Pharmaceuticals

17 pages, 1681 KB

Open AccessArticle

Pharmacokinetics, Safety, and Tolerability of (R)-Ketamine Hydrochloride Injection, a Novel Rapid-Acting Antidepressant, in Healthy Chinese Subjects

by Rui Wang, Yuqian Yang, Tong Zhou, Bingjie Zou and Li Ding

Pharmaceuticals 2025, 18(7), 1079; https://doi.org/10.3390/ph18071079 - 21 Jul 2025

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Abstract

Objectives: (R)-ketamine hydrochloride injection is a novel, rapid-acting antidepressant for the treatment of treatment-resistant depression. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of (R)-ketamine hydrochloride injection in healthy Chinese subjects following ascending single intravenous doses ranging [...] Read more.

Objectives: (R)-ketamine hydrochloride injection is a novel, rapid-acting antidepressant for the treatment of treatment-resistant depression. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of (R)-ketamine hydrochloride injection in healthy Chinese subjects following ascending single intravenous doses ranging from 10.0 mg to 180 mg. Methods: This randomized, double-blind, placebo-controlled study was conducted in 50 healthy male and female Chinese subjects after single ascending doses of (R)-ketamine hydrochloride injection (10.0, 30.0, 60.0, 120, and 180 mg). Ten subjects (including two subjects treated with a placebo) were included in each dose cohort. Pharmacokinetic characteristics, safety, and tolerability profiles of the study drug were evaluated. Results: After the intravenous doses administered from 10.0 mg to 180 mg of (R)-ketamine hydrochloride injection to the subjects, the C_max and AUC values for both (R)-ketamine and its metabolite (R)-norketamine in the subjects increased approximately proportionally to the doses. The average peak plasma concentration levels at the five dose cohorts ranged from 56.0 to 1424 ng/mL and 27.7 to 491 ng/mL for (R)-ketamine and (R)-norketamine, respectively. The adverse events of (R)-ketamine hydrochloride injection were temporary and recovered spontaneously without treatment. Conclusions: In summary, (R)-ketamine hydrochloride injection was safe and well tolerated in healthy Chinese subjects. The clinical study results laid a foundation for the further clinical studies of (R)-ketamine hydrochloride injection in patients. Full article

(This article belongs to the Section Pharmacology)

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18 pages, 5443 KB

Open AccessArticle

Toosendanin Induces Hepatotoxicity by Facilitating ALOX5-Mediated Lipid Peroxidation and Sensitizing Cells to Ferroptosis

by Jiajie Ni, Liru Huang, Yifan Tian, Changxin Zhao, Ziyi Zhou, Feihai Shen and Zhiying Huang

Pharmaceuticals 2025, 18(7), 1078; https://doi.org/10.3390/ph18071078 - 21 Jul 2025

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Abstract

Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying [...] Read more.

Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying mechanisms remain elusive. Methods: HepG2 cells were treated with TSN and analyzed using Western blotting and qPCR assays for related gene transcription and protein expression. Lipid peroxidation and ferroptosis markers were measured. Balb/c and C57BL/6 mice received various doses of TSN administration, and their liver function was assessed with serum biochemistry and histopathology. Network pharmacology and oxidative lipidomics were performed to identify key targets and metabolites. Results: TSN triggered ferroptosis both in vitro and in vivo, accompanied by the elevated expression of 5-lipoxygenase (ALOX5) and its downstream metabolites. The ALOX5 level modulated hepatocyte sensitivity to TSN-induced ferroptotic damage. An ALOX5 knockdown alleviated TSN-induced liver injury and ferroptosis in vivo. Conclusions: Our study demonstrated that TSN induces hepatotoxicity by facilitating ALOX5-mediated lipid peroxidation, thereby sensitizing cells to ferroptosis. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 3781 KB

Open AccessArticle

Ginsenoside Rg3 Adjunctively Increases the Efficacy of Gefitinib Against NSCLC by Regulating EGFR Copy Number

by Xinyi Lv, Yuehan Song, Tianhua Liu, Dingdan Zhang, Xinpeng Ye, Qingqing Wang, Rongrong Li, Jiayi Chen, Shujing Zhang, Xue Yu and Chunying Hou

Pharmaceuticals 2025, 18(7), 1077; https://doi.org/10.3390/ph18071077 - 21 Jul 2025

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Abstract

Background: Lung cancer has the highest morbidity and mortality of all tumors, and the development of TKI drugs targeting EGFR activating mutations has brought lung cancer treatment into the targeted era. In view of their low efficacy and susceptibility to drug resistance, [...] Read more.

Background: Lung cancer has the highest morbidity and mortality of all tumors, and the development of TKI drugs targeting EGFR activating mutations has brought lung cancer treatment into the targeted era. In view of their low efficacy and susceptibility to drug resistance, there is an urgent need to find strategies to increase their efficacy and reduce the incidence of drug resistance. Methods: In this study, we examined the distribution and probability of EGFR mutations in non-small cell lung cancer patients in the cBioPortal database and compared the survival prognosis of patients with normal and abnormal EGFR, NSCLC patients treated with and without TKI, and NSCLC patients with different EGFR gene copy numbers. We established a mouse lung cancer model and examined the histomorphological characteristics of lung tissues via hematoxylin and eosin staining. Additionally, changes in the copy number of the EGFR gene and its protein expression levels were detected using RT-qPCR and Western blotting. Furthermore, we quantified the concentration of the EGFR protein using ELISA. Results: We found no significant advantage of EGFR-TKI therapy over first-line chemotherapeutic agents in patients with EGFR-abnormal NSCLC. The reason for this may be related to the abnormal EGFR gene copy number; the higher the copy number increases, the worse the survival prognosis of the patients. In molecular biology experiments, we demonstrated that ginsenoside Rg3 down-regulated the copy number of 18, 19, 20, and 21 exons and protein expression of EGFR in lung adenocarcinoma cells. The results of in vivo pharmacodynamic assays confirmed that sequential administration of ginsenoside Rg3 with TKI drugs could achieve a gainful complementary effect. Conclusions: Ginsenoside Rg3 down-regulates the copy number of EGFR important exons in EGFR-mutant cells of lung adenocarcinoma and reduces EGFR protein expression, thus providing a high gainful complementary effect in combination with EGFR-TKI. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs: 2nd Edition)

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22 pages, 973 KB

Open AccessReview

Zebrafish Models of Induced Lymphangiogenesis: Current Advancements and Therapeutic Discovery

by Srdjan Boskovic and Kazuhide Shaun Okuda

Pharmaceuticals 2025, 18(7), 1076; https://doi.org/10.3390/ph18071076 - 21 Jul 2025

Viewed by 666

Abstract

Lymphangiogenesis, the formation of new lymphatic vessels, is essential for embryonic development and the maintenance of tissue fluid balance, as well as for responding to physiological challenges such as injury, inflammation, and oedema. This process is also aberrantly activated in pathological conditions including [...] Read more.

Lymphangiogenesis, the formation of new lymphatic vessels, is essential for embryonic development and the maintenance of tissue fluid balance, as well as for responding to physiological challenges such as injury, inflammation, and oedema. This process is also aberrantly activated in pathological conditions including lymphatic anomalies and cancer. Understanding the molecular and cellular mechanisms regulating induced lymphangiogenesis in various conditions is critical for the development of novel anti- or pro-lymphangiogenic therapeutic strategies. In recent years, the zebrafish has emerged as an important model organism for studying both physiological and pathological lymphangiogenesis. Its optical transparency, conserved lymphatic architecture and signalling pathways, and amenability to genetic manipulation and drug screening make it an especially well-suited model. In this review, we highlight zebrafish models used to investigate induced lymphangiogenesis in the context of regeneration, inflammation, fluid imbalance, and congenital lymphatic anomalies. We will also demonstrate how zebrafish are used to discover new drugs targeting lymphatic vessels under various conditions. Finally, we will discuss the current limitations of using zebrafish to model induced lymphangiogenesis and highlight potential future directions. The findings presented in this review underscore the undeniable value the zebrafish model brings to lymphatic research and therapeutic discovery. Full article

(This article belongs to the Section Medicinal Chemistry)

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20 pages, 1648 KB

Open AccessArticle

Semaglutide in MASLD Patients: Improved Survival and Liver Outcomes

by Mohamad Suki, Johnny Amer, Yael Milgrom, Muhammad Massarwa, Wadi Hazou, Yariv Tiram, Ofer Perzon, Yousra Sharif, Joseph Sackran, Revital Alon, Nachum Emil Eliezer Lourie, Itamar Raz, Ashraf Imam, Abed Khalaileh and Rifaat Safadi

Pharmaceuticals 2025, 18(7), 1075; https://doi.org/10.3390/ph18071075 - 21 Jul 2025

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Abstract

Introduction: Semaglutide (SEMA) has shown potential benefits in metabolic dysfunction-associated steatotic liver disease (MASLD). This large real-world study aimed to evaluate the effects of SEMA on MASLD patients’ clinical outcomes and liver-related complications. Results: Following propensity score matching based on 34 [...] Read more.

Introduction: Semaglutide (SEMA) has shown potential benefits in metabolic dysfunction-associated steatotic liver disease (MASLD). This large real-world study aimed to evaluate the effects of SEMA on MASLD patients’ clinical outcomes and liver-related complications. Results: Following propensity score matching based on 34 variables (demographics, comorbidities, laboratory tests, and medication history), SEMA-treated (n = 19,112) patients were compared with non-SEMA (n = 19,112) cases. Both cohorts were well-balanced, except for higher BMI in the SEMA group (36.60 ± 6.25 vs. 34.89 ± 6.84 kg/m²). After one year, the SEMA group demonstrated ~one BMI point reduction but maintained significantly higher BMI (35.51 ± 6.34 vs. 34.11 ± 6.64, p < 0.001). LDL, triglycerides, and HbA1c levels significantly improved with SEMA, as evidenced by decreased rates of poor metabolic markers (31.13% vs. 34.32%, p < 0.001). The SEMA-treated patients demonstrated significantly higher survival, lower cardiovascular risk, and reduced progression to advanced liver disease compared to controls. Discussion: In this large real-world cohort, SEMA use in MASLD patients was associated with significantly improved 1-year survival, cardiovascular, and liver-related outcomes. These benefits appear to result primarily from metabolic improvements and anti-inflammatory effects. Materials and Methods: Data were sourced from TriNetX, a global health research platform with de-identified electronic medical records spanning 135 million patients across 112 healthcare organizations worldwide. We included MASLD adults diagnosed according to ICD9 criteria. Assessed outcomes included survival, biochemical, hematologic, AFP, metabolic and cardiovascular parameters, advanced liver disease (ALD), synthetic function, and metabolic markers. Conclusions: Semaglutide may serve as an effective therapeutic strategy to improve outcomes in MASLD. Full article

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25 pages, 4050 KB

Open AccessReview

Network Pharmacology-Driven Sustainability: AI and Multi-Omics Synergy for Drug Discovery in Traditional Chinese Medicine

by Lifang Yang, Hanye Wang, Zhiyao Zhu, Ye Yang, Yin Xiong, Xiuming Cui and Yuan Liu

Pharmaceuticals 2025, 18(7), 1074; https://doi.org/10.3390/ph18071074 - 21 Jul 2025

Viewed by 1168

Abstract

Traditional Chinese medicine (TCM), a holistic medical system rooted in dialectical theories and natural product-based therapies, has served as a cornerstone of healthcare systems for millennia. While its empirical efficacy is widely recognized, the polypharmacological mechanisms stemming from its multi-component nature remain poorly [...] Read more.

Traditional Chinese medicine (TCM), a holistic medical system rooted in dialectical theories and natural product-based therapies, has served as a cornerstone of healthcare systems for millennia. While its empirical efficacy is widely recognized, the polypharmacological mechanisms stemming from its multi-component nature remain poorly characterized. The conventional trial-and-error approaches for bioactive compound screening from herbs raise sustainability concerns, including excessive resource consumption and suboptimal temporal efficiency. The integration of artificial intelligence (AI) and multi-omics technologies with network pharmacology (NP) has emerged as a transformative methodology aligned with TCM’s inherent “multi-component, multi-target, multi-pathway” therapeutic characteristics. This convergent review provides a computational framework to decode complex bioactive compound–target–pathway networks through two synergistic strategies, (i) NP-driven dynamics interaction network modeling and (ii) AI-enhanced multi-omics data mining, thereby accelerating drug discovery and reducing experimental costs. Our analysis of 7288 publications systematically maps NP-AI–omics integration workflows for natural product screening. The proposed framework enables sustainable drug discovery through data-driven compound prioritization, systematic repurposing of herbal formulations via mechanism-based validation, and the development of evidence-based novel TCM prescriptions. This paradigm bridges empirical TCM knowledge with mechanism-driven precision medicine, offering a theoretical basis for reconciling traditional medicine with modern pharmaceutical innovation. Full article

(This article belongs to the Special Issue Sustainable Approaches and Strategies for Bioactive Natural Compounds)

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10 pages, 721 KB

Open AccessArticle

Pharmacokinetic Analysis of the Bioavailability of AQUATURM^®, a Water-Soluble Curcumin Formulation, in Comparison to a Conventional Curcumin Tablet, in Human Subjects

by Lillian Jabur, Rishi Pandey, Meena Mikhael, Garry Niedermayer, Erika Gyengesi, David Mahns and Gerald Münch

Pharmaceuticals 2025, 18(7), 1073; https://doi.org/10.3390/ph18071073 - 21 Jul 2025

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Abstract

Background/Objectives: Curcumin, the principal bioactive component of Curcuma longa, is known for its anti-inflammatory, antioxidant, and neuroprotective properties. Despite its therapeutic potential, curcumin exhibits poor oral bioavailability due to low solubility, rapid metabolism, and limited gastrointestinal absorption. Various delivery systems have been developed [...] Read more.

Background/Objectives: Curcumin, the principal bioactive component of Curcuma longa, is known for its anti-inflammatory, antioxidant, and neuroprotective properties. Despite its therapeutic potential, curcumin exhibits poor oral bioavailability due to low solubility, rapid metabolism, and limited gastrointestinal absorption. Various delivery systems have been developed to overcome these limitations. This study aimed to evaluate and compare the pharmacokinetic profile of AQUATURM®, a novel, water-soluble curcumin formulation, with that of a widely available commercial curcumin supplement. Methods: A randomized, double-blind, two-period crossover study was conducted in 12 healthy adult participants (6 male, 6 female; aged 20–45 years). Each participant received a single oral dose of either AQUATURM® or the comparator product, followed by a 7-day washout period before receiving the alternate treatment. Blood samples were collected at multiple time points over a 12-h period post-dosing. Plasma curcumin concentrations were quantified using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). Results: AQUATURM® achieved a significantly higher systemic exposure compared to the comparator, with a more than 7-fold increase in area under the curve (AUC_0–12h) and higher peak plasma concentrations (Cmax). AQUATURM® also maintained detectable curcumin levels for the full 12-h observation period, whereas levels from the comparator fell below quantification limits in most participants after 4 h. Conclusions: AQUATURM® significantly enhances curcumin bioavailability in humans compared to a standard curcumin formulation. These pharmacokinetic improvements support its potential for greater clinical efficacy and warrant further evaluation in therapeutic setting Full article

(This article belongs to the Special Issue Phytochemicals and Analogues as Sources of Bioactive Substances of Pharmacological and Industrial Interest)

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35 pages, 8014 KB

Open AccessArticle

Chitosan Nanoparticles for Topical Drug Delivery in Chemotherapy-Induced Alopecia: A Comparative Study of Five Repurposed Pharmacological Agents

by Salma A. Fereig, John Youshia, Ghada M. El-Zaafarany, Mona G. Arafa and Mona M. A. Abdel-Mottaleb

Pharmaceuticals 2025, 18(7), 1071; https://doi.org/10.3390/ph18071071 - 21 Jul 2025

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Abstract

Background/Objectives: Chemotherapy-induced alopecia is a common and distressing side effect of cancer treatment, significantly impacting patients’ psychological well-being. Nanocarriers offer a promising strategy for targeted drug delivery to hair follicles, while chitosan nanoparticles have demonstrated hair-growth-promoting properties. This study explores the potential [...] Read more.

Background/Objectives: Chemotherapy-induced alopecia is a common and distressing side effect of cancer treatment, significantly impacting patients’ psychological well-being. Nanocarriers offer a promising strategy for targeted drug delivery to hair follicles, while chitosan nanoparticles have demonstrated hair-growth-promoting properties. This study explores the potential of chitosan nanoparticles as a topical delivery system for five pharmacological agents—phenobarbital, pioglitazone, rifampicin, N-acetylcysteine, and tacrolimus—to prevent chemotherapy-induced alopecia. Methods: Drug-loaded chitosan nanoparticles were prepared using the ionic gelation technique and characterized by particle size, zeta potential, entrapment efficiency, FT-IR spectroscopy, and TEM imaging. Their efficacy was assessed in a cyclophosphamide-induced alopecia model in C57BL/6 mice through macroscopic observation, histopathological examination, and scanning electron microscopy of regrown hair. Results: The prepared particles were spherical, cationic, and between 205 and 536 nm in size. The entrapment efficiencies ranged from 8% to 63%. All five drugs mitigated follicular dystrophy, shifting the hair follicle response from dystrophic catagen to dystrophic anagen. Phenobarbital demonstrated the most significant hair regrowth and quality improvements, followed by N-acetyl cysteine and pioglitazone. Tacrolimus showed moderate efficacy, while rifampicin was the least effective. Conclusions: These findings suggest that phenobarbital-loaded chitosan nanoparticles represent a promising approach for the prevention and treatment of chemotherapy-induced alopecia, warranting further investigation for clinical applications. Full article

(This article belongs to the Special Issue Advances in Topical and Mucosal Drug Delivery Systems)

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30 pages, 11312 KB

Open AccessArticle

Study on the Mechanism and Dose–Effect Relationship of Flavonoids in Different Extracts of Radix Hedysari Against Gastrointestinal Injury Induced by Chemotherapy

by Shasha Zhao, Miaomiao Yang, Zimu Yang, Hai He, Ziyang Wang, Xinyu Zhu, Zhijia Cui and Jing Shao

Pharmaceuticals 2025, 18(7), 1072; https://doi.org/10.3390/ph18071072 - 20 Jul 2025

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Abstract

Background: Previous studies have shown Radix Hedysari (RH)’s gastroprotective potential, but its active components and mechanisms remain uncharacterized. This study aimed to identify RH’s bioactive fractions, elucidate protection mechanisms, establish flavonoid dose-effect relationships, and determine the pharmacodynamic basis. Methods: Chemical profiling quantified [...] Read more.

Background: Previous studies have shown Radix Hedysari (RH)’s gastroprotective potential, but its active components and mechanisms remain uncharacterized. This study aimed to identify RH’s bioactive fractions, elucidate protection mechanisms, establish flavonoid dose-effect relationships, and determine the pharmacodynamic basis. Methods: Chemical profiling quantified eight flavonoids via HPLC. Network pharmacology screened targets/pathways using TCMSP, GeneCards databases. In vivo validation employed cisplatin–induced injury models in Wistar rats (n = 10/group). Assessments included: behavioral monitoring; organ indices; ELISA (MTL, VIP, IFN–γ, IgG, IL–6, TNF–α etc.); H&E; and Western blot:(SCF, c–Kit, p65). Dose–effect correlations were analyzed by PLS–DA. Results: Content determination indicated that Calycosin–7–glucoside and Ononin were notably enriched on both the n–BuOH part and the EtOAc part. Network pharmacology identified 5 core flavonoids and 8 targets enriched in IL–17/TNF signaling pathways. n–BuOH treatment minimized weight loss vs. MCG, increased spleen/thymus indices. n–BuOH and HPS normalized gastrointestinal, immune, inflammatory biomarkers (p < 0.01 vs. MCG). Histopathology confirmed superior mucosal protection in n–BuOH group vs. MCG. Western blot revealed n–BuOH significantly downregulated SCF, c–kit, and p65 expressions in both gastric and intestinal tissues (p < 0.001 vs. MCG). PLS–DA demonstrated Calycosin–7–glucoside had the strongest dose–effect correlation (VIP > 1) with protective outcomes. Conclusions: The n–BuOH fraction of RH is the primary bioactive component against chemotherapy–induced gastrointestinal injury, with Calycosin–7–glucoside as its key effector. Protection is mediated through SCF/c–Kit/NF–κB pathway inhibition, demonstrating significant dose–dependent efficacy. These findings support RH’s potential as a complementary therapy during chemotherapy. Full article

(This article belongs to the Special Issue Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds)

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15 pages, 1365 KB

Open AccessArticle

SUMOylation Regulates Neutrophil Phagocytosis and Migration

by Ran Zhang, Wanying Miao, Jin Zhang, Xinyuan Yu, Lihong Dang, Ata Ur Rehman, Feng Xu, Huaxin Sheng, G. Chad Hughes, Joseph P. Mathew, Jörn Karhausen and Wei Yang

Pharmaceuticals 2025, 18(7), 1070; https://doi.org/10.3390/ph18071070 - 20 Jul 2025

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Abstract

Introduction: Accumulating evidence indicates that neutrophils undergo reprogramming of their effector functions as they migrate from the bloodstream into an inflamed tissue. Here, we examined the role of the small ubiquitin-like modifier (SUMO) conjugation in modulating neutrophil functional changes in the inflammatory [...] Read more.

Introduction: Accumulating evidence indicates that neutrophils undergo reprogramming of their effector functions as they migrate from the bloodstream into an inflamed tissue. Here, we examined the role of the small ubiquitin-like modifier (SUMO) conjugation in modulating neutrophil functional changes in the inflammatory microenvironment. Methods: Primary human and murine neutrophils were used to assess SUMOylation levels in vitro by Western blotting and results were validated in clinical samples from patients undergoing surgery involving hypothermic circulatory arrest. SUMOylation was inhibited with TAK-981, and its impact on neutrophil migration, NETosis, and phagocytosis was assessed in vitro. The in vivo effect of TAK-981 on neutrophil tissue infiltration was further evaluated using a sterile sponge assay in mice. Results: Our results demonstrated that neutrophil SUMOylation was induced by factors of the inflammatory microenvironment (temperature and oxidative stress) and inflammatory stimulants in vitro, and under conditions of general inflammatory activation in patients. Further, we found that blocking SUMOylation with TAK-981 in vitro blunted neutrophil migration and phagocytosis but did not affect NETosis. Notably, TAK-981 treatment reduced neutrophil accumulation in sterile sponges in mice. Conclusions: Our work identifies SUMOylation as a novel mechanism of neutrophil tissue reprogramming. Blocking SUMOylation may provide a therapeutic option to limit the contribution of neutrophils to inflammation-associated tissue damage. Full article

(This article belongs to the Section Pharmacology)

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25 pages, 912 KB

Open AccessArticle

Association of SLCO1B3 and SLCO1B1 Polymorphisms with Methotrexate Efficacy and Toxicity in Saudi Rheumatoid Arthritis Patients

by Rania Magadmi, Ahlam M. Alharthi, Lina A. Alqurashi, Ibtisam M. Jali, Zeina W. Sharawi, Maha H. Jamal, Yasser Bawazir, Mohammad Mustafa, Sami M. Bahlas, Basma T. Jamal, Hassan Daghasi, Abdulrahman S. Altowairqi and Dalal Sameer Al Shaer

Pharmaceuticals 2025, 18(7), 1069; https://doi.org/10.3390/ph18071069 - 20 Jul 2025

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Abstract

Background: Methotrexate (MTX) remains the most commonly prescribed drug used to treat rheumatoid arthritis (RA). Polymorphisms in solute carrier organic anion transporter family member 1B3 (SLCO1B3) and SLCO1B1 may play a critical role in MTX pharmacokinetics and patient outcomes. However, research [...] Read more.

Background: Methotrexate (MTX) remains the most commonly prescribed drug used to treat rheumatoid arthritis (RA). Polymorphisms in solute carrier organic anion transporter family member 1B3 (SLCO1B3) and SLCO1B1 may play a critical role in MTX pharmacokinetics and patient outcomes. However, research on these polymorphisms in Saudi Arabia remains limited. We evaluated the association of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms with MTX efficacy and safety in Saudi patients with RA. Methods: This multicenter, case-control study included patients diagnosed with RA in Jeddah and Taif. Demographic and clinical data were collected and analyzed. Genotyping of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms was performed using Sanger sequencing. Statistical analyses, including logistic regression and haplotype analysis, were conducted to evaluate associations between these polymorphisms, MTX efficacy, and toxicity. Results: The study cohort comprised 100 patients with RA, with 46 showing a good response to MTX and 54 showing a poor response. Clinical predictors of MTX response were significantly higher in patients with poor response. Both SLCO1B3 polymorphisms (rs4149117, rs7311358) were significantly associated with anemia. Significant associations were found between SLCO1B1 (rs2306283) and gastrointestinal disturbances and anemia. The GAAT haplotype was significantly more prevalent among good responders, while the TGGT haplotype was significantly associated with poor responders. Conclusions: These results highlight the importance of genetic testing in predicting MTX treatment outcomes and tailoring personalized treatment plans for patients with RA to improve efficacy and minimize adverse effects. Full article

(This article belongs to the Special Issue The Application of Pharmacogenetics in Toxicity Prevention and Drug Effect Improvement)

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12 pages, 1336 KB

Open AccessReview

Bisphosphonates in the Management of Patients with Postmenopausal Osteoporosis; Back to the Future

by Socrates E. Papapoulos and Polyzois Makras

Pharmaceuticals 2025, 18(7), 1068; https://doi.org/10.3390/ph18071068 - 20 Jul 2025

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Abstract

Osteoporosis is a chronic disease associated with significant morbidity and mortality and requires long-term therapy. Efficacious and well-tolerated treatments are available, but their effect is either short-lived or lost following their discontinuation. The exception is bisphosphonates that reduce bone resorption and turnover, can [...] Read more.

Osteoporosis is a chronic disease associated with significant morbidity and mortality and requires long-term therapy. Efficacious and well-tolerated treatments are available, but their effect is either short-lived or lost following their discontinuation. The exception is bisphosphonates that reduce bone resorption and turnover, can be administered in regimens ranging from once-daily to once-yearly, and have been shown in randomized clinical trials to reduce the incidence of all osteoporotic fractures, but their effect persists following their discontinuation. This is due to their property of being taken-up selectively by the skeleton and being slowly released following treatment arrest. This property allows the discontinuation of bisphosphonate treatment for different periods of time, the so-called drug holiday, which reduces the risk of rare adverse events while maintaining the effect; an action particularly important for patients at very high risk of fractures for whom sequential therapy with different agents is currently advised. Thus, bisphosphonates, apart from being the treatment of choice for certain groups of patients, are also indispensable for the consolidation and maintenance of the gains of all other treatments, providing, in addition, the opportunity of temporary treatment arrest. Most patients with postmenopausal osteoporosis will, therefore, receive bisphosphonate at some stage during therapy of their disease, regardless of their initial fracture risk. Full article

(This article belongs to the Special Issue The Pharmacology of Bisphosphonates: New Advances)

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21 pages, 3324 KB

Open AccessArticle

Curcumin and Papain-Loaded Liposomal Natural Latex Dressings with Phototherapy: A Synergistic Approach to Diabetic Wound Healing

by Franciéle M. Silva, Jaqueline R. Silva, Wellington Rodrigues, Breno A. S. M. Sousa, Thamis F. S. Gomes, Mario F. F. Rosa, Suélia S. R. F. Rosa and Marcella L. B. Carneiro

Pharmaceuticals 2025, 18(7), 1067; https://doi.org/10.3390/ph18071067 - 20 Jul 2025

Viewed by 736

Abstract

Background: Wound healing in diabetic individuals is a prolonged process, often complicated by infections and impaired tissue regeneration. Innovative strategies combining natural bioactive compounds are needed to enhance repair. Methods: This study reports the development and characterization of natural latex-based biomembranes (NLBs) incorporated [...] Read more.

Background: Wound healing in diabetic individuals is a prolonged process, often complicated by infections and impaired tissue regeneration. Innovative strategies combining natural bioactive compounds are needed to enhance repair. Methods: This study reports the development and characterization of natural latex-based biomembranes (NLBs) incorporated with liposome-encapsulated curcumin and papain. The therapeutic efficacy of these composite dressings, in combination with red light-emitting diode (LED) phototherapy, was evaluated in a diabetic rat model. NLBs were produced by blending natural latex with multilamellar liposomes containing either curcumin, papain, or both. In vivo wound healing was assessed by applying the biomembranes to the dorsal lesions and administering red LED irradiation (650 ± 20 nm, 10 min every 48 h) over 11 days. Results: Fourier transform infrared spectroscopy (FTIR) confirmed that the integration of liposomes did not induce significant chemical alterations to the latex matrix. The treated diabetic rats exhibited enhanced wound contraction, with the curcumin and papain groups demonstrating up to 99% and 95% healing, respectively. Plasma fructosamine levels were significantly reduced (p < 0.05), indicating improved glycemic control. Conclusions: Combining NLBs with bioactive-loaded liposomes and phototherapy accelerated wound healing in diabetic rats. This multifunctional platform shows promise for the treatment of chronic wounds in diabetic patients. Full article

(This article belongs to the Section Pharmacology)

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13 pages, 230 KB

Open AccessBrief Report

Insomnia and Esketamine Add-On Therapy to Antidepressant Therapy in Patients with Treatment-Resistant Depression—A Pilot Study

by Daniel Szawarnoga, Joanna Fojcik, Michał Górski, Artur Pałasz and Marek Krzystanek

Pharmaceuticals 2025, 18(7), 1066; https://doi.org/10.3390/ph18071066 - 19 Jul 2025

Viewed by 631

Abstract

Background: Insomnia, as one of the most common sleep disorders, is a significant health problem, especially among patients suffering from drug-resistant depression. Problems related to the quality of sleep in that population can significantly affect the effectiveness of treatment and quality of life, [...] Read more.

Background: Insomnia, as one of the most common sleep disorders, is a significant health problem, especially among patients suffering from drug-resistant depression. Problems related to the quality of sleep in that population can significantly affect the effectiveness of treatment and quality of life, which is why it is necessary to search for effective therapeutic interventions in this area. Objective: The aim of this study was to compare the effectiveness of esketamine and other standard antidepressants in improving sleep quality in patients with drug-resistant depression. The main research question is whether and to what extent esketamine improves sleep parameters compared with other antidepressants. Methods: This study involves the analysis of data collected from 50 patients divided into two groups: those using esketamine in combination with other antidepressants and those using other antidepressants. The analysis of the results focuses on the assessment of differences in AIS scores between the groups assessed using the Athens Insomnia Scale (AIS). Results: Insomnia occurs much less frequently among people using esketamine than among people not using this drug. With the increase in the time of using esketamine and with the increase in the dose, the level of insomnia decreases. Conclusions: Esketamine brings about a rapid improvement in sleep quality, which is a significant advance in the treatment of drug-resistant depression. The obtained results not only confirm the effectiveness of esketamine but also show its advantage over traditional treatment methods in improving sleep quality. Full article

(This article belongs to the Special Issue Pharmacology of Antidepressants: Recent Advances)

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14 pages, 286 KB

Open AccessArticle

Comparative Efficacy and Safety of Two Different Formulations of Linear Hyaluronic Acid in Patients with Knee Osteoarthritis

by Vincenzo Rania, Cristina Vocca, Gianmarco Marcianò, Maria Cristina Caroleo, Lucia Muraca, Emanuele Toraldo, Francesca Greco, Caterina Palleria, Gian Pietro Emerenziani and Luca Gallelli

Pharmaceuticals 2025, 18(7), 1065; https://doi.org/10.3390/ph18071065 - 19 Jul 2025

Viewed by 531

Abstract

Introduction: Knee osteoarthritis (OA) is defined by articular cartilage loss, increased discomfort, and functional restrictions. Changes in lifestyle, painkillers, intra-articular injections, and, as a last resort, surgery are all part of clinical therapy. In this setting, intra-articular injections of hyaluronic acid (HA) [...] Read more.

Introduction: Knee osteoarthritis (OA) is defined by articular cartilage loss, increased discomfort, and functional restrictions. Changes in lifestyle, painkillers, intra-articular injections, and, as a last resort, surgery are all part of clinical therapy. In this setting, intra-articular injections of hyaluronic acid (HA) represent a relevant and diffused therapeutic option. Materials and Methods: A prospective observational study was performed from October 2024 to May 2025 in 70 patients with knee OA. HA was administered in three intra-articular injections and was followed up at 3 and 6 months from the last injection. Knee Injury and Osteoarthritis Outcome Score (KOOS) was evaluated as primary outcome measure; Visual Analogue Scale (VAS), time up and go test, six-minute walking test, general health assessment with 36-Item Short Form Health Survey (SF-36), Zung’s Self-Rating Anxiety Scale (Zung SAS), and Zung’s Self-Rating Depression Scale (Zung SDS) as secondary outcome measures. Results: We observed a statistically significant improvement in clinical scores at 3 months in both HA formulations compared to the control group. No relevant side effects were described during the study. Conclusion: Hyalubrix 30 mg/2 mL and DIART 1.8%/2 mL are two safe and effective therapeutic options to manage knee OA, offering benefits in pain control, functionality and emotional wellness. Full article

(This article belongs to the Section Pharmacology)

15 pages, 1206 KB

Open AccessArticle

Expanding the Therapeutic Profile of Topical Cannabidiol in Temporomandibular Disorders: Effects on Sleep Quality and Migraine Disability in Patients with Bruxism-Associated Muscle Pain

by Karolina Walczyńska-Dragon, Jakub Fiegler-Rudol, Stefan Baron and Aleksandra Nitecka-Buchta

Pharmaceuticals 2025, 18(7), 1064; https://doi.org/10.3390/ph18071064 - 19 Jul 2025

Viewed by 962

Abstract

Background: Cannabidiol (CBD) has demonstrated potential as a therapeutic agent for muscle tension, pain, and sleep bruxism, yet its broader impact on comorbid conditions such as sleep disturbance and migraine disability remains underexplored. This study aimed to assess the effects of topical [...] Read more.

Background: Cannabidiol (CBD) has demonstrated potential as a therapeutic agent for muscle tension, pain, and sleep bruxism, yet its broader impact on comorbid conditions such as sleep disturbance and migraine disability remains underexplored. This study aimed to assess the effects of topical CBD on sleep quality and migraine-related disability in patients with bruxism-associated muscular pain. Methods: In a randomized, double-blind clinical trial, 60 participants with bruxism were allocated equally into three groups: control (placebo gel), 5% CBD gel, and 10% CBD gel. Participants applied the gel intraorally to the masseter muscles nightly for 30 days. Sleep quality and migraine-related disability were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Migraine Disability Assessment Scale (MIDAS), respectively. Surface electromyography (sEMG) and the Bruxoff^® device were used for objective evaluation of muscle tension and bruxism intensity. Results: Both CBD treatment groups demonstrated statistically significant improvements in PSQI and MIDAS scores compared to the control group (p < 0.001). No significant differences were observed between the 5% and 10% CBD groups, suggesting comparable efficacy. The sEMG findings corroborated a reduction in muscle tension. Improvements in sleep and migraine outcomes were positively correlated with reductions in muscle activity and pain. Conclusions: Topical CBD gel significantly improved sleep quality and reduced migraine-related disability in patients with bruxism-associated muscular pain, supporting its role as a multifaceted therapeutic option in the management of TMD and related comorbidities. Further research is needed to confirm long-term benefits and determine optimal dosing strategies. Full article

(This article belongs to the Special Issue The Therapeutic Potential of Cannabidiol)

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58 pages, 16017 KB

Open AccessReview

Synthesis of Amino-gem-Bisphosphonate Derivatives and Their Application as Synthons for the Preparation of Biorelevant Compounds

by Mario Ordoñez and Rubén Oswaldo Argüello Velasco

Pharmaceuticals 2025, 18(7), 1063; https://doi.org/10.3390/ph18071063 - 18 Jul 2025

Viewed by 533

Abstract

In recent years, amino-gem-bisphosphonic acids and their esters have been considered a family of compounds of great chemical and pharmacological interest due to their important biological properties and their value as key synthons in the synthesis of more complex molecules with [...] Read more.

In recent years, amino-gem-bisphosphonic acids and their esters have been considered a family of compounds of great chemical and pharmacological interest due to their important biological properties and their value as key synthons in the synthesis of more complex molecules with biological interest. This explains why several research groups are interested in developing new methods for the preparation of these compounds. Therefore, we would like to report here a summary of the synthetic strategies published in the last fifteen years for the synthesis of acyclic and heterocyclic α-, β- and γ-amino-gem-bisphosphonates, as well as their application in the preparation of selected compounds of chemical and pharmacological interest. This information can be of general knowledge to researchers working in this area, as it provides the starting point for new methods and applications of these compounds. Full article

(This article belongs to the Special Issue The Pharmacology of Bisphosphonates: New Advances)

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14 pages, 929 KB

Open AccessArticle

Possible Association Between Concomitant Use of SSRIs with NSAIDs and an Increased Risk of Adverse Events Among People with Depressive Disorders: Data Mining of FDA Adverse Event Reporting System

by Yi Zhang, Xiaoyu Liu, Jianru Wu, Xuening Zhang, Fenfang Wei, Limin Li, Hongqiao Li, Xinru Wang, Bei Wang, Wenyu Wu and Xiang Hong

Pharmaceuticals 2025, 18(7), 1062; https://doi.org/10.3390/ph18071062 - 18 Jul 2025

Cited by 1 | Viewed by 853

Abstract

Background: Depression, a major global health issue, is commonly treated with selective serotonin reuptake inhibitors (SSRIs). Given the link between depression and inflammation, nonsteroidal anti-inflammatory drugs (NSAIDs) may have adjunctive benefits. Clinically, SSRIs and NSAIDs are often co-prescribed for comorbid pain or [...] Read more.

Background: Depression, a major global health issue, is commonly treated with selective serotonin reuptake inhibitors (SSRIs). Given the link between depression and inflammation, nonsteroidal anti-inflammatory drugs (NSAIDs) may have adjunctive benefits. Clinically, SSRIs and NSAIDs are often co-prescribed for comorbid pain or inflammatory conditions. However, both drug classes pose risks of adverse effects, and their interaction may lead to clinically significant drug–drug interactions. Objectives: This study analyzed FDA Adverse Event Reporting System (FAERS) data (2004–2024) to assess gastrointestinal bleeding, thrombocytopenia, and acute kidney injury (AKI) potential risks linked to SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, and sertraline) and NSAIDs (propionic/acetic/enolic acid derivatives, COX-2 inhibitors) in depression patients, alone and combined. Methods: Disproportionality analysis (crude reporting odds ratios, cROR) identified possible associations; drug interactions were evaluated using Ω shrinkage, additive, multiplicative, and combination risk ratio (CRR) models. Results: Gastrointestinal bleeding risk was potentially elevated with citalopram (cROR = 2.81), escitalopram (2.27), paroxetine (2.17), fluvoxamine (3.58), sertraline (1.69), and propionic acid NSAIDs (3.17). Thrombocytopenia showed a potential correlation with fluoxetine (2.11) and paroxetine (2.68). AKI risk may be increased with citalopram (1.39), escitalopram (1.36), fluvoxamine (3.24), and COX-2 inhibitors (2.24). DDI signal analysis suggested that citalopram in combination with propionic acid derivatives (additive model = 0.01, multiplicative model = 1.14, and CRR = 3.13) might increase the risk of bleeding. Paroxetine combined with NSAIDs (additive model = 0.014, multiplicative model = 2.65, and CRR = 2.99) could potentially increase the risk of thrombocytopenia. Sertraline combined with NSAIDs (Ω₀₂₅ = 0.94, multiplicative model = 2.14) might be associated with an increasing risk of AKI. Citalopram combined with propionic acid derivatives (Ω₀₂₅ = 1.08, multiplicative model = 2.17, and CRR = 2.42) could be associated with an increased risk of acute kidney injury. Conclusions: Certain combinations of SSRIs and NSAIDs might further elevate these risks of gastrointestinal bleeding, thrombocytopenia, and acute kidney injury in patients with depression. Given the potential drug–drug interactions, heightened clinical vigilance is advised when prescribing SSRIs and NSAIDs in combination to patients with depression. Full article

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

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18 pages, 6558 KB

Open AccessArticle

Integrated Omics Reveal Dendrobium nobile Lindl.’s Anti-Diabetic Mechanisms via Arginine/Proline and Glycerophospholipid Pathways

by Zhibo Wang, Xian Wang, Sifan Guo, Ying Cai, Dandan Xie, Yujuan Wang, Aihua Zhang, Jun Dai and Shi Qiu

Pharmaceuticals 2025, 18(7), 1061; https://doi.org/10.3390/ph18071061 - 18 Jul 2025

Viewed by 397

Abstract

Background/Objectives: Dendrobium nobile Lindl. (DNL), a traditional dietary supplement, exhibits therapeutic potential for type 2 diabetes mellitus (T2DM), yet its mechanisms remain unclear. Methods: T2DM was induced in db/db mice. DNL (10 g/kg/d) or metformin (65 mg/kg/d) was administered [...] Read more.

Background/Objectives: Dendrobium nobile Lindl. (DNL), a traditional dietary supplement, exhibits therapeutic potential for type 2 diabetes mellitus (T2DM), yet its mechanisms remain unclear. Methods: T2DM was induced in db/db mice. DNL (10 g/kg/d) or metformin (65 mg/kg/d) was administered for 4 weeks. This study integrated pharmacodynamic evaluation and multi-omics to elucidate DNL’s anti-diabetic effects in db/db mice. Results: DNL intervention significantly ameliorated T2DM phenotypes, reducing hyperglycemia, insulin resistance, and renal dysfunction. Metabolomics analysis identified 39 differential metabolites (19 upregulated, 20 downregulated) linked to citrate cycle, oxidative phosphorylation, and glycerophospholipid metabolism, while proteomics revealed 113 differentially expressed proteins, with multi-omics integration highlighting DNL’s modulation of three proteins (Ckm, Ache, Selenbp1) and four metabolites (4-guanidinobutanoic acid, phosphorylcholine, homocysteine, succinic acid) across arginine/proline metabolism, glycerophospholipid metabolism, and sulfur metabolism. Pathway analysis demonstrated DNL’s restoration of dysregulated processes, including inflammation suppression via NF-κB and PI3K-Akt pathways, enhanced insulin sensitivity through glycerophospholipid balance, and mitigation of oxidative stress via sulfur metabolism. Key correlations between metabolites and proteins underscored DNL’s multi-target action. Conclusions: These findings systematically decode therapeutic mechanisms of Dendrobium nobile Lindl., emphasizing its role in rectifying metabolic disorders and inflammatory signaling, thereby providing a molecular basis for its clinical application in T2DM management. Full article

(This article belongs to the Section Pharmacology)

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24 pages, 2632 KB

Open AccessArticle

Therapeutic Potential of Glucose Oxidase-Loaded Biogenic Mesoporous Silica Nanoparticles in Ovarian Cancer

by Andrea G. Uriostegui-Pena, Padmavati Sahare, Gabriel Luna-Bárcenas and Sujay Paul

Pharmaceuticals 2025, 18(7), 1060; https://doi.org/10.3390/ph18071060 - 18 Jul 2025

Viewed by 583

Abstract

Background/Objectives: Ovarian cancer (OC) remains one of the most lethal malignancies of the female reproductive system. Glucose oxidase (GOx) has emerged as a potential therapeutic agent in cancer treatment by inducing tumor starvation through glucose depletion. Nonetheless, its clinical application is constrained due [...] Read more.

Background/Objectives: Ovarian cancer (OC) remains one of the most lethal malignancies of the female reproductive system. Glucose oxidase (GOx) has emerged as a potential therapeutic agent in cancer treatment by inducing tumor starvation through glucose depletion. Nonetheless, its clinical application is constrained due to its systemic toxicity, immunogenicity, poor in vivo stability, and short half-life. These challenges can be addressed through nanotechnology; in particular, biogenic mesoporous silica nanoparticles (MSNs) offer promise as drug delivery systems (DDSs) that enhance therapeutic efficacy while minimizing side effects. Methods: Biogenic MSNs were extracted from the Equisetum myriochaetum plant via acid digestion, functionalized with 3-aminopropiltrietoxysilane (APTES) and glutaraldehyde (GTA), and loaded with GOx. The free and immobilized MSNs were characterized using FTIR, DLS, XRD, SEM/EDX, and BET techniques. A colorimetric approach was employed to quantify the enzymatic activity of both the free and immobilized GOx. The MTT assay was employed to assess the viability of SKOV3 cells. The obtained IC₅₀ concentration of the nanoformulation was administered to SKOV3 cells to analyze the expression of cancer-related genes using RT-qPCR. Results: IC₅₀ values of 60.77 ng/mL and 111.6 µg/mL were ascertained for the free and immobilized GOx, respectively. Moreover, a significant downregulation of the oncogene β-catenin (CTNNB1) was detected after 24 h with the nanoformulation. Conclusions: Our findings indicate that GOx-loaded biogenic MSNs may serve as a potential therapeutic agent for ovarian cancer. This is, to the best of our knowledge, the first report exploring the effect of GOx-loaded biogenic MSNs on SKOV3 cells. Full article

(This article belongs to the Special Issue Cutting-Edge Biotechnologies and Applications of Natural Products in Drug R&D and Disease Treatment)

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29 pages, 6133 KB

Open AccessArticle

Therapeutic Effects and Mechanisms of the Inhaled Traditional Chinese Medicine Compound ZHW on Allergic Rhinitis

by Yujin Shen, Xi Ma, Zhenzhen Du, Yang Li, Zhinan Mei and Ling Zhao

Pharmaceuticals 2025, 18(7), 1059; https://doi.org/10.3390/ph18071059 - 18 Jul 2025

Viewed by 471

Abstract

Background: Allergic rhinitis (AR) is a prevalent allergic disorder characterized by a complex pathogenesis. Drawing on traditional Chinese medicine theory and contemporary pharmacological principles, this study developed an inhalation-based herbal formulation, ZHW, to explore a novel non-invasive therapeutic approach. Objective: To investigate the [...] Read more.

Background: Allergic rhinitis (AR) is a prevalent allergic disorder characterized by a complex pathogenesis. Drawing on traditional Chinese medicine theory and contemporary pharmacological principles, this study developed an inhalation-based herbal formulation, ZHW, to explore a novel non-invasive therapeutic approach. Objective: To investigate the therapeutic effects of ZHW on AR and elucidate its underlying mechanisms and potential targets through an integrated analysis of network pharmacology and proteomics. Materials and Methods: The volatile components of ZHW were analyzed by gas chromatography–mass spectrometry (GC-MS). The mouse model of AR was induced by OVA sensitization. The therapeutic efficacy of ZHW was assessed based on nasal symptom scores, histopathological examination, and inflammatory cytokine levels. Furthermore, the underlying mechanisms and potential targets of ZHW were investigated through integrated network pharmacology and proteomics analyses. Results: GC-MS analysis identified 39 bioactive compounds in ZHW. Inhalation treatment with ZHW demonstrated significant anti-allergic effects in OVA-sensitized mice, as evidenced by (1) reduced sneezing frequency and nasal rubbing behaviors; (2) decreased serum levels of IL-4, histamine, and OVA-specific IgE; (3) attenuated IL-4 concentrations in both nasal lavage fluid and lung tissue; (4) diminished nasal mucosal thickening; and (5) suppression of inflammatory cell infiltration. Integrated network pharmacology and proteomics analyses indicated that ZHW’s therapeutic effects were mediated through the modulation of multiple pathways, including the PI3K-Akt signaling pathway, the B cell receptor signaling pathway, oxidative phosphorylation, and the FcεRI signaling pathway. Key molecular targets involved Rac1, MAPK1, and SYK. Molecular docking simulations revealed strong binding affinities between ZHW’s primary bioactive constituents (linalool, levomenthol, linoleic acid, Linoelaidic acid, and n-Valeric acid cis-3-hexenyl ester) and these target proteins. Conclusions: The herbal formulation ZHW demonstrates significant efficacy in alleviating allergic rhinitis symptoms through multi-target modulation of key signaling pathways, including PI3K-Akt- and FcεRI-mediated inflammatory responses. These findings substantiate ZHW’s therapeutic potential as a novel, non-invasive treatment for AR and provide a strong basis for the development of new AR therapies. Future clinical development will require systematic safety evaluation to ensure optimal therapeutic outcomes. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 1526 KB

Open AccessSystematic Review

Weight Loss Effects of Once-Weekly Semaglutide 2.4 mg in Adults with and Without Type 2 Diabetes: A Systematic Review and Meta-Analysis

by Boram Hong, Haesoo Kim, Daeun Lee and Kisok Kim

Pharmaceuticals 2025, 18(7), 1058; https://doi.org/10.3390/ph18071058 - 18 Jul 2025

Viewed by 2046

Abstract

Background/Objectives: Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is a well-established pharmacologic agent for inducing weight loss in individuals with obesity and is prescribed regardless of type 2 diabetes mellitus (DM) status. However, it remains unclear whether the weight-lowering efficacy of semaglutide [...] Read more.

Background/Objectives: Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is a well-established pharmacologic agent for inducing weight loss in individuals with obesity and is prescribed regardless of type 2 diabetes mellitus (DM) status. However, it remains unclear whether the weight-lowering efficacy of semaglutide differs significantly between individuals with and without DM. To address this question, we conducted a systematic review and meta-analysis comparing the effects of once-weekly subcutaneous semaglutide at 2.4 mg on weight loss in adults with and without DM. Methods: A comprehensive literature search was performed using the PubMed database to identify randomized controlled trials (RCTs) involving overweight or obese adults receiving semaglutide at 2.4 mg weekly for 40 to 70 weeks. Using a random-effects model, we estimated the weighted mean differences in body weight reduction between the two groups. Nine RCTs met the inclusion criteria, among which two provided subgroup data for participants with and without DM within the same trial population. Registration number in PROSPERO: CRD420251077610. Results: In participants with DM (n = 4 studies), semaglutide was associated with a weighted mean body weight reduction of −6.34% (95% confidence interval: −6.98 to −5.69), with negligible heterogeneity across studies (I² = 0.0%). By contrast, among participants without DM (n = 7 studies), the weighted estimate of weight loss was −11.57% (95% confidence interval: −12.94 to −10.19), with moderate heterogeneity observed (I² = 63.6%). Conclusions: The observed difference in weight loss efficacy between the groups was clinically meaningful. While once-weekly semaglutide at 2.4 mg elicited significant weight loss in both populations, the magnitude of effect was notably greater in those without DM. This disparity may be explained by metabolic characteristics frequently present in individuals with DM, such as insulin resistance, hyperinsulinemia, and compensatory mechanisms related to glycemic control. Full article

(This article belongs to the Section Pharmacology)

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24 pages, 1532 KB

Open AccessReview

Polymeric Nanoparticle-Mediated Photodynamic Therapy: A Synergistic Approach for Glioblastoma Treatment

by Bandar Aldhubiab and Rashed M. Almuqbil

Pharmaceuticals 2025, 18(7), 1057; https://doi.org/10.3390/ph18071057 - 18 Jul 2025

Viewed by 600

Abstract

Glioblastoma is the most common and aggressive malignant primary brain tumour. Patients with glioblastoma have a median survival of only around 14.6 months after diagnosis, despite the availability of various conventional multimodal treatments including chemotherapy, radiation therapy, and surgery. Therefore, photodynamic therapy (PDT) [...] Read more.

Glioblastoma is the most common and aggressive malignant primary brain tumour. Patients with glioblastoma have a median survival of only around 14.6 months after diagnosis, despite the availability of various conventional multimodal treatments including chemotherapy, radiation therapy, and surgery. Therefore, photodynamic therapy (PDT) has emerged as an advanced, selective and more controlled therapeutic approach, which has minimal systemic toxicity and fewer side effects. PDT is a less invasive therapy that targets all cells or tissues that possess the photosensitizer (PS) itself, without affecting the surrounding healthy tissues. Polymeric NPs (PNPs) as carriers can improve the targeting ability and stability of PSs and co-deliver various anticancer agents to achieve combined cancer therapy. Because of their versatile tuneable features, these PNPs have the capacity to open tight junctions of the blood–brain barrier (BBB), easily transport drugs across the BBB, protect against enzymatic degradation, prolong the systemic circulation, and sustainably release the drug. Conjugated polymer NPs, poly(lactic-co-glycolic acid)-based NPs, lipid–polymer hybrid NPs, and polyethylene-glycolated PNPs have demonstrated great potential in PDT owing to their unique biocompatibility and optical properties. Although the combination of PDT and PNPs has great potential and can provide several benefits over conventional cancer therapies, there are several limitations that are hindering its translation into clinical use. This review aims to summarize the recent advances in the combined use of PNPs and PDT in the case of glioblastoma treatment. By evaluating various types of PDT and PNPs, this review emphasizes how these innovative approaches can play an important role in overcoming glioblastoma-associated critical challenges, including BBB and tumour heterogeneity. Furthermore, this review also discusses the challenges and future directions for PNPs and PDT, which provides insight into the potential solutions to various problems that are hindering their clinical translation in glioblastoma treatment. Full article

(This article belongs to the Special Issue Tumor Therapy and Drug Delivery)

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21 pages, 1210 KB

Open AccessArticle

Taurine-Based Hybrid Drugs as Potential Anticancer Therapeutic Agents: In Vitro, In Vivo Evaluations

by Saltanat Nakypova, Andrey Smolobochkin, Tanzilya Rizbayeva, Rakhymzhan Turmanov, Almir Gazizov, Nurgali Akylbekov, Rakhmetulla Zhapparbergenov, Roza Narmanova, Saltanat Ibadullayeva, Alena Zalaltdinova, Marat Syzdykbayev, Julia Voronina, Anna Lyubina, Alexandra Voloshina, Elena Klimanova, Tatiana Sashenkova, Denis Mishchenko and Alexander Burilov

Pharmaceuticals 2025, 18(7), 1056; https://doi.org/10.3390/ph18071056 - 18 Jul 2025

Viewed by 575

Abstract

Background/Objectives: The development of antitumor agents possessing low toxicity against non-cancerous cells is still a challenge in medicinal chemistry. In this paper, we report the antitumor activity of “hybrid structures” derived from the amino acid taurine. We have synthesized 26 compounds, structures [...] Read more.

Background/Objectives: The development of antitumor agents possessing low toxicity against non-cancerous cells is still a challenge in medicinal chemistry. In this paper, we report the antitumor activity of “hybrid structures” derived from the amino acid taurine. We have synthesized 26 compounds, structures of which were confirmed using NMR, X-ray diffractometry, and other techniques. Cytotoxicity of the obtained compounds has been evaluated using three human cancer cell lines. Pyrrolidine 4p has exhibited the strongest antiproliferative activity against HL-60 cells with an IC₅₀ of 76.7 μM, while IC₅₀ against normal cells was 176.3 μM. Water-soluble derivatives of taurine have been tested for antileukemia activity in mice of the BDF1 line. Compound 4p has been identified as the leading compound, which increases the mean survival time of mice from 40 to 100% as compared to the control group. Together, these results prove that taurine-based hybrid structures can be a promising scaffold for the discovery of potential antiproliferative agents. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs: 2nd Edition)

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5 pages, 182 KB

Open AccessEditorial

Pharmacology and Toxicology of Opioids—Recent Advances and New Perspectives

by Joana Barbosa, Ricardo Jorge Dinis-Oliveira and Juliana Faria

Pharmaceuticals 2025, 18(7), 1055; https://doi.org/10.3390/ph18071055 - 18 Jul 2025

Viewed by 589

Abstract

This Special Issue of Pharmaceuticals comprises one review and four original research articles that explore the multifaceted pharmacological and toxicological profiles of both classical and atypical opioids across different clinical contexts and biological models [...] Full article

(This article belongs to the Special Issue Pharmacology and Toxicology of Opioids)

34 pages, 8372 KB

Open AccessArticle

Supercomputing Multi-Ligand Modeling, Simulation, Wavelet Analysis and Surface Plasmon Resonance to Develop Novel Combination Drugs: A Case Study of Arbidol and Baicalein Against Main Protease of SARS-CoV-2

by Hong Li, Hailong Su, Akari Komori, Shuxuan Yang, Hailang Luo, Angela Wei Hong Yang, Xiaomin Sun, Hongwei Li, Andrew Hung and Xiaoshan Zhao

Pharmaceuticals 2025, 18(7), 1054; https://doi.org/10.3390/ph18071054 - 17 Jul 2025

Viewed by 457

Abstract

Background/Objectives: Combination therapies using traditional Chinese medicine and Western drugs have gained attention for their enhanced therapeutic effects and reduced side effects. Toujie Quwen Granules (TQG), known for its antiviral properties, particularly against respiratory viruses, could offer new treatment strategies when combined [...] Read more.

Background/Objectives: Combination therapies using traditional Chinese medicine and Western drugs have gained attention for their enhanced therapeutic effects and reduced side effects. Toujie Quwen Granules (TQG), known for its antiviral properties, particularly against respiratory viruses, could offer new treatment strategies when combined with antiviral drugs like arbidol, especially for diseases such as Coronavirus disease. This study investigates the synergistic mechanisms between arbidol and components from TQG against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^pro). Methods: We identified compounds from TQG via existing data. Multi-ligand molecular docking, pharmacokinetic/toxicity screening, and preliminary simulations were performed to assess potential synergistic compounds with arbidol. UPLC-Q-Exactive Orbitrap-MS verified the presence of these compounds. Extended simulations and in vitro assays, including Luciferase and surface plasmon resonance, validated the findings. Results: Five compounds interacted with arbidol in synergy based on docking and preliminary dynamics simulation results. Only Baicalein (HQA004) could be identified in the herbal remedy by untargeted metabolomics, with ideal pharmacokinetic properties, and as a non-toxic compound. Extended simulations revealed that HQA004 enhanced arbidol’s antiviral activity via a “Far” Addition Mechanism #2, with an optimal 2:1 arbidol:HQA004 ratio. The movements of arbidol (diffusion and intramolecular conformational shifts) in the system were significantly reduced by HQA004, which may be the main reason for the synergism that occurred. In vitro experiments confirmed an increased inhibition of M^pro by the combination. Conclusions: HQA004 demonstrated synergistic potential with arbidol in inhibiting M^pro. The development of combination therapies integrating Western and herbal medicine is supported by these findings for effective antiviral treatments. Full article

(This article belongs to the Special Issue Antiviral Agents, 2024)

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24 pages, 3848 KB

Open AccessArticle

Synthesis and Biological Evaluation of Herceptin-Conjugated Liposomes Loaded with Lipocalin-2 siRNA for the Treatment of Inflammatory Breast Cancer

by Marienid Flores-Colón, Mariela Rivera-Serrano, Esther A. Peterson-Peguero, Pablo E. Vivas-Rivera, Fatima Valiyeva and Pablo E. Vivas-Mejía

Pharmaceuticals 2025, 18(7), 1053; https://doi.org/10.3390/ph18071053 - 17 Jul 2025

Viewed by 391

Abstract

Background: Inflammatory breast cancer (IBC) is a rare and aggressive subtype of breast cancer that accounts for 1–5% of BC patients and regularly affects women under 40 years of age. Approximately 50% of IBC cases are HER2+ and can be treated with the [...] Read more.

Background: Inflammatory breast cancer (IBC) is a rare and aggressive subtype of breast cancer that accounts for 1–5% of BC patients and regularly affects women under 40 years of age. Approximately 50% of IBC cases are HER2+ and can be treated with the monoclonal antibody-based therapy Herceptin (trastuzumab). However, resistance to Herceptin develops within a year, and effective second-line targeted therapies are currently unavailable for IBC patients. Lipocalin-2 (LCN2) is a promising therapeutic target for IBC due to its role in promoting tumor invasiveness, angiogenesis, and the inflammatory tumor microenvironment characteristic of IBC. Objective: We developed Herceptin-conjugated liposomes loaded with LCN2-targeted small-interference RNA (siRNA) for HER2+ IBCs. Methods: We synthesized DSPE-PEG(2000)-maleimide-Herceptin in a three-step process and formulated the liposomes together with DOPC, PEG(2000)-PE, cholesterol, and siRNA. Results: Dynamic light scattering confirmed the liposome size distribution, which was 66.7 nm for the Herceptin-conjugated liposome versus 43.0 nm in a non-functionalized liposome. Here, we report efficient internalization of this formulation into HER2+ IBC cells, reducing LCN2 levels by 30% and disrupting tumor emboli formation. RNA sequencing revealed 139 genes that were differentially expressed upon LCN2 knockdown, with 25 canonical pathways identified through Ingenuity Pathway Analysis. Conclusions: These findings suggest that LCN2-targeted siRNA within Herceptin-targeted liposomes represents a promising therapeutic strategy for IBC. Full article

(This article belongs to the Section Medicinal Chemistry)

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30 pages, 10669 KB

Open AccessArticle

Integration of Untargeted Metabolomics, Network Pharmacology, Single-Cell RNA Sequencing, and Molecular Dynamics Simulation Reveals GOT1, CYP1A2, and CA2 as Potential Targets of Huang Qin Decoction Preventing Colorectal Cancer Liver Metastasis

by Tiegang Li, Zheng Yan, Mingxuan Zhou, Wenyi Zhao, Fang Zhang, Silin Lv, Yufang Hou, Zifan Zeng, Liu Yang, Yixin Zhou, Zengni Zhu, Xinyi Ren and Min Yang

Pharmaceuticals 2025, 18(7), 1052; https://doi.org/10.3390/ph18071052 - 17 Jul 2025

Viewed by 622

Abstract

Background: Huang Qin Decoction (HQD) is a well-established Traditional Chinese Medicine (TCM) formulation recognized for its application in the treatment of colorectal cancer (CRC). However, the precise therapeutic mechanisms remain inadequately defined. Methods: This study integrates metabolomics from a mouse model and network [...] Read more.

Background: Huang Qin Decoction (HQD) is a well-established Traditional Chinese Medicine (TCM) formulation recognized for its application in the treatment of colorectal cancer (CRC). However, the precise therapeutic mechanisms remain inadequately defined. Methods: This study integrates metabolomics from a mouse model and network pharmacology to screen potential targets and bio-active ingredients of HQD. The pharmacological activity of HQD for CRC was evidenced via single-cell RNA sequencing (scRNA-seq), molecular docking, and molecular dynamics simulations. Atomic force microscopy (AFM) assays and cellular experimental validation were used to confirm the relative mechanisms. Results: The metabolite profile undergoes significant alterations, with metabolic reprogramming evident during the malignant progression of CRC liver metastasis. Network pharmacology analysis identified that HQD regulates several metabolic pathways, including arginine biosynthesis, alanine, aspartate, and glutamate metabolism, nitrogen metabolism, phenylalanine metabolism, and linoleic acid metabolism, by targeting key proteins such as aspartate aminotransferase (GOT1), cytochrome P450 1A2 (CYP1A2), and carbonic anhydrase 2 (CA2). ScRNA-seq analysis indicated that HQD may enhance the functionality of cytotoxic T cells, thereby reversing the immunosuppressive microenvironment. Virtual verification revealed a strong binding affinity between the identified hub targets and active constituents of HQD, a finding subsequently corroborated by AFM assays. Cellular experiments confirmed that naringenin treatment inhibits the proliferation, migration, and invasion of CRC cells by downregulating GOT1 expression and disrupting glutamine metabolism. Conclusions: Computational prediction and in vitro validation reveal the active ingredients, potential targets, and molecular mechanisms of HQD against CRC liver metastasis, thereby providing a scientific foundation for the application of TCM in CRC treatment. Full article

(This article belongs to the Section Natural Products)

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32 pages, 3865 KB

Open AccessArticle

Purine–Hydrazone Scaffolds as Potential Dual EGFR/HER2 Inhibitors

by Fatemah S. Albalawi, Mashooq A. Bhat, Ahmed H. Bakheit, A. F. M. Motiur Rahman, Nawaf A. Alsaif, Alan M. Jones and Isolda Romero-Canelon

Pharmaceuticals 2025, 18(7), 1051; https://doi.org/10.3390/ph18071051 - 17 Jul 2025

Viewed by 675

Abstract

Background/Objectives: The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new series of purine-containing hydrazones, 6 [...] Read more.

Background/Objectives: The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new series of purine-containing hydrazones, 6–24 (a,b), as anticancer agents targeting EGFR and HER2 kinases. Methods: The proposed compounds were initially screened in silico using molecular docking to investigate their binding affinity to the active sites of EGFR and HER2 kinase domains. Subsequently, the compounds were synthesized and evaluated in vitro for their antiproliferative activity, using the MTT assay, against the various cancer cell lines A549, SKOV-3, A2780, and SKBR-3, with lapatinib as the reference drug. The most active derivatives were then examined to determine their inhibitory activity against EGFR and HER2 kinases. Results: Among the assessed compounds, significant antiproliferative activity was demonstrated by 19a, 16b, and 22b. 19a exhibited substantial anticancer efficacy against A549 and SKBR-3, with IC₅₀ values of 0.81 µM and 1.41 µM, respectively. This activity surpassed lapatinib, which has an IC₅₀ of 11.57 µM on A549 and 8.54 µM on SKBR-3 cells. Furthermore, 19a, 16b, and 22b exhibited superior EGFR inhibitory efficacy compared with lapatinib (IC₅₀ = 0.13 µM), with IC₅₀ values of 0.08, 0.06, and 0.07 µM, respectively. Regarding HER2, 22b demonstrated the greatest potency with an IC₅₀ of 0.03 µM, equipotent to lapatinib (IC₅₀ = 0.03 µM). Flow cytometry analysis of A549 cells treated with 19a and 22b indicated their ability to arrest the cell cycle during the G1 phase and to trigger cellular apoptosis. Conclusions: Compounds 19a, 16b, and 22b represent intriguing candidates for the development of an anticancer agent targeting EGFR and HER2 kinases. Full article

(This article belongs to the Section Medicinal Chemistry)

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18 pages, 5900 KB

Open AccessArticle

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Modulate Chemoradiotherapy Response in Cervical Cancer Spheroids

by Kesara Nittayaboon, Piyatida Molika, Rassanee Bissanum, Kittinun Leetanaporn, Nipha Chumsuwan and Raphatphorn Navakanitworakul

Pharmaceuticals 2025, 18(7), 1050; https://doi.org/10.3390/ph18071050 - 17 Jul 2025

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Abstract

Background: Bone marrow mesenchymal stem cells (BM-MSCs) are significant in chemo- and radiotherapy resistance. Previous research has focused on BM-MSCs, demonstrating their functional involvement in cancer progression as mediators in the tumor microenvironment. They play multiple roles in tumorigenesis, angiogenesis, and metastasis. BM-MSC-derived [...] Read more.

Background: Bone marrow mesenchymal stem cells (BM-MSCs) are significant in chemo- and radiotherapy resistance. Previous research has focused on BM-MSCs, demonstrating their functional involvement in cancer progression as mediators in the tumor microenvironment. They play multiple roles in tumorigenesis, angiogenesis, and metastasis. BM-MSC-derived exosomes (BM-MSCs-exo) are small vesicles, typically 50–300 nm in diameter, isolated from BM-MSCs. Some studies have demonstrated the tumor-suppressive effects of BM-MSCs-exo. Objective: This study aimed to investigate their role in modulating the impact of chemoradiotherapy (CRT) in different types of cervical cancer spheroid cells. Methods: The spheroids after treatment were subject to size measurement, cell viability, and caspase activity. Then, the molecular mechanism was elucidated by Western blot analysis. Results: We observed a reduction in spheroid size and an increase in cell death in HeLa spheroids, while no significant changes in size or cell viability were found in SiHa spheroids. At the molecular level, CRT treatment combined with BM-MSCs-exo in HeLa spheroids induced apoptosis through the activation of the NF-κB pathway, specifically via the NF-κB1 (P50) transcription factor, leading to the upregulation of apoptosis-related molecules. In contrast, CRT combined with BM-MSCs-exo in SiHa spheroids exhibited an opposing effect: although cellular viability decreased, caspase activity also decreased, which correlated with increased HSP27 expression and the subsequent downregulation of apoptotic molecules. Conclusion: Our study provides deeper insight into the potential of BM-MSCs-exo in cervical cancer treatment, supporting the development of more effective and safer therapeutic strategies for clinical application. Full article

(This article belongs to the Special Issue 2D and 3D Culture Systems: Current Trends and Biomedical Applications)

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Pharmaceuticals, Volume 18, Issue 7 (July 2025) – 148 articles

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