Drug Delivery Device Design and Compatibility with Nitrogen Dioxide Gas Sterilization
Next-Generation Hydrogels for Biliary Organoid Engineering
Advancing PROTAC Discovery Through Artificial Intelligence: Opportunities, Challenges, and Future Directions
In Vitro and in Vivo Efficacy of Different Ointment Formulations Containing Centaurium erythraea Rafn. Aerial Extract
Review of Autism Spectrum Disorder (ASD): Epidemiology, Aetiology, Pathology, and Pharmacological Treatment

Journal Description

Pharmaceuticals

Pharmaceuticals is a peer-reviewed, open access journal of medicinal chemistry and related drug sciences, published monthly online by MDPI. The Academy of Pharmaceutical Sciences (APS) is affiliated with Pharmaceuticals and its members receive discounts on the article processing charges.

Open Access free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q1 (Pharmacology and Pharmacy) / CiteScore - Q1 (Pharmaceutical Science)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 16 days after submission; acceptance to publication is undertaken in 3.4 days (median values for papers published in this journal in the second half of 2025).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Testimonials: See what our editors and authors say about Pharmaceuticals.
International Electronic Conference on Medicinal Chemistry (https://sciforum.net/series/ecmc/latest)
Companion journals for Pharmaceuticals include: Pharmacoepidemiology, Psychoactives and Drugs and Drug Candidates.
Journal Clusters-Pharmaceutical Science: Scientia Pharmaceutica, Marine Drugs, Pharmaceuticals, Pharmaceutics, Pharmacy, Future Pharmacology, Pharmacoepidemiology, Drugs and Drug Candidates and Journal of Pharmaceutical and BioTech Industry.

Impact Factor: 4.8 (2024); 5-Year Impact Factor: 4.9 (2024)

Imprint Information Journal Flyer Open Access ISSN: 1424-8247

Latest Articles

25 pages, 1269 KB

Open AccessReview

Cefepime and New Cefepime/Beta-Lactamase Inhibitor Combination for the Treatment of Gram-Negative Bacteria: Chemical Structure and Mechanism of Action, Microbiological Target, Clinical Use and PK/PD Characteristics

by Davide Carcione, Gioconda Brigante, Antonella Carducci, Jari Intra, Simone Ambretti, Floriana Campanile, Gabriele Arcari, Nicasio Mancini, Dario Cattaneo, Floriana Gona, Mariagrazia Perilli, Alessandra Piccirilli, Nicholas Geremia, Verena Zerbato, Stefano Di Bella, Giovanna Maria Nicolò and Luigi Principe

Pharmaceuticals 2026, 19(2), 283; https://doi.org/10.3390/ph19020283 (registering DOI) - 7 Feb 2026

Abstract

The global spread of multidrug-resistant (MDR) Gram-negative bacteria, particularly extended-spectrum β-lactamase (ESBL)- and carbapenemase-producing Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii, presents a significant public health challenge by limiting effective antimicrobial treatment options. Cefepime, a fourth-generation cephalosporin with broad-spectrum activity, is increasingly compromised by β-lactamase production, efflux pumps, and porin loss. In response, novel cefepime-based β-lactam/β-lactamase inhibitor (BL/BLI) combinations have been developed to overcome these resistance mechanisms. This review examines preclinical and clinical studies on cefepime-based BL/BLI combinations, specifically cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, and cefepime/nacubactam, as found in the PubMed database. Key findings include the restoration of activity against class A ESBLs with cefepime/enmetazobactam, while cefepime/taniborbactam and cefepime/zidebactam show broader inhibition of serine β-lactamases and selected metallo-β-lactamases. Additionally, zidebactam and nacubactam target penicillin-binding protein 2, enhancing bactericidal potency. Preclinical and early-phase clinical trial data indicate potent in vitro activity and favorable pharmacokinetic/pharmacodynamic (PK/PD) profiles. Specifically, the combination of cefepime with enmetazobactam has demonstrated an optimal Cmax/MIC ratio of 8–10, supporting its efficacy in treating MDR Gram-negative infections. Phase III studies are ongoing to confirm efficacy in complicated infections. Cefepime-based BL/BLI combinations are emerging as promising carbapenem-sparing agents, offering broad-spectrum activity, dual mechanisms of action, and encouraging clinical outcomes. These findings support their inclusion in antimicrobial stewardship strategies aimed at mitigating resistance. Full article

(This article belongs to the Special Issue Novel Antimicrobials and the Antimicrobial Activity: New Advances)

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24 pages, 3944 KB

Open AccessArticle

Integrative Spatial Transcriptomics and Immunoinformatics for Prognostic Multi-Epitope Vaccine Construct Prediction Against Synovial Sarcoma

by Maha A. Aljumaa, Maher S. Alwethynani, Hanan Abdulrahman Sagini, Fakhria A. Al-Joufi and Ghulam Nabi

Pharmaceuticals 2026, 19(2), 282; https://doi.org/10.3390/ph19020282 (registering DOI) - 7 Feb 2026

Abstract

Background/Objectives: Synovial sarcoma (SS) is a rare and aggressive soft-tissue malignancy characterized by complex molecular alterations and poor prognosis, highlighting the need for targeted immunotherapeutic strategies. This study aimed to design a rational multi-epitope vaccine targeting the FKBP10 oncoprotein to elicit effective immune responses against SS. Methods: Transcriptomic data from the GEO dataset GSE144190, comprising 10 tumor and 9 normal tissue samples, were analyzed to identify differentially expressed genes (DEGs). Results: Our findings revealed significantly upregulated FKBP10 with a log2 fold change of 3.55, baseMean expression of 1521.84, and adjusted p-value of 8.37 × 10⁻²⁶. Mutational analysis across 7782 sarcoma samples indicated a low alteration frequency of ~1.5%, primarily missense variants. Functional mapping showed FKBP10 as a hub interacting with multiple collagen chains and chaperone proteins, implicating its role in extracellular matrix organization and protein folding. Linear B-cell epitope prediction identified 17 epitopes (6–21 amino acids), while T-cell mapping yielded 10 MHC class I and 9 MHC class II high-affinity epitopes, all antigenic (VaxiJen > 0.5) and non-allergenic. A multi-epitope vaccine was constructed incorporating a 50S ribosomal protein L22 adjuvant, linkers, and a 6× histidine tag. Physicochemical analysis showed a molecular weight of 36.43 kDa, pI 6.97, instability index 31.79, aliphatic index 64.88, and GRAVY −0.509, indicating stability and hydrophilicity. Structural modeling validated 82.5% residues in favored regions. Molecular docking revealed strong binding with TLR4 (−9.7 kcal/mol) and TLR9 (−9.4 kcal/mol), and 200 ns molecular dynamics simulations confirmed stable RMSD trajectories, low RMSF at binding residues (<4 Å), persistent hydrogen bonding, compact radius of gyration (38–42 Å for TLR4; ~20 Å for TLR9), favorable total energy (−1400 to −1500 kcal/mol for TLR4; −650 to −720 kcal/mol for TLR9), and stable SASA (~52,000–54,000 Å²). Conclusions: These findings demonstrate that the FKBP10 multi-epitope vaccine is structurally stable, immunogenic, and capable of engaging key innate immune receptors, supporting its potential as a promising immunotherapeutic candidate for synovial sarcoma. Full article

(This article belongs to the Special Issue Artificial Intelligence: New Molecules, Therapeutic Targets and Discovery of New Drugs)

15 pages, 8531 KB

Open AccessArticle

Simufilam in Alzheimer’s Disease: Assessment of Efficacy of a Controversial Drug in Human Neuronal Cell Culture

by Ankita Srivastava, Heather A. Renna, Tahmina Hossain, Thomas Palaia, Aaron Pinkhasov, Irving H. Gomolin, Joshua De Leon, Thomas Wisniewski and Allison B. Reiss

Pharmaceuticals 2026, 19(2), 281; https://doi.org/10.3390/ph19020281 (registering DOI) - 7 Feb 2026

Abstract

Background/Objectives: Alzheimer’s disease (AD) is a progressive multifactorial neurodegenerative disorder. Current AD therapies offer minimal benefits and do not prevent or repair neuronal damage. More effective therapeutic approaches are needed to restore normal bioenergetics and metabolic function to AD neurons. Simufilam is a small-molecule oral drug that targets filamin A, a scaffolding protein in brain cells. Phase III clinical trials of simufilam failed to show any significant cognitive or functional improvements in AD patients. The purpose of this study is to identify and explain the molecular mechanisms that may have contributed to this drug’s lack of clinical success. Methods: Our study investigates the effects of simufilam on amyloid processing, neuronal health, and mitochondrial functioning in the SH-SY5Y human neuronal cell model. SH-SY5Y cells were differentiated into neurons using 10 µM retinoic acid. Undifferentiated and differentiated SH-SY5Y were exposed to simufilam (5 µM, 50 µM; 24 hr). Results: Simufilam did not affect the expression of genes involved in amyloid processing. Amyloid precursor protein (APP), β-secretase, and α-secretase mRNA levels in simufilam-treated SH-SY5Y cells were all unchanged compared to untreated cells. However, amyloidogenic β-secretase protein was significantly increased (fold change 1.17) at 50 µM of simufilam only in differentiated SH-SY5Y cells without affecting APP or α-secretase protein expression. Simufilam at the 50 µM concentration reduced brain-derived neurotrophic factor protein levels (fold change 0.7) only in differentiated SH-SY5Y. Further, simufilam did not improve mitochondrial genes or structure. Conclusions: Our results align with clinical outcomes and indicate that insufficient activity across multiple tests of ability to impact processes related to neuronal health can serve as a preliminary indicator of limited clinical utility. Full article

(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease, 2nd Edition)

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16 pages, 2018 KB

Open AccessArticle

Hepatoprotective Effect of Cynarin on Alpha-Naphthyl Isothiocyanate-Induced Cholestatic Liver Injury: Associated Modulation of TXNIP/NLRP3 and HMGB1/NF-κB Signaling Cascades

by Hani M. Alrawili, Mahmoud Elshal, Marwa S. Serrya and Dina S. El-Agamy

Pharmaceuticals 2026, 19(2), 280; https://doi.org/10.3390/ph19020280 (registering DOI) - 7 Feb 2026

Abstract

Background: Cholestatic liver injury (CLI) is characterized by complex pathogenesis; however, oxidative stress-mediated inflammatory response due to bile acid accumulation in the liver is considered a primary cause. Cynarin (CN), an artichoke phytochemical, has demonstrated different biological activities, including antioxidant and anti-inflammatory ones. The current study aimed to explore the potential hepatoprotective effect of CN on CLI induced by alpha-naphthyl isothiocyanate (ANIT) in mice and investigate the possible involved mechanisms. Methods: Mice received CN (25 and 50 mg/kg) for four consecutive days and were challenged with ANIT (75 mg/kg) once on the second day. Liver injury was examined through biochemical determination of liver injury biomarkers and confirmed by histopathological evaluation. Oxidative stress biomarkers and pro-inflammatory cytokines were detected in the hepatic tissue. RT-PCR, Western blotting, and ELISA were applied to address gene and protein expression of potential underlying molecular targets, including thioredoxin-interacting protein (TXNIP), NLR family pyrin domain-containing 3 (NLRP3) inflammasome, and high-mobility group box 1 (HMGB1). Moreover, nuclear factor kappa-B (NF-κB) activation was determined by immunohistochemical analysis. Results: Our findings revealed that CN remarkably ameliorated ANIT-induced hepatic necro-inflammatory changes and biliary duct injury and restored redox balance in the liver. Mechanistically, CN markedly decreased the expression of TXNIP, NLRP3, active caspase-1, gasdermin D N-terminal (GSDMD-N), interleukin (IL)-1β, and IL-18, which were elevated upon ANIT administration. Moreover, CN suppressed ANIT-induced expression of HMGB1 and NF-κB. Conclusions: Our findings suggest that CN has a protective effect against ANIT-induced CLI in mice that is associated with modulation of the TXNIP/NLRP3 and HMGB1/NF-κB signaling cascades. Full article

(This article belongs to the Section Pharmacology)

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22 pages, 466 KB

Open AccessReview

Efficacy and Safety of Traditional Chinese Medicine Retention Enema for Endometriosis: A Systematic Review and Meta-Analysis

by Na-Yoen Kwon, Eun-Jin Kim, Yong-Taek Oh, Soo-Hyun Sung and Hyun-Kyung Sung

Pharmaceuticals 2026, 19(2), 279; https://doi.org/10.3390/ph19020279 - 6 Feb 2026

Abstract

Background/Objectives: Herbal retention enema is widely used in Traditional Chinese Medicine for the management of endometriosis; however, its clinical efficacy and safety have not been systematically evaluated. Methods: Ten electronic databases were searched up to May 2025 to identify randomized controlled trials evaluating herbal retention enema as a standalone treatment for endometriosis. Primary outcomes included total effective rate and pain-related measures. Risk of bias was assessed using the Cochrane RoB 2 tool. Results: Nine randomized controlled trials involving 614 participants were included. Compared with Western medical therapies, herbal retention enema was associated with greater overall clinical effectiveness (OR = 2.87) and significant improvement in dysmenorrhea. When compared with oral herbal medicine, herbal retention enema demonstrated a higher total effective rate (OR = 7.13). A trend toward improved pregnancy outcomes was observed (p = 0.05). No serious adverse events related to herbal retention enema were reported, and systemic adverse effects were less frequent than with hormonal therapies. Conclusions: Herbal retention enema may represent a potential complementary option for symptom management in endometriosis; however, the certainty of evidence remains low due to important methodological limitations in the included trials. However, given methodological limitations and heterogeneity among studies, further high-quality randomized controlled trials with standardized outcomes and long-term follow-up are required. Full article

(This article belongs to the Section Pharmacology)

18 pages, 323 KB

Open AccessReview

Reviving Old Antibiotics: New Indications and Therapeutic Perspectives—A Review

by Paweł Radkowski, Julia Oszytko, Kamil Sobolewski, Florian Trachte, Maja Czerwińska-Rogowska, Dariusz Onichimowski and Marta Majewska

Pharmaceuticals 2026, 19(2), 278; https://doi.org/10.3390/ph19020278 - 6 Feb 2026

Abstract

The rapid global spread of antimicrobial resistance (AMR) has significantly reduced the effectiveness of many modern antibiotics, creating an urgent need for alternative therapeutic strategies. One promising approach is the revival and repurposing of older antimicrobial agents whose clinical potential was previously limited by toxicity concerns, pharmacokinetic challenges, or the availability of newer drugs. Recent advances in drug delivery, dosing optimization, and antimicrobial stewardship have renewed interest in these compounds as viable options for the treatment of multidrug-resistant infections. The aim of this review is to provide a comparative, clinically oriented analysis of selected “old” antibiotics, fosfomycin, colistin, streptomycin, and vancomycin, with emphasis on their current therapeutic roles, pharmacokinetic/pharmacodynamic (PK/PD) targets, toxicity mitigation strategies, resistance mechanisms, and evidence supporting combination therapies and alternative routes of administration. This narrative review was conducted using a structured PubMed search and manual reference screening, focusing on clinical, PK/PD, and translational studies relevant to the contemporary use of legacy antibiotics. The review summarises current evidence on the re-emerging clinical applications of these agents, each discussed in the context of historical use, mechanism of action, resistance patterns, and newly identified indications. Attention is given to novel formulations, combination strategies, and alternative routes of administration that enhance efficacy while limiting toxicity, including applications in biofilm-associated infections. Overall, strategic repurposing of older antibiotics represents a valuable complementary approach in the fight against AMR and may extend the therapeutic lifespan of existing agents in an era of limited antibiotic innovation. Full article

(This article belongs to the Section Pharmacology)

26 pages, 2524 KB

Open AccessSystematic Review

Extraction Matrix Shapes the Efficacy of Gegen Qinlian Decoction in DSS-Induced Colitis: A Preclinical Systematic Review and Meta-Analysis

by Carlos R. Montes-de-Oca-Saucedo, Bruno Briceño-Villardaga, Sebastián R. Fuentes-Salinas and Adolfo Soto-Domínguez

Pharmaceuticals 2026, 19(2), 277; https://doi.org/10.3390/ph19020277 - 6 Feb 2026

Abstract

Background: Ulcerative colitis (UC) is a chronic inflammatory disease marked by mucosal injury and immune dysregulation. Gegen Qinlian Decoction (GQD) shows therapeutic potential, but extraction-dependent reproducibility remains unclear. Methods: We systematically searched PubMed, Scopus, and Web of Science for studies evaluating GQD aqueous decoctions or ethanolic extracts in DSS-induced colitis. Main outcome: Disease Activity Index (DAI). Key additional outcomes: colon length and histological injury; cytokines and microbiota were also assessed. Random-effects models with Hartung–Knapp–Sidik–Jonkman adjustment, subgroup analyses, and exploratory dose–response meta-regression were applied. Results: Eight studies were included (aqueous: 5; ethanolic: 3; 209 mice). GQD significantly improved DAI (SMD −2.17; p < 0.00001; I² = 43%), colon length (MD 1.18 cm; p < 0.00001; I² = 88%), and histological injury (SMD −3.02; p < 0.0001; I² = 51%). For DAI, both preparations favored GQD, with absent heterogeneity in aqueous studies (I² = 0%) vs. substantial variability in ethanolic extracts (I² = 75%). For histology, subgroup differences suggested a larger effect size with ethanolic extracts, with higher heterogeneity (I² = 60% vs. 0%). In the aqueous subset, GQD reduced inflammatory markers and increased microbial diversity. Dose–response meta-regression was performed within the aqueous subset as an exploratory analysis. Conclusions: Aqueous decoctions showed the most reproducible profile across key endpoints, whereas ethanolic extracts were more variable despite a larger histology point estimate, indicating that the extraction matrix meaningfully influences translational consistency in preclinical research. Full article

(This article belongs to the Special Issue Interdisciplinary Approaches to Preventing and Treating Inflammatory and Oxidative Diseases with Medicinal Plants and Bioactive Compounds)

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48 pages, 2744 KB

Open AccessReview

by Costanza Tacchi, Irma Convertino and Guido Bocci

Pharmaceuticals 2026, 19(2), 276; https://doi.org/10.3390/ph19020276 - 6 Feb 2026

Abstract

Background: The heterogeneity of immune-related adverse events (irAEs) in real-world evidence highlights the need to identify patterns, knowledge gaps, and priorities for future research. Objectives: To assess in labels the expected irAEs associated with immune checkpoint inhibitors (ICIs) in lung cancer, melanoma, breast cancer, and colon cancer and evaluate their incidence, clinical characteristics, management, and outcomes in real-world studies. Methods: Medicine Agency data sources (Food and Drug Administration and European Medicines Agency) were assessed for labeled irAEs associated with ICIs, and a comprehensive literature review according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for scoping review was performed by retrieving observational and target trial emulation studies conducted using data collected in administrative healthcare databases (AHDs) and in spontaneous reporting systems (SRSs) concerning the drugs and tumors of interest from PubMed. irAEs’ incidence, onset, management, and outcomes were retrieved. Results: ICI combination therapy increases irAE occurrence, and inter-agency differences emerged. From PubMed, 49 observational studies were included, 22 on SRSs and 27 on AHDs. The ICIs most frequently evaluated were pembrolizumab and nivolumab, and the irAEs most reported were “lower respiratory tract disorders (excluding obstruction and infection)” (SRSs) and “epidermal and dermal conditions” (AHDs) for both drugs. Missing information on survival analysis, therapy dechallenge and rechallenge, concomitant therapies, comorbidities, time to onset, and duration of irAEs were highlighted. Conclusions: This scoping review highlights the complex, multi-organ irAEs from ICIs, underlining the need for tailored monitoring and management based on both regulatory and real-world evidence. Full article

(This article belongs to the Section Pharmacology)

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25 pages, 6906 KB

Open AccessArticle

Artemisia Extracts Suppress H1N1 Influenza A Virus Infection by Targeting Viral HA/NA Proteins and Modulating the TLR4/MyD88/NF-κB Signaling Axis

by Zhongnan Hu, Hui Liu, Weihua Wu, Tayyab Ali, Adam Junka, Farukh S. Sharopov, Xuan Zou, Shisong Fang and Yanfang Sun

Pharmaceuticals 2026, 19(2), 275; https://doi.org/10.3390/ph19020275 - 6 Feb 2026

Abstract

Background: Influenza A virus is an acute respiratory virus that spreads quickly, affects a broad range of populations, and can lead to many complications and mortality. Artemisia L. species are widely used in traditional medicine, but their antiviral potential against H1N1 remains uncertain. Methodology: Network pharmacology and molecular docking were used to computationally explore their potential function in this domain, and to investigate how their invasion mechanisms and adsorption occur. UPLC-MS/MS analysis identified the main components of the extracts. The anti-H1N1 mechanism of Artemisia L. extracts was studied in vitro. Results: Network pharmacology identified 95 key targets between Artemisia L. and IAV, with quercetin and luteolin as core active compounds. Molecular docking predicted strong binding affinities between these compounds and influenza virus proteins. UPLC-MS/MS analysis identified 75, 100, and 64 chemical components in ACBE, AALE, and ACTE, respectively, mainly flavonoids and terpenoids. Artemisia L. extracts exhibited both preventive and therapeutic effects against H1N1, reducing progeny virus NP mRNA and protein levels. In vitro experiments showed that higher concentrations of the extracts prevent virus attachment to MDCK cells by denaturing the HA protein. NA plays an essential role in progeny virus release. We found that a high concentration of ACTE can inhibit NA up to 85%, and ACBE showed a low inhibitory effect on NA. Conclusions: In terms of therapeutic effects, Artemisia L. extracts can regulate intracellular inflammatory factors via the TLR4/NF-κB/MyD88 signaling pathways and reduce the expression of IL-1β, IL-6, TNF-α, TLR4, NF-κB, p65, and MyD88 at the mRNA level, thereby inhibiting H1N1 virus replication. These results suggest that bioactive components in Artemisia L. extracts may inhibit H1N1, potentially leading to the development of natural-product-based anti-influenza agents. Full article

(This article belongs to the Special Issue Bioactive Natural Extracts: Advances in Pharmacological and Therapeutic Research)

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5 pages, 161 KB

Open AccessEditorial

Editorial: New Strategies to Combat Antimicrobial Resistance in Infectious Diseases

by Antonia Efstathiou and Dimitra K. Toubanaki

Pharmaceuticals 2026, 19(2), 274; https://doi.org/10.3390/ph19020274 - 6 Feb 2026

Abstract

One of the greatest challenges of our era, and of modern medicine, is the accelerating rise of antimicrobial resistance (AMR) [...] Full article

(This article belongs to the Special Issue New Approaches to Fighting Infectious Diseases: Overcoming the Antimicrobial Resistance in Current Treatments)

2 pages, 138 KB

Open AccessCorrection

Correction: Anastasiou et al. MicroRNA Signatures and Machine Learning Models for Predicting Cardiotoxicity in HER2-Positive Breast Cancer Patients. Pharmaceuticals 2025, 18, 1908

by Maria Anastasiou, Evangelos Oikonomou, Panagiotis Theofilis, Maria Gazouli, George-Angelos Papamikroulis, Athina Goliopoulou, Vasiliki Tsigkou, Vasiliki Skandami, Angeliki Margoni, Kyriaki Cholidou, Amanda Psyrri, Konstantinos Tsioufis, Flora Zagouri, Gerasimos Siasos and Dimitris Tousoulis

Pharmaceuticals 2026, 19(2), 273; https://doi.org/10.3390/ph19020273 - 6 Feb 2026

Abstract

Text Correction [...] Full article

(This article belongs to the Section Pharmacology)

19 pages, 945 KB

Open AccessArticle

Modulation of Ochratoxin A-Induced Oxidative Stress and Gene Expression by Bilberries (Vaccinium myrtillus L.) in an In Vitro Intestinal Model

by Denisia Pașca, Alessandra Cimbalo, Pilar Vila-Donat, Lorena Filip, Oana Mîrza, Doina Miere, Felicia Loghin and Lara Manyes

Pharmaceuticals 2026, 19(2), 272; https://doi.org/10.3390/ph19020272 - 5 Feb 2026

Abstract

Background/Objectives: Mycotoxin contamination in grain-derived foods is still a major food safety concern; thus, innovative mitigation approaches need to be continuously developed. This study investigated the influence of bilberry (Vaccinium myrtillus L.) incorporated into a food matrix on ochratoxin A (OTA)-induced cellular responses using a dietary-relevant in vitro intestinal model. Methods: Four bread types were prepared: control (C), OTA-contaminated (OTA), bilberry-enriched (VM), and OTA + VM (OTA-VM). Simulated intestinal digests of these breads were applied to differentiated Caco-2 cells for 24 h. Apoptotic and necrotic cell populations, as well as reactive oxygen species (ROS) levels, were quantified by flow cytometry, while RT-qPCR assessed the expression of 10 genes related to mitochondrial function, oxidative stress response, and intestinal barrier integrity. Results: Exposure to OTA resulted in increased cytotoxicity, reflected by a higher proportion of necrotic cells (5.11 ± 0.35%), and elevated ROS levels compared with control cells. Co-exposure to bilberry-enriched digests was associated with attenuation of apoptotic responses, a reduced proportion of necrotic cells (2.16 ± 0.61%) and a 16% decrease in ROS levels. Gene expression profiles in the VM group were comparable to control, whereas OTA exposure led to downregulation of several genes related to oxidative stress response and intestinal barrier integrity (e.g., CLDN2, OCLN, SLC7A11). In the OTA-VM group, a partial recovery of gene expression was observed. Conclusions: These findings suggest that bilberry incorporation into a food matrix may modulate OTA-induced cellular stress responses by attenuating oxidative imbalance and supporting the expression of genes associated with antioxidant defense and epithelial barrier integrity. Bilberries may therefore represent a promising functional ingredient for influencing intestinal cellular responses to dietary mycotoxin exposure. Full article

(This article belongs to the Section Natural Products)

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25 pages, 965 KB

Open AccessReview

Bridging Innovation and Practice in Type 2 Diabetes Mellitus: Novel Antidiabetic Therapies and the Expanding Role of Community Pharmacists

by Marios Spanakis, Agapi Fournaraki, Frantzeska Nimee, Christos Kontogiorgis and Emmanouil K. Symvoulakis

Pharmaceuticals 2026, 19(2), 271; https://doi.org/10.3390/ph19020271 - 5 Feb 2026

Abstract

Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), represents a rapidly expanding global health challenge with substantial public health and economic consequences. Recent advances in antidiabetic therapy—including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dual GIP/GLP-1 receptor agonists, and sodium–glucose cotransporter-2 (SGLT-2) inhibitors—have transformed diabetes management by providing benefits beyond glycemic control, such as cardiovascular and renal protection, weight reduction, and improved quality of life. As the therapeutic landscape becomes increasingly complex and patient-centered, ensuring the safe and effective use of these agents in real-world settings has emerged as a key concern for pharmacoepidemiology and pharmacovigilance. Community pharmacists, as highly accessible healthcare professionals, play an expanding role in diabetes care through medication optimization, patient education, adherence support, and monitoring of adverse drug reactions in primary care. Evidence from systematic reviews and meta-analyses indicates that pharmacist-led interventions improve glycemic outcomes, enhance self-care behaviors, and facilitate the appropriate adoption of contemporary antidiabetic therapies. This narrative review synthesizes current evidence on novel pharmacological treatments for T2DM and examines the evolving contribution of community pharmacists in translating therapeutic innovation into routine practice. Barriers to implementation and future perspectives for integrating pharmacist-led services into diabetes management and pharmacovigilance frameworks are also discussed. Full article

(This article belongs to the Section Pharmacology)

13 pages, 408 KB

Open AccessReview

Buprenorphine Oral Lyophilisate for Treatment of Opioid Use Disorder: Pharmacology and Clinical Efficacy

by Michael Soyka and Svenja Bolz

Pharmaceuticals 2026, 19(2), 270; https://doi.org/10.3390/ph19020270 - 5 Feb 2026

Abstract

Background/Objectives: Opioid use disorder (OUD) is a chronic relapsing condition associated with elevated mortality and substantial psychiatric and somatic comorbidity. Oral methadone and sublingual and depot buprenorphine are the undisputed gold standard in opioid agonist treatment (OAT). More recently, another oral buprenorphine formulation, buprenorphine lyophilisate (BUP-Lyo), has been introduced into clinical practice, offering potentially faster bioavailability and simplified administration. This review aims to summarize the available clinical and pharmacological data on BUP-Lyo and assess its potential role within current OAT strategies. Methods: A targeted Medline search was performed to identify publications reporting pharmacological characteristics, safety, efficacy, and clinical use of BUP-Lyo. Additional information was requested from the manufacturer. Relevant sources were reviewed narratively with a focus on OUD treatment, with particular attention to the pharmacological and clinical profile of the compound. Results: Few studies on BUP-Lyo have been published to date. As a rapid-dispersion formulation placed on the tongue, BUP-Lyo provides faster bioavailability and a quicker route of administration compared with conventional sublingual buprenorphine. These properties may reduce the need for post-administration supervision and could lessen risks of misuse or diversion. Available evidence supports its safety, efficacy, and feasibility within routine OAT, and the clinical implications of these characteristics are discussed. Conclusions: BUP-Lyo expands the range of available buprenorphine formulations and offers practical advantages through accelerated absorption and simplified administration. While initial data are encouraging, the limited evidence base underscores the need for further longitudinal and post-marketing studies to define its clinical position in the management of OUD. Full article

(This article belongs to the Special Issue Pharmacology and Toxicology of Opioids, 2nd Edition)

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21 pages, 3140 KB

Open AccessArticle

Stability Under Different Stress Treatments of a Virus-like Particle Vaccine Based on a Recombinant Hepatitis E Vaccine

by Zhiyun Qi, Sha Guo, Hanhan Li, Xijie Xia, Shuangshuang Qi, Enlian Tang, Zhenhao Zhou, Yiping Wang, Chuanfei Yu, Xing Wu and Hao Wu

Pharmaceuticals 2026, 19(2), 269; https://doi.org/10.3390/ph19020269 - 5 Feb 2026

Abstract

Background/Objectives: Virus-like particles (VLPs) are effective vaccine platforms but are susceptible to degradation, which compromises stability and immunogenicity. A key challenge is the lack of sensitive early indicators of instability. This study aimed to systematically evaluate the stability of an aluminum-free recombinant hepatitis E virus VLP vaccine under various stresses and identify predictive markers of instability. Methods: The VLP vaccine was subjected to thermal stress (4 °C, 25 °C, 37 °C, 56 °C for up to 28 d), repeated freeze–thaw cycles (up to 30 cycles), and mechanical agitation (orbital shaking at 100 and 300 rpm for up to 12 d). Stability was assessed using a multi-parameter panel monitoring critical quality attributes: conformational and colloidal stability, formation of high-molecular-weight species, mean particle size, polydispersity index, charge heterogeneity, and antigen content. Results: Changes in charge heterogeneity were the earliest indicator of instability, detectable within 3 days at 25 °C, 8 h at 37 °C, and 4 h at 56 °C, preceding losses in structural integrity or antigen-binding function. The VLPs remained stable at 25 °C for 28 d. Freeze–thaw cycles induced a basic shift in charge variants without compromising structure or function, while high-intensity shaking (300 rpm) caused aggregation after 3–6 d. The effects of common excipients were also characterized. Conclusions: Charge-variant analysis serves as a sensitive and predictive marker for VLP vaccine instability. The study delineates the distinct impacts of different stress factors and provides critical data for optimizing formulation design and storage strategies to enhance VLP vaccine stability. Full article

(This article belongs to the Section Biopharmaceuticals)

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27 pages, 4382 KB

Open AccessArticle

The Use of Biomass from In Vitro Fungal Cultures as a Bioactive Ingredient with Antimicrobial Activity in Hydrogel Dressings

by Agata Krakowska, Iwona Skiba-Kurek, Joanna Zontek-Wilkowska, Paulina Koczurkiewicz-Adamczyk, Bożena Muszyńska and Tomasz Skalski

Pharmaceuticals 2026, 19(2), 268; https://doi.org/10.3390/ph19020268 - 5 Feb 2026

Abstract

Background/Objectives: Chronic wounds represent a significant clinical burden and require multimodal treatment strategies targeting inflammation, infection, moisture balance, and tissue remodeling, as defined by the TIME framework. This study aimed to evaluate the therapeutic potential of innovative hydrogel dressings enriched with fungal biomass, designed to exploit natural bioactive compounds—such as antimicrobial peptides and proteolytic enzymes—to enhance wound healing while maintaining high biocompatibility. Methods: Hydrogel dressings incorporating selected fungal biomasses were fabricated and characterized for physicochemical and biological performance. Key material properties relevant to wound care, including hydrophilicity and porosity, were analyzed to assess exudate management capacity and maintenance of a moist wound environment. Antimicrobial activity was tested against common wound pathogens, and species–pathogen interactions were evaluated using generalized linear modeling. In vitro biocompatibility was assessed using human keratinocytes and compared with conventional silver nanoparticle–based dressings. Results: The developed hydrogels demonstrated properties suitable for clinical application, including superhydrophilicity and high porosity, supporting effective exudate control and moisture retention. Significant broad-spectrum antimicrobial activity was observed, particularly against Staphylococcus aureus and Pseudomonas aeruginosa, with effects dependent on fungal species. Statistical modeling revealed highly significant interactions between fungal species and pathogens in inhibition zones (p < 0.001). Hydrogels containing Pleurotus ostreatus and Agaricus bisporus showed broad activity against Escherichia coli, P. aeruginosa, and S. aureus, whereas Enterococcus faecalis exhibited resistance. Fungal biomass–based dressings displayed superior keratinocyte biocompatibility compared to silver nanoparticle controls. Conclusions: Fungal biomass–reinforced hydrogels offer a promising, safer, multifunctional alternative for infected chronic wound management, supporting both antimicrobial action and tissue regeneration. Full article

(This article belongs to the Special Issue Natural Products Derived from Fungi and Their Biological Activities, 2nd Edition)

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19 pages, 859 KB

Open AccessArticle

Drivers of Methotrexate Polyglutamate Concentration in Erythrocytes: Insights from Immune-Mediated Inflammatory Diseases and Pediatric Acute Lymphoblastic Leukemia

by Janani Sundaresan, Wout J. Hamelink, Renske C. F. Hebing, Maartje van de Meeberg, Montse Janssen Bonás, Inge M. van der Sluis, Pascal H. P. de Jong, Martijn Heymans, Robert de Jonge, Maurits C. F. J. de Rotte and Maja Bulatović-Ćalasan

Pharmaceuticals 2026, 19(2), 267; https://doi.org/10.3390/ph19020267 - 4 Feb 2026

Abstract

Background/Objectives: Methotrexate (MTX) is a cornerstone drug used to treat immune-mediated inflammatory diseases (IMIDs) in low doses (10–30 mg/week), and malignancies in high doses (5000 mg/m²/2 weeks). Its active metabolites, Methotrexate polyglutamates (MTX-PG_2–5), quantified in erythrocytes, are associated with efficacy. This study aimed to compare erythrocyte MTX-PG concentrations in patients with IMIDs and pediatric acute lymphoblastic leukemia (ped-ALL) treated with low-dose or high-dose MTX, respectively, and to identify clinical, demographic, and treatment-related factors influencing their concentration. Methods: A total of 567 patients with rheumatoid arthritis, juvenile idiopathic arthritis, Crohn’s disease, sarcoidosis, and ped-ALL were included. Erythrocyte MTX-PG concentration data was collected after 3 months (2.5 months for ped-ALL patients) of MTX-use. Multivariate linear regressing modelling adjusting for age, sex, body mass index (BMI), smoking status, starting MTX dose, route of MTX administration, use of predniso(lo)ne, disease-modifying anti-rheumatic drugs (DMARDs), and folic (or folinic) acid was performed. Results: Intravenous high-dose MTX increased MTX-PG_4&5 accumulation. Despite 50-fold higher doses in ped-ALL, MTX-PG_2–5sum concentrations were similar to those seen with subcutaneous low-dose MTX used in IMIDs. Age positively influenced MTX-PG concentrations, while DMARD use reduced MTX-PG_2–3&5 concentrations. Interestingly, predniso(lo)ne use was associated with higher MTX-PG_4&5 concentrations and folic (or folinic) acid with higher MTX-PG_3–5 concentrations. Conclusions: This is the first study to compare erythrocyte MTX-PG concentration in low-dose and high-dose patients. Intravenous high-dose MTX administration increased long-chain MTX-PG_4&5 concentrations, with MTX-PG_2–5sum concentrations similar compared to low-dose subcutaneous MTX use. This study demonstrated that route of administration, age, and concomitant therapies such as DMARDs, predniso(lo)ne, and folic (or folinic) acid significantly influence MTX-PG concentrations. Full article

(This article belongs to the Special Issue Mathematical Modeling in Drug Metabolism and Pharmacokinetics)

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19 pages, 3251 KB

Open AccessArticle

Saroglitazar Mitigated Cyclophosphamide-Induced Testicular Injury: Crosstalk Between Oxidative Stress, Inflammation and Apoptosis

by Bandar H. Alanazi, Omnia A. Nour and Marwa S. Serrya

Pharmaceuticals 2026, 19(2), 266; https://doi.org/10.3390/ph19020266 - 4 Feb 2026

Abstract

Background: Cyclophosphamide (CYC) is an effective chemotherapeutic agent and immunosuppressant drug. Former research showed that CYC induces testicular toxicity through oxidative stress, inflammation and apoptosis. Saroglitazar (SAR) is a dual PPARα/γ agonist, used for treatment of diabetic dyslipidemia. Purpose: This study aimed to elucidate the protective impact of SAR against CYC-linked testicular toxicity. Methods: Randomly, thirty adult male rats were alienated into control group, SAR (4 mg/kg) group, CYC (200 mg/kg) group, CYC+SAR (2 mg/kg) group and CYC+SAR (4 mg/kg) group. SAR was orally administered at two doses (2 and 4 mg/kg) for 7 days. CYC was injected intraperitoneally at dose (200 mg/kg) at day 7. Results: In comparison to the CYC group, SAR at the dose of 2 and 4 mg/kg significantly increased testis weight, testicular index, sperm count, serum testosterone and serum luteinizing hormone. Additionally, SAR at both doses induced a significant reduction in testicular MDA content in addition to increased testicular levels of GSH and TAC. Furthermore, SAR markedly upregulated testicular levels of PPARγ, Nrf2 and HO-1 in addition to decreased testicular expression of NF-κB, IL-6 and TNF-α, illustrating its antioxidant and anti-inflammatory effect. SAR also significantly decreased testicular expression of caspase-3 and Bax and increased Bcl2 expression, indicating its anti-apoptotic effect. Conclusions: SAR at doses (2 and 4 mg/kg) could ameliorate CYC-induced testicular injury in rats, possibly through antioxidant, anti-inflammatory and anti-apoptotic effect. Full article

(This article belongs to the Section Pharmacology)

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24 pages, 4871 KB

Open AccessArticle

Excavating Precursors from the Traditional Chinese Pair Herbs Polygala tenuifolia and Gastrodia elata: Synthesis, Anticonvulsant Activity Evaluation of 3,4,5-Trimethoxycinnamic Acid (TMCA) Peptide Analogs

by Zefeng Zhao, Mengchen Lei, Yujun Bai and Haifa Qiao

Pharmaceuticals 2026, 19(2), 265; https://doi.org/10.3390/ph19020265 - 3 Feb 2026

Abstract

Background: Epilepsy comprises a range of disorders affecting the central nervous system (CNS) characterized by recurrent seizures, impacting approximately 60 million individuals globally. In this study, we designed and derived a series of peptide analogs 1–30 of 3,4,5-trimethoxycinnamic acid (TMCA) from the herbal combinations of Polygala tenuifolia and Gastrodia elata, recognized in Traditional Chinese Medicine (TCM). Methods: All the analogs were synthesized, and their anticonvulsant efficacy was subsequently assessed. The anticonvulsant activity of all TMCA analogs was evaluated using two acute seizure models in mice: the maximal electroshock (MES) and the sc-pentylenetetrazole (PTZ) models. Furthermore, we explored the electroencephalogram (EEG) and double-labeling immunofluorescence experiments were carried out as well. Results: Our findings indicated that compounds 11, 19, 22, and 23 demonstrated favorable anticonvulsant activities during the initial assessment. Compounds 19 and 23 also played roles in controlling the onset of epilepsy in EEG, modulating levels of GABA aminotransferase (GABA-AT)/gamma-aminobutyric acid type A receptor (GABA_AR), interacting with active sites of GABA-AT and GABA_AR obtained from docking simulation methods. Conclusions: Novel derivatives in this study provide new cores for further design and optimization inspired by TCM herb pair drugs P. tenuifolia and G. elata, with the aim of exploring new anticonvulsant agents. Full article

(This article belongs to the Section Medicinal Chemistry)

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20 pages, 4816 KB

Open AccessArticle

An LLM-Based Intelligent Agent and Its Application in Making the Lanolin Saponification Process Greener

by Qinglin Wang, Yu Wang and Xingchu Gong

Pharmaceuticals 2026, 19(2), 264; https://doi.org/10.3390/ph19020264 - 3 Feb 2026

Abstract

Objectives: The industrial production of lanolin alcohol currently employs batch saponification, which suffers from high energy consumption, prolonged processing time, and excessive solid waste generation, rendering it incompatible with green chemistry principles. This study aimed to develop an efficient, sustainable saponification process by addressing these limitations through integrating large language models (LLMs) with microfluidic technology. Methods: An LLM-based intelligent agent called SapoMind (version 1.0) was constructed. SapoMind employs LLMs as its software core and a continuous-flow microreactor as the experimental platform. Its performance was enhanced through supervised fine-tuning. The system enables automated recommendation of saponification process parameters, autonomous experimental design, and automatic execution of experiments. Saponification conditions were automatically optimized considering product quality, energy consumption, material consumption, and time consumption. Results: The optimal continuous-flow saponification conditions were determined as 70 °C reaction temperature and 9 min residence time, producing lanolin alcohol complying with European Pharmacopoeia standards. Compared to batch processing, the optimized process reduced carbon emissions by 53% and solid waste by 37%, with the greenness score increasing from 82 to 93. Conclusions: This study demonstrates the effectiveness of LLM-driven intelligent agents in optimizing green chemical processes. SapoMind offers significant environmental and operational benefits for lanolin alcohol production. Full article

(This article belongs to the Special Issue Pharmaceutical Process Engineering: Experimental and Computational Innovation)

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