Pharmaceuticals

26 pages, 5728 KB

Open AccessArticle

Oncolytic Virus VV-GMCSF-Lact and Human GM-CSF Against GL261 Glioma in Immunocompetent Mice

by Alisa B. Ageenko, Natalia S. Vasileva, Anna S. Chesnokova, Dmitriy V. Semenov, Arina A. Byvakina, Maya A. Dymova, Aleksandra V. Sen’kova, Anna A. Nushtaeva, Anastasia A. Leonteva, Yulya I. Savinovskaya, Galina V. Kochneva, Vladimir A. Richter and Elena V. Kuligina

Pharmaceuticals 2026, 19(3), 434; https://doi.org/10.3390/ph19030434 - 6 Mar 2026

Abstract

Background/Objectives: Oncolytic viruses are an immunotherapeutic approach that can modulate the tumor microenvironment (TME), transforming immunologically ‘cold’ tumors into ‘hot’ ones. Insertion of genes encoding immunomodulatory proteins can further enhance antitumor immune responses. In this study, we compared the antitumor and immunomodulatory effects [...] Read more.

Background/Objectives: Oncolytic viruses are an immunotherapeutic approach that can modulate the tumor microenvironment (TME), transforming immunologically ‘cold’ tumors into ‘hot’ ones. Insertion of genes encoding immunomodulatory proteins can further enhance antitumor immune responses. In this study, we compared the antitumor and immunomodulatory effects of the double recombinant vaccinia virus VV-GMCSF-Lact, which carries the human GM-CSF gene, with those of recombinant human GM-CSF (rhGM-CSF) in an immunocompetent murine GL261 glioma model. Methods: The study was conducted using a subcutaneous GL261 glioma model in immunocompetent C57BL/6 mice, comparing intratumoral VV-GMCSF-Lact and rhGM-CSF treatments with evaluation of immune cell populations by flow cytometry, tumor morphology by H&E staining, and tumor transcriptome profiles by RNA sequencing. Results: Flow cytometry showed that VV-GMCSF-Lact reduced the number of immunosuppressive cells in the TME of subcutaneously transplanted gliomas, targeting different components of the TME depending on animal sex. The immunotherapeutic effects of rhGM-CSF were less pronounced and primarily affected peripheral immune cells. Histological analysis revealed a decrease in mitotic figures in tumors from female mice after viral therapy. Transcriptome profiling of GL261 tumors demonstrated divergent gene expression patterns and cellular compositions between treatment groups. VV-GMCSF-Lact treatment was associated with a decreased proportion of malignant GL261 cells and CD8⁺ T lymphocytes, while rhGM-CSF treatment increased proportions of MDSCs, macrophages, NK cells, and tumor-associated neutrophils. Conclusions: Taken together, our data demonstrate that VV-GMCSF-Lact induces antitumor immune responses in murine GL261 glioma in vivo and modulates the tumor microenvironment more effectively than rhGM-CSF alone, supporting its potential for developing new strategies for glioma treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Brain Cancer: Recent Advances and Future Trends)

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16 pages, 5616 KB

Open AccessArticle

Geopropolis from Melipona orbignyi and Melipona quadrifasciata anthidioides Enhances Oxidative Stress Resistance and Lifespan in Caenorhabditis elegans

by Helder Freitas dos Santos, Jaqueline Ferreira Campos, José Benedito Perrella Balestieri, Daniel Ferreira Leite, Alex Santos Oliveira, Wellington Henrique Botelho, Paola dos Santos da Rocha, Debora da Silva Baldivia, Sikiru Olaitan Balogun, Kely de Picoli Souza and Edson Lucas dos Santos

Pharmaceuticals 2026, 19(3), 433; https://doi.org/10.3390/ph19030433 - 6 Mar 2026

Abstract

Background: Oxidative stress arises from an imbalance in redox homeostasis, leading to the accumulation of reactive oxygen species. This condition is associated with premature aging, as well as the progression of several chronic noncommunicable diseases. Among the natural products, geopropolis stands out as [...] Read more.

Background: Oxidative stress arises from an imbalance in redox homeostasis, leading to the accumulation of reactive oxygen species. This condition is associated with premature aging, as well as the progression of several chronic noncommunicable diseases. Among the natural products, geopropolis stands out as a source of molecules with different biological properties. Despite reports of its therapeutic potential, data on the effects on biomolecules and lifespan remains unexplored. Objectives: In this context, we investigated the effects of hydroethanolic geopropolis extracts of Melipona orbignyi and Melipona quadrifasciata anthidioides on in vitro and in vivo protection against oxidative stress, as well as their toxicity and effects on lifespan. Methods: Firstly, we assessed the effect on protein integrity under AAPH-induced oxidative stress and on DNA stability following exposure to hydrogen peroxide and UV radiation. Furthermore, we evaluated the extracts toxicity, protection against juglone-induced oxidative stress and thermal stress, and effects on longevity in a Caenorhabditis elegans preclinical model. Results: In vitro, both extracts protected bovine serum albumin (BSA) from AAPH-induced oxidation, with maximum BSA integrity reaching 98.2 ± 1.8% (HGMO) and 91.7 ± 3.0% (HGMQ). In a UV/H₂O₂ plasmid assay, both extracts protected against oxidative DNA fragmentation across the tested range, achieving 100% protection (fully preserved DNA integrity) at the highest evaluated concentrations. In vivo, HGMO and HGMQ showed no acute toxicity (24–48 h), with survival comparable to controls, and increased survival under juglone-induced oxidative stress (80 µM, 24 h), with maximum viability gains of 37.3% (HGMO) and 23.9% (HGMQ). Both extracts extended lifespan, increasing maximum lifespan from 24 to 32 days (+33%). Conclusions: Overall, these findings support geopropolis extracts as promising candidates for biotechnological products targeting oxidative stress and healthy aging. Full article

(This article belongs to the Special Issue Therapeutic Methods Against Acute and Chronic Diseases and Oxidative Stress)

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23 pages, 1685 KB

Open AccessReview

Current Status and Perspectives of Antibacterial Agents Belonging to 2-Oxazolidinones

by Jessica Ceramella, Annaluisa Mariconda, Domenico Iacopetta, Maria Marra, Alessia Catalano, Paola Checconi, Stefano Aquaro, Carmela Saturnino, Pasquale Longo and Maria Stefania Sinicropi

Pharmaceuticals 2026, 19(3), 432; https://doi.org/10.3390/ph19030432 - 6 Mar 2026

Abstract

In the last three decades, 2-oxazolidinones have emerged as an important class of inhibitors of bacterial protein synthesis, effective in the treatment of multidrug-resistant (MDR) bacterial infections. From a public health perspective, the importance of 2-oxazolidinones is related to the treatment of tuberculosis [...] Read more.

In the last three decades, 2-oxazolidinones have emerged as an important class of inhibitors of bacterial protein synthesis, effective in the treatment of multidrug-resistant (MDR) bacterial infections. From a public health perspective, the importance of 2-oxazolidinones is related to the treatment of tuberculosis (TB), primarily MDR-TB and extensively drug-resistant XDR-TB. Linezolid, the first oxazolidinone antibiotic approved by FDA, is still used in therapy despite common adverse events, such as myelosuppression and serotonergic toxicity, as well as the increasing percentage of linezolid-resistant bacteria (Staphylococcus aureus, enterococci and methicillin-resistant S. aureus). Tedizolid phosphate was the second commercially available oxazolidinone antibiotic approved, followed by other oxazolidinones (contezolid, radezolid, ranbezolid, sutezolid, delpazolid, cadazolid, TBI-233 and MK-7762) that are in clinical study. Contezolid is approved in China and cadazolid has entered phase III clinical trials. This comprehensive review intends to provide an overview of the compounds belonging to this class already in use in therapy and/or clinical studies and to portray the most significant and recent outcomes regarding new oxazolidinones under study. Three literature databases, i.e., PubMed/MEDLINE, Google Scholar and Scopus, were used for the literature search, particularly focusing on the last five years, and screened using different keywords. The design of new drugs belonging to this class may be of considerable interest to researchers and clinicians, contributing to the discovery of new antibiotics that retain antibacterial activity but have fewer side effects. Full article

(This article belongs to the Topic Challenges and Future Prospects of Antibacterial Therapy, 2nd Edition)

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14 pages, 4273 KB

Open AccessArticle

The Senolytic Drug Navitoclax Protects the Brain After Experimental Ischemic Stroke

by Dianoush Falahatgaroshibi, Júlia Baixauli-Martín, María C. Burguete, Mikahela A. López-Morales, Alicia Aliena-Valero, José E. Peris and Juan B. Salom

Pharmaceuticals 2026, 19(3), 431; https://doi.org/10.3390/ph19030431 - 6 Mar 2026

Abstract

Background/Objectives: Senescence has been recently described in brain cells following ischemic stroke. The potential of targeting senescence as an effective therapeutic approach in the treatment of ischemic stroke requires further investigation. This study evaluated the effects of the senolytic drug navitoclax after [...] Read more.

Background/Objectives: Senescence has been recently described in brain cells following ischemic stroke. The potential of targeting senescence as an effective therapeutic approach in the treatment of ischemic stroke requires further investigation. This study evaluated the effects of the senolytic drug navitoclax after experimental ischemic stroke. Methods: Navitoclax was injected into male young Wistar rats at doses of 10 and 30 mg/kg (i.p.). to evaluate its pharmacokinetics, cerebral levels and potential to cause thrombocytopenia. Subsequently, a second group of rats underwent 60 min of transient middle cerebral artery occlusion (tMCAO). Navitoclax (10 mg/kg, i.p.) or vehicle was injected every other day between days 3 and 13 after tMCAO. Neurofunctional performance, infarct size, and senescence markers were assessed on day 14. Results: Navitoclax (10 mg/kg) administration resulted in a maximum plasma concentration of 0.702 mg/L and half-life of 11.33 h. Additionally, a brain concentration of 0.04 ± 0.02 µg/g was detected. Moderate thrombocytopenia was induced by 10 mg/kg, and to a greater extent by 30 mg/kg. Navitoclax (6 × 10 mg/kg) improved neurofunctional impairment, as indicated by significant decrease by 66% in the total time for the tape removal test, and significantly reduced infarct area by 52% when compared to vehicle. Moreover, navitoclax significantly reduced levels of SA-β-gal (by 80%), lipofuscin (by 91%), and Checkpoint kinase 2 (Chk2; by 69%) in the ischemic hemisphere. Conclusions: Navitoclax protects the brain after ischemic stroke by improving neurofunctional outcome and reducing infarct size, which is associated with reducing senescence markers. Although moderate thrombocytopenia warrants caution, targeting senescence emerges as a promising therapeutic strategy for ischemic stroke. Full article

(This article belongs to the Special Issue Ischemic Stroke: Current and Emerging Treatment Strategies)

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20 pages, 2662 KB

Open AccessArticle

Supersaturated Isotretinoin: Scrutiny into Solid States Attributes

by Rana Sejare, Sze Hui Ooi, Xin Yi Teoh, Ahmed Bassam Farhan and Siok Yee Chan

Pharmaceuticals 2026, 19(3), 430; https://doi.org/10.3390/ph19030430 - 6 Mar 2026

Abstract

Background/Objectives: The formulation development of Isotretinoin (ISN) is limited by its solubility and stability issues. This study aimed to characterise the BCS class II drug ISN, particularly the possible different solid state and formulate amorphous solid dispersion aiming for a supersaturation state. [...] Read more.

Background/Objectives: The formulation development of Isotretinoin (ISN) is limited by its solubility and stability issues. This study aimed to characterise the BCS class II drug ISN, particularly the possible different solid state and formulate amorphous solid dispersion aiming for a supersaturation state. Methods: ISN’s physical states are investigated in its raw form, quench-cooled form, physical mixture with the polymer and corresponding solid dispersion form. Quench-cooled ISN was prepared in situ using DSC. Carrier stabilisation of ISN was attempted using the solid dispersion technique. Hereby, the solid dispersion of drug-polymer PVPVA at a ratio of 1:3 was prepared using the solvent evaporation method. Solid dispersion, physical mixture and raw ISN were characterised for the saturated solubility. Physical characterisation of the samples was performed using DSC, ATR-FTIR and a light microscope. Results: Two polymorphs of ISN (forms I and II) were found in the raw ISN, with form II being thermodynamically more stable. ISN possesses strong crystallinity and resistance to amorphisation under the applied quench-cooling condition without the presence of a carrier system. The conjugated polyene structure in ISN contributes to the polymorphic transformation and isomerisation. The incorporation of PVPVA in the solid dispersion system successfully improved the water solubility (sixfold) of ISN despite a combination of crystalline and amorphous components being present in the system. Conclusions: ISN is a class II drug crystal molecule. Taking advantage of solubility and possibility in the polymorphic transformation of ISN in a binary system, we concluded that ISN could potentially be formulated into its corresponding crystalline solid dispersion form. Full article

(This article belongs to the Section Pharmaceutical Technology)

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16 pages, 1959 KB

Open AccessArticle

Selective Anticancer Effects of a P-I Metalloproteinase from Bothrops Moojeni Snake Venom (BthMP) on Lung Cancer Cells

by Vinícius Queiroz Oliveira, Luísa Carregosa Santos, Leonardo Oliveira Silva Bastos Andrade, Lucas Miranda Marques, Amélia Cristina Mendes de Magalhães Gusmão, Thiago Macedo Lopes Correia, Samuel Cota Teixeira, Eloisa Amália Vieira Ferro, Veridiana de Melo Rodrigues, Sarah Natalie Cirilo Gimenes, Mônica Colombini, Patricia Bianca Clissa, Sabri Saeed Sanabani and Daiana Silva Lopes

Pharmaceuticals 2026, 19(3), 428; https://doi.org/10.3390/ph19030428 - 6 Mar 2026

Abstract

Background: Lung cancer remains a leading cause of mortality, mainly due to aggressive metastasis and therapeutic resistance. Snake venom metalloproteinases (svMPs), particularly the P-I class, are promising sources for novel antitumor agents. Objectives: This study investigated the impacts of BthMP, a P-I svMPs [...] Read more.

Background: Lung cancer remains a leading cause of mortality, mainly due to aggressive metastasis and therapeutic resistance. Snake venom metalloproteinases (svMPs), particularly the P-I class, are promising sources for novel antitumor agents. Objectives: This study investigated the impacts of BthMP, a P-I svMPs from Bothrops moojeni venom, on human lung carcinoma (A549) cells in comparison to non-cancerous human bronchial epithelial cells (BEAS-2B). Methods and Results: BthMP demonstrated potent and selective anti-cancer activity. It significantly inhibited key metastatic processes in A549 cells, including adhesion, migration, and invasion, while suppressing long-term proliferation, as shown by reduced colony formation and increased lactate dehydrogenase (LDH) release. Mechanistically, BthMP induced a massive increase in intracellular reactive oxygen species (ROS) by over 2000% and elevated nitric oxide (NO) by 35% in A549 cells, driving a state of lethal oxidative stress. Crucially, these cytotoxic and anti-metastatic effects were minimal in BEAS-2B cells; BthMP even suppressed basal ROS and NO levels in this non-cancerous line. The anti-migratory effects of BthMP were completely dependent on its zinc-based catalytic activity, as they were abolished by pretreatment with ethylenediaminetetraacetic acid. By simultaneously disrupting cell–matrix interactions and inducing selective, catastrophic oxidative stress in cancer cells, BthMP presents a dual-pronged anti-metastatic mechanism. Conclusions: These findings establish BthMP as a promising therapeutic scaffold for developing novel treatments against lung cancer progression. Full article

(This article belongs to the Section Natural Products)

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29 pages, 1229 KB

Open AccessReview

Structural Modification of Selected Essential Oil Components for Potential Anticancer Applications: A Review

by Vuyolwethu Khwaza and Vuyani Maqanda

Pharmaceuticals 2026, 19(3), 427; https://doi.org/10.3390/ph19030427 - 5 Mar 2026

Abstract

Monoterpenes (thymol, carvacrol, menthol) and phenylpropanoids (eugenol and cinnamaldehyde) and their related derivatives are naturally occurring bioactive compounds found in essential oils (EOs) and have attracted considerable interest as anticancer agents; however, their direct therapeutic use in cancer treatment is often limited by [...] Read more.

Monoterpenes (thymol, carvacrol, menthol) and phenylpropanoids (eugenol and cinnamaldehyde) and their related derivatives are naturally occurring bioactive compounds found in essential oils (EOs) and have attracted considerable interest as anticancer agents; however, their direct therapeutic use in cancer treatment is often limited by factors such as low bioavailability, moderate potency, and lack of target specificity. Recent studies have demonstrated that rational structural modification of these EO scaffolds can substantially enhance their anticancer potential. This review critically evaluates the different structural modification strategies applied to EO components, including pharmacophore hybridization, heterocycle incorporation (e.g., triazoles, oxadiazoles, chalcones), esterification, halogenation, metal complexation, and nanoparticle conjugation. The review compares these approaches across the selected EO components, highlighting their impact on anticancer potency, and mechanistic relevance. However, the current evidence base is heterogeneous, with considerable variability in experimental conditions, selectivity assessments, and reliance on in vitro or in silico findings, which limits direct cross-study comparisons and translational interpretation. Overall, structural modification of EO components represents a promising strategy for generating novel anticancer lead compounds, but future progress will depend on standardized biological evaluation, rigorous in vivo validation, and comprehensive pharmacokinetic and toxicity profiling to realistically define their clinical potential. Full article

(This article belongs to the Special Issue Natural Products for Therapeutic Potential)

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24 pages, 10139 KB

Open AccessArticle

7-Prenyloxycoumarins as Promising Antileishmanial Agents: In Vitro, In Vivo, and In Silico Evaluation Against Leishmania amazonensis

by Dirlei Nico, Daniel Clemente de Moraes, Anna Claudia Silva, Igor Nunes Taveira, Yasmin da Silva Fontes, Rosangela Sabbatini Capella Lopes, Cláudio Cerqueira Lopes and Antonio Ferreira-Pereira

Pharmaceuticals 2026, 19(3), 426; https://doi.org/10.3390/ph19030426 - 5 Mar 2026

Abstract

Background/Objectives: Leishmaniasis remains a major neglected tropical disease, and current chemotherapeutic options are limited by toxicity and resistance in Leishmania species, including L. amazonensis. Prenylated coumarins have emerged as promising bioactive scaffolds. Altissimacoumarin D and its analogues inhibit fungal efflux pumps associated [...] Read more.

Background/Objectives: Leishmaniasis remains a major neglected tropical disease, and current chemotherapeutic options are limited by toxicity and resistance in Leishmania species, including L. amazonensis. Prenylated coumarins have emerged as promising bioactive scaffolds. Altissimacoumarin D and its analogues inhibit fungal efflux pumps associated with resistance. However, their antileishmanial potential and mechanisms of action remain unclear. Here, we evaluated the in vitro, in vivo, and in silico effects of altissimacoumarin D and seven analogues against L. amazonensis. Methods: In vitro assays were performed to identify active compounds and assess toxicity in keratinocytes. In vivo experiments in hamsters evaluated antileishmanial activity and renal and hepatic toxicity. In silico analyses were conducted to investigate the mechanism of action of the substances. Results: In vitro assays showed that ACS47, ACS48, and ACS51 were the most active and safe compounds. In a hamster infection model, daily administration of ACS47 and ACS48 (2.5 mg/kg) significantly reduced parasite burden and lesion size, while maintaining normal renal and hepatic biochemical parameters. Histological analysis correlated reduced lesion size with marked decreases in amastigote density. Based on in silico analysis, spermidine synthase was supported as a plausible molecular target. Conclusions: Collectively, these findings identify ACS47 and ACS48 as promising lead compounds for future antileishmanial drug development. Full article

(This article belongs to the Special Issue Pharmacological Treatments for Parasitic Diseases)

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16 pages, 1118 KB

Open AccessReview

Clinical Evidence on the Use of Propolis for Oral Mucositis

by Matheus de Morais Assis, Barbara Hana Silva Morales Pino, Larissa Kaori Maquedano, Felipe Gustavo Carvalho, Fernando Augusto Lima Marson and Giovanna Barbarini Longato

Pharmaceuticals 2026, 19(3), 425; https://doi.org/10.3390/ph19030425 - 5 Mar 2026

Abstract

Cancer represents a major global public health challenge, and its treatments, such as chemotherapy and radiotherapy, are frequently associated with adverse effects. Among these, oral mucositis (OM) stands out as a debilitating inflammatory condition that compromises quality of life and may lead to [...] Read more.

Cancer represents a major global public health challenge, and its treatments, such as chemotherapy and radiotherapy, are frequently associated with adverse effects. Among these, oral mucositis (OM) stands out as a debilitating inflammatory condition that compromises quality of life and may lead to interruption of cancer therapy. Given the limited efficacy of conventional treatments, propolis has been investigated as a natural therapeutic alternative due to its antioxidant, anti-inflammatory, and antimicrobial properties. This narrative literature review, conducted between 2012 and 2025, included studies indexed in the Public Medical Database (PubMed), Scientific Electronic Library Online (SciELO), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Google Scholar, and ClinicalTrials.gov databases. We analyzed clinical trials that evaluated different forms of propolis administration, such as gel, mouthwashes, oral solutions, and topical applications, in patients with various types of cancer undergoing radiotherapy, chemotherapy, or combined treatment. The results demonstrated a significant reduction in pain, dysphagia, dysgeusia, and OM severity, as well as a delay in the onset and progression of lesions, with a low incidence of adverse effects. However, variability in the chemical composition of propolis and the lack of standardized protocols still limit the reproducibility and comparability of the findings. Overall, these results reinforce the therapeutic potential of propolis for the prevention and treatment of OM in oncology patients, while underscoring the need for long-term, randomized clinical trials to establish optimal concentrations, pharmacological formulations, and standardized application protocols. Full article

(This article belongs to the Special Issue Applications of Beehive Products for Wound Repair and Skin Care)

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27 pages, 3106 KB

Open AccessArticle

Preparation and Investigation of Artemisia annua L.-Loaded Alginate Hydrogels with Excipients

by Boglárka Papp, Zsolt Szűcs, Sándor Gonda, Zoltán Cziáky, Richárd Kajtár, István Lekli, Ádám Haimhoffer, Ágnes Klusóczki, Liza Józsa, Ágota Pető, Nodirali S. Normakhamatov, Zoltán Ujhelyi, Ildikó Bácskay and Pálma Fehér

Pharmaceuticals 2026, 19(3), 424; https://doi.org/10.3390/ph19030424 - 5 Mar 2026

Abstract

Background: Artemisia annua L. is a medicinal plant with documented antimicrobial, antioxidant, and anti-inflammatory properties. Although widely studied for internal therapeutic applications, its topical use—especially in hydrogel-based systems—has not been thoroughly investigated. The aim of this study was to develop sodium alginate [...] Read more.

Background: Artemisia annua L. is a medicinal plant with documented antimicrobial, antioxidant, and anti-inflammatory properties. Although widely studied for internal therapeutic applications, its topical use—especially in hydrogel-based systems—has not been thoroughly investigated. The aim of this study was to develop sodium alginate hydrogels containing Artemisia annua extract, supplemented with hyaluronic acid and dexpanthenol, and to evaluate their physicochemical characteristics as well as their biological activities in vitro and in vivo. Methods: Select bioactive constituents of the Artemisia annua extract were quantified using liquid chromatography coupled with electrospray ionization mass spectrometry (LC-ESI-MS). Hydrogels were prepared by cross-linking sodium alginate with a calcium carbonate–glucono-delta-lactone system and were formulated with or without hyaluronic acid and dexpanthenol. Physicochemical evaluations included measurements of moisture content, water-retention capacity, gelation time, and pH. The hydrogel microstructure was examined by scanning electron microscopy (SEM). Antioxidant activity was assessed using three methods: the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, the ferric reducing antioxidant power (FRAP) assay, and the cupric reducing antioxidant capacity (CUPRAC) assay. Biocompatibility and regenerative effects were analyzed using cell viability assays and an in vitro scratch wound model on human keratinocyte cells. In vivo wound-healing efficacy was examined in rats with full-thickness skin excisions. Results: The extract contained high levels of methylated flavonoids and sesquiterpenes characteristic of Artemisia annua. Hydrogels supplemented with hyaluronic acid and dexpanthenol exhibited improved hydration stability and higher porosity. All formulations demonstrated measurable antioxidant activity, and those containing hyaluronic acid showed the strongest effects. The preparations were biocompatible and enhanced keratinocyte migration in vitro, with the combined hyaluronic acid–dexpanthenol formulation promoting the fastest wound closure. In vivo, Artemisia annua hydrogels accelerated wound healing by two to three days compared with untreated wounds. Conclusions: These results confirm the promise of Artemisia annua hydrogels for topical wound care and highlight the beneficial contributions of hyaluronic acid and dexpanthenol to their structural and therapeutic performance. Full article

(This article belongs to the Special Issue Natural Products for Skin Applications)

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14 pages, 816 KB

Open AccessArticle

Preliminary Evidence on the Efficacy and Tolerability of Quetiapine in Dual Disorders: A Prospective, Multicentric, Real-World Study

by Alessio Mosca, Clara Cavallotto, Stefania Chiappini, Giacomo d’Andrea, Francesco Di Carlo, Carlotta Marrangone, Rita Allegretti, Nicola Ciraselli, Maria Pepe, Luigi Dattoli, Beatrice Petrosino, Andrea Di Cesare, Valerio Ricci, Marco Di Nicola, Mauro Pettorruso and Giovanni Martinotti

Pharmaceuticals 2026, 19(3), 423; https://doi.org/10.3390/ph19030423 - 5 Mar 2026

Abstract

Background: Dual disorders (DDs) describe the coexistence of substance use disorder (SUD) and another mental health condition, commonly within psychotic and affective categories. These conditions represent a significant challenge in clinical management due to their bidirectional interactions and complexity. This study aims [...] Read more.

Background: Dual disorders (DDs) describe the coexistence of substance use disorder (SUD) and another mental health condition, commonly within psychotic and affective categories. These conditions represent a significant challenge in clinical management due to their bidirectional interactions and complexity. This study aims to evaluate the efficacy and safety of quetiapine, a second-generation antipsychotic, in patients with schizophrenia spectrum disorders and comorbid substance use disorders. Methods: A total of 28 participants with schizophrenia spectrum disorder and comorbid SUD underwent psychometric evaluations at baseline (T0), one month (T1) and three months post-initiation of quetiapine treatment (T2), administered at a mean dosage of 165 mg/day. Key outcome measures included psychopathological burden (PANSS), aggressivity (MOAS), substance craving (VAS Craving), and quality of life (Q-LES-Q-SF scales). Results: Quetiapine demonstrated significant reductions in psychopathological symptoms, with decreased PANSS total scores (p < 0.001). Positive symptoms (p < 0.001), negative symptoms (p = 0.002), substance craving (p = 0.001), and aggressivity (p = 0.006) also showed notable reductions. Quality of life significantly improved across Q-LES-Q-SF scores (p < 0.001). Quetiapine was well-tolerated, with no dropouts related to drug-induced side effects. Conclusions: This study provides preliminary evidence supporting the efficacy and safety of quetiapine in individuals with dual disorders. Improvements in psychopathology, substance craving, and quality of life underscore the importance of integrating tailored and comprehensive treatment strategies to address the multifaceted challenges of this challenging population. Full article

(This article belongs to the Special Issue Clinical Advances in the Neuropharmacological Treatment of Substance Use Disorders: 2nd Edition)

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20 pages, 1163 KB

Open AccessArticle

Novel 8-trifluoromethylquinobenzothiazines—Synthesis and Evaluation for Antiproliferative and Antibacterial Activity

by Daria Klimoszek, Anna Majewska, Małgorzata Jeleń, Marta Struga, Beata Morak-Młodawska and Małgorzata Dołowy

Pharmaceuticals 2026, 19(3), 422; https://doi.org/10.3390/ph19030422 - 4 Mar 2026

Abstract

Background: Phenothiazine derivatives bearing trifluoromethyl substituents have attracted increasing interest as multifunctional scaffolds in drug repositioning strategies, particularly in cancer and infectious diseases. Structural modification of classical phenothiazines by incorporation of a quinoline moiety has previously been shown to enhance biological activity. [...] Read more.

Background: Phenothiazine derivatives bearing trifluoromethyl substituents have attracted increasing interest as multifunctional scaffolds in drug repositioning strategies, particularly in cancer and infectious diseases. Structural modification of classical phenothiazines by incorporation of a quinoline moiety has previously been shown to enhance biological activity. Objectives: The present study aimed to develop an efficient synthesis of 8-trifluoromethylquinobenzothiazines and to evaluate the anticancer and antibacterial potential of their N-substituted analogues inspired by triflupromazine, trifluoperazine, and fluphenazine. Methods: 6H-8-Trifluoromethylquinobenzothiazine was synthesized by cyclization of 2-amino-4-trifluoromethylbenzenethiol and 3-bromo-2-chloroquinoline. The resulting quinobenzothiazine, unsubstituted at the nitrogen atom, was subjected to N-alkylation reactions to afford eleven new 6-dialkylaminoalkyl derivatives. Structural elucidation was performed using NMR and HRMS techniques. Anticancer activity was evaluated by MTT assay against human breast (MDA-MB-231), pancreatic (Mia-PaCa-2), and lung (A-549) carcinoma cell lines, as well as normal HaCaT keratinocytes. Antibacterial activity was assessed by MIC/MBC determination against selected Gram-positive and Gram-negative reference strains and clinical isolates. Results: Among the synthesized compounds, derivatives 8 and 12 exhibited the most favorable anticancer profiles, showing micromolar cytotoxicity (IC₅₀ ≈ 4–10 µM) against lung and pancreatic cancer cells combined with moderate selectivity toward cancer cells over normal keratinocytes. Compound 6 displayed lower cytotoxic potency but a notably high selectivity index due to minimal toxicity toward normal cells. In antibacterial assays, compound 3 exhibited activity against Gram-positive bacteria, including a methicillin-resistant Staphylococcus aureus isolate, with MIC values ranging from 7.8 to 15.6 µg/mL. The corresponding MBC values were equal to or twofold higher than the MICs (MBC/MIC = 1–2), fulfilling commonly accepted criteria for bactericidal activity (MBC/MIC ≤ 4). OD-based growth kinetics confirmed concentration-dependent inhibition of S. aureus growth. Conclusions: The obtained results identify 8-trifluoromethylquinobenzothiazines as a promising class of multifunctional compounds. Selected derivatives combine anticancer activity with acceptable selectivity or display potent antibacterial effects against clinically relevant Gram-positive pathogens. Full article

(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)

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20 pages, 3887 KB

Open AccessArticle

Safety Assessment of the Ethanolic Seed Extract of Mucuna pruriens var. pruriens: Acute and Chronic Oral Toxicity Studies in Sprague–Dawley Rats

by Supaporn Intatham, Kanjana Jaijoy, Sunee Chansakaow and Seewaboon Sireeratawong

Pharmaceuticals 2026, 19(3), 421; https://doi.org/10.3390/ph19030421 - 4 Mar 2026

Abstract

Background/Objectives: Mucuna pruriens (Linn.) DC. var. pruriens is a leguminous plant whose seeds have been used in traditional medicine, including for the enhancement of sexual function. However, scientific evidence regarding its toxicological safety remains limited. Accordingly, the present study aimed to investigate [...] Read more.

Background/Objectives: Mucuna pruriens (Linn.) DC. var. pruriens is a leguminous plant whose seeds have been used in traditional medicine, including for the enhancement of sexual function. However, scientific evidence regarding its toxicological safety remains limited. Accordingly, the present study aimed to investigate the acute and chronic oral toxicity of the ethanolic seed extract of M. pruriens var. pruriens in Sprague–Dawley rats. Methods: Acute oral toxicity was assessed in female rats following a single oral administration of the ethanolic seed extract of M. pruriens var. pruriens at a dose of 5000 mg/kg body weight, with animals monitored for general behavior, clinical signs, and mortality over a 14-day period. Chronic oral toxicity was evaluated in female and male rats administered the ethanolic seed extract of M. pruriens var. pruriens at doses of 100, 500, and 2500 mg/kg body weight daily for 270 days. Animals were monitored for general behavior, clinical signs, and health status throughout the study. Hematological, blood chemistry, gross pathological, and histopathological assessments were conducted at study termination. Results: In the acute oral toxicity study, no mortality or treatment-related behavioral abnormalities or clinical signs were observed in female rats receiving the ethanolic seed extract of M. pruriens var. pruriens, and findings were comparable to those of the control group. In the chronic oral toxicity study, no mortality occurred in any treatment group. Although statistically significant increases or decreases were observed in certain body weight, organ weight, hematological, and blood biochemical parameters compared with the control group, all values remained within established reference ranges. When considered together with the absence of abnormal behavioral changes, clinical signs, and gross pathological or histopathological alterations in major organs, these findings indicate that long-term oral administration of the ethanolic seed extract of M. pruriens var. pruriens did not result in chronic toxicity. Conclusions: The ethanolic seed extract of M. pruriens var. pruriens did not produce acute or chronic oral toxicity in Sprague–Dawley rats. Nevertheless, further clinical investigations are recommended to confirm its long-term safety for human use. Full article

(This article belongs to the Special Issue Plant-Derived Natural Compounds as Bioactive Molecules with Beneficial Effects on Human Health, 2nd Edition)

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23 pages, 2173 KB

Open AccessArticle

Thiazole as a Promising Scaffold for the Treatment of Schistosomiasis: In Vitro and In Vivo Activity Against Different Developmental Stages of Schistosoma mansoni

by João Victor Ritinto da Rocha, Wilza Wanessa Melo França, Arthur Lessa Machado, Lucas Andrade Oliveira Cavalcante, Maria Tairla Viana Gonçalves, Thierry Wesley de Albuquerque Aguiar, Diego Santa Clara Marques, Pedro Henrique do Bomfim Nascimento, Hallysson Douglas Andrade de Araújo, Iranildo José da Cruz Filho, Maria do Carmo Alves de Lima and André de Lima Aires

Pharmaceuticals 2026, 19(3), 420; https://doi.org/10.3390/ph19030420 - 4 Mar 2026

Abstract

Background: Schistosomiasis affects more than 250 million people, and praziquantel remains the only drug available for treatment; however, its activity is restricted to adult worms. Previously, our group evaluated six thiazole derivatives (PBT1–PBT6) in vitro against adult Schistosoma [...] Read more.

Background: Schistosomiasis affects more than 250 million people, and praziquantel remains the only drug available for treatment; however, its activity is restricted to adult worms. Previously, our group evaluated six thiazole derivatives (PBT1–PBT6) in vitro against adult Schistosoma mansoni, identifying PBT2, PBT5, and PBT6 as the most active compounds. The present study aimed to evaluate the in vitro activity of PBT2, PBT5, and PBT6 against schistosomula and juvenile worms, as well as their in vivo efficacy against adult S. mansoni. Methods: Mechanically transformed schistosomula and juvenile worms recovered from mice (21 days post-infection) were incubated with the compounds (12.5–200 μM). Cytotoxicity was assessed using murine splenocytes and peritoneal macrophages exposed to the same concentration range. For in vivo evaluation, infected mice were orally treated with compounds (50, 100, or 200 mg/kg) for five consecutive days. Results: All compounds induced 100% mortality in schistosomula and juvenile worms within 3 h of exposure at 100 and 200 μM. Parasite cell viability was markedly reduced (>90%) at concentrations between 50 and 200 μM. The LC₅₀ values ranged from 15.3 to 30.9 μM for schistosomula and from 27.8 to 34.9 μM for juvenile worms, with low cytotoxicity observed in mammalian cells (CC₅₀ ≥ 193.9 μM). In vivo treatment resulted in significant reductions in fecal egg counts (~80% at 200 mg/kg), total worm burden (~60%), and egg loads in liver and intestinal tissues, in addition to an increased proportion of dead eggs in the intestine. Conclusions: The evaluated thiazole derivatives demonstrated potent in vitro activity against immature stages of S. mansoni and significant in vivo efficacy against adult parasites, accompanied by favorable changes in key parasitological parameters. These findings reinforce the potential of thiazole-based compounds as promising multistage schistosomicidal candidates. Full article

(This article belongs to the Special Issue Advances in Antiparasitic Drug Research)

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26 pages, 2847 KB

Open AccessArticle

Adiponectin Inhibits Oxidative Stress and Tight Junction Protein Loss: Evidence from a Hepatic Encephalopathy Mouse Model and Brain Endothelial Cells

by Dong Jun Song, Seol Won Jeong, Seoyeon Ahn, Danbi Jo, Che-Hun Jung, Jiwoun Park, Sangjun Lee and Juhyun Song

Pharmaceuticals 2026, 19(3), 419; https://doi.org/10.3390/ph19030419 - 4 Mar 2026

Abstract

Background/Objectives: Hepatic encephalopathy (HE) is characterized by hyperammonemia, neuroinflammation, oxidative stress, and blood–brain barrier (BBB) dysfunction, with brain endothelial cells being highly vulnerable to ammonia-induced damage. Adiponectin is a cytoprotective adipokine that may enhance endothelial resilience; however, its specific role under hyperammonemic [...] Read more.

Background/Objectives: Hepatic encephalopathy (HE) is characterized by hyperammonemia, neuroinflammation, oxidative stress, and blood–brain barrier (BBB) dysfunction, with brain endothelial cells being highly vulnerable to ammonia-induced damage. Adiponectin is a cytoprotective adipokine that may enhance endothelial resilience; however, its specific role under hyperammonemic conditions remains unclear. This study aims to investigate the protective effects of adiponectin on brain endothelial function and BBB integrity. Methods: In vivo, male C57BL/6J mice underwent bile duct ligation (BDL) surgery and received daily intraperitoneal adiponectin injections (10 μg/kg/day) for 6 days, starting 5 days post-surgery. On day 11, brain tissues and serum were collected for molecular and cytokine analyses. In vitro, mouse brain endothelial cells (bEnd.3) were pretreated with adiponectin before exposure to ammonia. Assays for tight junction preservation, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and total RNA sequencing were performed. Results: In BDL mice, adiponectin increased the expression of the tight junction protein claudin-5 and synaptic marker PSD95 across the cortex, hippocampus, and striatum, while reducing pro-oxidant (Cyp2e1, Cyp4a1) and apoptotic (Caspase-9) markers. In vitro, adiponectin pretreatment maintained tight junction proteins, suppressed inflammatory markers, restored mitochondrial membrane potential, and decreased ROS generation in ammonia-exposed bEnd.3 cells. Transcriptomic profiling revealed that adiponectin modulates stress-related gene expression under hyperammonemic conditions. Conclusions: Adiponectin enhances cellular stress resistance and maintains BBB structural integrity under ammonia-induced toxicity. These findings suggest that adiponectin serves as a promising therapeutic target for mitigating neurovascular unit dysfunction in hepatic encephalopathy. Full article

(This article belongs to the Section Medicinal Chemistry)

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17 pages, 1812 KB

Open AccessArticle

Exploration of Novel Indole Compounds with Potential Activity Against Breast Cancer: Synthesis, Characterization and Anti-Cancer Activity Evaluation

by Eid E. Salama, Ashtar A. Alrayes, Saad Alrashdi, Ahmed T. A. Boraei, Nagwa I. Ahmed, Salah Eid, Karam S. El-Nasser, Haitham Kalil and Ahmed A. M. Sarhan

Pharmaceuticals 2026, 19(3), 418; https://doi.org/10.3390/ph19030418 - 4 Mar 2026

Abstract

Background/Objectives: Cancer remains one of the most significant challenges in modern medicine, requiring the continuous development of novel molecular scaffolds with anticancer potential that act through multiple pathways. Heterocyclic compounds incorporating indole, triazole, oxadiazole, and thiadiazine motifs have attracted considerable attention due to [...] Read more.

Background/Objectives: Cancer remains one of the most significant challenges in modern medicine, requiring the continuous development of novel molecular scaffolds with anticancer potential that act through multiple pathways. Heterocyclic compounds incorporating indole, triazole, oxadiazole, and thiadiazine motifs have attracted considerable attention due to their diverse pharmacological activities. This study aimed to design, synthesize, and evaluate new hybrid heterocyclic systems, including 1,2,4-triazole, 1,3,4-oxadiazole, and thiadiazine motifs, targeting liver and breast cancer. Methods: A series of indolyl-based heterocyclic compounds was synthesized using efficient and environmentally friendly protocols. Indolyl-triazol-thiadiazin-6-ol 5 was prepared via solvent-free fusion of esters 2 and 3 or the corresponding acid 4. Oxadiazole derivatives were produced by reacting hydrazide intermediates with carbon disulfide. Triazole derivatives were synthesized via cylization of thiosemicarbazide 9 in aqueous KOH (4.0 N). Structural characterization was performed using Fourier Transform InfraRed (FTIR), ¹H and ¹³C NMR spectroscopy, and electron impact mass spectrometry (EIMS). Cytotoxic activity was evaluated against liver and breast cancer cell lines, and VEGFR-2 kinase inhibition was assessed for selected derivatives. Results: The synthesized compounds demonstrated notable cytotoxicity activity, with compounds 4, 5, and 9 exhibiting IC₅₀ values in the low micromolar range. Enzymatic assays revealed that compounds 4 and 9 showed strong VEGFR-2 inhibition (97.9% and 96.4%, respectively), indicating apoptosis-inducing effects. Conclusions: The synthesized indolyl-based hybrid heterocycles represent a promising chemotype with in vitro cytotoxic activity and VEGFR-2 inhibitory effects, supporting further investigation, optimization, and mechanistic studies to evaluate their potential lead for anticancer drug development. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 891 KB

Open AccessSystematic Review

Advanced Medical Therapies for Perianal Fistulizing Crohn’s Disease: A Systematic Review of Clinical, Radiological, Surgical, and Composite Outcomes

by Fares Jamal, Tayo Segun-Omosehin, Taylor Viggiano, Hamza Khan, Alejandro J. Gonzalez, Geoff Thomas, Sandra Elmasry and Talha A. Malik

Pharmaceuticals 2026, 19(3), 417; https://doi.org/10.3390/ph19030417 - 4 Mar 2026

Abstract

Background: Perianal fistulizing Crohn’s disease (CD) is associated with significant morbidity and remains difficult to treat. Although advanced medical therapies are widely used, much of the available evidence derives from heterogeneous fistula populations or luminal CD trials, with limited perianal-specific synthesis and [...] Read more.

Background: Perianal fistulizing Crohn’s disease (CD) is associated with significant morbidity and remains difficult to treat. Although advanced medical therapies are widely used, much of the available evidence derives from heterogeneous fistula populations or luminal CD trials, with limited perianal-specific synthesis and inconsistent outcome definitions. We conducted a systematic review focusing exclusively on perianal-specific clinical, radiologic, and composite outcomes in adults with perianal fistula (PAF) CD. Methods: We performed a systematic review in accordance with PRISMA 2020. Electronic databases were searched from inception through November 2025. We included randomized controlled trials and cohort studies enrolling adults with CD reporting outcomes specific to PAF. Interventions included biologics and small-molecule therapies, compared with placebo or other therapies. Due to substantial heterogeneity in outcome definitions and study designs, a meta-analysis was not performed. Risk of bias was assessed using Risk of Bias 2 (RoB 2) for randomized trials and the Newcastle–Ottawa Scale for observational studies. Results: Seven studies including >1200 participants with PAF-CD met inclusion criteria. Follow-up ranged from 24 weeks to 5 years. Across studies, outcome definitions and assessment modalities varied. Upadacitinib demonstrated significantly higher clinical fistula closure compared with placebo across multiple dose regimens at 52 weeks. In observational comparisons, ustekinumab and vedolizumab were associated with higher clinical closure rates than anti-TNF therapies. However, infliximab demonstrated higher closure rates than adalimumab as a first-line treatment. The definition for radiologic remission was less consistent across studies and often did not parallel clinical outcomes. Composite clinical–radiologic remission and response were reported in a limited number of studies, with filgotinib showing higher composite outcomes in comparison to placebo in a phase 2 trial. Surgical interventions, relapse outcomes, biomarkers [C-reactive protein (CRP)/fecal calprotectin (FCP)], and patient-reported outcomes were variably reported and not consistently significant across comparisons. Conclusions: Evidence for advanced therapies in PAF CD remains limited by heterogeneity in endpoint definitions, subjectivity in clinical observation, inconsistent radiologic reporting, and reliance on subgroup or observational comparisons. While anti-TNF therapy remains the most established option in guidelines, emerging data suggest significant benefits with ustekinumab, vedolizumab, and JAK inhibitors in selected patients. There is a need for PAF-specific, adequately powered randomized trials using standardized composite clinical and radiologic endpoints. Full article

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21 pages, 1719 KB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of N,N-Diphenylaniline-Based Derivatives as Antiproliferative Agents and ABL TK Inhibitors Against CML

by Belgin Sever and Halilibrahim Ciftci

Pharmaceuticals 2026, 19(3), 416; https://doi.org/10.3390/ph19030416 - 4 Mar 2026

Abstract

Background/Objectives: Targeting ABL tyrosine kinase (TK) remains a cornerstone of chronic myeloid leukemia (CML) therapy. Methods: In this study, a series of novel 4-((2-(4-(aryl)thiazol-2-yl)hydrazineylidene)methyl)-N,N-diphenylaniline derivatives (1–12) were synthesized through the reaction of 2-(4-(diphenylamino)benzylidene)hydrazine-1-carbothioamide (intermediate A) [...] Read more.

Background/Objectives: Targeting ABL tyrosine kinase (TK) remains a cornerstone of chronic myeloid leukemia (CML) therapy. Methods: In this study, a series of novel 4-((2-(4-(aryl)thiazol-2-yl)hydrazineylidene)methyl)-N,N-diphenylaniline derivatives (1–12) were synthesized through the reaction of 2-(4-(diphenylamino)benzylidene)hydrazine-1-carbothioamide (intermediate A) with substituted 2-bromo-1-arylethanones. Cytotoxic activity was evaluated in K562 CML cells using the MTT assay. The most active compound was further assessed in HL-60 acute myeloid leukemia (AML) cells and healthy peripheral blood mononuclear cells (PBMCs). Apoptosis induction was analyzed by Annexin V/ethidium homodimer staining, while ABL TK inhibition was determined using the ADP-Glo kinase assay. Molecular docking studies were performed to investigate binding interactions within the ATP-binding site of ABL TK, and pharmacokinetic properties were also predicted. Results: Intermediate A demonstrated superior antiproliferative activity compared to derivatives 1–12 and exhibited cytotoxicity comparable to imatinib in K562 cells (IC₅₀ = 6.15 ± 1.26 µM vs. 5.14 ± 1.44 µM, respectively). In HL-60 cells, intermediate A showed an IC₅₀ of 12.04 ± 1.70 µM, similar to imatinib. Notably, intermediate A displayed enhanced selectivity toward K562 cells over PBMCs (SI = 12.9) relative to imatinib (SI = 6.2). The compound significantly induced apoptosis in K562 cells and inhibited ABL TK activity. Docking studies revealed a distinct binding orientation within the ATP-binding pocket of ABL TK. The compound showed acceptable predicted physicochemical and ADME characteristics based on in silico analysis. Conclusions: Intermediate A emerges as a significant anti-CML candidate exhibiting potent cytotoxic, apoptotic, and moderate ABL TK inhibitory activity, together with a favorable selectivity profile. Full article

(This article belongs to the Special Issue Structural and Computationally Driven Molecule Design in Drug Discovery: 2nd Edition)

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31 pages, 3576 KB

Open AccessArticle

Stratified Therapeutic Drug Monitoring Could Potentially Improve the Efficacy and Safety of Oxcarbazepine in Children with Epilepsy: Novel Insights from a Single-Center, Large-Sample, Retrospective Real-World Study

by Yi-Jing Liu, Xi-Li Sun, Yue Li, Xiao-Peng Lu, Chun-Feng Wu, Hu Guo and Feng Chen

Pharmaceuticals 2026, 19(3), 415; https://doi.org/10.3390/ph19030415 - 3 Mar 2026

Abstract

Objective: This study aimed to characterize the population exposure, efficacy, and safety profiles of oxcarbazepine (OXC) in Chinese children with epilepsy using real-world data, define its optimal therapeutic range, and inform individualized therapy. Methods: This single-center retrospective cohort study included pediatric [...] Read more.

Objective: This study aimed to characterize the population exposure, efficacy, and safety profiles of oxcarbazepine (OXC) in Chinese children with epilepsy using real-world data, define its optimal therapeutic range, and inform individualized therapy. Methods: This single-center retrospective cohort study included pediatric patients (<18 years) who received OXC therapy between September 2021 and August 2024, with follow-up continuing until February 2025. The concentration of the active metabolite 10,11-dihydro-10-hydroxycarbamazepine (MHD) in plasma was monitored. A mixed-effects model identified factors influencing MHD exposure. Logistic regression and Cox proportional hazards models were used to analyze the concentration–efficacy relationship, while Kaplan–Meier and time-to-onset analyses were performed to characterize adverse events. Results: Among 824 included patients (1976 concentration samples), body weight, age, treatment duration, and epilepsy type significantly influenced MHD’s exposure levels. The 12-month overall response rate was higher in monotherapy than add-on therapy (82.9% vs. 60.4%). A plasma MHD concentration ≥ 10 μg/mL was identified as a critical “risk transition point” for treatment failure (PSM-adjusted OR = 2.42, p < 0.001). Multivariate logistic analysis confirmed higher concentrations, specific etiologies, and polytherapy as risk factors for inefficacy. Cox regression further revealed that concentrations ≥ 10 μg/mL and specific etiologies were predictors of reduced long-term treatment persistence. Adverse events occurred in 30.5% of patients; for most, the risk did not change over time. Conclusions: This study tentatively proposed a therapeutic reference range (3.0–20.0 µg/mL) of MHD for Chinese children with epilepsy and identified a concentration ≥ 10 μg/mL as a “risk transition point”. The findings provide practical, evidence-based insights for tailoring OXC therapy and managing potential risks. Full article

(This article belongs to the Collection Therapeutic Agents for Neurological Disorders)

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