Pharmaceuticals

19 pages, 1347 KB

Open AccessReview

Novel Synthetic Opioids (NSOs) and Their Evolving Crisis: Utilising NPSfinder^® as a Real-Time Predictive Tool

by Elena Deligianni, Davide Arillotta, Alessandro Vento, John Martin Corkery, Georgios Papazisis, Antonis Goulas, Lisa Lione and Fabrizio Schifano

Pharmaceuticals 2026, 19(1), 17; https://doi.org/10.3390/ph19010017 (registering DOI) - 21 Dec 2025

Abstract

Background/Objectives: The rapidly evolving crisis of Novel Synthetic Opioids (NSOs) poses a serious and growing threat for global public health. NSOs include prescription/non-prescription opioids (fentanyl, non-fentanyl analogues), herbal derivatives, and other emerging analogues that are of critical concern due to their high potency, [...] Read more.

Background/Objectives: The rapidly evolving crisis of Novel Synthetic Opioids (NSOs) poses a serious and growing threat for global public health. NSOs include prescription/non-prescription opioids (fentanyl, non-fentanyl analogues), herbal derivatives, and other emerging analogues that are of critical concern due to their high potency, misuse potential, and addiction and intoxication risk. There remains an important gap in real-time, systematic monitoring of NSOs emergence, especially in online communities where these substances appear for the first time. This study aimed to employ the NPSfinder^® automated web-crawling tool to detect, monitor, analyse, and evaluate the evolving NSOs scene. Methods: Data were collected during two time-periods, i.e., 2017–2019 and 2023, from selected high traffic psychonaut online platforms to better understand trends in opioids market evolution and adaptability and compare NPSfinder^® findings with other well-known Early Warning Systems (EWSs) databases to assess detection overlap and early identification capacity. Results: Within the selected time-periods, a total of 446 NSOs were detected by NPSfinder^®; fentanyl analogues (n = 249) were dominant, with a notable rise in non-fentanyl analogues, especially nitazene-like compounds, in 2023. Over 57% of these NSOs were not captured by any of the other EWSs, confirming the tool’s strong capacity to identify early threats. Conclusions: Overall, the low overlap across EWS databases underscores the global challenges in comprehensive opioid detection and surveillance. Future studies should integrate web-crawler findings with real-world datasets. It will be vital to combine these efforts with toxicological, mortality, and clinical outcome analyses, especially for emerging research compounds, to inform targeted harm-reduction strategies. Full article

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

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27 pages, 1469 KB

Open AccessReview

Pharmacokinetics and Childhood Obesity: Pathophysiological Basis and Challenges in Choosing the Ideal Body Size Descriptor

by Yolanda Hernández-Gago, José Germán Sánchez-Hernández, Pedro J. Alcala Minagorre, Belén Rodríguez-Marrodán, Laura Hernández Sabater, María José Cabañas Poy and Ana Cristina Rodríguez Negrín

Pharmaceuticals 2026, 19(1), 16; https://doi.org/10.3390/ph19010016 (registering DOI) - 21 Dec 2025

Abstract

Despite the progressive increase in obesity and associated chronic diseases in children, there is limited evidence on the optimal dosage of most medications for obese children and adolescents. This review analyzes the influence of pathophysiological changes on pharmacokinetics and pharmacodynamics and evaluates the [...] Read more.

Despite the progressive increase in obesity and associated chronic diseases in children, there is limited evidence on the optimal dosage of most medications for obese children and adolescents. This review analyzes the influence of pathophysiological changes on pharmacokinetics and pharmacodynamics and evaluates the body size descriptors used in clinical practice. Patients with obesity present significant pathophysiological alterations, such as a substantial increase in fat/lean mass ratio, increased blood flow and cardiac output, and changes in plasma protein binding, which may affect the volume of distribution of drugs and the adjustment of the loading dose. In these patients, the distribution volume of hydrophilic drugs appears to slightly increase, while it varies widely—depending on the drug and other factors such as affinity for other tissues—for lipophilic drugs. On the other hand, a reduction in tissue perfusion, alterations to liver enzyme activity, and an increase in liver and kidney mass and blood flow have been reported, indicating a possible modification in drug clearance and necessitating adjustments to maintenance regimens. Furthermore, while there are multiple size descriptors, it is difficult to establish a single dosing strategy for the obese population, given the lack of studies confirming the extent of changes in pharmacokinetic processes, which will also depend on the properties of each drug, such as liposolubility and elimination pathways. New strategies need to be developed to characterize pharmacokinetic and pharmacodynamic changes in the obese pediatric population in order to optimize dosing regimens and improve the safety and efficacy of treatments. Full article

(This article belongs to the Special Issue Pediatric Drug Therapy: Safety, Efficacy, and Personalized Medicine)

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20 pages, 13311 KB

Open AccessArticle

7-Ketolithocholic Acid Exerts Anti-Renal Fibrotic Effects Through FXR-Mediated Inhibition of TGF-β/Smad and Wnt/β-Catenin Pathways

by Qicheng Guo, Lianye Peng, Jingyi Zhang, Junming Hu, Yinyin Wang, Jiali Wei and Zhihao Zhang

Pharmaceuticals 2026, 19(1), 15; https://doi.org/10.3390/ph19010015 (registering DOI) - 21 Dec 2025

Abstract

Background/Objectives: To explore the protective effects of 7-Ketolithocholic acid (7-KLCA) against renal fibrosis and its mechanism, focusing on its interaction with farnesoid X receptor (FXR). Methods: In vitro, TGF-β-induced fibrosis in HK-2/NRK-49F cells and LPS-induced inflammation in HK-2 cells were detected by CCK-8, [...] Read more.

Background/Objectives: To explore the protective effects of 7-Ketolithocholic acid (7-KLCA) against renal fibrosis and its mechanism, focusing on its interaction with farnesoid X receptor (FXR). Methods: In vitro, TGF-β-induced fibrosis in HK-2/NRK-49F cells and LPS-induced inflammation in HK-2 cells were detected by CCK-8, Western blot, and qPCR. In vivo, unilateral ureteral obstruction (UUO) and adenine (Ade)-induced mouse models were treated with a low/high-dose 7-KLCA or losartan. Renal injury was evaluated via H&E/Masson staining, serum creatinine (SCR), and blood urea nitrogen (BUN) levels. The 7-KLCA-FXR interaction was verified by molecular docking, CETSA, and DARTS. FXR downstream genes and related proteins were measured by WB and qPCR. Results: 7-KLCA inhibited the expression of fibrotic proteins (fibronectin, collagen-I) and reduced the LPS-induced release of inflammatory factors (IL-1β, IL-6). In mice, it alleviated renal swelling, collagen deposition, and tubular damage, while lowering serum SCR and BUN levels. Mechanistically, 7-KLCA stably bound to the FXR ligand-binding domain, enhanced its thermal stability and degradation resistance. It upregulated FXR and its downstream genes SHP and FGF15, thereby inhibiting the activation of TGF-β/Smad and Wnt/β-catenin pathways. Conclusions: This is the first study to clarify the molecular mechanism through which 7-KLCA targets FXR and dually suppresses the key pro-fibrotic pathways TGF-β/Smad and Wnt/β-catenin, thereby exerting anti-renal fibrosis effects. Full article

(This article belongs to the Special Issue Novel Drug Candidates for the Treatment of Cardiac and Renal Diseases)

15 pages, 1239 KB

Open AccessArticle

Cytopenias as Adverse Drug Reactions: A 10-Year Analysis of Reporting Structure, Rate, and Trend

by Ivana Stević, Slobodan M. Janković, Marija Mihailović, Ivana Jović, Marina Odalović, Valentina Marinković and Dragana Lakić

Pharmaceuticals 2026, 19(1), 14; https://doi.org/10.3390/ph19010014 (registering DOI) - 20 Dec 2025

Abstract

Background/Objectives: Underreporting is very common in drug-induced cytopenias (DICs) due to the late onset of symptoms and the need for laboratory confirmation and monitoring. This research aimed to analyze spontaneously reported adverse drug reaction (ADR) cases of leucopenia, anemia, thrombocytopenia, and total [...] Read more.

Background/Objectives: Underreporting is very common in drug-induced cytopenias (DICs) due to the late onset of symptoms and the need for laboratory confirmation and monitoring. This research aimed to analyze spontaneously reported adverse drug reaction (ADR) cases of leucopenia, anemia, thrombocytopenia, and total cytopenia, including their reporting structure, rate, and trend, globally (World) and in Serbia. Methods: Based on real-world data from VigiBase, analyses of the DIC reporting structure, rate, and trend over 10 years (2014–2023) were performed. The reporting rate was calculated and expressed as the number of reports per 1,000,000 inhabitants per year (ADR/million/year). Statistics included descriptions, a chi-square test, joinpoint analysis, and measures of variability. Results: Leucopenia was reported more often in Serbia compared to World (1.26 versus 0.96 reports/million/year, respectively), anemia more often in World (2.09 versus 1.75 reports/million/year), while thrombocytopenia reporting was comparable (1.83 reports/million/year globally versus 1.82 reports/million/year in Serbia). In Serbia, there was a constant increase in reporting throughout the observed period, regardless of the cytopenia type, while globally, anemia reports decreased over time. Most of the reported DICs were serious and occurred in females aged 45–64 years. In Serbia, 76.34% of DICs were reported by physicians compared to 31.72% globally. Conclusions: Although upward trends in DIC reporting are observed, variability in reporting between years was greater in Serbia than in World. Many measures are needed to promote the early detection of DICs, with the priority of increasing access to blood count results for all healthcare workers, including pharmacists. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Adverse Drug Reactions: 2nd Edition)

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43 pages, 1898 KB

Open AccessReview

Advances in Colorectal Cancer: Epidemiology, Gender and Sex Differences in Biomarkers and Their Perspectives for Novel Biosensing Detection Methods

by Konstantina K. Georgoulia, Vasileios Tsekouras and Sofia Mavrikou

Pharmaceuticals 2026, 19(1), 13; https://doi.org/10.3390/ph19010013 (registering DOI) - 20 Dec 2025

Abstract

Colorectal cancer (CRC) remains a major cause of morbidity and mortality worldwide, with its incidence and biological behavior influenced by both genetic and environmental factors. Emerging evidence highlights notable sex differences in CRC, with men generally exhibiting higher incidence rates and poorer prognoses, [...] Read more.

Colorectal cancer (CRC) remains a major cause of morbidity and mortality worldwide, with its incidence and biological behavior influenced by both genetic and environmental factors. Emerging evidence highlights notable sex differences in CRC, with men generally exhibiting higher incidence rates and poorer prognoses, while women often display stronger immune responses and distinct molecular profiles. Traditional screening tools, such as colonoscopy and fecal-based tests, have improved survival through early detection but are limited by invasiveness, cost, and adherence issues. In this context, biosensors have emerged as innovative diagnostic platforms capable of rapid, sensitive, and non-invasive detection of CRC-associated biomarkers, including genetic, epigenetic, and metabolic alterations. These technologies integrate biological recognition elements with nanomaterials, microfluidics, and digital systems, enabling the analysis of biomarkers such as proteins, nucleic acids, autoantibodies, epigenetic marks, and metabolic or VOC signatures from blood, stool, or breath and supporting point-of-care applications. Electrochemical, optical, piezoelectric, and FET platforms enable label-free or ultrasensitive multiplexed readouts and align with liquid biopsy workflows. Despite challenges related to standardization, robustness in complex matrices, and clinical validation, advances in nanotechnology, multi-analyte biosensing with artificial intelligence are enhancing biosensor performance. Integrating biosensor-based diagnostics with knowledge of sex-specific molecular and hormonal pathways may lead to more precise and equitable approaches in CRC detection, selection of therapeutic regimes and management. Full article

(This article belongs to the Special Issue Application of Biosensors in Pharmaceutical Research)

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45 pages, 1288 KB

Open AccessReview

A Review of Traditional Chinese Medicine Formulations and Natural Active Ingredients with Therapeutic Potential for Male Infertility Targeting Oxidative Stress

by Zhen Peng, Ning Zhang, Fengting Yin, Ling Kong, Hui Sun, Chang Liu, Yaning Wu, Chenyue Wang and Xijun Wang

Pharmaceuticals 2026, 19(1), 12; https://doi.org/10.3390/ph19010012 (registering DOI) - 20 Dec 2025

Abstract

Male infertility has emerged as a significant global concern, with male factors accounting for approximately 30% to 50% of infertility cases. Oxidative stress is recognized as the primary pathological mechanism affecting sperm structure and function. The development and application of chemically synthesized drug [...] Read more.

Male infertility has emerged as a significant global concern, with male factors accounting for approximately 30% to 50% of infertility cases. Oxidative stress is recognized as the primary pathological mechanism affecting sperm structure and function. The development and application of chemically synthesized drug therapies are limited by lengthy research and development processes and significant adverse effects. Conversely, Traditional Chinese Medicine (TCM) compounds offer promising clinical applications for enhancing male reproductive function, attributed to their distinctive advantages of multi-target coordination and holistic regulation. This paper systematically reviews classical TCM compounds, such as those that tonify the kidney and benefit essence, warm and invigorate kidney Yang, and replenish Qi and nourish blood. It also examines the molecular mechanisms of active natural ingredients, including flavonoids, polyphenols, terpenes, alkaloids, and polysaccharides. These compounds improve male fertility by modulating oxidative stress-related signaling pathways. Furthermore, this review anticipates future research trajectories and potential applications within this domain, with the objective of establishing a theoretical basis for the clinical treatment of idiopathic male infertility and the development of novel pharmacological interventions. Full article

(This article belongs to the Topic From Food to Medicine: Applications of Natural Bioactive Compounds)

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16 pages, 5692 KB

Open AccessArticle

Using a Natural Clay Mineral as an Active Drug Carrier to Promote Hair Growth

by Zhiqing Liu, Wenhua Huang, Shanhua Xu, Meilan Nan, Xian Cui, Yue Wang, Zhehu Jin, Wan Meng, Jingbi Meng and Longquan Pi

Pharmaceuticals 2026, 19(1), 11; https://doi.org/10.3390/ph19010011 (registering DOI) - 20 Dec 2025

Abstract

Background: Topical minoxidil remains the only FDA-approved treatment for hair loss, yet its clinical efficacy is compromised by organic-solvent-induced scalp irritation and poor patient adherence. This study aimed to evaluate natural illite as a carrier for minoxidil and to explore its potential hair-growth-promoting [...] Read more.

Background: Topical minoxidil remains the only FDA-approved treatment for hair loss, yet its clinical efficacy is compromised by organic-solvent-induced scalp irritation and poor patient adherence. This study aimed to evaluate natural illite as a carrier for minoxidil and to explore its potential hair-growth-promoting mechanisms. Methods: Thermal–acid-modified illite was engineered as a spray-dried, hydroalcohol-free minoxidil carrier for topical application. Hair regrowth efficacy was assessed in C57BL/6 mice via a 14-day depilation model. Mechanisms were elucidated via RNA-seq, Ki67/TUNEL immunofluorescence, and p-STAT3 immunohistochemistry. Results: Modified illite resulted in a 4.2-fold surface area increase and successful minoxidil loading. The minoxidil/illite formulation demonstrated efficacy equivalent to that of free minoxidil while also eliminating solvent toxicity. Mechanistic analysis revealed that illite functions as an active carrier: both the illite-alone and minoxidil/illite-treated groups exhibited increased Ki67⁺ proliferation and reduced TUNEL⁺ apoptosis. Transcriptomic profiling demonstrated dual mechanisms—enrichment of Myc proliferation pathways and suppression of IL-6 inflammatory signaling (p < 0.001)—with reduced p-STAT3 expression confirmed by immunohistochemistry. Conclusions: These findings suggest that an illite-based carrier can enable topical delivery of minoxidil with preserved efficacy and that illite itself exhibits intrinsic hair-growth-promoting activity via anti-inflammatory and pro-proliferative mechanisms, which may help alleviate adherence barriers associated with conventional topical alopecia therapy. Full article

(This article belongs to the Section Pharmaceutical Technology)

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25 pages, 4686 KB

Open AccessReview

Beyond Direct Fibrinolysis: Novel Approaches to Thrombolysis

by Alexey M. Shibeko, Nikita S. Nikitin, Nadezhda A. Podoplelova, Valentin A. Manuvera and Vassili N. Lazarev

Pharmaceuticals 2026, 19(1), 10; https://doi.org/10.3390/ph19010010 (registering DOI) - 20 Dec 2025

Abstract

Fibrinolysis is a natural component of hemostasis in which a no-longer-needed clot is gradually dissolved to restore blood flow. Under pathological thrombotic conditions, this process can be pharmacologically enhanced to promote clot removal. However, thrombolytic therapy has limited efficacy and is associated with [...] Read more.

Fibrinolysis is a natural component of hemostasis in which a no-longer-needed clot is gradually dissolved to restore blood flow. Under pathological thrombotic conditions, this process can be pharmacologically enhanced to promote clot removal. However, thrombolytic therapy has limited efficacy and is associated with a risk of bleeding complications, including intracranial hemorrhage. Fibrinolysis targets only the fibrin-rich part of the thrombus, whereas a substantial fraction of the clot is enriched with non-fibrin components such as extracellular DNA, von Willebrand factor, and extracellular matrix proteins, including collagen, fibronectin, and laminin. These structural regions, which may constitute half or more of the clot volume, remain resistant to classical fibrinolytic agents. To overcome these limitations, recent therapeutic strategies aim to degrade these non-fibrin elements to improve thrombolytic efficacy and reduce adverse effects. In this review, we summarize current trends in pharmacological clot dissolution, discuss novel agents in clinical use and development, and outline how targeting non-fibrin components may influence the future of thrombolytic therapy. Full article

(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)

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15 pages, 637 KB

Open AccessArticle

Real-World Prescribing Patterns of SGLT2 Inhibitors and GLP-1 Receptor Agonists in Older Adults with Type 2 Diabetes and Cardiometabolic Disease

by Ibrahim S. Alhomoud and Khalid A. Alamer

Pharmaceuticals 2026, 19(1), 9; https://doi.org/10.3390/ph19010009 (registering DOI) - 20 Dec 2025

Abstract

Background/Objectives: Older adults with type 2 diabetes frequently have cardiovascular or kidney disease, and current guidelines strongly recommend the use of SGLT2 inhibitors or GLP-1 receptor agonists in these high-risk populations. This study aimed to critically evaluate their real-world utilization in a tertiary [...] Read more.

Background/Objectives: Older adults with type 2 diabetes frequently have cardiovascular or kidney disease, and current guidelines strongly recommend the use of SGLT2 inhibitors or GLP-1 receptor agonists in these high-risk populations. This study aimed to critically evaluate their real-world utilization in a tertiary care setting to identify gaps in prescribing and opportunities for improvement. Methods: A retrospective cross-sectional analysis was conducted using electronic medical records from a tertiary academic hospital in Saudi Arabia (June 2019–May 2023). Patients aged ≥65 years with type 2 diabetes and documented ASCVD, heart failure, or CKD were classified as guideline-eligible. Prescribing rates, trends, specialty variation, and associated factors were assessed. Results: Among 223 older high-risk patients with type 2 diabetes, 83.4% received an SGLT2 inhibitor or GLP-1 receptor agonist. However, only 1.6% (223 out of 14,146 older adults) were identified in the electronic medical record as having ASCVD, heart failure, or CKD, suggesting potential underdiagnosis or incomplete recognition of guideline-eligible comorbidities. Overall, just 7.4% of older adults with type 2 diabetes were prescribed either therapy. Notably, approximately one-quarter of prescriptions originated from specialties not routinely involved in cardiometabolic care, indicating variability in prescribing patterns. Multivariable analysis showed that older age, female sex, and unmarried status were associated with lower odds of receiving therapy, while patients seen in cardiology or internal medicine had higher odds than those seen in primary care. Conclusions: Prescribing of GLP-1 receptor agonists and SGLT2 inhibitors was aligned with guideline recommendations in documented high-risk patients. Nevertheless, overall utilization remained low, indicating gaps in the recognition of cardiometabolic comorbidities. Enhancing routine cardiovascular and kidney risk assessment may improve therapy optimization. Full article

(This article belongs to the Section Pharmacology)

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32 pages, 1283 KB

Open AccessReview

Studying Candida Biofilms Across Species: Experimental Models, Structural Diversity, and Clinical Implications

by Damiano Squitieri, Silvia Rizzo, Riccardo Torelli, Melinda Mariotti, Maurizio Sanguinetti, Margherita Cacaci and Francesca Bugli

Pharmaceuticals 2026, 19(1), 8; https://doi.org/10.3390/ph19010008 (registering DOI) - 19 Dec 2025

Abstract

Candida biofilms play a critical role in clinical settings, contributing to persistent and device-associated infections and conferring resistance to antifungal agents, particularly in immunocompromised or hospitalized patients. Biofilm formation varies among Candida species, including C. albicans and non-albicans species, such as C. glabrata [...] Read more.

Candida biofilms play a critical role in clinical settings, contributing to persistent and device-associated infections and conferring resistance to antifungal agents, particularly in immunocompromised or hospitalized patients. Biofilm formation varies among Candida species, including C. albicans and non-albicans species, such as C. glabrata, C. tropicalis, C. parapsilosis, and C. auris, due to species-specific transcriptional networks that regulate modes of biofilm development, extracellular matrix composition, and metabolic reprogramming. These differences influence biofilm responses to treatment and the severity of infections, which can be further complicated in polymicrobial biofilms that modulate colonization and virulence. Understanding the mechanisms driving biofilm formation and interspecies interactions is essential for developing effective therapies and requires appropriate experimental models. Available models range from simplified in vitro systems to more complex ex vivo and in vivo approaches. Static in vitro models remain widely used due to their simplicity and reproducibility, but they poorly mimic physiological conditions and require careful standardization. Ex vivo tissue models offer a balance between practicality and biological relevance, enabling the study of biofilm physiology, host–microbe interactions and immune responses. In vivo models, primarily in mice, remain the gold standard for testing antifungal therapies, while alternative systems such as Galleria mellonella larvae provide simpler, cost-effective approaches. Advanced in vitro platforms, including organ-on-chip systems, bridge the gap between simplified tests and physiological relevance by simulating fluid dynamics, tissue architecture, and immune complexity. This review aims to examine Candida biofilms across species, highlighting differences in structural diversity and clinical implications, and to provide a guide to the most widely used experimental models supporting studies on Candida biofilm biology for the development of new therapeutic targets or drug testing. Full article

(This article belongs to the Section Biopharmaceuticals)

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28 pages, 1566 KB

Open AccessArticle

Ai-Fen Solid Dispersions: Preparation, Characterization, and Enhanced Therapeutic Efficacy in a Rat Model of Oral Ulceration

by Bing-Nan Liu, Kai-Lang Mu, Chang-Liu Shao, Ping-Xuan Xie, Jun-Li Xie, Mei-Hui He, Yu-Chen Liu, Ke Zhong, Yuan Yuan, Xiao-Min Tang and Yu-Xin Pang

Pharmaceuticals 2026, 19(1), 7; https://doi.org/10.3390/ph19010007 - 19 Dec 2025

Abstract

Background/Objectives: Recurrent oral ulceration (ROU) is the most prevalent disorder of the oral mucosa, affecting approximately 20% of the global population. Current therapies are limited by adverse effects and high recurrence rates. Ai-Fen, enriched in the anti-inflammatory monoterpenoid L-borneol (54.3% w/w [...] Read more.

Background/Objectives: Recurrent oral ulceration (ROU) is the most prevalent disorder of the oral mucosa, affecting approximately 20% of the global population. Current therapies are limited by adverse effects and high recurrence rates. Ai-Fen, enriched in the anti-inflammatory monoterpenoid L-borneol (54.3% w/w), exhibits therapeutic potential but suffers from poor aqueous solubility and low bioavailability. This study aimed to improve the physicochemical properties and in vivo efficacy of Ai-Fen through the preparation of solid dispersions. Methods: Ai-Fen solid dispersions (AF-SD) were prepared by a melt-fusion method using polyethylene glycol 6000 (PEG 6000) as the carrier. An L₉(3³) orthogonal design was employed to optimize three critical parameters: drug-to-carrier ratio, melting temperature, and melting duration. The resulting dispersions were systematically characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), and Fourier-transform infrared spectroscopy (FTIR). A chemically induced ROU model in rats (n = 8 per group) was established to evaluate the effects of AF-SD on ulcer area, serum inflammatory cytokines (TNF-α, IL-6), vascular endothelial growth factor (VEGF) levels, and histopathological outcomes. Results: The optimal formulation was obtained at a drug-to-carrier ratio of 1:2, a melting temperature of 70 °C, and a melting time of 5 min. Under these conditions, L-borneol release increased 2.5-fold. DSC and PXRD confirmed complete conversion of Ai-Fen to an amorphous state, while FTIR revealed a 13 cm⁻¹ red shift in the O-H stretching band, indicating hydrogen-bond formation. In vivo, AF-SD reduced ulcer area by 60.7% (p < 0.001) and achieved a healing rate of 74.16%. Serum TNF-α and IL-6 decreased by 55.5% and 49.6%, respectively (both p < 0.001), whereas VEGF increased by 89.6% (p < 0.001). Histological analysis confirmed marked reduction in inflammatory infiltration, accelerated re-epithelialization (score 2.50), and a 5.9-fold increase in neovascularization. Conclusions: AF-SD markedly enhanced the bioavailability of Ai-Fen through amorphization and accelerated ROU healing, likely via dual mechanisms involving suppression of nuclear factor kappa-B (NF-κB)-mediated inflammation and promotion of angiogenesis. This formulation strategy provides a promising approach for modernizing traditional herbal medicines. Full article

(This article belongs to the Section Pharmaceutical Technology)

14 pages, 746 KB

Open AccessArticle

CYP2C:TG Haplotype in Native Mexicans, Molecular Ancestry and Its Implications for CYP2C19 Genotype–Phenotype Correlation

by Carla González de la Cruz, Nadine de Godoy Torso, Juan Antonio Villatoro-García, Carmen Mata-Martín, Fernanda Rodrigues-Soares, Carlos Galaviz-Hernández, Eva Peñas-Lledó, Martha Sosa-Macías, Adrián LLerena and RIBEF-IBEROFEN Consortium

Pharmaceuticals 2026, 19(1), 6; https://doi.org/10.3390/ph19010006 - 19 Dec 2025

Abstract

Background: Recent studies have associated the presence of the CYP2C:TG haplotype with increased metabolism of CYP2C19 substrates such as escitalopram and sertraline, suggesting a potential regulatory interaction between CYP2C18 and CYP2C19. However, this association has not been demonstrated for other [...] Read more.

Background: Recent studies have associated the presence of the CYP2C:TG haplotype with increased metabolism of CYP2C19 substrates such as escitalopram and sertraline, suggesting a potential regulatory interaction between CYP2C18 and CYP2C19. However, this association has not been demonstrated for other CYP2C19 substrates. Objective: This study aims to elucidate the role of the CYP2C:TG haplotype in modulating CYP2C19 activity using the omeprazole metabolic ratio (MR) within a cocktail drug approach, to characterize its distribution and prevalence among Native Mexican populations, and to evaluate its potential impact on CYP2C19 metabolic phenotypes. Materials and Methods: A total of 256 volunteers from various ethnic native groups from Mexico were genotyped for CYP2C19 (*2, *3, *4, *5, *17) and the CYP2C haplotype (rs2860840 and rs11188059). The MR of omeprazole to 5-hydroxyomeprazole was analyzed to determine individual CYP2C19 metabolic phenotypes and assess metabolic capacity. Results: The CYP2C:TG haplotype was the most prevalent (42.77%), followed by CYP2C:CG (35.74%) and CYP2C:TA (21.48%). The CYP2C:TG haplotype was consistently associated with the CYP2C19*1 allele. Significant differences in logMR values were observed between individuals with and without the TG haplotype (p = 0.02). A trend toward increased metabolic activity associated with CYP2C:TG was observed across most CYP2C19 metabolizer groups, except for rapid metabolizers. No significant association was found between molecular ancestry and the presence or functionality of the haplotype. Conclusions: The CYP2C:TG haplotype appears to be associated with increased CYP2C19 activity, warranting further functional validation before clinical implementation. Full article

(This article belongs to the Section Pharmacology)

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30 pages, 10236 KB

Open AccessArticle

In Silico Investigation of Amidine-Based BACE-1 Inhibitors Against Alzheimer’s Disease: SAR, Pharmacokinetics, Molecular Docking and Dynamic Simulations

by Vaibhav Gandhi, Varun Dewaker, Uma Agarwal, Vaishali M. Patil, Sung Taek Park, Hyeong Su Kim and Saroj Verma

Pharmaceuticals 2026, 19(1), 5; https://doi.org/10.3390/ph19010005 - 19 Dec 2025

Abstract

Background/Objective: Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β plaques, derived from the amyloid precursor protein through sequential cleavage by β-secretase 1 (BACE-1) and γ-secretase. BACE-1 is therefore a key drug target for designing of selective inhibitors to avoid off-target effects [...] Read more.

Background/Objective: Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β plaques, derived from the amyloid precursor protein through sequential cleavage by β-secretase 1 (BACE-1) and γ-secretase. BACE-1 is therefore a key drug target for designing of selective inhibitors to avoid off-target effects associated with BACE-2 inhibition. The objective of this study was to design novel BACE-1 inhibitors using a structure-based drug design approach. Methods: A focused compound library was designed based on the SAR of N-(4-fluorophenyl)formamide derivatives. In silico ADME predictions were performed to assess pharmacokinetic suitability. Compounds showing favorable ADME profiles were subjected to molecular docking against the BACE-1 enzyme. The top-scoring hit, compound 9.7 (−5.48 (kcal/mol), was further evaluated using a 200 ns MD simulation to assess the stability of its binding interactions with BACE-1. Results: Designed compounds indicated acceptable physicochemical and ADME characteristics. Molecular docking identified compound 9.7 as exhibiting favorable binding interactions with binding pocket residues of BACE-1. The 200 ns MD simulation further confirmed the stability of the docked complex. MD simulations confirmed that 9.7 forms stable interactions with the catalytic residue ASP32 and key hydrophobic residues TRP115 and PHE108 of BACE-1. These important interactions are absent in the reference compound verubecestat. Conclusions: The multi-step computational analysis suggests that compound 9.7 is a promising and selective BACE-1 inhibitor. Its favorable ADME profile, favorable docking interactions, and stable MD simulation behavior highlight its potential as a hit compound for further optimization in the development of anti-Alzheimer’s agents. Full article

(This article belongs to the Section Medicinal Chemistry)

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18 pages, 639 KB

Open AccessArticle

Synthesis, Characterization, Antimicrobial and Anticancer Evaluation of Novel Heterocyclic Diazene Compounds Derived from 8-Quinolinol

by Ion Burcă, Alexandra-Mihaela Diaconescu, Valentin Badea and Francisc Péter

Pharmaceuticals 2026, 19(1), 4; https://doi.org/10.3390/ph19010004 - 19 Dec 2025

Abstract

Background: 8-Quinolinol and its derivatives are drawing significant attention across various disciplines due to their remarkable versatility. These compounds are well-known for their exceptional chelating ability, forming stable metal complexes via their nitrogen and oxygen electron donor atoms. This main characteristic determines [...] Read more.

Background: 8-Quinolinol and its derivatives are drawing significant attention across various disciplines due to their remarkable versatility. These compounds are well-known for their exceptional chelating ability, forming stable metal complexes via their nitrogen and oxygen electron donor atoms. This main characteristic determines their broad utility. Biological activity can also be explained by the chelating capacity, which allows 8-quinolinol to bind to essential metal ions such as Fe, Zn, Cu, and others. This chelation disrupts metal-dependent biological processes in target cells or organisms, leading to a range of effects, including antimicrobial, anticancer, antifungal, and neuroprotective activities. On the other hand, the biological activity of pyrazole derivatives is attributed to their heterocyclic structure, which allows for interactions with biological targets that can lead to enzyme inhibition, receptor antagonism, radical scavenging, and other effects. Objective: This work aimed to synthesize and characterize novel diazene compounds derived from 8-quinolinol or 2-methyl-8-quinolinol and pyrazole amines, and to evaluate their antimicrobial and anticancer activities. Methods: The compounds have been synthesized by coupling diazonium salts obtained from the diazotization of heterocyclic amines with 8-quinolinol and its derivative, 2-methyl-8-quinolinol. The careful selection of reaction conditions enabled the synthesis of high-purity products. The compounds were characterized by 1D and 2D NMR, FT-IR spectroscopy, UV-Vis spectroscopy, and LC-HRMS analysis. The biological activity of the newly synthesized compounds was evaluated following the protocols of EU-OPENSCREEN, a European Research Infrastructure Consortium (ERIC) initiative dedicated to supporting early drug discovery. Results: By combining diazonium salts obtained from 3-methyl-1H-pyrazol-5-amine and ethyl 5-amino-3-methyl-1H-pyrazole-4-carboxylate with the aforementioned coupling agents, four novel 8-quinolinol derivatives were synthesized. The further hydrolysis of the ethoxy carbonyl functional group allowed its conversion to a carboxylic functional group, thus expanding the series of new compounds to six members. Several compounds from the series have proven to be biologically active against several human pathogenic microorganisms and the Hep-G2 cancer cell line. Conclusions: The combination of two well-known biologically active scaffolds through a classic diazo coupling reaction allowed the synthesis of novel biologically active compounds, which showed promising results as possible antifungal and anticancer agents. These results represent a foundation for future studies, which will include a broader biological screening and in vivo studies. Full article

(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)

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16 pages, 3734 KB

Open AccessArticle

Elucidation of a Novel Dual Binding Site on Tubulin: Theoretical Insights and Prospective Hybrid Inhibitors

by Dmytro Khylyuk, Oleg M. Demchuk, Rafał Kurczab, Barbara Miroslaw and Monika Wujec

Pharmaceuticals 2026, 19(1), 3; https://doi.org/10.3390/ph19010003 - 19 Dec 2025

Abstract

Background/Objectives: Microtubule-targeting agents remain foundational components of anticancer chemotherapy, yet their clinical utility is constrained by resistance and toxicity. Methods: Here, we present a theoretical exploration of a plausible “dual” binding pocket that spans the α-tubulin pironetin site and the inter-subunit todalam site. [...] Read more.

Background/Objectives: Microtubule-targeting agents remain foundational components of anticancer chemotherapy, yet their clinical utility is constrained by resistance and toxicity. Methods: Here, we present a theoretical exploration of a plausible “dual” binding pocket that spans the α-tubulin pironetin site and the inter-subunit todalam site. Eight virtual chimeric ligands, each merging key pharmacophoric elements of pironetin and todalam, were constructed and covalently docked to Cys316 of α-tubulin. Results: Covalent docking followed by 200 ns all-atom molecular dynamics simulations revealed that two derivatives (compounds 4 and 8) stably occupy the merged cavity, simultaneously anchoring in the pironetin region via Michael addition and in the todalam region via π-stacking and hydrogen bonding. These hybrids preserved the critical hydrogen-bonding networks of both parent ligands and exhibited low ligand RMSD values (~1.5 Å) and compact radii of gyration throughout the simulations, indicating a tight, persistent binding. Estimated HYDE affinities of 1.5 µM for compound 4 and 17.6 µM for compound 8, calculated with SeeSAR, suggest that covalent engagement can compensate for moderate non-covalent binding scores. Conclusions: In summary, our results provide compelling grounds for developing a new class of α-tubulin inhibitors that engage the hybrid pocket, laying a foundation for the structure-guided synthesis of first-in-class dual-site compounds capable of overcoming resistance to conventional microtubule-targeting drugs. Full article

(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry, 2nd Edition)

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16 pages, 1606 KB

Open AccessArticle

Gut Microbiota Modulation in Asthma—An In Vitro Study

by Paulina Kleniewska, Paulina Natalia Kopa-Stojak and Rafał Pawliczak

Pharmaceuticals 2026, 19(1), 2; https://doi.org/10.3390/ph19010002 - 19 Dec 2025

Abstract

Objectives: The aim of this work was to investigate whether Bacteroides vulgatus (BV), Clostridium perfringens (CP), Parabacteroides distasonis (PD), and Ruminococcus albus (RA) lysates modulate the secretion of IL-17, INF-γ, IL-2, and TGF-β 1 by human HT-29 cells, PBMCs, and monocytes (MON). Results: [...] Read more.

Objectives: The aim of this work was to investigate whether Bacteroides vulgatus (BV), Clostridium perfringens (CP), Parabacteroides distasonis (PD), and Ruminococcus albus (RA) lysates modulate the secretion of IL-17, INF-γ, IL-2, and TGF-β 1 by human HT-29 cells, PBMCs, and monocytes (MON). Results: CP lysate significantly lowered IL-17 secretion by HT-29 cells vs. control (p < 0.05), but only at a dose of 100 µg. RA lysate reduced IL-17 secretion by HT-29 cells vs. control (p < 0.05), but only at a dose of 400 µg, whereas PD lysate significantly decreased IL-17 secretion by HT-29 cells vs. control (p < 0.05) at both doses. The secretion of IL-17 by PBMCs was significantly reduced after administration of BV and PD lysates (100 µg). BV and PD lysates (400 µg) also significantly decreased IL-17 secretion by MON vs. control (p < 0.05). The secretion of INF-γ by HT-29 cells was significantly lowered vs. control (p < 0.05) after administration of PD and CP lysates (400 µg). CP lysates (100 µg and 400 µg) also significantly reduced INF-γ secretion by MON compared with control (p < 0.05). The secretion of INF-γ by PBMCs was significantly reduced vs. control (p < 0.05) after administration of BV and CP lysates (400 µg). Conclusions: In PBMCs, HT-29 cells, and MON, INF-γ and IL-17 concentrations were significantly lowered by selected bacterial lysates in a dose-dependent manner. However, the low values detected in this experiment may not have an impact on systemic immune status. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 1812 KB

Open AccessArticle

Evaluation of the In Vitro Synergistic Activity of Ceftazidime/Avibactam Against Stenotrophomonas maltophilia Strains in Planktonic and Biofilm Cell Cultures

by Damla Damar-Çelik, Emel Mataraci-Kara, Ayşe İstanbullu-Tosun, Selin Melis Çakmak, Bilge Sümbül and Berna Özbek-Çelik

Pharmaceuticals 2026, 19(1), 1; https://doi.org/10.3390/ph19010001 - 19 Dec 2025

Abstract

Background/Objectives: Stenotrophomonas maltophilia (SM) is a significant cause of hospital-acquired infections in immunocompromised and critical care patients. This study investigates the impact of combining ceftazidime/avibactam (CZA) with conventional antibiotics on SM obtained from various sources in planktonic and biofilm cell cultures. Methods [...] Read more.

Background/Objectives: Stenotrophomonas maltophilia (SM) is a significant cause of hospital-acquired infections in immunocompromised and critical care patients. This study investigates the impact of combining ceftazidime/avibactam (CZA) with conventional antibiotics on SM obtained from various sources in planktonic and biofilm cell cultures. Methods: Using broth microdilution, the MICs of different antibiotics, including CZA, were determined on 37 SM strains. CZA’s bactericidal and synergistic effectiveness were examined through in vitro time–kill curve tests with tigecycline (TGC), chloramphenicol (CHL), levofloxacin (LVX), colistin (CS), and amikacin (AMK). In addition, synergistic activity was investigated against SM biofilm cell cultures, and antibiotic Mutant Prevention Concentrations (MPCs) were tested against SM isolates. Results: Compared to ceftazidime (CAZ), CZA was four times more efficient against 37 SM strains. Unlike TGC and CHL, CS, AMK, and CZA had 2–4 times higher MBCs than MICs. All studied antibiotics were bactericidal at 1× or 4× MIC doses against SM bacteria, except for CZA. The combinations of CZA with LVX and CZA with AMK or CS demonstrated synergistic effects in four out of seven (57%) strains and in three out of seven (43%) strains, respectively, when tested at doses equivalent to the MIC. Moreover, all antibiotic combinations with CZA showed a synergistic effect at dosages four times the MIC. Additionally, CZA and the tested drugs synergistically inhibited SM biofilm formation, and MPC values were 8–16 times the MIC. Conclusions: The results of this study indicate that combining CZA with LVX and CS was more effective against SM strains. These combinations might provide alternatives for treating SM pathogens in both planktonic and biofilm cell cultures. Full article

(This article belongs to the Special Issue Next-Generation Antibiotic Strategies Against Drug-Resistant Bacteria)

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23 pages, 1577 KB

Open AccessArticle

Antibacterial and Antifungal Properties of Ocotea indecora Essential Oil and Its Nanoemulsion

by Francisco Paiva Machado, Julia C. Scaffo, Leonardo A. Pinto, Renata F. A. Pereira, Sorele Fiaux, Luiz Antonio M. Keller, Eduardo Ricci-Júnior, Ana Paula dos Santos Matos, Fabio Aguiar-Alves, Caio P. Fernandes, Jorge A. D. Duarte and Leandro Rocha

Pharmaceuticals 2025, 18(12), 1909; https://doi.org/10.3390/ph18121909 - 18 Dec 2025

Abstract

Background: Antimicrobial resistance and fungal contamination remain major threats to public health and agriculture, emphasizing the need for innovative alternatives. Plant-derived products are a promising alternative, and nanoformulations may further enhance their activity. Objective: This study investigated the antimicrobial potential of Ocotea indecora [...] Read more.

Background: Antimicrobial resistance and fungal contamination remain major threats to public health and agriculture, emphasizing the need for innovative alternatives. Plant-derived products are a promising alternative, and nanoformulations may further enhance their activity. Objective: This study investigated the antimicrobial potential of Ocotea indecora essential oil and its nanoemulsion. Methods/Results: The essential oil chemical characterization by GC-MS revealed sesquirosefuran (91.61%) as the main constituent. A factorial design guided the selection of an optimized nanoemulsion, which exhibited spherical nanometric droplets (79 nm and 0.029 PdI) with long-term stability. The essential oil inhibited the growth of Gram-positive and Gram-negative strains at 1 to 2 mg/mL, while the nanoemulsion enhanced bactericidal activity against Staphylococcus aureus. In contrast, antifungal assays revealed a more pronounced effect, with the nanoemulsion lowering the minimum inhibitory concentrations (625 µg/mL) against Thielaviopsis ethacetica, thereby enhancing the inhibitory activity of the essential oil (2.5 mg/mL). Morphological alterations, including thinner hyphae and impaired sporulation, were also detected, suggesting a reduction in fungal virulence. Conclusions: In summary, O. indecora essential oil shows promising antimicrobial potential, and nanoemulsification proved particularly effective in potentiating fungistatic activity while offering limited enhancement of bactericidal effects. The results support the potential of O. indecora derivatives as natural candidates for the development of novel antimicrobial strategies. Full article

(This article belongs to the Special Issue Essential Oil-Based Nanoemulsions)

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18 pages, 988 KB

Open AccessArticle

MicroRNA Signatures and Machine Learning Models for Predicting Cardiotoxicity in HER2-Positive Breast Cancer Patients

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 2025, 18(12), 1908; https://doi.org/10.3390/ph18121908 - 18 Dec 2025

Abstract

Background: HER2-positive breast cancer patients receiving chemotherapy and targeted therapy (including anthracyclines and trastuzumab) face an elevated risk of cardiotoxicity, which can lead to long-term cardiovascular complications. Identifying predictive biomarkers is essential for early intervention. Circulating microRNAs (miRNAs), known regulators of gene expression [...] Read more.

Background: HER2-positive breast cancer patients receiving chemotherapy and targeted therapy (including anthracyclines and trastuzumab) face an elevated risk of cardiotoxicity, which can lead to long-term cardiovascular complications. Identifying predictive biomarkers is essential for early intervention. Circulating microRNAs (miRNAs), known regulators of gene expression and cardiovascular function, have emerged as potential indicators of cardiotoxicity. This study aims to evaluate the differential expression of circulating miRNAs in HER2-positive breast cancer patients undergoing chemotherapy and to assess their prognostic ability for therapy-induced cardiotoxicity using machine learning models. Methods: Forty-seven patients were assessed for cardiac toxicity at baseline and every 3 months, up to 15 months. Blood samples were collected at baseline. MiRNA expression profiling for 84 microRNAs was performed using the miRCURY LNA miRNA PCR Panel. Differential expression was calculated via the 2−∆∆Ct method. The five most upregulated and five most downregulated miRNAs were further assessed using univariate logistic regression and receiver operating characteristic (ROC) analysis. Five machine learning models (Decision Tree, Random Forest (RF), Support Vector Machine (SVM), Gradient Boosting Machine (GBM), k-Nearest Neighbors (KNN)) were developed to classify cardiotoxicity based on miRNA expression. Results: Forty-five miRNAs showed significant differential expression between cardiac toxic and non-toxic groups. ROC analysis identified hsa-miR-155-5p (AUC 0.76, p = 0.006) and hsa-miR-124-3p (AUC 0.75, p = 0.007) as the strongest predictors. kNN, SVM, and RF models demonstrated high prognostic accuracy. The decision tree model identified hsa-miR-17-5p and hsa-miR-185-5p as key classifiers. SVM and RF highlighted additional miRNAs associated with cardiotoxicity (SVM: hsa-miR-143-3p, hsa-miR-133b, hsa-miR-145-5p, hsa-miR-185-5p, hsa-miR-199a-5p, RF: hsa-miR-185-5p, hsa-miR-145-5p, hsa-miR-17-5p, hsa-miR-144-3p, and hsa-miR-133a-3p). Performance metrics revealed that SVM, kNN, and RF models outperformed the decision tree in overall prognostic accuracy. Pathway enrichment analysis of top-ranked miRNAs demonstrated significant involvement in apoptosis, p53, MAPK, and focal adhesion pathways, all known to be implicated in chemotherapy-induced cardiac stress and remodeling. Conclusions: Circulating miRNAs show promise as biomarkers for predicting cardiotoxicity in breast cancer patients. Machine learning approaches may enhance miRNA-based risk stratification, enabling personalized monitoring and early cardioprotective interventions. Full article

(This article belongs to the Special Issue Chemotherapeutic and Targeted Drugs in Antitumor Therapy)

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