The UK Longitudinal Linkage Collaboration: the Trusted Research Environment for data linkage in longitudinal population research

Abstract: We have created an unprecedented interdisciplinary infrastructure integrating data from UK-wide LPS linked to participants' health (NHS), administrative (DWP, HMRC) and place-based records (e.g. environmental pollutants, proximity to healthy assets). Researchers can apply to access all these data via a single application. This organisation is a collaboration of over 25 of the UK's most established LPS with over 425,000 participant records. With new LPS joining, the resource will comprise more than 2 million linked participant's records by 2027. The UK LLC enables integrated and curated data for pooled analysis within a functionally anonymous Digital Economy Act and ISO 27001 accredited TRE. Initially this resource was only available to UK researchers, will be open to international researchers in 2026. This data flow is enabled by: (1) a model where a Trusted Third Party processes participant identifiers for many different data owners; (2) creation of a novel longitudinal data pipeline, enabling linkage, data extraction and update of records over time; (3) an access framework where a Linked Data Access Panel considers applications on behalf of data owners (e.g., the NHS), with review by a public panel and distributing applications to LPS for approval. UK LLC provides a simple-to-access strategic research-ready platform for longitudinal research to investigate cross-cutting themes such as understanding health and social inequalities, health-social-environmental interactions. The greater availability of large scale, diverse linked data will help provide the numbers for researchers to study rarer outcomes and seldom-reached populations.

Boyd A
Flaig R
Oakley J
Campbell K
Evans Stela McLachlan K
Thomas Emma Turner R

United Kingdom
Longitudinal Studies
Humans
Information Storage and Retrieval
Cooperative Behavior


Use of data linkage and LEO data in the evaluation of the Basic Income Pilot in Wales

Abstract: The presentation will outline the data linkage methodology underpinning the evaluation of Wales' Basic Income Pilot (BIP), with a particular focus on connecting BIP participant data to the Longitudinal Education Outcomes (LEO) datasets. The BIP is a landmark pilot providing care-leavers with a monthly income for two years. The evaluation aims to assess the education and labour market outcomes of BIP recipients compared to their non-recipient peers. The LEO dataset integrates multiple educational datasets, as well as employment and benefits data from the Department for Work and Pensions (DWP) and His Majesty's Revenue and Customs (HMRC) providing a comprehensive view of education and employment outcomes. To facilitate this analysis, a secure and privacy-conscious linkage process has been designed. The BIP monitoring database, containing personal identifiers for pilot recipients, will be matched to the constituent education datasets held within LEO, using select data points. The linkage will take place within the Welsh Government, which already holds all the relevant datasets. This internal linkage avoids the need to transfer any personal data externally, minimising privacy risks and ensuring compliance with data governance protocols. Following linkage, the evaluation contractors will receive an anonymised, flagged dataset via the Welsh Government Secure e-Research Platform, containing the LEO data relevant to the BIP recipients. Contractors will not be able to identify individuals, preserving participant confidentiality. Access to the data is further restricted to accredited researchers. This approach demonstrates a robust, ethical model for linking administrative data in policy evaluation, balancing analytical needs with stringent privacy protections.

International journal of population data science

Wales
Humans
Pilot Projects
Income
Information Storage and Retrieval
Employment
Longitudinal Studies


Diversity of record pairs and mental models in clerical review: What reviewers use to decide matches

Abstract: Clerical review is an integral step of many data linkage systems. It employs human expertise to assess record pairs for which a decision model, such as probabilistic record linkage, has not been able to make a match (two records refer to the same individual) or non-match (two records refer to different individuals) decision. While clerical review is used in many practical applications, there is surprising little research that systematically investigates how to best conduct this important step in the data linkage process.In this work, we explore one aspect of clerical review: How does the diversity of the record pairs selected for manual review affect the final linkage quality? To investigate this question, we generated diverse samples of difficult to classify record pairs from a large public population database, where each sample contained 100 pairs of true matches and 100 pairs of true non-matches. The samples differed in (1) the number of unique similarity patterns they had (calculated over a set of compared quasi-identifiers such as names and addresses), and (2) the actual set of quasi-identifiers available for manual review. All authors conducted a blinded manual assessment of all samples.Our results indicate that the diversity of the agreement patterns is less important for making informed decisions compared to the set of quasi-identifiers available for review. Furthermore, reviewers seem to make decisions based on mental models of how they think a match or non-match looks like. Our results will help design improved approaches for clerical review in practical linkage applications.

Dharmawimala Y
Christen P
Ziyad S
Lam J
Vidanage A
Schnell R

Humans
Information Storage and Retrieval


Using mental health and education data for research and policy insights: A ten-year retrospective of a South London data linkage

Abstract: Since 2015, South London and Maudsley NHS Foundation Trust (London, United Kingdom) has maintained a data linkage between its de-identified Child and Adolescent Mental Health Services records and the Department for Education's National Pupil Database. Most recently refreshed up to the 2023/24 academic year, this linkage is used to conduct population and clinical research spanning mental health and education. In this presentation, we will outline the linkage's evolution, including governance and data-sharing frameworks that we have navigated, changes encountered in the decade since its original formation, and key learnings. We will discuss public engagement activities we have undertaken around the linkage, including novel approaches to directly involve children and young people in complex analytical decisions. Finally, we will showcase the wide array of research that has arisen from this linkage, spanning depression, Attention-Deficit/Hyperactivity Disorder (ADHD), educational attainment, special educational needs support, and more. Many of our findings have informed policymakers. Our most recent study replicates a longitudinal analysis first conducted in Norway, showing diminishing associations between ADHD and end-of-school exam performance. This demonstrates how the growing availability of data linkages permits international research replication. By identifying overlapping trends, countries can work jointly on policy solutions in full confidence that many of us are grappling with the same challenges, despite having mental health and education systems that diverge operationally. In the decade since its inception, this linkage has exemplified how administrative data drives research and policy, and there is greater opportunity than ever before for global collaboration.

Humans
London
Mental Health
Retrospective Studies
Adolescent
Child
Mental Health Services
Health Policy
Information Storage and Retrieval


Harmonised Health Outcomes Across Administrative Data: Lessons, Opportunities, and Challenges from UK Biobank

Abstract: To develop a resource that maps health outcomes across coding schemas in linked administrative data in UK Biobank, addressing the challenge of identifying equivalent outcomes from multiple sources. UK Biobank is a prospective cohort study of ∼500,000 adults, recruited between 2006-2010, with follow up for health outcomes through linkage with administrative data. Clinical codes include Read Version 2 (Read2) and Clinical Terms Version 3 (CTV3) from primary care, and International Classification of Diseases (ICD) 9th and 10th editions (ICD-9 and ICD-10) from hospitals, cancer registries, and death records; self-reported conditions were also reported at recruitment. We reviewed existing mapping resources and mapped clinical codes in different schemas to 4-digit ICD-10 codes. We successfully mapped 81% of Read2 (N = 12,448), 93% of CTV3 (24,188), 92% of ICD-9 (3,060), and 100% of self-reported codes (509) to ICD-10 codes. Although existing resources frequently allowed one-to-one mapping of ICD-10 codes (94% of the mapped codes for Read2, 58% of CTV3, and 79% of ICD-9), the remaining codes required extensive clinical review, which is ongoing. The conversion increased the granularity of health outcomes by 3.8 times from 2,000 3-digit to 7,500 4-digit ICD-10 codes. The mapping quality will be evaluated using phecodes, and by assessing consistency across data sources. Our approach preserves clinical detail, increases coding granularity, uncovers nuanced outcomes, and enables precise, internationally comparable research using enriched UK Biobank data. Although harmonisation supports cross-cohort research, validation of outcomes across data sources remains essential to avoid misclassification and minimise bias.

Domzaridou E
Lacey B
Conroy M
Allen N
Li Nuffield Y


Multiple Sclerosis and ethnicity in Wales: a SAIL Databank study

Abstract: Multiple Sclerosis (MS) is the commonest non-traumatic cause of disability in younger people. Prevalence of MS by deprivation and ethnicity is rarely reported, as ethnicity is not accurately or consistently recorded in national datasets. Ethnicity data within the Secure Anonymised Information Linkage (SAIL) Databank is stored in clinical datasets that are linkable to the Welsh Demographic Service (WDS) but data collection is variable. We linked WDS to data from the Office of National Statistics (ONS) which has complete ethnicity and birthplace data from the most recent 2021 census. WDS and ONS data were merged to determine census age, sex, birthplace, ethnicity and Welsh Index of Multiple Deprivation (WIMD). An algorithm (Nicholas, 2024) identified people with MS (pwMS) in Wales. 3.1M ONS and 3.2M WDS were linked producing 2.5M unique records of whom 5934 had MS. MS prevalence (per 100,000) was highest aged 51-60 (445.9 [424.6-467.9]); higher in females than males (325.2 [315.6-335] versus 131.7 [125.3-138.3]) and significantly lower in Asian (58.2 [41-80.3]) or Black (126.8 [80.3-190.2]) ethnicity versus white (240 [233.9-246.3]). PwMS in Wales were less likely to be born outside of the UK (96.4%) versus the Welsh population (93.9%). 853 pwMS (14.9%) were in the most deprived WIMD quintile, compared to 18.8% of the Welsh population (p<0.001). Linkage of population-wide datasets enables an overview of MS prevalence by age, sex, ethnicity and social deprivation. Further work is needed to improve linkage between datasets.

Witts J
Tallantyre E
Rodgers J
Nicholas R
Middleton R

Adolescent
Adult
Aged
Female
Humans
Male
Middle Aged
Young Adult
Databases, Factual
Ethnicity
Multiple Sclerosis
Prevalence
Wales
Black People
Asian People
White People


From Data Linkage to Simulation: A New Framework for Evaluating Aged Care Policies

Abstract: The global rise in older populations has profound implications for health and social systems. Governments are investing in policies to support ageing in the community, yet robust evidence of effectiveness is limited. We are conducting population-level comparative effectiveness studies of Australian government policies in delaying transition to residential aged care (RAC). A comprehensive regional Electronic Health Record dataset will be established within the National Centre for Healthy Ageing (NCHA) and linked to national aged care, health and social data, the first linkage of this kind in Australia. A policy-specific framework for target trial emulation, according to the TARGET Statement, will be developed. Patient journey mapping and expert consensus will identify high-value covariates for statistical models. Uncoded covariates will be AI-derived from unstructured clinical notes using Natural Language Processing. The trial emulation framework and enriched linked dataset will underpin agent-based modelling to simulate diverse future policy scenarios. >200,000 older residents (2015-2026) have been identified for linkage (median age 70, 55% female) providing 80% power to detect a 5.5% reduction in RAC transitions. A reference committee of government, consumer, provider, and clinical representatives meets quarterly to guide data strategy and policy relevance. Journey mapping with ∼50 older people and carers in receipt of relevant policies is underway and a preliminary framework of simulation modelling established. This project harnesses advances in data linkage, simulation modelling, AI, and research infrastructure at the NCHA to deliver rapid, robust evaluation and simulation of aged care policies, while pioneering innovative data-enhancement techniques.

Andrew N
Collyer T
Beare R
Carver A
Long K
Churilov L
Ilomäki J
Sq Tan G
Ung D
Kilkenny M
Lannin N

Humans
Australia
Female
Health Policy
Aged
Male
Electronic Health Records
Computer Simulation
Information Storage and Retrieval
Health Services for the Aged


[Development and application of multidimensional comprehensive evaluation system for flowability of TCM powders based on principal component analysis]

Abstract: To address the problem that conventional evaluation methods struggle to comprehensively characterize the complex flow behavior of TCM powders, this study utilized an FT4 powder rheometer to perform a multidimensional characterization of 24 representative samples, including decoction pieces, extracts, excipients, and granules. In addition to traditional static parameters like angle of repose(α) and Carr index(IC), the study focused on dynamic rheological characteristics, specifically basic flow energy(BFE) and flow rate index(FRI),alongside shear and bulk property indicators such as cohesion(C_o) and flow function coefficient(FFc). Data analysis revealed that individual indicators frequently yield conflicting assessments for the same sample, underscoring the dimensional limitations of isolated metrics. By leveraging correlation analysis and principal component analysis(PCA), the study extracted core contributing factors to construct a weighted flowability comprehensive index(FCI). The results indicated that the FCI successfully integrated multi-source heterogeneous data, showing strong alignment with core flowability parameters and enabling precise classification of powder flow grades. This index offers a robust quantitative framework for enhancing stability assessment and quality control in TCM powder preparation processes.

Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica

Hu HQ
Wan XH
Liu Y
Hu H
Liu YH
Li YH
Peng CC
Wu ZF

Powders
Drugs, Chinese Herbal
Principal Component Analysis
Rheology
Quality Control
Chemistry, Pharmaceutical


[Crystal form issues and development prospects of TCM solid preparations]

Abstract: As the dominant dosage form in clinical practice of TCM, solid preparations face core challenges concerning quality stability and consistent therapeutic efficacy. Clinical observations have revealed efficacy variations among different preparation forms of the same TCM or even among products of the same preparation from different manufacturers. Such variations are attributed not only to the complexity of the production process but also to the physicochemical states of the drug substances, among which crystal forms likely serve as a critical factor influencing the drug state and subsequent efficacy divergence. TCM crystal forms, as a fundamental microscopic attribute of active ingredients in TCM, directly determine physicochemical properties and biological activities of drugs, representing a root cause of quality fluctuation and efficacy variation. Currently, significant progress has been made in the study of TCM crystal forms based on TCM active ingredients and compound preparations. A comprehensive technical framework encompassing preparation, characterization, and property analysis has been established. Its core value lies in revealing the scientific essence of "identical composition but heterogeneous activity", and it is expected to provide quantitative and precise technical support for quality control across the entire TCM industry chain. However, research on the crystal forms of TCM solid preparations remains a major challenge. Whether it concerns the discovery, characterization, and identification of preferred crystal forms in Chinese patent medicines, or the quality control of crystal forms of Chinese patent medicines and their impact on clinical efficacy, these areas remain largely unexplored territory awaiting further investigation. This article proposed the crystal form issues in TCM solid preparations. It comprehensively reviewed the research landscape of TCM crystal forms, spanning from single components to compound preparations, systematically elucidated the associated technical systems and category characteristics of TCM crystal forms, and innovatively proposed a crystal form-based strategy for quality control. This perspective provides a novel research framework for enhancing the quality control of TCM solid preparations and discovering new formula-derived nanoparticle drugs, holding significant importance for enhancing the standardization of TCM solid preparations, ensuring clinical efficacy, and advancing the development of TCM nanoscience.

Drugs, Chinese Herbal
Crystallization
Quality Control
Humans
Medicine, Chinese Traditional
Chemistry, Pharmaceutical
Drug Compounding


[Analysis and reflection on pharmacological effects and novel formulation technologies of lumbrokinase from Pheretima]

Abstract: Lumbrokinase, a serine protease complex extracted from Pheretima, possesses specific fibrinolytic activity and is clinically used for thrombolytic therapy in cardiovascular and cerebrovascular diseases. Due to its low bleeding risk profile, novel formulation technologies have significantly enhanced its therapeutic efficacy in acute thrombotic diseases. This study discussed the physicochemical properties, absorption properties, pharmacological effects, formulation strategies, and existing challenges of lumbrokinase, providing a comprehensive analysis for its future application and development.

Luo WY
Zhao FY
Huang JF
Zhang XW
Huang XY
Fu Y
Jiang W
Li WS
Yue PF

Animals
Humans
Fibrinolytic Agents
Serine Endopeptidases
Drug Compounding
Chemistry, Pharmaceutical
Endopeptidases


Precision Immunosuppression in Kidney Transplantation: A Comprehensive Review

Abstract: Individualized immunosuppression represents a paradigm shift in kidney transplant from traditional "trial-and-error" dosing strategies toward individualized regimens. Precision immunosuppression is informed by pharmacogenetics, biomarkers, therapeutic drug monitoring, and recently artificial intelligence-based prediction models, although stratified risk assessment of patients is still mandatory. This review investigated the current evidence on individualized induction and maintenance immunosuppression. In addition, the roles of pharmacokinetics, pharmacogenomics, and emerging biomarker platforms were reviewed and future pathways for tailored posttransplant care were outlined. In summary, the data indicate that optimized immunosuppressive therapy improves graft outcomes, reduces toxicity, and enables targeted minimization strategies in selected recipients.

Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation

Humans
Kidney Transplantation
Immunosuppressive Agents
Graft Rejection
Graft Survival
Treatment Outcome
Risk Factors
Precision Medicine
Predictive Value of Tests
Risk Assessment
Drug Monitoring
Pharmacogenetics
Drug Dosage Calculations
Biomarkers


From Small Data to Big Decisions: How Clinical Pharmacology Shapes Rare Disease Development

Abstract: Rare‑disease drug development is constrained by small and heterogeneous patient populations, limited natural‑history data, and the impracticality of large, randomized trials. Despite increasing regulatory acceptance of totality-of-evidence and mechanism-based development pathways, generating reliable, decision-ready evidence under these constraints remains challenging. This review describes how clinical pharmacology contributes within an evidence‑integration and decision‑support framework through quantitative, model‑informed approaches to address this gap. By integrating nonclinical data, pharmacokinetics, pharmacodynamics, biomarkers, natural‑history information, and clinical efficacy and safety outcomes, and through close collaboration with clinical, statistical, and translational experts, clinical pharmacology supports interpretation of treatment effects and quantitative characterization of uncertainty when conventional evidence is limited. In practice, these approaches inform key development decisions, including dose selection, innovative trial designs, extrapolation and bridging across populations, use of external controls, and evaluation of biomarkers and surrogate endpoints. Importantly, such practices help align regulatory expectations with patient needs, particularly in pediatric and ultra‑rare settings, by enabling appropriate dosing, reduced trial and patient burden, and quantitative assessment of benefit/risk. Examples from rare‑disease programs illustrate how integrated quantitative evidence has supported regulatory decisions, including label expansion and accelerated approval when data may be sparse, heterogeneous, or evolving. Looking ahead, emerging technologies such as artificial intelligence, digital biomarkers, and individualized approaches are expected to further advance rare‑disease drug development. With this evolving landscape, clinical pharmacology is expected to continue playing an important role in evaluating mechanistic plausibility, ensuring analytic rigor, and translating small datasets into meaningful evidence to inform development and regulatory decisions in rare diseases.

Xu Y
Verone-Boyle A
Schmitz N
Zahir H
Willis BA

Humans
Rare Diseases
Pharmacology, Clinical
Drug Development
Big Data


Innovative Clinical Pharmacology, Modeling, and Simulation Strategies for Accelerating Rare Disease Drug Development

Abstract: Clinical drug development for rare diseases continues to face significant challenges due to disease heterogeneity, fewer available patients, and incomplete understanding of pathogenesis, resulting in trials with limited clinical data, thus constraining traditional development pathways. Clinical pharmacology, modeling, and simulation-based approaches can help address these challenges by informing decision-making, mitigating uncertainty, and guiding optimal dose and regimen selection for the appropriate patient population. These approaches help streamline trial designs by reducing the scope and number of clinical trial evaluations, using exposure-response analyses to optimize dosing, the use of mechanistic-physiologically based pharmacokinetics (M-PBPK)-based approaches for biopharmaceutical and formulation optimization, evaluations of drug-drug interactions, and organ impairment. These strategies increase development efficiency across all stages of drug development, thereby improving the probability of success. This review highlights case studies that applied innovative clinical and quantitative pharmacology approaches across early and late stages of drug development and regulatory decision-making in rare diseases. The specific examples illustrate the application of pharmacokinetics/pharmacodynamics (PK/PD) and model-informed drug development (MIDD) strategies to support dose and regimen selection, enabling efficient use of direct or adaptive trial designs, facilitating bridging across populations and indications, biopharmaceutics-based transitions, and generating integrated PK/PD evidence to support labeling. Examples include drug repurposing, characterizing PK/PD in early phase to inform late-phase development, population PK analysis to guide trial dosing and label recommendations, using phenotype-targeted study design to address disease heterogeneity, expanding dosing regimen across indications using MIDD, quantitatively evaluating immunogenicity to support mitigation strategies, biomarker bridging, and applying M-PBPK to predict clinical PK in organ impairment populations.

Oberoi RK
Peer CJ
Tripathi A
Mohammad AS
Sun Y
Der K
Song Y
Huang J
Upreti VV

Humans
Rare Diseases
Drug Development
Pharmacology, Clinical
Models, Biological
Computer Simulation


Sex-Related Differences in Physiologically-Based Biopharmaceutics Modeling

Abstract: Physiologically based pharmacokinetic (PBPK) and physiologically-based biopharmaceutics (PBBM) modeling are valuable tools in drug development, allowing mechanistic predictions of drug absorption and disposition. However, sex-related differences in gastrointestinal physiology are often underrepresented in virtual populations, potentially limiting prediction accuracy. This study aimed to evaluate how sex-related physiological differences are incorporated into commonly used PBPK platforms and to illustrate their impact on pharmacokinetic predictions using ketoprofen as a case study. Three PBPK platforms were systematically reviewed to assess predefined sex-specific gastrointestinal parameters. All three platforms incorporated sex-related differences in general anatomy and physiology but overlooked sex-specific variability in gastrointestinal tract parameters. In addition, three PBBM models of ketoprofen were developed and verified in males and subsequently extrapolated to females using default and refined sex-specific parameters. Under default female settings, the models overpredicted Cmax and underestimated Tmax, resulting in concentration-time profiles that were nearly indistinguishable from those of males. Refining gastrointestinal tract parameters for females population improved prediction performance and better reflected observed sex differences. These findings indicate that current PBPK platforms may require user-defined adjustments to adequately represent sex-specific gastrointestinal physiology and that incorporating such parameters could lead to more representative PBBM applications.

CPT: pharmacometrics & systems pharmacology

Chavarría-Rojas M
Murshed M
Lorier M
Fotaki N
Ibarra M

Female
Humans
Models, Biological
Ketoprofen
Male
Biopharmaceutics
Gastrointestinal Tract
Sex Factors
Sex Characteristics


The Application and Advancement of Herbal Medicine in Gastrointestinal Cancers: A Bibliometrix Visualization and Pan-cancer Analysis

Abstract: Herbal medicine has emerged as an important area of investigation in gastrointestinal cancers owing to its multitarget therapeutic potential and growing integration with modern oncology. However, the rapid expansion of the literature has resulted in a fragmented understanding of the field's knowledge structure, research evolution, and emerging directions. A bibliometric analysis was performed using publications retrieved from the Web of Science Core Collection between 2016 and 2025. Bibliometrix, VOSviewer, and CiteSpace were employed to evaluate publication trends, collaboration networks, thematic evolution, and knowledge foundations. To further assess the biological relevance of major research themes, representative molecular markers associated with apoptosis, cell-cycle regulation, and epithelial biology were examined using transcriptomic data integrated from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project through the Gene Expression Profiling Interactive Analysis (GEPIA) platform. A total of 1,985 publications were included. Research activity increased substantially over the study period, particularly after 2020. Bibliometric analyses revealed a progressive transition from traditional investigations of apoptosis, proliferation, and metastasis toward emerging themes involving tumor microenvironment regulation, ferroptosis, gut microbiota interactions, network pharmacology, and molecular docking. Knowledge structure analyses demonstrated increasing integration of experimental oncology, bioinformatics, and traditional Chinese medicine research. China dominated global publication output, while the United States exhibited the strongest international collaborative profile. Exploratory transcriptomic validation showed that representative molecular markers (BCL2, CCND1, and CDH1) exhibited differential expression patterns across multiple gastrointestinal malignancies, supporting the biological relevance of the dominant research themes identified through bibliometric analyses. Research on herbal medicine for gastrointestinal cancers is transitioning from descriptive pharmacological investigations toward mechanism-oriented, data-driven, and translational research. By integrating bibliometric visualization with exploratory pan-gastrointestinal-cancer transcriptomic validation, this study provides a comprehensive overview of the field's evolution and offers a complementary framework linking knowledge mapping with molecular-level evidence. These findings provide biological context for emerging research priorities and may facilitate future biomarker discovery and precision-oriented herbal medicine research for gastrointestinal cancers.

Zhao L
Wang H
Jiang Y
Zhao Z
Liang Q
Li Y
Wang J
Zhong W
Xu Y
Zeng X
Liu T
Yang Y
Wu Q
Xu K

Humans
Gastrointestinal Neoplasms
Bibliometrics
Herbal Medicine


IoT-enabled wireless neural implant for chronic, programmable neuropharmacology and optogenetics

Abstract: Wireless in vivo neuropharmacology and optogenetics offer a powerful way to link molecular signaling, defined neural populations, and behavior in freely moving animals. However, existing implantable wireless systems developed for this purpose often suffer from imprecise dosing, backflow contamination, and nonrefillable reservoirs, and their reliance on experimenter presence can itself alter neural activity and behavior. Here, we introduce a remotely actuated and programmable implant for drug delivery and optical stimulation (RAPIDO), which integrates a refillable, replaceable, and backflow-free fluidic module with a microscale inorganic light-emitting diode probe in a single miniaturized implant. A replaceable cartridge with an integrated unidirectional valve enables rapid refilling with contamination-free dosing, while a programmable electrochemical pump provides multilevel flow-rate control and linear dose modulation. Dual wireless modes combine smartphone control for on-site interactive experiments with internet connectivity for remotely scheduled, observer-free operation. In freely behaving rodents, RAPIDO enabled repeated wireless pharmacological modulation of locomotor behavior and independent optogenetic manipulation of intracellular signaling during cocaine conditioning. This platform establishes a foundation for chronic multimodal neuromodulation, supporting long-term circuit studies across distributed laboratories.

Jeong EY
Park JW
Cho S
Han D
Kim CY
Kim SW
Lee W
Kim WY
Kim JH
Jeong JW

Optogenetics
Animals
Wireless Technology
Neuropharmacology
Rats
Cocaine
Drug Delivery Systems
Mice


Formulation development of a biphasic release tablet-in-tablet system containing ketorolac tromethamine

Abstract: Ketorolac tromethamine (KT) is a potent nonsteroidal anti-inflammatory drug (NSAID) used for moderate to severe pain management. Its short elimination half-life necessitates frequent dosing, which can reduce patient compliance. The objective of this study was to formulate, develop, and optimize a novel biphasic-release tablet-in-tablet (TIT) system for KT to provide immediate pain relief followed by extended drug release. A TIT system was designed, comprising an immediate-release (IR) outer layer and an extended-release (ER) core matrix. The ER core was optimized using a 32 full factorial design, with the amounts of HPMC K100M and HPMC K4M as independent variables. Formulations were evaluated for pre- and post-compression parameters, drug-excipient compatibility, and in vitro drug release. The drug release kinetics and mechanism were analyzed using various mathematical models. The optimal ER core formulation (F1) exhibited a drug release of 4.6% at 0.5 h and 66.1% at 12 h, closely matching the theoretical profile (similarity factor f2 = 51). Release kinetics followed the first-order model and the Korsmeyer-Peppas model indicated an anomalous (non-Fickian) release mechanism (n = 0.831). The corresponding TIT formulation (F11) demonstrated desired physicochemical properties: hardness of 75 N, friability of 0.59%, and rapid outer layer disintegration (<50 s). The TIT provided an initial burst release (~30%) within 30 minutes, followed by sustained release exceeding 90% over 24 hours. This TIT system represents a promising alternative to conventional KT tablets for effective pain management.

Zou P
Zeng Y
Liao XR
Xie XY
Li YK
Ma YH
Liu H

Ketorolac Tromethamine
Tablets
Delayed-Action Preparations
Drug Liberation
Chemistry, Pharmaceutical
Anti-Inflammatory Agents, Non-Steroidal
Kinetics
Excipients


Assessment of Sorbitol as a Pharmaceutical Excipient in Oral Liquid Pediatric Formulations Submitted to the U.S. FDA

Abstract: Sorbitol is a commonly used excipient in pediatric oral liquid formulations. Previous research revealed that sorbitol as an excipient can diminish the bioavailability of concomitant drugs. The reported cases and amount of sorbitol in pediatric formulations has not been explored, thus the aims of this study were to (1) examine the number of reports of sorbitol as an excipient in orally administered drugs with liquid formulations used in pediatrics, and (2) estimate the maximum amount of sorbitol that may be consumed per day for each drug. A compilation of drug products containing sorbitol as an excipient was retrieved from the Interagency Agreement between the National Institute of Child Health and Human Development (NICHD) and the Food and Drug Administration (FDA), and products with oral liquid formulations were selected. Maximum daily sorbitol amount was categorized into level 0 (< 3,200 mg), level 1 (3,200 mg to < 10,200 mg), level 2 (10,200 mg to < 13,400 mg), and level 3 (≥ 13,400 mg). Results indicated that sorbitol amount ranged between 0.06% and 45.7% weight to volume (w/v) across several therapeutic areas with the most prevalent being drugs intended for nervous system disorders. Corticosteroid drug products had the highest daily exposures to sorbitol, with amounts surpassing 45 grams. Percentages of products at levels 3, 2, 1 and 0 were 11.5%, 7.1%, 39.3%, and 42%, respectively. The potential impact of sorbitol content in pediatric formulations and the best practices for its use in pediatric polypharmacy needs to be further investigated.

Abulwerdi GA
Cote B
Abdel-Rahman S
Fletcher EP
Burckart GJ

United States Food and Drug Administration


Development and Optimization of Antioxidant Poly Herbal Peel-off Mask using Doe Based Approach

Abstract: Antioxidants protect the skin from free radicals, which are associated with signs of aging, pigmentation, and loss of elasticity. Combining antioxidants in cosmetic formulations may provide broader antioxidant potential. This study focuses on the formulation and optimization of a polyherbal antioxidant peel-off mask using extracts of Ocimum sanctum (Tulsi), Moringa oleifera (Moringa), and Trigonella foenum-graecum (Fenugreek), which are reported to possess antioxidant and skin-beneficial properties. The formulation and optimization of the polyherbal peel-off mask were carried out using Central Composite Design (CCD). Polyvinyl alcohol (PVA) and carbomer 940 served as film-forming agents, while triethanolamine was used to adjust viscosity. The optimized formulation was evaluated for physicochemical characteristics, in vitro antioxidant activity, and irritation potential using the HET-CAM assay. The optimized formulation exhibited a drying time of 25.3 minutes and an applicability score of 18.82. Physicochemical evaluation showed acceptable homogeneity, smooth texture, and pH suitable for topical application. In vitro antioxidant assays demonstrated a lower IC50 value for the polyherbal mask compared to the standard vitamin C formulation, indicating notable antioxidant activity. Furthermore, the CAM (chorio-allantoic membrane) irritation test showed no observable signs of irritation such as hemorrhage, lysis, or coagulation under the study conditions. This study successfully formulated and optimized a polyherbal peel-off mask with promising in vitro antioxidant activity and acceptable physicochemical characteristics. The use of Central Composite Design (CCD) enabled systematic optimization of the formulation variables. The findings suggest the potential applicability of the developed herbal formulation for cosmetic skincare applications; however, further stability studies and in vivo safety and efficacy evaluations are required.

International journal of pharmaceutical compounding

Ramakrishnan D
Mr J
Joy J
Jojo GM
Abbas FS

Antioxidants
Plant Extracts
Animals
Drug Compounding
Cosmetics
Chemistry, Pharmaceutical
Skin


Herbal Medicine Processing By-Products as Bioactive Resources: In Vivo Evidence for Antioxidant, Anti-Inflammatory, and Immunomodulatory Effects

Abstract: Processing herbal medicine generates substantial quantities of by-products that are discarded as waste. These residues may retain polysaccharides, flavonoids, saponins, terpenoids, and other constituents with pharmacological relevance. This review discusses the bioactive potential of by-products derived from single traditional Chinese and Korean herbal medicines, with emphasis on antioxidant, anti-inflammatory, and immunomodulatory mechanisms documented in preclinical in vivo studies. Representative in vivo evidence suggests that selected residues, marc fractions, fermentation products, and re-extracted by-products were reported to modulate oxidative stress markers, inflammatory cytokines, immune responses, and tissue-protective pathways across diverse experimental models. Processing method appears to be a key determinant of activity, as fermentation, high-temperature/high-pressure treatment, re-extraction, and targeted purification may enhance or diversify residual bioactivity. Current evidence remains limited by inconsistent chemical characterization, heterogeneous animal models, and incomplete reporting of experimental design. Re-evaluating herbal medicine processing by-products as bioactive resources may support sustainable herbal medicine manufacturing and circular bioeconomy frameworks.

Antioxidants
Anti-Inflammatory Agents
Humans
Animals
Immunologic Factors
Herbal Medicine
Immunomodulating Agents
Plants, Medicinal


Exclusive Feature Papers in Synthetic Medicinal Chemistry

Abstract: The collection of manuscripts presented in this issue exemplifies the breadth and vitality of contemporary medicinal chemistry, demonstrating how innovative molecular design, sophisticated synthetic methodologies, and biologically driven investigations continue to expand the frontiers of chemical and pharmaceutical sciences [...].

Chemistry, Pharmaceutical
Chemistry Techniques, Synthetic
Humans
Drug Design


Interpretable Spectral Evidence Learning from Vis/NIR Imaging for Non-Destructive Authentication of Herbal Medicines

Abstract: Rapid and non-destructive authentication of herbal medicines is important for quality control and market supervision. This study established an interpretable spectral evidence learning framework for visible and near-infrared (Vis/NIR) imaging-based authentication of Codonopsis Radix (CR) and Aurantii Fructus (AF). Compact 31-band mean gray-value spectra were analyzed at ROI and sample levels. CR sample-level spectra were obtained by ROI-group averaging, whereas AF records were retained as individual sample spectra with image-group information used for leakage-controlled validation. Raw spectra, Savitzky-Golay smoothing, multiplicative scatter correction, and standard normal variate correction were compared with machine-learning and deep-learning classifiers. A fold-contained lightweight diffusion (LD) module was further introduced to provide class-conditioned spectral augmentation and denoising-error evidence. Under grouped cross-validation, the strongest non-LD Linear SVM models achieved accuracy/macro-F1 values of 0.9231/0.9238 for CR and 0.9025/0.9018 for AF. After LD augmentation, the best LD-augmented SVM models reached macro-F1 values of 0.9427 and 0.9197, respectively. Across all evaluated model-dataset combinations, LD increased the overall mean macro-F1 from 0.7302 to 0.8189. Model-aligned wavelength evidence and top-wavelength subset tests further showed that selected LED-band subsets retained useful discriminative information within the present imaging configuration. These results support the feasibility of compact Vis/NIR image-based authentication of herbal materials under grouped validation.

Spectroscopy, Near-Infrared
Herbal Medicine
Drugs, Chinese Herbal
Support Vector Machine
Machine Learning
Plants, Medicinal


Genetic Landscape of NAT2 in the Moroccan Population: Implications for Isoniazid Pharmacogenetics in Tuberculosis

Abstract: The NAT2 gene encodes N-acetyltransferase 2, an enzyme critically involved in the biotransformation of numerous xenobiotics and aromatic amines, including isoniazid, a cornerstone drug in tuberculosis therapy. Genetic polymorphisms in NAT2 lead to variable acetylation rates, clinically categorized as poor, intermediate, or rapid metabolizer phenotypes influencing drug efficacy and toxicity. This study aims to characterize the NAT2 polymorphisms in 240 Moroccan individuals using pre-existing clinical exome sequencing data. A total of fourteen variants were identified in the NAT2 coding region, with the most frequent being c.341 T>C (50%), c.803G>A (48.95%), c.481C>T (48.33%), and c.282C>T (29.16%). Diplotype-based phenotype prediction showed that 148 individuals (61.67%) were poor metabolizers, 71 (29.58%) intermediate metabolizers, and 14 (5.83%) rapid metabolizers. Seven individuals could not be classified due to the presence of variants with unreported diplotype-phenotype correlations. These findings provide a comprehensive pharmacogenetic profile of NAT2 in the Moroccan population and support the implementation of diplotype-guided isoniazid dosing strategies in tuberculosis-endemic settings.

Benyahya N
El-Hamri MA
Lyahyai J
Ratbi I
Cherkaoui I
Rchiad Z
Sefiani A

Humans
Arylamine N-Acetyltransferase
Isoniazid
Morocco
Antitubercular Agents
Tuberculosis
Female
Pharmacogenetics
Male
Exome Sequencing
Phenotype
Adult
Polymorphism, Single Nucleotide
Pharmacogenomic Variants


Understanding public perspectives on direct-to-consumer pharmacogenomic testing in the UK: a qualitative study

Abstract: Direct-to-consumer (DTC) pharmacogenomic (PGx) testing is expanding rapidly in the UK, yet no dedicated regulatory framework currently governs these services. Although a 2021 parliamentary inquiry recommended stronger safeguards and clearer technical standards for genomic testing, these proposals have not been applied to PGx. This study explores public attitudes toward DTC PGx testing, focusing on expectations for pre-test information, quality standards, and NHS data use. We conducted focus groups with members of the public, both with and without prior experience of purchasing DTC PGx tests, or other online health tests. Focus groups were audio-recorded with consent, transcribed, and analysed thematically. We identified three themes: (mis)understanding towards and awareness of DTC PGx testing; altruistic motivation and equity concerns; and (mis)trust. Participants were generally enthusiastic about PGx testing, as long as issues of equity, data protection, and regulation were addressed, with data sharing concerns being particularly prominent.

Mathieson A
Brunton L
Gillibrand S
Moldovan R
McDermott JH

Direct-To-Consumer Screening and Testing


Pharmacogenetic Risk Factors for Thiopurine-Induced Leukopenia in Patients with Inflammatory Bowel Disease

Abstract: Thiopurines remain an effective treatment for maintaining remission in inflammatory bowel disease (IBD), yet their use is often limited by thiopurine-induced leukopenia (TIL), a potentially life-threatening adverse effect. We aimed to investigate pharmacogenetic associations with TIL in patients with IBD. We retrospectively analyzed 218 thiopurine-treated patients from two independent IBD cohorts with whole-exome sequencing. Pharmacogenetic subgroups were defined using Clinical Pharmacogenetics Implementation Consortium star allele-based molecular phenotypes or genotype-based classifications. Genetic associations with TIL, defined as white blood cell count ≤3000/µL, were analyzed using Andersen-Gill models adjusted for clinical covariates. NUDT15 intermediate metabolizers [hazard ratio (HR) 5.21, p<0.001], poor metabolizers (HR 6.42, p<0.001), and IL6 heterozygotes (HR 4.35, p<0.001) showed reproducible, independent associations with increased TIL risk. Incorporating IL6 into the traditional TPMT/NUDT15 model significantly improved sensitivity (p=0.0156) and negative predictive value (p=0.046). Our findings confirm the central role of NUDT15 in TIL susceptibility and identify IL6 as a novel, independent contributor in Korean patients with IBD. Incorporating IL6 into existing pre-emptive pharmacogenetic testing may support safer thiopurine therapy.

Humans
Leukopenia
Inflammatory Bowel Diseases
Female
Male
Risk Factors
Pyrophosphatases
Retrospective Studies
Nudix Hydrolases
Adult
Pharmacogenetics
Interleukin-6
Mercaptopurine
Middle Aged
Azathioprine
Genotype
Methyltransferases


A Pharmaco-Epidemiological Research Program Leveraging a Nationwide Database of Kidney Transplantation

Abstract: The pharmaco-epidemiological research program in kidney transplantation (PERP-KT) aims to evaluate, for the principal maintenance immunosuppressive drugs (MISDs): the influence of model-informed precision dosing on graft and patient survival; long-term exposure-effects relationships; and the benefit-harm balance of their combinations and time sequences in patient groups or clinical settings not adequately evaluated in comparative randomized clinical trials. It also aims to develop a hybrid, dynamic, deep learning model capable of predicting the rate of renal graft function decline, thereby providing a platform for individualized prediction of the benefits and risks associated with MISDs. After obtaining all regulatory andd ethical approvals, de-identified extracts of three national databases were linked to create the nationwide PERP-KT dataset, which is hosted within the highly secure environment of the French Health Data Hub. CRISTAL (the exhaustive registry of the French Agence de la Biomédecine) comprises data from 49 886 kidney donors and the corresponding 47 842 transplant recipients between 2005 and 2020. Following iterative deterministic matching and extensive quality control procedures, CRISTAL data were successfully linked to: the French national Health Data System (SNDS), which records reimbursed healthcare utilization, for 30 782 kidney transplant recipients; and to ISBA, a web-based platform for Bayesian dose adjustment of MISDs that contains pharmacological data, for 17 700 kidney grafts and 17 576 recipients. More than 20 pharmaco-epidemiological studies will leverage the database's extensive follow-up, large population size and richness of clinical, healtcare-utilization, and pharmacological data.

Marquet P
Humeau A
Crépin S
Benoist C
Couderc S
Monchaud C
Labriffe M
Saint-Marcoux F

Kidney Transplantation
Humans
Databases, Factual
Immunosuppressive Agents
Pharmacoepidemiology
France
Graft Survival
Female
Male
Graft Rejection
Registries
Middle Aged
Adult


Late-stage functionalization with strain-release warheads enables tunable covalent inhibition

Abstract: Covalent inhibition continues to gain momentum as a strategy for selective protein modulation in both therapeutic and chemical biology contexts. Covalent reactive groups (CRGs) typically engage nucleophilic residues such as cysteine, resulting in targeted protein inactivation. However, common electrophiles such as acrylamides often suffer from nonselective reactivity, leading to off-target effects and toxicity. To overcome these limitations, we developed a modular sulfur(IV) reagent platform for the mild, late-stage installation of sulfonyl- and sulfonimidoyl-bicyclobutane motifs with complete cysteine selectivity. This methodology enables access to diverse sulfur(VI) CRGs with tunable strain-release reactivity. Incorporation into US Food and Drug Administration-approved covalent inhibitors demonstrated effective bioisosteric replacement of acrylamides and the potential of strain-release CRGs for selective protein targeting. Preclinical studies in mice have validated this approach, highlighting its promise for next-generation covalent drug design.

Shultz ZP
Lee-Sam A
Chang YP
Sun L
Grassie D
Gabellini A
Pedretty K
Scattolin T
Izumi V
Fang B
Sansil S
Kakumanu R
Wojtas L
Koomen J
Schönbrunn E
Monastyrskyi A
Duckett D
Lopchuk JM

Animals
Mice
Acrylamides
Bioisosterism
Cysteine
Drug Design
Proteins
Sulfur


Formulation and evaluation of sustained-release pitavastatin-loaded chitosan nanoparticles for enhanced anti-hyperlipidemic activity

Abstract: Pitavastatin (PVN), a BCS class-II drug, exhibits poor aqueous solubility leading to limited oral bioavailability and therapeutic efficacy. This study aimed to enhance the solubility and anti-hyperlipidemic efficacy of Pitavastatin (PVN) by encapsulating it in chitosan-based polymeric nanoparticles. Pitavastatin-loaded chitosan nanoparticles (NPs) were prepared using the ionic gelation method. Formulations were characterized by particle size, zeta potential, drug loading, In-vitro drug release and surface morphology. Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermal analysis (TGA and DSC), ex-vivo intestinal permeability and in-vivo pharmacodynamic analysis were also performed. The size of PVN-loaded NP ranged from 219.9±1.11 to 292.7±2.29 nm with PDI 0.2-0.4, surface charge of +28.4 ± 0.43 to 32.5 ± 1.02 mV and entrapment efficiency 65±1.12-93±1.23%. Solubility in different media (PBS (pH 6.8), 0.1N HCl (pH 1.2) and distilled water showed a 56-102-fold increase compared to PVN. SEM analysis revealed a smooth surface and spherical geometry of the NP. FTIR analysis confirmed that there was no physicochemical interaction between PVN and chitosan in NP formulations (NP1-NP5). XRD and thermal analysis indicated the amorphous nature of PVN-loaded NP. In-vitro drug release from NP formulations (NPI-NP5) ranged from 80.97±4.80 to 81±3.90% indicating sustained release, while ex-vivo intestinal permeability was 1.5-fold higher than PVN. The optimized formulation (NP1) followed Higuchi release model, indicating Fickian diffusion. Pharmacodynamic analysis of lipid profiles in hyperlipidemic albino rats suggested that NP1 reduced low-density lipoprotein (LDL) by 33±1.24 %, total cholesterol by 29±2.13% and triglycerides by 23±1.21%, showing better results than PVN. Chitosan-based Pitavastatin nanoparticles successfully enhanced drug solubility and provided sustained release, leading to improved ex-vivo permeability and greater in-vivo anti-hyperlipidemic activity in albino rats. This approach represents a promising strategy for enhancing therapeutic potential of Pitavastatin.

Pakistan journal of pharmaceutical sciences

Arshad A
Zaman M
Riaz H
Haider MS
Ishaq W
Adnan S
Masood Z
Ahmed H
Ameer N
Rahman HMA
Waqas M
Farooq M

Spectroscopy, Fourier Transform Infrared


Predicting pHmax and Salt Disproportionation Risk for Basic Drugs

Abstract: Pharmaceutical salts are commonly used to enhance the bioavailability of poorly water-soluble drugs. The maximum solubility in water and the physical stability of a salt are closely linked to its pHmax, the pH at which both the free form (acid or base) and the salt can coexist. However, several aspects related to pHmax are only partially addressed or unexplored: (1) before salt screening, which usually consumes significant materials and efforts, whether pHmax can be predicted based on molecular properties; (2) whether salt disproportionation proceeds via a solid-state or water-mediated mechanism; and (3) whether disproportionation risk can be graded systematically and predicted. In this work, the relationship between pHmax and the physical properties of the basic compounds was examined, and a regression model was constructed based on their correlations. The pHmax values of 106 monosalts for 35 basic drugs were compiled from the literature. In the data set examined, the pHmax is strongly correlated with the pKa of the drug (2-10), but not significantly with the pKa of the counter-acid (-8 to 5), and is slightly influenced by the molecular weights of the drug and counter-acid. Accordingly, before salt screening, pHmax of a monosalt can be predicted as a function of the drug pKa and the relevant molecular weights. Across a pH range of 1-11, for the 106 monosalts studied, 74% of the predicted pHmax values were found to be within experimental errors. To determine whether disproportionation between pharmaceutical salts of basic drugs and basic excipients is a solid-state reaction or not, differential scanning calorimetry (DSC) is performed. The results showed that a solid-state reaction did not occur even at high temperatures where the excipient either melted or was liquefied above its glass transition temperature. Disproportionation risk levels were systematically defined based on development requirements and were exemplified using model HCl salts (sertraline, prazosin, phenazopyridine, and pioglitazone) across a wide pHmax range. The risk level shows a strong correlation with the pH difference between the equilibrium pH of the excipient (pHee) and the pHmax of the salt. Notably, the risk level increases more sharply with the pH difference (pHee - pHmax) for highly hygroscopic excipients. A prediction workflow for disproportionation risk level is proposed based on the above correlation and the self-disproportionation type of pharmaceutical salts.

Yao X
Yu M
Chen F
Du S
Kallemeyn LC
Bergman J
Lesslie MW
Chen S
Sheikh AY

Hydrogen-Ion Concentration
Salts
Solubility
Pharmaceutical Preparations
Drug Stability
Bulk Drugs
Water
Chemistry, Pharmaceutical


A Cautionary Note for Plasmode Simulation Studies in the Setting of Causal Inference

Abstract: Plasmode simulation has become an important tool for evaluating operating characteristics of different statistical methods in complex settings, such as pharmacoepidemiological studies of treatment effectiveness using electronic health records (EHR) data. These studies provide insight into how estimator performance is impacted by challenges including rare events, small sample size and so forth that can indicate which among a set of methods performs best in a real-world dataset. Plasmode simulation combines data resampled from a real-world dataset with data from a probabilistic model to generate a known truth for an estimand in realistic data. There are different potential plasmode strategies currently in use. We compare two popular plasmode simulation frameworks for the evaluation of methods estimating a point treatment estimand. We provide numerical evidence and a theoretical result that shows one of these frameworks can cause certain estimators to incorrectly appear overly biased. Detailed simulation studies using both model-generated and real-world EHR data demonstrate these pitfalls remain at large sample sizes and when analyzing data from a randomized controlled trial. We conclude with guidance for the choice of a plasmode framework that maintains good theoretical properties to allow a fair evaluation of statistical methods while also maintaining the desired similarity to real data.

Shaw PA
Gruber S
Williamson BD
Desai R
Shortreed SM
Krakauer C
Nelson JC
van der Laan MJ

Computer Simulation
Humans
Models, Statistical
Electronic Health Records
Randomized Controlled Trials as Topic
Causality
Pharmacoepidemiology
Data Interpretation, Statistical
Bias
Sample Size


Development and in vivo pharmacokinetic evaluation of a phospholipid complex self-nanoemulsifying drug delivery system (PLC-SNEDDS) for enhanced oral bioavailability of cannabidiol

Abstract: Cannabidiol (CBD) exhibits poor oral bioavailability (approximately 6%) due to low solubility and excessive first-pass metabolism, limiting its therapeutic potential. This study introduces a novel phospholipid complex self-nanoemulsifying drug delivery system (CBD-PLC-SNEDDS) to enhance CBD delivery. CBD-PLC was integrated into an optimized SNEDDS via Design of Experiments (DoE), yielding nanoemulsions with 118.9 ± 0.77 nm particle size, 0.258 PDI, and -21.9 mV zeta potential. Physicochemical characterization (DSC, FTIR) confirmed amorphization and physical encapsulation without chemical alteration. In vitro dissolution showed 100% CBD release within 1 h for CBD-PLC-SNEDDS vs. 8 h for CBD-SNEDDS. Stability studies (ICH guidelines) retained 94.73% ± 0.62% CBD at 25 °C/60% RH and 80.21% ± 0.61% at 40 °C/75% RH after 4 months with preservatives. In vivo pharmacokinetics in Sprague-Dawley rats (n = 9, 20 mg/kg oral; 4 mg/kg IV) demonstrated that CBD-PLC-SNEDDS significantly enhanced systemic exposure, achieving a calculated absolute bioavailability (F) of 92%, compared to 47% for the oleic acid control. The formulation yielded a 5-fold higher C max (593 ± 246 vs 118 ± 63 ng/mL) doubled AUC0-∞ (88 vs. 45 h·kg·ng/mL/mg), faster T max (2 ± 0.3 vs. 7.4 ± 2.3 h), and extended T 1/2 (3.7 ± 0.9 vs. 1.9 ± 0.6 h) versus control. CBD-PLC alone yielded only 39%. IVIVC modelling via Wagner-Nelson deconvolution established a strong correlation (R2 > 0.7) between in vitro dissolution and in vivo absorption, validating the system's predictive performance. This synergistic PLC-SNEDDS platform outperforms prior systems, offering a scalable template for lipophilic drugs and paving the way for clinical CBD therapeutics.

Muta T
Mukhopadhyay S
Noll B
Song Y
Garg S

Cannabidiol
Animals
Biological Availability
Phospholipids
Administration, Oral
Emulsions
Rats, Sprague-Dawley
Rats
Particle Size
Male
Drug Delivery Systems
Solubility
Nanoparticles
Nanoparticle Drug Delivery System
Drug Stability
Chemistry, Pharmaceutical
Drug Liberation


Developments in Clinical Psychopharmacology From 2000 Through 2026: A Personal Perspective

Abstract: The first column in this 2-part series covered the history of clinical psychopharmacology from the author's perspective from 1975 to 2000. This column covers the last 26 years of clinical psychopharmacology as experienced by the author from 2000 to 2026. It focuses on the following major areas: (1) system-level neurobiology of neuropsychiatric drugs with an early focus on antidepressants; (2) circuit-based drug discovery; (3) pharmacokinetic, pharmacodynamic, and metabolic determination of psychotropic drug response as encompassed by Preskorn's Organizing Equation; (4) therapeutic drug monitoring (TDM) and pharmacology safety based on the use of TDM's ability to measure the functional as opposed to just the genetic capability of a patient to metabolize a medication; (5) enzyme-mediated drug-drug interactions; (6) multiple medication use in everyday clinical practice; (7) the results and implications of the results of the NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study; and (8) early phase clinical investigation of novel central nervous system mechanisms. The column illustrates the author's goal to bring science to the practice of psychiatry, beginning in the mid-1970s, when psychoanalysis dominated psychiatric thinking, up through 2026, within our current limits of understanding. It also illustrates how, at least for one psychiatrist, knowledge in our field has evolved and his reason for having this goal.

Humans
Psychopharmacology
History, 20th Century
History, 21st Century
Psychotropic Drugs
Antidepressive Agents
Drug Monitoring
Drug Discovery
Mental Disorders

Journal Article
Historical Article
Review


Safety of Pharmaceutical Nanosuspensions in Drug Delivery: Evidence, Knowledge Gaps, and Safety-By-Design Strategies

Abstract: Poor aqueous solubility remains a major barrier to small-molecule drug development. Pharmaceutical nanosuspensions, composed mainly of drug nanocrystals stabilized by small amounts of excipients, can improve dissolution and have been translated into several oral products and long-acting injectables. However, their simple compositions do not make them biologically inert. Nanosizing changes the surface area, dissolution, interfacial properties, aggregation, and interactions with biological fluids, thereby affecting local and systemic safety. This review examines nanosuspension safety from a product-level perspective. It focuses on formulation states generated during storage, handling, administration, and biological exposure, with attention to particle-size distribution, large-particle tails, stabilizer coverage and free excipient, crystal form, dissolution behavior, redispersibility, and in-use stability. These attributes are linked to blood compatibility, complement activation, immune responses, route-specific toxicity, biodistribution, macrophage-associated retention, depot persistence, clinical experience, and regulatory translation. Current evidence supports nanosuspensions under well-controlled conditions, especially for oral nanocrystal products and selected long-acting injectables. Key uncertainties remain for repeated intravenous use, chronic pulmonary exposure, particle-specific biodistribution, depot reversibility, long-term tissue exposure, and vulnerable populations. Safety assessment should, therefore, connect critical quality attributes with route-relevant exposure and biological responses, providing a basis for safety by design.

Humans
Nanoparticles
Suspensions
Animals
Solubility
Drug Delivery Systems
Particle Size
Excipients
Administration, Oral
Chemistry, Pharmaceutical
Drug Compounding
Tissue Distribution
Drug Stability


Selected highlights from the 26th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs

Abstract: Clinical pharmacology plays a crucial role in the successful treatment and prevention of HIV and other viral infections. Information from the field of clinical pharmacology leads to the development of novel antiviral treatments, supports the evaluation of efficacy and safety of antiviral therapies, informs the management of drug-drug interactions, and defines the optimal dosing and drug selection for special populations. The International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs recently held its 26th meeting. This review focuses on selected abstracts presented at the 2025 workshop and provides insights to assist clinicians in applying this new knowledge to clinical practice.

Humans
Antiviral Agents
HIV Infections
Pharmacology, Clinical
Drug Interactions
Hepatitis, Viral, Human


Phytotherapeutics self-microemulsifying systems in pellet dosage form for enhanced intestinal drug delivery: formulation, stability, and in-vivo performance

Abstract: Self-microemulsifying drug delivery systems (SMEDDS) containing volatile phytotherapeutics such as thymol (T), carvacrol (C), and eugenol (E) present significant formulation challenges, even when solidified. Their instability and interactions with coatings often hinder intestinal delivery. To address these limitations, we developed solid SMEDDS consisting of pellets (microcrystalline cellulose/magnesium aluminometasilicate/chitosan) and enteric capsules (CEC) for enhanced intestinal delivery. Based on solubility and pseudo-ternary phase diagrams, SMEDDS formulations (SES1-3) differing in component ratios (glycerol monooleate/caprylocaproyl macrogol-8 glycerides/diethylene glycol monoethyl ether) with 5% w/w of each drug were identified, demonstrating nano-scale droplet sizes (PDI <0.4) and showing no phase separation over 6 months. Thermodynamic stability and liquid-state NMR revealed particle size variations with preserved structural integrity. The lead formulation SES1 exhibited superior ex-vivo intestinal permeation (T-SES1). CECs filled with T-, C-, and E-loaded SES1 pellets, respectively, prepared via extrusion/spheronization, exhibited in-vitro gastro-resistant release, and achieved > 85% drug release within 120  min after a pH change to 6.8 during a one-year stability study (25 °C; 60% RH). FTIR-ATR analysis of the CEC internal surface confirmed the temperature-dependent restructuring of hypromellose and E sorption, a phenomenon not observed with C or T, which is likely attributable to physicochemical distinctions. Oral administration of CEC with T-SES1-pellets (0.5  mg/kg) in piglets demonstrated a delayed peak plasma concentration (Cmax 11.67  ng/mL at 9 h) and sustained systemic exposure (AUC 119.8 ng·h/mL). These in-vivo findings substantiate the gastro-protective effect and enhanced intestinal absorption, positioning the pellet/CEC system as a promising strategy for the application of volatile phytotherapeutics in current pharmacotherapy.

Koutná G
Kotouček J
Macků J
Kubová K
Urbanová M
Janisová L
Šeděnková I
Muselík J
Vysloužil J
Mašek J
Mašková E
Pavelková M
Vetchý D
Brus J

Animals
Drug Delivery Systems
Emulsions
Solubility
Intestinal Absorption
Particle Size
Drug Stability
Chemistry, Pharmaceutical
Excipients
Swine
Administration, Oral


Optimizing Chitosan-based Posaconazole Dry Powder Formulation Using Box-Behnken Design: The Role of Leucine in Enhancing Performance

Abstract: The objective of this study was to develop and optimize a dry powder inhalation formulation of Posaconazole-loaded Chitosan Nanoparticles (POS-CSNPs) using a Quality by Design (QbD) approach. The aim was to enhance pulmonary drug delivery and antifungal efficacy, particularly against Rhizopus oryzae, by improving drug encapsulation, particle dispersion, and lung deposition using leucine as a performance enhancer. A Box-Behnken Design (BBD) was employed to evaluate the effects of Chitosan-to- Tripolyphosphate (CS:TPP) ratio, stirring speed, and polymer concentration on particle size, Polydispersity Index (PDI), and Entrapment Efficiency (EE). Nanoparticles were prepared via ionic gelation and spray-dried with varying concentrations of lactose and leucine. Characterization techniques included FTIR for drug-excipient compatibility, Dynamic Light Scattering (DLS) for size and zeta potential, TEM for morphology, and XRD for crystallinity. In vitro drug release, pulmonary deposition using a twin-stage impinger, antifungal activity, and stability under ICH conditions were assessed. The optimized formulation had a particle size of 248.20 ± 6.82 nm, PDI of 0.225 ± 0.010, zeta potential of 21.92 ± 0.84 mV, and EE of 68.17 ± 1.73%. In vitro release showed sustained drug delivery over 48 hours. The Fine Particle Fraction (FPF) reached 68.9% in leucine-based formulations, and antifungal activity was significantly higher compared to the pure drug, with a zone of inhibition of 21 ± 0.5 mm. The results demonstrated improved particle characteristics, drug release, and antifungal efficacy. Leucine significantly enhanced dispersibility and deposition. However, scale-up and batch consistency remain challenges. Further in vivo studies are needed to confirm clinical applicability. The study successfully developed a stable, effective dry powder POS-CSNP formulation with enhanced pulmonary delivery and antifungal activity, offering potential for improved treatment of pulmonary fungal infections.

Chitosan
Antifungal Agents
Triazoles
Leucine
Particle Size
Nanoparticles
Drug Compounding
Rhizopus oryzae
Administration, Inhalation
Drug Liberation
Powders
Chemistry, Pharmaceutical
Excipients
Dry Powder Inhalers
Drug Carriers


Evaluating AI-Generated Molecules for Drug Discovery: From Generic Metrics to Translational Readiness

Abstract: Artificial intelligence-driven molecular generation has become an increasingly used computational approach for proposing candidate chemical structures in early-stage drug discovery, yet the practical value of the molecules produced is often difficult to judge. Many studies still rely mainly on model-level metrics such as validity, uniqueness, novelty, and diversity. These metrics describe whether a generator produces parsable, non-redundant structures that extend beyond a reference set, but they do not show whether the molecules are chemically credible, biologically relevant, or experimentally actionable. AI-generated molecules are best treated as testable hypotheses requiring staged, complementary evidence rather than judgments based on generic generative statistics. We discuss the interpretive limits of common metrics, examine complementary levels of evaluation including medicinal chemistry feasibility, target relevance and prediction reliability, structure-based plausibility, and translational readiness, and identify recurring failure modes such as false novelty, reward exploitation, predictor bias, docking overinterpretation, and selective reporting. We propose a six-stage, failure-aware evaluation framework spanning molecular correctness, medicinal chemistry feasibility, novelty and diversity in context, target relevance and prediction reliability, structure-based plausibility, and translational readiness. This framework does not replace experimental validation; instead, it helps align computational claims with the strength of supporting evidence and promotes more transparent and reproducible evaluation of AI-generated molecules in drug discovery.

International journal of molecular sciences

Drug Discovery
Artificial Intelligence
Generative Artificial Intelligence
Humans
Chemistry, Pharmaceutical


Direct targeting of GLUT1 in cancer: A decade of inhibitor discovery and medicinal chemistry insights

Abstract: Glucose transporter 1 (GLUT1), the most extensively distributed member of the glucose transporter protein family, plays a pivotal role in regulating glucose metabolism and is indispensable for cellular growth, proliferation, and differentiation. Various metabolic disorders arise from the dysregulation of GLUT1 expression, which disrupts glucose homeostasis. The upregulation of GLUT1 has been identified in multiple cancer cells, facilitating tumor progression, metastasis, and resistance to treatment. Recent years have seen a surge in the discovery of GLUT1 inhibitors exhibiting improved selectivity and efficacy. Herein, we introduce the structure and biological function of GLUT1, GLUT1 related oncogenesis, and primarily focuses on recent advancements in the study of GLUT1 inhibitors over the last decade. Notably, this review is restricted to inhibitors that act through direct interaction with the GLUT1 protein, excluding agents that exert indirect effects via upstream signaling or metabolic regulation.

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents

Humans
Glucose Transporter Type 1
Neoplasms
Antineoplastic Agents
Drug Discovery
Animals
Chemistry, Pharmaceutical


Piperazine derivatives as anticancer agents: a medicinal chemistry review of structure, mechanism, and clinical translation

Abstract: Piperazine has become essential for designing anticancer drugs because of its basicity, conformational flexibility, and capacity to serve as a solubilizing agent and molecular linker between hybrid pharmacophores. Researchers have found piperazine to function as a medicinal chemistry component that helps develop bioactive scaffolds through its capacity to control solubility, linker design, and target binding properties. The review presents a comprehensive assessment of piperazine-based anticancer drug research published between 2015 and 2025 through its evaluation of clinically relevant medicinal chemistry findings. The literature is organized based on piperazine's three main functional roles, which include its use as a linker and solubilizing/basic motif and direct target-recognition element. The study examines major cancer types through scaffold-based structure-activity relationship (SAR) analysis, which includes breast cancer, liver cancer, colon cancer, cervical cancer, prostate cancer, brain cancer, and leukemia models. The research demonstrated that various derivatives achieved IC₅₀ values in the low-nanomolar to low-micromolar range in MCF-7, HepG2, and HCT-116, HeLa, PC-3, and K562 cell lines. Researchers have demonstrated how protonatable piperazine nitrogens improve aqueous solubility and formulation development, and interactions of enzyme and kinase active sites with acidic residues, which results in better binding strength and selectivity. The review presents major translational obstacles, which include excessive dependence on 2D in vitro studies, insufficient in vivo and ADME/PK information, and limited progress in clinical applications. The research studies the development of clinically usable piperazine-based anticancer drugs through novel methods, which include green chemistry, click chemistry, molecular docking, and QSAR-focused design.

Humans
Antineoplastic Agents
Structure-Activity Relationship
Piperazines
Neoplasms
Chemistry, Pharmaceutical
Piperazine


Pyridine-containing antitumor agents: structure-oriented medicinal chemistry, structure-activity relationships, and ADMET liabilities

Abstract: Pyridine is a common nitrogen-containing heteroaromatic motif in antitumor medicinal chemistry, but its design value is highly context dependent. Here, we synthesize structure-oriented medicinal chemistry principles that govern the use of pyridine-related motifs in antitumor drug design. We discuss pyridine-containing antitumor agents with emphasis on target recognition, scaffold organization, structure-activity relationship (SAR), drug metabolism and pharmacokinetics (DMPK), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) liabilities. Representative approved drugs, antibody-drug conjugate (ADC) payloads, targeted degraders, and polypyridyl metal complexes are used to illustrate how pyridine-related motifs can support binding, property tuning, and modality adaptation. By grouping representative compounds according to the medicinal chemistry function of their pyridine-related motifs, this review provides a practical framework for future scaffold design. Overall, pyridine should not be viewed as a universally beneficial privileged scaffold; it is better treated as a context-dependent design module that requires validation through integrated structural, SAR, ADMET, and translational evidence.

Pyridines
Humans
Structure-Activity Relationship
Antineoplastic Agents
Chemistry, Pharmaceutical
Animals
Drug Design


Development of a New Portable Genetic Analyzer for Point-of-Care Molecular Genetics and Pharmacogenomics Analysis

Abstract: Traditional medicine is now moving from the "one-size-fits-all" model toward personalized medicine, where diagnostic and therapeutic decisions are guided by the patient's unique genetic profile. Recent advances in genomics and pharmacogenomics have facilitated the identification of genetic variants linked to disease susceptibility and progression, as well as variability in drug response. However, translating these findings into clinical practice remains challenging, primarily due to the high cost and sophisticated genetic analysis infrastructure, which is only available in centralized genetic laboratories. A newly developed Portable Genetic Analyzer (PortaGen) was designed for point-of-care molecular genetics and pharmacogenomics analysis and evaluated in this study. PortaGen integrates 3D-printed parts and laptop-based centralized software control, along with digital recording and storage of results to support decentralized genetic testing. The prototype portable device was validated in comparison with an established portable polymerase chain reaction (PCR) workstation that complies with current operational standards and a reference laboratory-based method. Genotyping analysis was performed using ARMS-PCR (Amplification Refractory Mutation System Polymerase Chain Reaction) to detect and analyze CYP2C19 genetic variants (CYP2C19 ∗ 2; rs4244285, and CYP2C19 ∗ 17; rs12248560), relevant to pharmacogenomics, as well as the HBB: c.93-21(G>A) genetic variant, the most common variant leading to β-thalassemia. Concordance in genotyping calls between the new device, the established portable workstation, and the reference method was assessed using percentage agreement and Cohen's kappa coefficient, demonstrating consistently high concordance with statistically significant results (p < 0.05). These findings demonstrate that the new portable genotyping analyzer has improved throughput, visualization, and workflow efficiency into a suitcase-sized, portable point-of-care molecular genetic analysis device, which holds promise to advance personalized medicine interventions in a scalable and affordable fashion.

Poulida I
Karamperis K
Routsi IK
Sarris I
Mantzouranis G
Kostopoulos V
Mitropoulou C
Patrinos GP

Humans
Point-of-Care Systems
Cytochrome P-450 CYP2C19
Pharmacogenetics
Precision Medicine
Genotype
Genetic Testing
Rapid Diagnostic Tests


[Comparing synthetic data generation methods in pharmacoepidemiology: reconciling reproducibility with privacy protection]

Abstract: the use of real-world (RW) data has become an integral part of pharmacoepidemiological research and regulatory assessment. However, access to individual-level data, especially for purposes other than the original ones (secondary use), is often restricted by legal and ethical constraints related to privacy protection. In this context, generating synthetic data, defined as artificially generated data that reproduce the statistical properties and relationships of real data without containing information traceable to real individuals, offers an innovative opportunity to balance privacy protection with the need to generate RW evidence to support regulatory decision-making. to compare two methods of generating tabular synthetic data: synthpop, based on transparent and interpretable inferential methodologies, and Conditional Tabular-Generative Adversarial Networks (CT-GANs), which leverage deep learning approaches to reproduce complex multivariate distributions. The focus is on evaluating the ability of both approaches to preserve the statistical structure of real data and reduce the risk of disclosure/re-identification. comparative study of two synthetic data generation methods. a large anonymized RW dataset including 42,926 patients hospitalized for COVID-19 in Italy during the early phase of the pandemic. The dataset was obtained through record linkage of administrative databases and the COVID-19 registry using the TheShinISS tool. synthetic versions of the original dataset were generated using both synthpop and CT-GAN methods. Real and synthetic data were compared using three type of measures: 1. general utility measures (univariate, bivariate, and global), including comparison of variable distributions using plots, descriptive statistics, standardized mean differences (SMD), and Propensity Score Mean Squared Error; 2. specific utility measures, assessing the similarity of associations estimates from univariate and multivariable Cox models by evaluating the overlap of 95% confidence intervals (CI) of hazard ratios (HR), and comparison of Kaplan-Meier curves using the log-rank test; 3. disclosure (re-identification) measures, estimating the risk of identity and attribute disclosure using dedicated metrics (Unique in Original - UiO, replicated Uniques - repU, Disclosive in Original - Dorig, Disclosive in Synthetic Correct Original - DiSCO). in terms of general utility, results confirmed the superiority of synthpop over CT-GAN, with more than half of the variables exceeding the acceptable SMD threshold. Moreover, synthpop showed higher specific utility than CT-GAN, with a median overlap of 95%CI of HR of 75% (interquartile range, IQR: 66%-95%) compared with 0% (IQR: 0%-6%) for CT-GAN. Concerning disclosure measures, although the original dataset already presented a negligible risk of identity disclosure (UiO=0.23%), making synthesis largely redundant, both methods further reduced this risk (synthpop: repU=0.06%; GAN: repU=0.05%). in this study, considering the three evaluated aspects, synthpop performed better in balancing statistical accuracy and privacy protection. It also offered greater methodological transparency based on explicit statistical models and required lower computational time. These findings contribute to the ongoing debate on the potential use of synthetic data in research and regulatory assessments supporting their integration into RW data analysis workflows. The disclosure measures adopted may serve as a practical starting point, however, the definition of shared standards for these measures, as well as acceptable disclosure risk thresholds, would be desirable and should be developed collaboratively by the scientific community and data protection authorities. Future studies should focus on generating synthetic data where non-explicit relationships exist in real data (i.e., relationships that are not directly attributable to additive or multiplicative structures).

Mayer F
Fazio ML
Cutillo M
Stendardo G
Spila Alegiani S
Trifirò G
Massari M

Humans
Generative Adversarial Networks
Pharmacoepidemiology
Reproducibility of Results
Privacy
Confidentiality
Italy

Journal Article
Comparative Study
English Abstract


Carboxymethylation and Evaluation of Cassava (Manihot esculenta) Starch as a Potential Super-Disintegrant in Tablet Formulations

Abstract: Cassava (Manihot esculenta) is a significant source of starch in Ethiopia, with potential pharmaceutical applications. However, native starches often require modifications to enhance their utility, particularly as disintegrants. Carboxymethylation is a well-known modification that improves swelling and disintegration capacity. Therefore, this study is aimed at evaluating carboxymethylated cassava starch (CMCS) as a tablet disintegrant. CMCSs were produced using monochloroacetic acid under varying reaction conditions. Structural modification was confirmed with FTIR spectroscopy. Physicochemical and powder properties, including degree of substitution (DS), swelling power, viscosity, and flow behavior, were characterized using standard methods. Tablets were prepared using the direct compression method. The tablets were assessed for physical characteristics, disintegration, and dissolution to compare the disintegrant performance of CMCS, native cassava starch (NCS), and sodium starch glycolate (SSG). Nine CMCS batches were obtained from the modification process and confirmed by FTIR analysis. CMCSs showed improved characteristics such as hydration capacity, swelling power, and solubility compared to NCS. Specifically, CMCS7 (DS = 0.227) exhibited comparable flow, swelling, hydration, and viscosity to SSG. Thus, it was selected as an optimal batch to be used as a disintegrant. Tablets formulated with CMCS7 exhibited superior mechanical strength, low friability, and higher disintegration efficiency ratios compared to NCS while performing comparably to SSG. Tablets containing CMCS showed comparable disintegration to SSG and enhanced initial dissolution. CMCS demonstrated promising disintegrant properties and could serve as a potential alternative local super-disintegrant in pharmaceutical tablet formulations.

Abraha T
Molla F
Teklebrhan A
Hussen H
Getachew A


How Negative Controls Are Used in Pharmacoepidemiology: A Methodological Scoping Review of Real-World Observational Studies of Glucagon-Like Peptide-1 Receptor Agonists

Abstract: Negative controls (NCs) are increasingly used in real-world observational studies to detect residual confounding and systematic bias, but their implementation and reporting remain heterogeneous in applied pharmacoepidemiology. We conducted a methodological scoping review to characterize how NCs were selected, implemented, reported, and interpreted in real-world studies evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for non-indicated clinical outcomes. We systematically searched PubMed and Embase from database inception through November 2025 and additionally screened reference lists of included studies. Eligible studies used real-world data, applied an observational analytic framework to evaluate GLP-1 RAs, focused on non-indicated outcomes, and explicitly incorporated NCs for bias detection, falsification, validation, or empirical calibration. Among 489 records identified, 42 studies met the inclusion criteria. Most studies were cohort-based and were conducted in diabetes-related populations using electronic health records or administrative claims. Negative control outcomes (NCOs) were the dominant approach, whereas negative control exposures (NCEs), positive controls, and empirical calibration were less common. An explicit rationale for NC selection was reported in most studies, but none of the included studies explicitly discussed the assumptions underlying NC analysis. Most NC findings were reported as null or consistent with expectations, and were primarily used to support validity or robustness rather than to materially alter interpretation. Overall, our findings suggest that the current use of NCs in GLP-1 RA observational research has increased, while standardized implementation and reporting have lagged. Greater transparency regarding why NCs were selected, what source of bias they were intended to probe, how results were interpreted, and whether they changed analytic conclusions may improve the credibility and interpretability of real-world evidence in this rapidly evolving therapeutic area.


Medicinal Chemistry of Agents for Cancer Therapy and Diagnosis From Uruguay

Abstract: This review summarizes the evolution of our research on anticancer agents, from early efforts on hypoxia-selective cytotoxins to more recent developments in chemoprevention, molecular targeting, and radiopharmacy. Initial studies focused on the design of N-oxide-containing heterocycles as bioreductive-prodrugs activated under tumor hypoxia. While early triazine N-oxides and furoxans showed limited selectivity, these studies underscored the importance of redox-properties in biological activities. This led to the identification of phenazine 5,10-dioxides as a more suitable pharmacophore, affording compounds with improved potency- and hypoxia-selectivity, supported by mechanistic-, physicochemical-, and in vivo studies. Parallel efforts explored metal-based complexes and formulation strategies enhancing bioavailability and therapeutic performance. Alongside these efforts, cancer chemopreventive-agents were investigated, particularly chalcone-derived scaffolds and related hybrids capable of modulating phase I/II enzymes through Nrf2 activation. Additionally, attention has shifted toward targeted- and diagnostic-approaches, including radiopharmaceuticals for hypoxia-imaging and the use of biomolecular recognition systems, such as aptamers, polypeptides, and antibodies, to selectively address tumor-associated biomarkers. These strategies include aptamer-based biotherapeutics for drug delivery and imaging, as well as approaches combining tyrosine kinase receptor targeting with BNCT. Furthermore, bioorthogonal-methodologies have been explored enabling selective in situ activation and targeting. Together, these studies illustrate a multidisciplinary approach integrating chemistry, biology, and pharmacology toward more selective anticancer strategies.

Lavaggi ML
García MF
Cabrera M
Couto M
Cerecetto H

Humans
Antineoplastic Agents
Neoplasms
Animals
Chemistry, Pharmaceutical


Application of Bioisosteres in the Design and Discovery of FDA-Approved Drugs and Advanced Clinical Candidates

Abstract: Since its introduction in 1951, bioisosterism has become a cornerstone strategy in drug design and development, enabling chemists to rationally modify molecular structures to optimize biological and physicochemical properties. In this perspective, we examine 57 FDA-approved drugs and 18 advanced drug candidates wherein bioisosteric replacements were successfully employed to address a range of developability challenges encountered during lead optimization. These strategic substitutions have led to significant improvements in potency, selectivity, solubility, and metabolic stability, while simultaneously mitigating issues related to lipophilicity, plasma protein binding, and the formation of reactive metabolites. Together, these examples highlight the enduring impact of bioisosterism as a versatile tool for fine-tuning drug candidates and overcoming the multifaceted challenges of modern medicinal chemistry.

United States Food and Drug Administration


Retrospective Analysis of the Impact of the "Escape from Flatland" Publication on the Merck & Co., Inc., Small Molecule Portfolio

Abstract: Sixteen years ago, the fraction of sp3 centers (Fsp3) in a molecule was correlated with clinical progression, solubility, and promiscuity in Lovering's "Escape from Flatland" papers. These trends captivated academia and industry alike, motivating a flurry of strategies to incorporate sp3 carbons into targets for medicinal chemistry. Given this widespread impact, we performed a retrospective analysis on the small molecule portfolio of Merck & Co., Inc., Rahway, New Jersey, USA (hereinafter "MSD"). We probe how Fsp3 changed with year of synthesis and target class from 2000 to 2024, and whether Fsp3 impacted compound progression. To investigate explanations for these trends, we analyze Fsp3's influence on lipophilicity, permeability, solubility, and off-target potency and compare these findings with previous studies. Leveraging MSD's compound collection (millions of small molecules), we provide further context for the originally reported correlations and novel insights into incorporating Fsp3 effectively in future drug designs.

Garry OL
Cheng AC
Northrup AB
Merchant RR
Yeung CS

Humans
Small Molecule Libraries
Solubility
Drug Industry
Drug Discovery
Chemistry, Pharmaceutical


Preliminary Application of Antihypertensive Gene Detection in the Treatment of Hypertension

Abstract: BACKGROUND Hypertension management is often suboptimal due to interindividual variability in drug response. Pharmacogenomics testing may guide personalized therapy by identifying genetic polymorphisms affecting drug efficacy and safety. This study aimed to evaluate whether pharmacogenomics-guided therapy improves blood pressure control and treatment compliance and reduces rehospitalization in patients with hypertension. MATERIAL AND METHODS In this prospective randomized controlled trial, 900 patients with hypertension were assigned to a control group (CG, n=450) receiving conventional care or a study group (SG, n=450) receiving pharmacogenomic-guided therapy. Six gene loci (CYP2D6, CYP2C9, AGTR1, ACE, NPPA, CYP3A5) related to 5 antihypertensive drug classes were tested. Outcomes included blood pressure control rate, compliance, adverse reactions, drug adjustments, and 6-month readmission rate. RESULTS The SG achieved significantly higher blood pressure control rates at 3 months (80.7% vs 70.2%, P<0.001) and 6 months (78.4% vs 65.1%, P<0.001) compared with the CG. Treatment compliance was also higher in the SG (98.0% vs 74.0%, P<0.001). angiotensin-converting enzyme inhibitor-related dry cough incidence was lower in the SG (1.6% vs 8.3%, P<0.001). The SG required fewer drug adjustments during hospitalization and had a lower 6-month readmission rate (2.4% vs 8.9%, P<0.001). CONCLUSIONS Pharmacogenomic-guided individualized therapy improves blood pressure control, enhances treatment adherence, reduces specific adverse reactions, and decreases rehospitalization. These findings support integrating pharmacogenomic testing into personalized hypertension management.

Medical science monitor : international medical journal of experimental and clinical research

Humans
Hypertension
Antihypertensive Agents
Female
Blood Pressure
Male
Middle Aged
Prospective Studies
Pharmacogenetics
Pharmacogenomic Testing
Treatment Outcome
Aged
Precision Medicine

Journal Article
Randomized Controlled Trial


A Review on Modular Peptide Anchoring Strategies for Functionalizing Liposomal Nanocarriers: Advancing Non-covalent Design Toward Targeted Cancer Therapy

Abstract: Targeted drug delivery systems play a crucial role in improving the effectiveness and precision of cancer treatments. Liposomes have been widely investigated as drug carriers due to their versatility. Traditional methods for functionalizing liposomes involve covalent bonding of targeting ligands, which, while effective, can be complex and may affect the activity of the ligands. In contrast, non-covalent peptide insertion offers a simpler, more adaptable approach for incorporating targeting peptides into liposomal membranes using mechanisms such as hydrophobic interactions and electrostatic forces. This review examines non-covalent peptide-liposome interactions as the primary focus. We analyze mechanisms, incorporation techniques, and therapeutic applications with emphasis on formulation-relevant criteria including stability, manufacturability, and clinical translation. Critical evaluation of comparative advantages and limitations of each strategy provides decision frameworks for formulation scientists. We also address manufacturing challenges, quality control strategies, and regulatory considerations that influence clinical translation.

Hydrophobic and Hydrophilic Interactions


Pharmacology, Medicinal Chemistry, and Therapeutic Potential of Imidazoline Receptor Ligands

Abstract: The imidazoline receptor (IR) system, comprising the I1R, I2R, and I3R subtypes, consists of binding sites involved in cardiovascular, metabolic, and neurological disorders. This review updates the 2004 compilation by Dardonville and Rozas on IR ligands, emphasizing promising ligands, subtype selectivity, and pharmacological profiling. Representative ligands for each subtype are analyzed to highlight key pharmacological aspects, including affinity, selectivity, and functional activity, integrating findings from preclinical and clinical studies. Critical molecular targets such as Nischarin/IRAS for I1R and MAO-B-associated sites for I2R are discussed in the context of ligand design and CNS penetration. I1R-selective ligands, exemplified by rilmenidine, show improved selectivity over α2-adrenoceptors and exhibit antihypertensive, metabolic, and neuroprotective effects. I2R ligands display neuroprotective, anti-inflammatory, and analgesic activities, with CR4056 progressing to Phase II trials. PET imaging with [11C]BU99008 has validated I2R upregulation as a biomarker for neurodegeneration. Overall, the IR system presents therapeutic opportunities: I1R for cardiovascular and metabolic disorders, I2R for pain and neurodegeneration, and I3R for diabetes. Continued ligand optimization and receptor characterization are essential for clinical translation.

Imidazoline Receptors
Humans
Ligands
Animals
Neuroprotective Agents
Chemistry, Pharmaceutical
Analgesics


Ageing-driven gastrointestinal variability in Parkinson's disease: implications for oral levodopa pharmacokinetics and formulation design

Abstract: Parkinson's disease is a distinctly age-associated neurodegenerative disorder in which oral levodopa remains the therapeutic foundation, particularly in older adults. Yet with advancing age, the reliability of oral therapy progressively declines not simply due to inadequate dosing, but because ageing reshapes the gastrointestinal environment on which drug absorption depends. This review integrates evidence spanning neuromuscular decline, epithelial barrier fragility, altered luminal chemistry, immune dysregulation, microbiome remodelling, and enteric neurodegeneration to explain how the ageing gut generates exposure instability. Delayed gastric emptying, inconsistent proximal intestinal delivery, microbial drug metabolism, and real-world administration constraints collectively amplify pharmacokinetic variability, producing erratic onset, fluctuating plasma profiles, and reduced therapeutic predictability. Using levodopa as a clinically established model system, we extend these insights to the broader challenge of ensuring reliable performance of oral therapies in ageing populations. We argue that therapeutic success in older adults depends less on maximizing mean bioavailability and more on stabilising exposure under heterogeneous physiological and practical conditions. Accordingly, the review integrates ageing-associated gastrointestinal decline, altered luminal and epithelial determinants of drug absorption, pharmacokinetic instability, and formulation design responses into a unified translational framework for ageing-aware oral therapy. By reframing levodopa failure as a consequence of ageing-driven gut-drug instability, this review proposes an ageing-aware formulation framework and identifies exposure-stability endpoints to guide the development and evaluation of physiologically resilient oral therapies for older adults.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V

Humans
Levodopa
Parkinson Disease
Aging
Administration, Oral
Antiparkinson Agents
Gastrointestinal Tract
Animals
Intestinal Absorption
Biological Availability
Chemistry, Pharmaceutical
Drug Compounding