherence, yet the impact of oral cavity dilution and salivary pH on the sensory performance of formulations remains poorly characterized. This study provides the first systematic, biorelevant evaluation of how dilution and physiologically relevant pH affect the palatability of three commercially available hyoscine butylbromide (HBB) syrup brands (X, Y, and Z), extending prior characterization of undiluted formulations. Samples were evaluated using an Alpha Astree II electronic tongue (ChemFET array). Dilution with water and with 2 mL or 5 mL phosphate-buffered saline (PBS) at pH 6.2, 6.8, and 7.4 replicated residual salivary volumes and physiological pH across pediatric and adult populations. Pure HBB API solutions were tested in parallel. Principal component analysis (>85% cumulative variance) confirmed robust discrimination across all conditions. Water dilution increased bitterness across all brands by disrupting excipient matrix integrity, with cellulosic polymer-containing Brands X (HEC) and Y (HPMC) retaining superior taste masking over polymer-free Brand Z. PBS dilution revealed pH-dependent, brand-specific palatability responses: at pH 6.2, 6.8, and 7.4, the hierarchy was consistently Y > X > Z, confirming the robust superiority of Brand Y's HPMC-based taste-masking system across the full physiological salivary pH range. Notably, Brand X exhibited substantially higher ANS sweetness scores than Brand Y at 2 mL pH 7.4 PBS, reflecting differential sweetener system sensitivity to near-neutral PBS ionic conditions. Increasing simulated salivary volume from 2 mL to 5 mL amplified bitterness and attenuated sourness across all brands. Taste-masking strategies that rely solely on sweeteners, without viscosity-building polymers, are inadequate under biorelevant oral conditions. pH-stratified assessment is essential for comprehensive characterization of palatability in pediatric oral liquid formulations.

Abstract: Background/Objectives: Minzasolmin is a weakly basic drug developed as a potential therapy in Parkinson’s. Amongst the strategies that have been developed to enhance API solubility, pH modification is an effective and patient-centric one that improves solubility by creating a microenvironmental pH around the drug. The objective of this study was to evaluate different formulation approaches to develop an immediate-release tablet or capsule containing fumaric acid as pH-modifier. Methods: Ten formulations were developed varying the degree of contact between the API and pH-modifier. These formulations were then tested in three Biorelevant dissolution conditions to estimate their robustness towards variations in gastric pH. Results: In vitro data showed the best dissolution rate with the over-encapsulated tablet prototype, even in highly buffered achlorhydric conditions and was therefore the most robust formulation toward elevated gastric pH. However, in low buffered achlorhydric conditions the monolayer tablet with acid exhibited similar dissolution rate and prototypes with less close contact between the API and the organic acid also demonstrated improved dissolution rates. Conclusions: These results suggested that the acidic microenvironment may not require such a high degree of contact between the API and the pH-modifier. Selected prototypes will be evaluated in vivo in a future study to evaluate the bio-relevance of the approach.

Abstract: Polymeric microneedles have emerged as promising platforms for minimally invasive drug delivery, yet their clinical translation remains limited despite extensive proof-of-concept research. This review critically examines polymeric microneedles from a function-driven design perspective, linking classification, fabrication, and material selection to the principal determinants of performance and translational success. Particular attention is given to the interplay among microneedle geometry, polymer properties, skin biomechanics, and application conditions, which collectively define the mechanical window required for reliable insertion. Drug release is considered a programmable design function that should be aligned with dose and pharmacological objectives, while polymer dissolution, degradation, persistence, and potential accumulation are evaluated in relation to safety and regulatory acceptance. Stimuli-responsive and hybrid systems are also assessed by weighing their functional benefits against the additional complexity they introduce. Recurring mechanical, pharmacokinetic, manufacturing, and clinical design–performance mismatches are identified as major contributors to the gap between laboratory success and clinical implementation. Based on these findings, a function-driven framework is proposed that integrates therapeutic objectives, insertion performance, release kinetics, manufacturability, and safety from the earliest stages of development, thereby supporting the rational design of clinically viable next-generation microneedle systems.

Abstract: Background/Objectives: Infectious diseases remain a major burden on global public health, exacerbated by the serious threat of antimicrobial resistance and the limitations of conventional pharmaceutical formulations. This review aims to analyze the current state of 3D printing technology in the development of drug delivery systems tailored to the treatment of infectious diseases, emphasizing its capabilities across various routes of administration, current challenges, and potential clinical prospects. Methods: A literature search was conducted in ScienceDirect for research articles published between 2020 and May 2026 using the terms “antibiotic” AND “3D printing” AND “drug delivery.” Retrieved articles were selected, filtered, and categorized according to their route of administration. Results: Additive manufacturing allows for precise control of dosage, geometry, and release kinetics, facilitating personalized treatments for infectious diseases. Semi-solid extrusion has become the dominant technique due to its compatibility with various biomaterials and thermolabile active pharmaceutical ingredients. Topical applications represent the most advanced area, integrating multifunctional properties such as stimuli response and wound healing. Furthermore, 3D printing has demonstrated significant efficacy in expanding delivery platforms for vaginal, ocular, and oral routes. Conclusions: Pharmaceutical 3D printing is evolving from a manufacturing tool for personalized dosage forms to an advanced platform for designing multifunctional therapeutic systems. Overcoming current regulatory, clinical validation, and manufacturing challenges will be crucial to translating these innovations into routine clinical practice to combat infectious diseases and antimicrobial resistance.

Abstract: Sickle cell disease (SCD) — the most common severe monogenic disorder worldwide, affecting an estimated 7.74 million people and accounting for roughly 515,000 births each year, with nearly 80% of the global burden concentrated in sub-Saharan Africa — remains a disease for which the modern targeted-therapeutics pipeline has repeatedly underdelivered. Voxelotor, the first rationally designed small-molecule hemoglobin-oxygen-affinity modulator, was voluntarily withdrawn from every world market in September 2024 after post-marketing data suggested an unfavorable benefit-risk balance; crizanlizumab's European marketing authorization was revoked in 2023 after its confirmatory STAND trial failed to demonstrate efficacy; and the two FDA-approved gene therapies, Casgevy and Lyfgenia, remain inaccessible to the overwhelming majority of the global SCD population owing to million-dollar price tags and the specialized transplant infrastructure they require. Against this backdrop, natural product chemistry — long practiced empirically across malaria- and SCD-endemic regions, and increasingly interrogated with modern phytochemical, pharmacokinetic, and computational tools — represents a scientifically active and practically urgent alternative discovery axis. This review provides a comprehensive synthesis of that literature. We first summarize the molecular pathophysiology of HbS polymerization and the specific structural targets (the T-state polymerization interface, the R-state Val1α allosteric pocket, and oxidative/membrane targets) that both synthetic and natural anti-sickling agents engage. We then catalogue the major chemical classes of natural anti-sickling agents — polyphenols and flavonoids, phenolic aldehydes exemplified by vanillin and its pyridyl derivatives, alkaloids, terpenoids, and standardized polyherbal formulations such as the Nigerian-developed Niprisan/NIPRD-94 — together with the specific plant sources (Cajanus cajan, Pterocarpus osun, Zanthoxylum zanthoxyloides, Carica papaya, Detarium microcarpum, Uapaca heudelotii, and others) from which they have been isolated. A dedicated section addresses the pharmacokinetic dimension explicitly requested for this review: the generally poor oral bioavailability, rapid conjugative metabolism, and short half-lives that most polyphenolic natural anti-sickling agents share, as well as the nanoformulation, derivatization, and polyherbal combination strategies being explored to overcome these limitations. We then synthesize the rapidly growing — but methodologically uneven — computational docking literature that has emerged over 2023–2026, tabulating the target structures, software, and binding-affinity results reported for natural-product ligands docked against sickle and carbonmonoxy hemoglobin structures, including direct comparisons to voxelotor as a co-docked reference standard. We close by proposing an integrated discovery pipeline — spanning extraction, in vitro anti-sickling assay, computational docking/ADMET triage, and pharmacokinetic-guided derivatization — for advancing natural-product leads toward genuinely next-generation anti-sickling agents, and by mapping the specific evidentiary and methodological gaps that currently separate this literature from that standard.

Abstract: Mushroom-derived products are increasingly recognized as promising immunomodulatory therapeutics. This study aimed to evaluate the immunomodulatory properties of polysaccharides and characterize secondary metabolites from Trametes hirsuta (Wulfen) Lloyd. Sterol derivatives were isolated using column chromatography, while polysaccharides were obtained via hot water extraction, purified by ethanol precipitation, and dialyzed. Polysaccharide content was measured with the phenol-sulfuric acid method. Antioxidant activity was assessed using DPPH and FRAP assays. The volatile fraction was obtained by hydrodistillation and analyzed by GC-MS Spectrometry. The total phenolic content was determined by the Folin-Ciocalteu method. The cytotoxicity of the polysaccharide fraction on THP-1 cells was evaluated using the XTT assay in 2D and 3D cultures and its effects on IL-1β and TNF-α secretion were assessed. Identified compounds included ergosterol, ergosterol peroxide and ergosteryl acetate, and the phenolic compound 3,2,6-di-tert-butyl-4-(hydroxymethyl) benzoic acid, which was identified for the first time in T. hirsuta. The polysaccharide content was quantified at 53.10 ± 2.87%. Cytotoxicity testing showed non-toxic doses of 10 and 240 μg/mL in 2D cultures, and 10 and 670 μg/mL in 3D cultures. Using these concentrations, the extract induced a dose-dependent increase in IL-1β and TNF-α secretion. Total phenolic content of the methanol extract was 41.64 ± 3.81 mg gallic acid equivalent per gram of dry weight. The essential oil was rich in alcohols (19.64%) and aldehydes (16.43%). The methanol extract exhibited the highest antioxidant activity in FRAP assay (408.1667±0.1116 mmol Fe2+/gram dry weight). These findings support the immunomodulatory activity of T. hirsuta polysaccharides and warrant further investigation of their underlying receptor-mediated mechanisms.

Abstract: Background. Most pharmacy regulators now mandate continuing professional development, replacing or adding to traditional ongoing education. However, the broad evidence supporting this change has not been well characterized. Objective. This mapping aims to explore the scope, design, geography, and impact of research on continuing education and professional development for practicing pharmacists and pharmacy technicians. It also seeks to identify which links in the implicit chain, from requirement to patient outcome, have been examined. We distinguish three often-overlapping dimensions: the mechanism (what practitioners are asked to do, such as accrual or documented cycles), the requirement (whether participation is mandatory), and the warrant (the record's claimed proof). Five research questions are posed to address the determinants of map, mechanism, mandate, warrant, and engagement. Methods. An evidence map of PubMed was created using eight structured queries that focused on fundamentals, effectiveness, reviews, revalidation, barriers, settings in low- and middle-income countries, digital delivery, and the technician workforce. These queries retrieved a total of 1,145 records over two rounds. Of these, 743 were unique entries, and 724 were eligible for screening. The screening process involved reviewing titles and abstracts, and each selected study was categorized by topic, design, country, sample size, and the highest Kirkpatrick level of evidence for outcomes. Both screening and data extraction were completed in a single step using a language model for classification, while design and outcome coding were verified by a single author. When multiple publications reported the same study, they were linked, ensuring that counts reflect individual studies rather than reports. Results. Following an extensive search and a detailed audit, 359 studies met the inclusion criteria, of which 201 (56.0%) were published after 2020. The majority were surveys conducted at a single time point (129, 35.9%) or evaluations of a single group before and after an intervention (63, 17.5%). Only 12 studies (4.6%) included a comparison group, of which six were randomized trials. Outcome measurements mainly focused on knowledge, skills, and attitudes (161, 44.8%). Fifty-two studies (14.5%) examined behavior change, and just 3 (0.8%, 95% CI 0.3 to 2.4) assessed patient or system outcomes. All three were uncontrolled, and no controlled study measured outcomes beyond behavior. Only 4 of the 12 comparative studies considered the cycle itself; the remaining 8 compared different continuing education formats. No study evaluated the impact of introducing, removing, or varying a requirement against any outcome. One study independently measured engagement and competence over a single register and found that every pharmacist who failed the external competence review had previously passed the engagement review. Conclusions. Among the four links in the field’s implicit chain from requirement to patient outcome, one has not been tested in pharmacists at all, while another has been examined by four studies. The warrant claim based on this chain is challenged where it has been tested. The strongest positive claim, supported by evidence, is that the cycle influences pharmacists' actions more than accrual-based education does. This conclusion relies on self-reported behavior from a single, unblinded trial involving 100 pharmacists, reported across three papers, with effects diminishing over three years. No pharmacy trial has directly compared these approaches against patient outcomes, and the closest relevant research in medicine has been conducted twice without showing a signal. Therefore, the most valuable questions in the field are narrower than replication. They are whether the cycle offers additional benefits beyond any educational intervention, whether that effect can be sustained, and whether employer-led levers, such as protected time, are effective.

Abstract: Insulin delivery via the buccal route has shown long-standing promise for diabetes therapy, but clinical translation remains limited. Most systems address only part of the delivery problem, whereas a viable product must simultaneously provide adequate insulin residence time, effective mucus and epithelial permeation, stability, dose consistency, safety, and manufacturability. This review examines the biological and formulation barriers that limit buccal insulin delivery and compares the major platform types, including mucoadhesive films and patches, nanocarrier-based systems, deformable vesicles, chemistry-led permeation approaches, and device-enabled strategies. Stability, alongside limited permeability, is considered a key barrier, while aggregation and excipient-related instability remain insufficiently addressed. The review also discusses why promising preclinical findings often fail to translate, exhibiting low bioavailability, variability, safety concerns, and scale-up challenges recurring across platforms. Overall, further progress in buccal insulin delivery will depend on formulation strategies that better integrate permeation enhancement, stability preservation, and translational feasibility.

Abstract: The effect of matrices remains an important source of variation in LC-MS/MS-based bioanalysis due to the presence of co-eluting endogenous and exogenous compounds which affect the ionization processes of analytes. The current paper critically reviews the physicochemical principles of matrix effects in atmospheric pressure ionization (API) interfaces, emphasizing on the principle of electrospray ionization (ESI). Particular attention will be devoted to droplet formation and desolvation kinetics, surface activity effects, charge partitioning, conductivity effects, and ion-molecule reactions in gas phase that control ion suppression/enhancement. Comparative review of the ESI vs APCI ionization mechanisms will allow identifying distinctive features associated with their resistance to the matrix effect. In contrast to various practical recommendations that can be found in the literature, this paper emphasizes the use of different experimental approaches for assessing ionization variations based on post-column addition, post-extraction matrix addition, matrix factor calculation, and internal standardization. The discussion is informed by harmonized principles presented in international bioanalytical validation guidelines, specifically ICH M10, while acknowledging differences among global regulatory authorities. Notably, matrix effects are considered within the framework of indirect regulatory control, where method validation is established by accuracy and precision performance (±15% for quality control samples and ±20% at the lower limit of quantification), rather than by specified matrix effect threshold values. Mitigation approaches are assessed mechanistically, covering selective sample preparation, chromatographic selectivity, ion source parameter optimization, and the use of stable isotope-labeled internal standards. Emerging trends, such as microflow liquid chromatography, high-resolution mass spectrometry, automated methods, and artificial intelligence-assisted optimization, are critically discussed for their potential to enhance reproducibility in complex biological samples such as plasma, tissues, and dried blood spots. Taken together, this review outlines a framework for systematic assessment and control of matrix effects in contemporary LC-MS/MS bioanalysis that is mechanistic, structured, and aligned with regulatory requirements. In contrast to previous narrative reviews, this review article presents a framework that combines ionization science, validation approach, and regulatory thinking in a single model for matrix effect control.

Abstract: Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of obesity and type 2 diabetes mellitus (T2DM). Although randomized clinical trials have demonstrated substantial weight loss and metabolic benefits, real-world evidence is needed to assess their effectiveness, safety, prescribing patterns, and use in routine clinical practice. Objective: To evaluate the effectiveness and safety of GLP-1 receptor agonists in routine clinical practice and to identify factors associated with treatment outcomes in a nationwide multicenter cohort recruited through Spanish community pharmacies. Methods: A nationwide multicentre cross-sectional study with retrospective data collection was conducted between January and April 2026 across community pharmacies in Spain. Adult patients receiving GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists were consecutively enrolled and classified according to therapeutic indication (obesity or T2DM). Changes in body weight and body mass index (BMI) were assessed using paired-samples t-tests, while multivariable linear regression explored independent determinants of weight loss. Safety signals were initially evaluated using disproportionality analyses based on Odds Ratios (ORs). Subsequently, multivariable logistic regression was performed to identify independent predictors of digestive adverse drug reactions after adjustment for demographic characteristics, treatment-related variables, lifestyle factors, and concomitant glucose-lowering therapies. Results: A total of 531 patients were included (52.2% obesity; 47.8% T2DM; mean age 56.5 ± 12.5 years; 66.7% women). Patients achieved a significant mean weight loss of 12.17 ± 10.64 kg, corresponding to an 11.71% ± 9.40% reduction from baseline (p < 0.001). Overall, 73.9% and 54.1% of participants achieved ≥5% and ≥10% weight loss, respectively. Relative weight loss was comparable across incretin-based therapies. Gastrointestinal adverse drug reactions were the most frequently reported safety outcomes. Disproportionality analyses identified brand-specific safety signals, including increased reporting of nausea/vomiting with Wegovy® and constipation with Mounjaro®, whereas concomitant insulin and SGLT2 inhibitor therapy were associated with dizziness and urinary disorders, respectively. In the multivariable logistic regression model, increasing age emerged as the only independent predictor associated with a lower likelihood of digestive adverse drug reactions (adjusted OR 0.97 per year; 95% CI 0.96–0.99; p = 0.003), while no independent associations were observed for GLP-1RA agent, treatment duration, lifestyle variables, or concomitant glucose-lowering medications after adjustment. Conclusions: Incretin-based therapies were associated with clinically meaningful weight loss in routine clinical practice, supporting the generalizability of findings from randomized clinical trials. Safety profiles differed according to treatment and concomitant therapies, highlighting the importance of individualized monitoring in community pharmacy settings. These findings support the development of a standardized pharmacy-led dispensing and follow-up protocol to optimize patient safety and treatment adherence.

Abstract: (1) Objective: This study aims to evaluate the pre-admission pharmacist for high-risk obstetric patients’ admissions on medication management processes, workflow efficiency, and staff satisfaction. (2) Methods: Data collected over a 12-month period, from March 2025 to February 2026, were analysed. Data collected included clinic type, patient attendance, mode of pharmacist review, and follow-up requirements. Multidisciplinary healthcare professionals were invited to complete a satisfaction survey to identify themes relating to service value, workflow impact, and opportunities for improvement. (3) Results: A total of 1039 interviews with obstetric patients equating to an average of 19.98 interviews per week. A total of 999 patients were involved in the 1039 interviews held, 40/999 (4%) patients required additional follow-up telephone interview and 14 patients (14/999, 1.4%) requiring in-person interview for interpreter services, detailed discussion or hearing impairment. Thirty-two staff responded to a survey and demonstrated a consistent trend across anaesthetists, nursing and midwifery staff and pharmacists. All respondents either agreed or strongly agreed that PAC pharmacist in obstetric setting was valuable and beneficial to clinical workflow and medication management processes, and that they were satisfied with the PAC pharmacy service. (4) Conclusion: The PAC pharmacist demonstrated a positive impact on medication management for obstetric patients within the pre-admission setting.

Abstract: Background / Objectives: Colorectal cancer is a leading cause of global cancer-related mortality. Capecitabine, a 5-fluorouracil prodrug, effectively targets colorectal cancer but suffers from an extremely short half-life, requiring frequent administration. Bilosomes (membrane-stabilized bile salts) are vesicular systems that improve gastrointestinal stability, prevent drug leakage, and extend residence time. This study aimed to develop capecitabine-loaded bilosomes to overcome these pharmacokinetic drawbacks and enhance therapeutic efficacy. Methods: In a 3² full factorial design, nine capecitabine-loaded bilosomes were generated utilizing a central composite design within the framework of response surface methodology. Entrapment efficiency, in vitro drug release, and its kinetics vesicle size, zeta potential, and their kinetics were evaluated. The optimized capecitabine-loaded bilosomes formulation was exposed to further investigations, such as ATR-FTIR, DSC, X-ray diffractometry study, stability studies, pharmacokinetic study, and in vivo studies, including detection of matrix metalloproteinase-9 and vascular endothelial growth factor A by Real-Time polymerase chain reaction, evaluation of colon biomarker, and examination of colon tissue through histopathology. Results: The prepared capecitabine-loaded bilosomes were nanosized spheres with suitable entrapment efficiency and a high zeta potential. After treatment with capecitabine-loaded bilosomes, the data collected from living organisms indicated a notable reduction in the serum value of carbohydrate antigen 19.9 and cancer embryonic antigen, gene expression values of matrix metalloproteinase-9, and vascular endothelial growth factor A. Histopathological study showed almost restoration of colonic features with a lesser extent of epithelial lining and crypt dysplasia. Conclusion: The present study findings demonstrate that capecitabine-loaded bilosomes possess high anti-tumor activity against colorectal cancer.

Abstract:

Angiotensin II (AngII) binds to the AngII type 1 receptor (AT¹R) in either A-mode (on-switch; G-protein-mediated contraction) or D-mode (off-switch; arrestin-mediated desensitization/tachyphylaxis). Angiotensin receptor blockers (ARB) can desensitize AT¹Rs by binding to an allosteric regulatory B-site, which overlaps with the AngII A/D binding site in the extracellular binding pocket of the receptor. ARBs shift the receptor conformation from A/D-mode to agonist-independent D*-mode, resulting in receptor internalization. Binding of ligands to the inverse agonist binding site (B-site) can promote (lock in) the D*-mode conformation of the receptor (desensitization) or disengage (lock out) the D-mode conformation (upsensitization, reduction of tolerance). Computer-aided docking (CAD) studies show that ARBs, particularly bisartan ACC519TT, bind with high affinity to several G protein-coupled receptors (GPCRs), including AT¹R, adrenergic (alpha 1 and 2), opioid (mu and delta), and muscarinic 3 receptors, suggesting that the electrostatic architecture of the B-site has been preserved across a broad spectrum of GPCRs. Consistent with CAD findings, ACC519TT significantly reduced dilation responses of mouse colon and small intestine to the opioid receptor agonist, oxycodone. Functional studies in rabbit iliac artery rings demonstrated the ability of lisinopril to significantly reduce AngII-induced contraction, comparable to candesartan. However, CAD studies show that lisinopril has a markedly lower affinity than candesartan for AT¹R, illustrating that the similar effect to AngII dose-response may be due to the time-dependent receptor internalization. For agonists, D-site versus A-site activity may provide insight regarding dependency potential (addiction ratio, D/A). Agonists cross-talk among different GPCRs creates the potential for a sophisticated interplay, possibly involving endogenous ligands not yet identified, with the notable exception of angiotensin antipeptide.

Abstract: Background: The rapid emergence of oral anticancer medications (OAMs) has increased demand for specialized Clinical Pharmacy Services (OAM CPS). Concurrently, Canadian cross-sectional data highlights severe undergraduate gaps, with fewer than 14% of community pharmacists reporting adequate undergraduate OAM training. We designed, implemented, and evaluated a pharmacist-led Oral Anticancer Medication Clinical Co-op Program (OAMCCP) to bridge this experiential education gap while safely and cost-effectively expanding institutional capacity. Methods: Launched in Fall 2022, the OAMCCP integrated one PharmD student per 16-week term into a multidisciplinary oncology specialty pharmacy. Trainees executed core ambulatory oncology clinical pharmacy key performance indicators (AOcpKPIs), including Best Possible Medication Histories (BPMH), drug-drug interaction (DDI) screenings, and proactive toxicity follow-up. Crucially, 100% of student tasks were verified by a licensed oncology pharmacist to maintain absolute patient safety. Impact was quantified via task logging over 15 weeks, standardized 10-point patient satisfaction surveys, and payroll expenditure comparisons. Results: Trainees completed 673 clinical tasks (56.1 tasks/week), contributing 19.2 hours of direct clinical support weekly—effectively adding +0.5 Full-Time Equivalent (FTE) to service capacity with zero safety compromises. Mean patient satisfaction was 9.6/10 (n = 29), with students independently managing inquiries in 96.5% of encounters. Financially, a 1.0 FTE student (\(44,700/year cost) captured clinical capacity valued at \)80,600/year (0.5 FTE pharmacist equivalence). Conclusion: The OAMCCP resolves experiential training gaps while presenting a safe, scalable, and financially viable human resource framework that expands oncology pharmacy services.

Abstract: Background. Therapeutic inertia — conventionally defined as the failure to initiate or intensify pharmacotherapy when clinical treatment targets are unmet and used in that under-titration sense throughout this review — is a pervasive and underappreciated source of preventable harm in ambulatory medicine. Despite decades of evidence-based guidelines and increasingly efficacious pharmacological agents, most patients with common chronic diseases remain on suboptimal medication doses, accruing avoidable morbidity, irreversible end-organ damage, and premature mortality. Objective. To characterize, in a unified cross-disease framework, the prevalence, clinical consequences, and economic burden of therapeutic inertia in pharmacologic dose titration across sixteen chronic conditions, and to summarize the case for new categories of intervention. Methods. Narrative review of peer-reviewed literature, clinical guidelines, and published health economic analyses. Searches were performed in PubMed and MEDLINE through April 2026 using condition-specific terms combined with “therapeutic inertia,” “clinical inertia,” “treatment intensification,” and “dose optimization.” Priority was given to systematic reviews, meta-analyses, prospective cohort studies, and large registry and database analyses since 2015, supplemented by seminal earlier studies and current guideline documents. U.S.-based sources were prioritized for epidemiologic and economic estimates. Results. Across sixteen conditions spanning cardiovascular, endocrine, obstructive airway, gastrointestinal, musculoskeletal, urologic, neurodegenerative, movement, sleep, and tobacco-dependence disorders, dose-optimization inertia or suboptimal pharmacotherapy maintenance is highly prevalent, ranging from approximately 55% (type 2 diabetes) to 99% (heart failure with reduced ejection fraction) across eligible patients or clinical encounters, among the nine conditions with a verifiable single-study point estimate (see Figure 1). Ten conditions produce life-threatening sequelae; six produce irreversibly debilitating functional and quality-of-life impairment without immediate life-threatening sequelae (osteoarthritis, benign prostatic hyperplasia, lower urinary tract symptoms/overactive bladder, essential tremor, restless leg syndrome, and Parkinson’s disease). Suboptimal titration is consistently associated with accelerated disease progression, irreversible end-organ damage inadequate symptom control, and preventable healthcare utilization. Aggregate annual U.S. direct and indirect costs for these conditions exceed $2.4 trillion, across the fifteen of sixteen conditions for which a comparable dollar-denominated estimate exists (essential tremor is excluded because the literature reports only relative cost multipliers). Existing technologies including provider education, EHR alerts, telehealth, standard remote patient monitoring, and digital therapeutics each operate within, rather than outside of, the structural constraints that produce inertia. Conclusions. Therapeutic inertia in pharmacologic dose titration is a systemic, cross-disease failure with shared structural determinants and no currently deployed solution capable of addressing it at population scale. The sixteen conditions reviewed collectively affect more than half of the adult U.S. population and account for majority of preventable mortality and disability in ambulatory care. The disparity between what evidence-based pharmacotherapy can achieve and what clinical systems reliably deliver represents one of the most consequential unmet needs in modern ambulatory medicine, and the populations bearing the greatest burden are those least served by current programs.

Abstract: Retinol and curcumin are bioactive compounds with promising dermatological applications; however, their poor aqueous solubility, instability, and limited bioavailability may restrict their therapeutic performance. This study aimed to develop and evaluate retinol-curcumin nanoemulsions (RCNEs) as a co-delivery system with antioxidant, anti-inflammatory, antibacterial, and in vitro safety potential. Curcumin and retinol were quantified using UV-visible spectrophotometry, and the nanoemulsions were prepared by mixing the aqueous and oily phases followed by sonication. The prepared formulations were evaluated for particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency, loading efficiency, and stability under different storage conditions. Antioxidant activity was determined using the DPPH radical scavenging assay, cytotoxicity was evaluated using the MTT assay on EaHY.926 endothelial cells, anti-inflammatory activity was assessed by measuring TNF-α inhibition, and antibacterial activity was tested against Staphylococcus aureus and Escherichia coli using the Kirby-Bauer well diffusion method. The optimized RCNE formulation showed an average particle size of 117 ± 0.1 nm, PDI of 0.138 ± 0.010, and zeta potential of −12.7 ± 0.2 mV. Encapsulation efficiencies were 77.0±1.1% for curcumin and 91.1±0.8% for retinol. RCNEs exhibited the strongest antioxidant activity, with an EC₅₀ of 56.04±1.95 µg/mL compared with 90.03±3.15 µg/mL for curcumin nanoemulsions and 227.3±8.4 µg/mL for retinol nanoemulsions (p≤0.05). The RCNE formulation also produced the highest TNF-α inhibitory activity, reducing TNF-α concentration to 76.5±5.2 pg/mL and achieving 86.2±1.8% inhibition, which was significantly higher than curcumin nanoemulsions (36.6±2.4%) and retinol nanoemulsions (39.1±2.1%) (p≤0.05). No marked cytotoxicity was observed within the tested concentration range. The formulation also demonstrated antibacterial activity against both tested bacterial strains, with larger inhibition zones against E. coli. These findings suggest that RCNEs may serve as a promising in vitro platform for co-delivering retinol and curcumin in topical pharmaceutical applications.

Abstract: Metabolic diseases, such as obesity, type 2 diabetes (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), emerge from chronic nutrient overload that progressively disrupts cellular homeostasis and precipitates persistent inflammatory remodeling. Two stress-adaptive programs sit at the center of such pathological transition: autophagy, the homeostatic engine responsible for lysosomal recycling and organelle quality control, and cellular senescence, a tissue repair system that becomes deleterious when persistent, driving dysfunction through stable growth arrest and senescence-associated secretory phenotype (SASP)-associated inflammatory remodeling. Emerging evidence identifies lysine acetylation as a nutrient-sensitive molecular rheostat that orchestrates the reciprocal regulation of these two processes across metabolic tissues. Because acetylation dynamics are governed by the availability of acetyl-CoA and the NAD⁺-dependent deacetylation capacity of sirtuins, metabolic stress reshapes the enzymatic balance between acetyltransferases (KATs, e.g., p300/CBP) and deacetylases. This shift triggers a “double blow” to cellular health; the simultaneous suppression of autophagic flux and the epigenetic stabilization of senescent state. This review synthesizes mechanistic evidence showing how acetylation inhibits autophagy at multiple checkpoints, ranging from the activity of core autophagy proteins to lysosomal biogenesis, while concurrently reinforcing senescence through chromatin hyperacetylation and the activation of non-histone effectors such as NF-κB, p53 and FOXO proteins. We place particular emphasis on the mTORC1-p300-SIRT1 axis as the primary integration hub coupling nutrient status to this dual regulation. Finally, we discuss tissue-specific manifestations in the liver, adipose tissue, and other metabolic organs and highlight emerging therapeutic strategies, such as KAT inhibition/sirtuin activation, aimed at restoring the acetylation rheostat to improve autophagic competence while restraining senescence-driven metabolic decline.

Abstract: Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) with antipyretic, analgesic, and anti-inflammatory activity; however, its low aqueous solubility limits its dissolution rate and, consequently, its oral bioavailability. This study aimed to develop and physicochemically characterize an ibuprofen-loaded self-nanoemulsifying drug de-livery system (SNEDDS) using a Box–Behnken experimental design. Fifteen formulations were prepared and evaluated based on CQAs: cloud point, robustness to dilution, self-emulsification time, droplet size, zeta potential, and polydispersity index (PDI). The experimental responses were subjected to statistical analysis; robustness to dilution as the only response yielding a statistically valid and predictive model within the studied design space, which was used as the sole optimization criterion. The optimal formulation was evaluated and characterized according to previously established CQAs and subjected to physical/kinetic stability testing and stress testing over one month. The optimized formulation exhibited rapid self-emulsification, with a self-emulsification time of 37.02 s, a cloud point of 64.87 °C, and high robustness to dilution across different pH conditions and dilution volumes. Moreover, it exhibited a mean droplet size below 157.54 nm, a zeta potential of −15.43 ± 0.58 mV, and a PDI of 0.251, suggesting adequate colloidal stability and uniformity of the dispersed system. These physicochemical attributes support the potential of the developed system as a platform for further biopharmaceutical evaluation of ibuprofen oral delivery.

Abstract: This brief report evaluated June 2026 frontier generative artificial intelligence models on the Japanese National License Examination for Pharmacists. Four models (ChatGPT GPT-5.5, Gemini 3.5 Flash, Claude Opus 4.8, and Claude Fable 5) were tested using all 345 questions from the 107th examination, including image-based items in the original Japanese format. Overall accuracy counted refusals as incorrect, and conditional accuracy among answered questions was calculated for Fable 5. GPT-5.5, 3.5 Flash, and Opus 4.8 achieved near-saturation accuracies of 99.1%, 98.3%, and 96.8%, respectively. Fable 5 achieved 69.9% overall accuracy but 98.8% conditional accuracy among answered questions, refusing 101 questions (29.3%), especially in Biology (90.0%) and Pharmacology (72.5%). Frontier models showed near-saturation performance, but refusal-aware evaluation is necessary for pharmacy benchmarks.

Abstract: Background/Objectives: Traditionally classified as nutrients or micronutrients, vitamins can now be viewed as multi-functional excipients that have considerable potential within the context of pharmaceutical formulation science. Due to their physicochemical characteristics, antioxidant nature, and stabilizing action, vitamins are able to serve functions that go beyond their nutritional applications. These include but are not limited to solubility, increased permeation, controlled release, as well as synergistic stabilization and enhancement of the active ingredient(s). Results: The current work presents the synthesis of information available to date regarding the classification, mechanisms, and excipient properties of vitamins and their role in novel drug delivery systems development. In addition to the conventional classification into water-soluble and fat-soluble, some other classification criteria are used based on the chemical nature of vitamins. Water-soluble vitamins are mainly used to facilitate oxidation and pH adjustments whereas fat-soluble vitamins are mostly employed in lipid-based systems due to solubilizing and antioxidative effects. Conclusion: Vitamin-based mechanisms such as the surfactant effect of TPGS (vitamin E), oxidation and reduction reactions in vitamin C, or hydrotropy in niacinamide illustrate active involvement of vitamins in enhancing bioavailability and improving the formulation. Novel areas of application range from vitamin-functionalized nanocarriers to receptor-targeted ligands and incorporation into 3D-printed drug delivery platforms.