Pharmaceuticals

35 pages, 457 KB

Open AccessEditor’s ChoiceReview

Hybrid Cooperative Complexes of Low- and High-Molecular-Weight Hyaluronic Acid in Aesthetic Medicine

by Goran Tintor, Tin Cohadzic, Josipa Bukic, Dario Leskur, Lovre Zekan, Doris Rusic and Mladen Dudukovic

Pharmaceuticals 2026, 19(1), 73; https://doi.org/10.3390/ph19010073 - 30 Dec 2025

Viewed by 2105

Abstract

In this review we present a comprehensive overview of the published literature related to the use of Hybrid Cooperative Complexes (HCCs) of low- and high-molecular-weight hyaluronic acid in aesthetic medicine. HCCs have been developed to overcome the shortcomings of traditional hyaluronic based dermal [...] Read more.

In this review we present a comprehensive overview of the published literature related to the use of Hybrid Cooperative Complexes (HCCs) of low- and high-molecular-weight hyaluronic acid in aesthetic medicine. HCCs have been developed to overcome the shortcomings of traditional hyaluronic based dermal fillers. Specifically, HCCs deliver both high- and low-molecular-weight hyaluronic acid (HA), maximizing their complementary effects. They are biocompatible and formulated without the addition of foreign agents. Cooperative hydrogen bonds extend their durability and make them more resistant to hyaluronidase compared to high-molecular-weight HA. The rheological properties of HCC formulations allow for easy exertion through the needle and diffusion in the tissue compared to high-molecular-weight HA alone. In vitro studies have shown that HCCs improve vitality of fibroblasts, keratinocytes and adipocytes, and stimulate production of collagen and elastin. Studies on scratched co-cultures of immortalized human keratinocytes and human dermal fibroblasts demonstrated that HCCs accelerate wound closure. Furthermore, HCCs delayed senescence of mesenchymal stromal cells to a greater extent than high-molecular-weight HA or low-molecular-weight HA alone. Clinical studies show a reduction in wrinkle severity, improvement in skin roughness profile and reduction of skin laxity with pronounced improvement in superficial skin hydration lasting up to 6 months. The formulation intended for restoration of fat compartments demonstrated reduction in cheek volume loss and improvement in skin thickness. Subjects report moderate-to-high satisfaction and are likely to recommend the treatment. Limitations of the published studies are also addressed, as well as reported adverse events and published safety data. Full article

(This article belongs to the Special Issue Bioactive Substances and Skin Health: The Role of Pharmacy and Nutrition—Properties and Technology)

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24 pages, 1512 KB

Open AccessEditor’s ChoiceReview

Puberty Starts in the Gut: Intestinal Clues to Early Puberty-Rethinking Biomarkers in Pediatric Endocrinology

by Otilia Elena Frăsinariu, Teodora Cristina Vintilă, Ioana Vasiliu, Violeta Ștreangă, Aniela Rugină, Oana Raluca Temneanu, Ionuț Daniel Iancu, Andreea Iațentiuc, Elena Jechel and Alexandru Florescu

Pharmaceuticals 2026, 19(1), 49; https://doi.org/10.3390/ph19010049 - 25 Dec 2025

Cited by 2 | Viewed by 2033

Abstract

Central precocious puberty (CPP) may be influenced by gut microbiota through changes in short-chain fatty acids (SCFAs), β-glucuronidase activity, and enterohepatic estrogen recycling. This narrative review integrates current evidence from human and animal studies exploring microbial contributions to pubertal timing. Across multiple cohorts, [...] Read more.

Central precocious puberty (CPP) may be influenced by gut microbiota through changes in short-chain fatty acids (SCFAs), β-glucuronidase activity, and enterohepatic estrogen recycling. This narrative review integrates current evidence from human and animal studies exploring microbial contributions to pubertal timing. Across multiple cohorts, CPP is associated with loss of SCFA-producing commensals, such as Bacteroides, and increased abundance of taxa like Alistipes, Ruminococcus, and Lachnoclostridium. These microbial shifts are linked to altered SCFA profiles, diminished anti-inflammatory and neuroendocrine modulation, and enhanced reabsorption of estrogens via microbial β-glucuronidase activity. Experimental models support a causal connection: gut dysbiosis accelerates pubertal onset, whereas microbiota-targeted interventions can restore hormonal balance and delay activation of the HPG axis. While some overlap with obesity-associated microbiota exists, the endocrine-specific microbial changes observed in CPP suggest partially distinct mechanisms. Overall, the gut microbiota emerges as both a modulator and potential biomarker of early pubertal onset. Its integration into pediatric endocrine frameworks could improve early risk assessment and guide future interventions, though further validation through standardized, longitudinal, and diverse population studies is still required. Full article

(This article belongs to the Special Issue The Regulatory Roles of the Gut Microbiota in Multisystem Diseases)

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39 pages, 1367 KB

Open AccessEditor’s ChoiceReview

The Therapeutic Pipeline for Eosinophilic Esophagitis: Current Landscape and Future Directions

by Andrea Pasta, Luisa Bertin, Amir Mari, Francesco Calabrese, Amir Farah, Giulia Navazzotti, Matteo Ghisa, Vincenzo Savarino, Edoardo Vincenzo Savarino, Edoardo Giovanni Giannini and Elisa Marabotto

Pharmaceuticals 2025, 18(12), 1882; https://doi.org/10.3390/ph18121882 - 12 Dec 2025

Cited by 2 | Viewed by 3586

Abstract

Eosinophilic esophagitis (EoE) has emerged as a major cause of dysphagia and food impaction worldwide. This narrative review traces the evolving therapeutic pipeline for EoE, highlighting agents spanning from late-stage clinical development to final approval. We summarize mechanistic insights that have driven a [...] Read more.

Eosinophilic esophagitis (EoE) has emerged as a major cause of dysphagia and food impaction worldwide. This narrative review traces the evolving therapeutic pipeline for EoE, highlighting agents spanning from late-stage clinical development to final approval. We summarize mechanistic insights that have driven a shift from broad immunosuppression to precise inhibition of type-2 inflammatory pathways, including blockade of key interleukin pathways. Randomized trials have demonstrated histologic and symptomatic gains, yet regulatory approvals and optimal positioning within treatment algorithms are pending. Parallel innovations in drug delivery aim to maximize mucosal exposure while minimizing systemic burden. Key challenges include heterogeneity in disease phenotype, paucity of long-term safety data, and the need for non-invasive biomarkers to guide precision prescribing. Cost considerations and patient preferences will shape adoption. By integrating advances across immunology, formulation science and clinical trial design, the therapeutic pipeline for EoE holds promise to transform care from empirical suppression to mechanism-based disease modification. Full article

(This article belongs to the Special Issue New and Emerging Treatment Strategies for Gastrointestinal Diseases)

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24 pages, 3190 KB

Open AccessEditor’s ChoiceArticle

Ga-68-Labeled Affibody Molecule-Based Radiopharmaceutical Targeting Platelet Derived Growth Factor Receptor Beta for Detection of Active Fibrosis in Patients with Myocardial Infarction

by Irina Velikyan, Karl-Henrik Grinnemo, Viktor Flodin, Stefan James, Ulrika Thelander, Michael Wagner, Sergey Rodin, Tanja Kero, Olle Korsgren and Olof Eriksson

Pharmaceuticals 2025, 18(12), 1833; https://doi.org/10.3390/ph18121833 - 1 Dec 2025

Cited by 1 | Viewed by 959

Abstract

Introduction: Platelet-derived growth factor receptor beta (PDGFRβ) is a key regulator of fibrogenesis. Non-invasive imaging of PDGFRβ expression may offer a novel approach to assess fibrotic remodeling, particularly in cardiac patients’ post-intervention, where fibrosis poses clinical risk. This study presents the GMP-compliant [...] Read more.

Introduction: Platelet-derived growth factor receptor beta (PDGFRβ) is a key regulator of fibrogenesis. Non-invasive imaging of PDGFRβ expression may offer a novel approach to assess fibrotic remodeling, particularly in cardiac patients’ post-intervention, where fibrosis poses clinical risk. This study presents the GMP-compliant production of a novel PDGFRβ-targeted PET radiopharmaceutical, [⁶⁸Ga]Ga-DOTA-Z09591 ([⁶⁸Ga]Ga-ATH001), and its preclinical evaluation in mouse and human myocardial tissue, along with initial clinical imaging in patients with ST-elevation myocardial infarction (STEMI). Methods: The precursor was chemically synthesized and radiolabeled with gallium-68 using a fully automated, GMP-compatible system and a pharmaceutical-grade ⁶⁸Ge/⁶⁸Ga generator. Autoradiography, H&E, Sirius Red, Masson’s trichrome, and IHC staining were performed on infarcted mouse hearts and human myocardial biopsies. In vivo PET/MRI with [⁶⁸Ga]Ga-ATH001, ¹⁵O-H₂O, and gadolinium contrast was conducted in STEMI patients one week post-percutaneous coronary intervention. Results: [⁶⁸Ga]Ga-ATH001 was produced with high radiochemical yield and purity. Autoradiography demonstrated specific, receptor-mediated binding of [⁶⁸Ga]Ga-ATH001, co-localizing with PDGFRβ immunoreactivity, collagen deposition, and tissue damage. In STEMI patients, focal tracer uptake was observed in infarcted myocardium correlating with MRI-detected structural abnormalities and perfusion defects on ¹⁵O-H₂O PET. Uptake in unaffected myocardium was low and homogeneous, consistent with minimal physiological PDGFRβ expression. Conclusions: [⁶⁸Ga]Ga-ATH001 was successfully developed and validated for phase 0 clinical study. The tracer demonstrated PDGFRβ-specific binding in human fibrotic myocardium and enabled non-invasive detection of myocardial fibrogenic activity in STEMI patients. These findings support further clinical evaluation of [⁶⁸Ga]Ga-ATH001 as a targeted molecular imaging agent for early assessment of post-infarction fibrosis. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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22 pages, 22951 KB

Open AccessEditor’s ChoiceReview

Advancing PROTAC Discovery Through Artificial Intelligence: Opportunities, Challenges, and Future Directions

by Kwang-Su Park and Minji Jeon

Pharmaceuticals 2025, 18(12), 1793; https://doi.org/10.3390/ph18121793 - 25 Nov 2025

Cited by 5 | Viewed by 3296

Abstract

Proteolysis Targeting Chimeras (PROTACs) represent a transformative modality in drug discovery, enabling the selective degradation of disease-relevant proteins through the ubiquitin proteasome system. Despite their therapeutic promise, the rational design of PROTACs remains a complex and resource-intensive process, involving multiple parameters such as [...] Read more.

Proteolysis Targeting Chimeras (PROTACs) represent a transformative modality in drug discovery, enabling the selective degradation of disease-relevant proteins through the ubiquitin proteasome system. Despite their therapeutic promise, the rational design of PROTACs remains a complex and resource-intensive process, involving multiple parameters such as target and ligase compatibility, ternary complex formation, linker optimization, and degradation efficiency. Recent advances in artificial intelligence (AI) have provided new strategies to address these obstacles, ranging from structure-based modeling of ternary complexes to degradability prediction, generative linker design, and pharmacokinetic property estimation. This review aims to explore how AI can be leveraged directly or indirectly in the PROTAC development pipeline. First, we analyze existing applications of AI, such as ternary complex structure prediction, degradability prediction, linker design, and ADME prediction. We further discuss how other approaches from the related fields may be adapted to address the challenges of PROTAC discovery. Lastly, we discuss challenges that current AI models face, such as limited data, poor interpretability, and low generalizability. Taken together, overcoming these barriers will enable AI-driven strategies to accelerate PROTAC discovery and provide a more rational framework for targeted protein degrader development. Full article

(This article belongs to the Special Issue Computer-Aided Drug Design and Drug Discovery, 2nd Edition)

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21 pages, 2981 KB

Open AccessEditor’s ChoiceArticle

Impact of Ethanol on Electrostatic Behaviour of Fluorocarbon Pharmaceutical Propellants

by Lochana Ranatunge, Manoochehr Rasekh, Hussein Ahmad and Wamadeva Balachandran

Pharmaceuticals 2025, 18(11), 1755; https://doi.org/10.3390/ph18111755 - 18 Nov 2025

Cited by 1 | Viewed by 788

Abstract

Background/Objectives: Triboelectrification in fluid systems, and specifically in hydrofluorocarbon (HFC)-based propellants, used in pressurised metered-dose inhalers (pMDIs) remains understudied despite its impact on aerosol behaviour and does delivery. This study investigates how ethanol concentration affects charge generation and dissipation in HFC-152a (1,1-difluoroethane; R152a) [...] Read more.

Background/Objectives: Triboelectrification in fluid systems, and specifically in hydrofluorocarbon (HFC)-based propellants, used in pressurised metered-dose inhalers (pMDIs) remains understudied despite its impact on aerosol behaviour and does delivery. This study investigates how ethanol concentration affects charge generation and dissipation in HFC-152a (1,1-difluoroethane; R152a) flowing through low-density polyethylene (LDPE) tubing, a common valve-stem material in pMDIs. Methods: Controlled experiments measured electrical current, charge accumulation, and flow stability for HFC-152a with varying ethanol concentrations in LDPE tubing. Statistical analysis (two-way ANOVA, p < 0.05) assessed the effects of the propellant and material. Comparative tests include R134a (1,1,1,2-tetrafluoroethane) and R227ea (1,1,1,2,3,3,3-heptafluoropropane), and the tubing materials are polybutylene terephthalate (PBT), polyvinyl chloride (VINYL), polyoxymethylene (POM), and LDPE. Results: Increasing ethanol concentration produced larger measured currents, reduced net charge accumulation, and improved flow stability; these effects are attributed to ethanol’s higher dielectric constant and conductivity enhancing charge mobility and dissipation. Significant propellant x material interactions were found (p < 0.05): R152a generated the largest responses with PBT and VINYL (~16 nA and ~5.6 nA, respectively), R227ea showed higher responses with POM and LDPE (~8 nA), and R134a delivered the highest flow rates across materials but exhibited limited electrical responsiveness. Conclusions: Ethanol addition mitigates undesirable electrostatic effects in HFC-based propellants by promoting charge dissipation. The results demonstrate the strong material dependence of triboelectric behaviour and underline the importance of optimising propellant–polymer pairings to minimise the electrostatic adhesion of aerosolised particles and improve pMDI drug delivery performance. Full article

(This article belongs to the Special Issue Advances in Drug Analysis and Drug Development, 2nd Edition)

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20 pages, 1717 KB

Open AccessEditor’s ChoiceArticle

Coleus aromaticus Benth.—A Plant with Strong Anticancer and Antioxidant Potential In Vitro

by Justyna Stefanowicz-Hajduk, Anna Hering, Rafał Hałasa, Szymon Masiak, Karolina Turczyn, J. Renata Ochocka and Monika Asztemborska

Pharmaceuticals 2025, 18(11), 1756; https://doi.org/10.3390/ph18111756 - 18 Nov 2025

Viewed by 1503

Abstract

Background/Objectives: Gastrointestinal cancers, including gastric and colon cancers, constitute a serious threat to global health due to their high incidence and limited treatment outcomes. Thus, natural products are becoming increasingly popular as potential chemopreventive agents. Coleus aromaticus Benth. is mainly used as [...] Read more.

Background/Objectives: Gastrointestinal cancers, including gastric and colon cancers, constitute a serious threat to global health due to their high incidence and limited treatment outcomes. Thus, natural products are becoming increasingly popular as potential chemopreventive agents. Coleus aromaticus Benth. is mainly used as a tasty addition to dishes and juices due to its aromatic and nutritional properties. The plant has many biological and pharmacological effects that require deeper evaluation. In this study, anticancer, antioxidant, and antimicrobial activities of ethanol, ethanol/water extracts, and juice from C. aromaticus leaves were evaluated. Methods: (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) MTT assay, DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonate)), molybdenum reducing power assay, and broth microdilution technique were used, respectively. Additionally, total phenolic (TPC) and total flavonoid content (TFC) with basic phytochemical composition of volatile compounds by GC-MS and GC-FID were assessed. Results: The results indicate that the strongest anticancer activity was provided by the ethanol extract with IC₅₀ values of 4.94 ± 0.48 and 24.99 ± 1.80 µg/mL on human gastric AGS cells and human colorectal HCT 116 cells, respectively. The antioxidant potential was also the highest for the ethanol extract with IC₅₀ values of 13.34 ± 0.11 (ABTS), 22.90 ± 1.30 (DPPH), and 290.17 ± 4.23 µg/mL (molybdenum reducing power). Antimicrobial experiments revealed that ethanol and ethanol/water extracts were the most potent on Clostridium perfringens (MIC value was <0.02 mg/mL). Phytochemical analysis showed a significant content of phenolic and flavonoid compounds in the ethanol extract (75.87 ± 0.96 mg gallic acid equivalent/g dry extract and 176.01 ± 3.58 mg quercetin equivalent/g dry extract, respectively). Furthermore, all the extracts contained carvacrol (49.09, 28.15, and 25.68% of volatile fraction in ethanol, ethanol/water extracts and juice, respectively). Camphor and oleamide were also detected in large quantity. Conclusions: C. aromaticus can be considered as a potential agent in the prevention and treatment of gastrointestinal cancers, especially the ethanol extract from the plant leaves due to its strong anticancer and antioxidant properties. Full article

(This article belongs to the Special Issue Natural Compounds as Potential Anticancer, Anti-inflammatory and Antioxidant Agents in Medicine)

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14 pages, 1862 KB

Open AccessEditor’s ChoiceArticle

Genistein Inhibits Fine-Dust-Induced Matrix Metalloproteinase-1 in Human Keratinocytes

by Dong Keun Song, Yun Young Jeong, Eunmiri Roh, Hyun Young Shin and Jong-Eun Kim

Pharmaceuticals 2025, 18(11), 1750; https://doi.org/10.3390/ph18111750 - 17 Nov 2025

Viewed by 873

Abstract

Background/Objectives: Particulate matter (PM), which comprises airborne pollutants characterized by small sizes (typically from 5 to 8 μm in Korea), adversely affect skin health and accelerate aging by inducing oxidative stress and upregulating the expression of matrix metalloproteinase-1 (MMP-1), an enzyme responsible for [...] Read more.

Background/Objectives: Particulate matter (PM), which comprises airborne pollutants characterized by small sizes (typically from 5 to 8 μm in Korea), adversely affect skin health and accelerate aging by inducing oxidative stress and upregulating the expression of matrix metalloproteinase-1 (MMP-1), an enzyme responsible for collagen degradation. The skin, which is the largest organ and the primary barrier against harmful external stimuli such as air pollution, is particularly vulnerable to continuous PM exposure, which can cause skin aging and carcinogenesis. Given the effects of PM on skin aging, identifying compounds that can mitigate these adverse effects is crucial. Genistein is a naturally occurring isoflavone that has not been extensively studied in the context of PM-induced skin aging. Methods: In this study, we investigated the protective effects of genistein against PM-induced skin aging in HaCaT human keratinocytes. Results: Our results demonstrated that genistein treatment significantly reduced PM-induced MMP-1 expression, indicating a protective effect against collagen degradation. Additionally, genistein decreased the expression of the transcription factors activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB), both of which are involved in the regulation of MMP-1. Furthermore, genistein markedly reduced the production of reactive oxygen species (ROS), a key marker of oxidative stress induced by PM exposure. Conclusions: These findings suggest that genistein exerts protective effects against PM-induced skin aging by attenuating collagen degradation and oxidative stress, indicating its potential as a therapeutic agent for improving skin aging associated with PM exposure. Full article

(This article belongs to the Special Issue Bioactive Compounds Derived from Plants and Their Medicinal Potential, 2nd Edition)

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19 pages, 1231 KB

Open AccessEditor’s ChoiceReview

Potential Implications of Body Mass Composition Changes in Heart Failure Patients in the Era of SGLT2i, GLP-1 RA, and GIP/GLP-1 RA

by Katarzyna Gryglewska-Wawrzak, Agnieszka Kapłon-Cieślicka, Agnieszka Pawlak, Anna Tomaszuk-Kazberuk, Paweł Rubiś, Jacek Niedziela and Agata Bielecka-Dąbrowa

Pharmaceuticals 2025, 18(11), 1726; https://doi.org/10.3390/ph18111726 - 13 Nov 2025

Viewed by 1747

Abstract

Obesity is a complex, multifactorial disease wherein the excessive accumulation of adipose tissue leads to adverse health outcomes, such as diabetes, cardiovascular disease and musculoskeletal disorders. Obesity also impacts both the risk and the clinical prognosis of heart failure (HF). The accumulation of [...] Read more.

Obesity is a complex, multifactorial disease wherein the excessive accumulation of adipose tissue leads to adverse health outcomes, such as diabetes, cardiovascular disease and musculoskeletal disorders. Obesity also impacts both the risk and the clinical prognosis of heart failure (HF). The accumulation of adipose tissue results in metabolic dysregulation, including increased levels of pro-inflammatory cytokines and adipokines. These alterations are strongly associated with the development and progression of HF. Another significant comorbidity in patients with HF is sarcopenia, characterized by progressive loss of muscle mass and strength, affecting the quality of life. The study aims to critically synthesize the mechanisms by which modern pharmacological treatments—sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dual GIPR/GLP-1R agonists—modulate body mass composition, and to analyze the specific implications of these changes (e.g., visceral fat reduction versus lean mass loss) for heart failure (HF) prognosis and management. Full article

(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy, 2nd Edition)

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17 pages, 501 KB

Open AccessEditor’s ChoiceArticle

How Regulation 536/2014 Is Changing Academic Research with Therapeutic Radiopharmaceuticals: A Local Experience

by Valentina Di Iorio, Stefano Boschi, Erika Brugugnoli, Maddalena Sansovini, Federica Matteucci, Carla Masini and Manuela Monti

Pharmaceuticals 2025, 18(11), 1709; https://doi.org/10.3390/ph18111709 - 11 Nov 2025

Cited by 2 | Viewed by 990

Abstract

Background/Objectives: This report examines the future of academic studies involving investigational therapeutic radiopharmaceuticals within the framework of Regulation (EU) No. 536/2014. It discusses the impact of Good Manufacturing Practice (GMP) requirements (EudraLex-Volume 4-Good Manufacturing Practice guidelines) on the development of radiopharmaceuticals, based [...] Read more.

Background/Objectives: This report examines the future of academic studies involving investigational therapeutic radiopharmaceuticals within the framework of Regulation (EU) No. 536/2014. It discusses the impact of Good Manufacturing Practice (GMP) requirements (EudraLex-Volume 4-Good Manufacturing Practice guidelines) on the development of radiopharmaceuticals, based on local experience and analysis. Methods: The report was drafted by analysing multiple factors, including the European regulatory context regarding EMA guidance for investigational medicinal products (IMPs) and GMP requirements for radiopharmaceuticals, as well as position papers from various scientific associations. An analysis of all the relevant changes was conducted by a multidisciplinary team comprising radiopharmacists, nuclear medicine physicians, research experts and technology transfer specialists. They conducted a literature review to examine the clinical implications of the regulatory change and assess the impact of Regulation 536/2014 on academic clinical trials. Results: IRST has around 20 years’ experience in radiopharmaceutical clinical research. From 2008 to 2025, it conducted 16 clinical trials with radiopharmaceuticals under the Directive, and it is currently promoting five studies under the Regulation. During this time, more than 1000 patients were enrolled. The transition was based on staff training in quality documentation, the constitution of a contract research organisation (CRO) to ensure data quality and transfer, careful budget planning, the evaluation of innovative business models and the role of a Contract Development and Manufacturing Organization (CDMO). These integrated approaches enabled IRST to transform regulatory constraints into an opportunity to enhance its organisational model, improve data reliability, and strengthen its position as a centre of excellence for radiopharmaceutical research and production. Conclusions: The implementation of EU Regulation 536/2014 has significantly impacted academic research centres, especially those specialising in radiopharmaceuticals. Adhering to Good Manufacturing Practice (GMP) for therapeutic radiopharmaceuticals requires a considerable investment in infrastructure and personnel. However, the regulation also presents opportunities for research centres to enhance their capabilities. Meeting GMP standards can help institutions improve the quality and reliability of their clinical trials, potentially making them more competitive in the international research arena. Full article

(This article belongs to the Collection Will (Radio)Theranostics Hold Up in the 21st Century—and Why?)

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27 pages, 1334 KB

Open AccessEditor’s ChoiceReview

Cardiovascular Therapeutics at the Crossroads: Pharmacological, Genetic, and Digital Frontiers

by Erica Vetrano, Alfredo Caturano, Davide Nilo, Giovanni Di Lorenzo, Giuseppina Tagliaferri, Alessia Piacevole, Mariarosaria Donnarumma, Ilaria Iadicicco, Sabrina Picco, Simona Maria Moretto, Maria Rocco, Raffaele Galiero, Vincenzo Russo, Raffaele Marfella, Luca Rinaldi, Leonilde Bonfrate and Ferdinando Carlo Sasso

Pharmaceuticals 2025, 18(11), 1703; https://doi.org/10.3390/ph18111703 - 10 Nov 2025

Cited by 1 | Viewed by 2779

Abstract

Therapeutic innovation in cardiovascular medicine is rapidly overcoming the limitations of conventional strategies, providing more targeted, durable, and multidimensional solutions. Key advances include next-generation lipid-lowering agents such as PCSK9 inhibitors, inclisiran, and bempedoic acid, as well as metabolic drugs like SGLT2 inhibitors, GLP-1 [...] Read more.

Therapeutic innovation in cardiovascular medicine is rapidly overcoming the limitations of conventional strategies, providing more targeted, durable, and multidimensional solutions. Key advances include next-generation lipid-lowering agents such as PCSK9 inhibitors, inclisiran, and bempedoic acid, as well as metabolic drugs like SGLT2 inhibitors, GLP-1 receptor agonists, and dual GIP/GLP-1 agonists, which offer cardiovascular and renal benefits beyond glucose control. At the same time, gene therapies, RNA-based interventions, genome editing tools, and nanocarriers are paving the way for precision medicine tailored to individual patient profiles. In parallel, digital innovations, including artificial intelligence, remote monitoring, and telehealth platforms, are transforming care delivery by enhancing adherence, enabling earlier intervention, and refining risk stratification. Collectively, these developments signify a paradigm shift toward a more personalized, proactive, and systems-based model of cardiovascular care. Full article

(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy, 2nd Edition)

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27 pages, 2069 KB

Open AccessEditor’s ChoiceArticle

In Vitro and in Vivo Efficacy of Different Ointment Formulations Containing Centaurium erythraea Rafn. Aerial Extract

by Anett Jolán Karetka, Boglárka Papp, István Lekli, Ana-Maria Vlase, Annamária Pallag, Laura Grațiela Vicaș, Antonia-Maria Lestyán, Liza Józsa, Dóra Kósa, Ágota Pető, Zoltán Ujhelyi, Fruzsina Nacsa, Ildikó Bácskay, Pálma Fehér and Tünde Jurca

Pharmaceuticals 2025, 18(11), 1681; https://doi.org/10.3390/ph18111681 - 6 Nov 2025

Viewed by 2381

Abstract

Background: Centaurium erythraea Rafn. (C. erythraea) is a medicinal plant traditionally used in European folk medicine for the treatment of wounds, skin inflammations, and other dermatological conditions, in addition to its well-documented systemic antioxidant and anti-inflammatory effects. However, its [...] Read more.

Background: Centaurium erythraea Rafn. (C. erythraea) is a medicinal plant traditionally used in European folk medicine for the treatment of wounds, skin inflammations, and other dermatological conditions, in addition to its well-documented systemic antioxidant and anti-inflammatory effects. However, its topical applications remain insufficiently investigated, particularly using plant material collected from Romania. The purpose of this study was to prepare different ointment formulations containing C. erythraea Rafn. extract obtained from the aerial parts of the plant, using various excipients, and to evaluate their in vitro and in vivo efficacy. Methods: The phytochemical profile of C. erythraea extract was characterized using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The lyophilized extract was pre-dissolved in different solubilizing agents—Transcutol^® P (diethylene glycol monoethyl ether), Capryol^® 90 (propylene glycol monocaprylate), or a combination of both—and then incorporated into five ointment formulations. Texture analysis and an in vitro membrane diffusion study were performed. The antioxidant capacity of the formulations was assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, ferric reducing antioxidant power (FRAP), and total phenolic content (TPC) assays. Anti-inflammatory activity was evaluated in vitro using tumor necrosis factor-alpha (TNF-α)-induced interleukin-1 beta (IL-1β) production in human keratinocyte (HaCaT) cells, and in vivo using a carrageenan-induced rat paw edema model. Results: LC–MS/MS identified 18 polyphenolic compounds, with hyperoside (3.78 ± 0.05 µg/mL), protocatechuic acid (1.13 ± 0.06 µg/mL), chlorogenic acid (1.07 ± 0.06 µg/mL), and quercetin (0.53 ± 0.03 µg/mL) as the principal constituents. The formulation containing both Transcutol^® P and Capryol^® 90 exhibited the most pronounced antioxidant activity (65% DPPH inhibition; 69.71 ± 0.83 mg gallic acid equivalent/mL) and significantly reduced IL-1β levels by 45.7% compared to the inflamed control. In vivo, this formulation showed comparable anti-edematous effects to a methylprednisolone ointment. Furthermore, it demonstrated the highest skin permeation efficiency, with a quercetin diffusion coefficient of 35.12 × 10⁻⁵ cm²/min. Conclusions: These findings highlight the therapeutic potential of C. erythraea extract from aerial parts in topical formulations and underscore the enhancing role of Transcutol^® P and Capryol^® 90 in improving both the pharmacodynamic and pharmacokinetic properties of bioactive compounds. Full article

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

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16 pages, 3337 KB

Open AccessEditor’s ChoiceArticle

Comparison of Cholic Acid (MT921) and Deoxycholic Acid (DCA) in Fat Reduction Efficacy and Skin Adverse Reactions in Mini Pigs and Rodent Models

by Sujin Cho, Deu John M. Cruz, Minhee Shin, Jaeyoon Byun, Junho Lee and Seongsung Kwak

Pharmaceuticals 2025, 18(11), 1643; https://doi.org/10.3390/ph18111643 - 30 Oct 2025

Viewed by 3119

Abstract

Background/Objectives: This study compared fat reduction efficacy of cholic acid-based formulation (MT921) and deoxycholic acid (DCA), as well as skin adverse reactions (ADR), in mini pigs, mice, and rats. DCA is the active pharmaceutical ingredient found in several fat-dissolving injectables, such as Kybella [...] Read more.

Background/Objectives: This study compared fat reduction efficacy of cholic acid-based formulation (MT921) and deoxycholic acid (DCA), as well as skin adverse reactions (ADR), in mini pigs, mice, and rats. DCA is the active pharmaceutical ingredient found in several fat-dissolving injectables, such as Kybella^®, V-OLET^®, and Bellacholine^®. Methods: In one study, single subcutaneous (s.c.) injections of 1.5% MT921 and 1% DCA were administered to the back of a mini pig at different sites and time points to ascertain histopathological events. In another study, three mini pigs received six repeated s.c. injections of 1.5% MT921 and 1% DCA at 4-week intervals, and changes in subcutaneous fat volume were monitored by magnetic resonance imaging (MRI), along with visual examination for ADRs. Additional ADRs were assessed in rodents, such as ulcerative dermatitis (UD) following MT921 and DCA s.c. injections in ICR/CD1 mice, and footpad edema after intraplantar injections in SD rats. Results: In mini pigs, 1.5% MT921 and 1% DCA induced comparable localized fat necrosis, accompanied by inflammatory cell influx and fibrosis. Also, repeated injections of 1.5% MT921 and 1% DCA induced comparable fat volume reduction in outer subcutaneous layer, though changes in middle subcutaneous layer was unaffected. Notably, MT921 evoked milder ADR based on lower incidence of hematoma and absence of nodules in mini pigs, less severe UD in mice, and reduced edema in rats. Conclusions: Local injections of 1.5% MT921 demonstrated fat-reduction efficacy comparable to 1% DCA while eliciting fewer and milder ADRs, supporting MT921 as a promising alternative lipolytic agent. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 461 KB

Open AccessEditor’s ChoiceReview

Innovative Strategies to Enhance the Bioavailability of Cannabidiol: Nanotechnology and Advanced Delivery Systems

by Magdalena Paczkowska-Walendowska, Piotr Trzaskoma, Aleksandra Dziopa, Arash Moeini, Michał Soczawa, Zbigniew Krasiński and Judyta Cielecka-Piontek

Pharmaceuticals 2025, 18(11), 1637; https://doi.org/10.3390/ph18111637 - 29 Oct 2025

Cited by 5 | Viewed by 3777

Abstract

Cannabidiol (CBD), a phytocannabinoid with therapeutic potential for neurological and other conditions, faces significant challenges in bioavailability due to its low water solubility, high lipophilicity, and extensive first-pass metabolism. Researchers have developed advanced nanodelivery systems addressing these limitations to enhance CBD’s absorption, stability, [...] Read more.

Cannabidiol (CBD), a phytocannabinoid with therapeutic potential for neurological and other conditions, faces significant challenges in bioavailability due to its low water solubility, high lipophilicity, and extensive first-pass metabolism. Researchers have developed advanced nanodelivery systems addressing these limitations to enhance CBD’s absorption, stability, and efficacy. This review provides not only a comprehensive summary of current nanotechnological delivery strategies for CBD, including nanoemulsions, liposomes, polymeric micelles, nanosuspensions, and cyclodextrin inclusion complexes, but also introduces a distinct comparative and integrative perspective. Unlike previous reviews, our work synthesizes preclinical and clinical evidence while highlighting the novel integration of nanotechnology with bioenhancers and personalized medicine approaches. We further emphasize the emerging concepts of hybrid and smart nanocarriers, which have not yet been systematically discussed, positioning them as next-generation solutions to overcome CBD’s bioavailability challenges and paving the way for precision therapeutics. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of Cannabinoids)

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58 pages, 6052 KB

Open AccessEditor’s ChoiceReview

Cyclodextrin-Based Formulations as a Promising Strategy to Overcome the Blood–Brain Barrier: Historical Overview and Prospects in Glioblastoma Treatment

by Federica De Gaetano, Noemi Totaro and Cinzia Anna Ventura

Pharmaceuticals 2025, 18(11), 1626; https://doi.org/10.3390/ph18111626 - 28 Oct 2025

Cited by 6 | Viewed by 2607

Abstract

Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers affecting the central nervous system (CNS), predominantly in adults. Despite significant advancements in this field, GB treatment still relies primarily on conventional approaches, including surgical resection, radiotherapy, and chemotherapy, which, due to [...] Read more.

Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers affecting the central nervous system (CNS), predominantly in adults. Despite significant advancements in this field, GB treatment still relies primarily on conventional approaches, including surgical resection, radiotherapy, and chemotherapy, which, due to its complex pathological characteristics, resistance mechanisms, and restrictive nature of the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), remain of limited efficacy. In this context, the development of innovative therapeutic strategies able to overcome these barriers, induce cancer cell death, and improve patient prognosis is crucial. Recently, nanoparticle platforms and focused ultrasounds seem to be promising approaches for cancer treatment. Nanoparticles enable targeting and controlled release, whilst focused ultrasounds enhance tissue permeation, increasing drug accumulation in a specific organ. However, nanoparticles can suffer from synthesis complexity, long-term biocompatibility and accumulation in the body with consequent toxicity, whereas focused ultrasounds require specialized equipment and can potentially cause thermal damage, hemorrhage, or cavitation injury. Cyclodextrins (CYDs) possess good properties and represent a versatile and safer alternative able to improve drug stability, solubility, and bioavailability, and depending on the type, dose, and administration route, can reduce local and systemic toxicity. Thus, CYDs emerge as promising novel excipients in GB treatment. Despite these advantages, CYD complexes suffer from receptor specificity, reducing their potential in precision medicine. By combining CYD complexes with polymeric or lipidic platforms, the advantages of CYD safety and drug solubilization together with their specific targeting can be obtained, thus enhancing selectivity and maximizing efficacy while minimizing recurrence and systemic toxicity. This review provides a comprehensive overview of GB pathology, conventional treatments, and emerging CYD-based strategies aimed at enhancing drug delivery and therapeutic efficacy. Full article

(This article belongs to the Section Pharmaceutical Technology)

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15 pages, 4423 KB

Open AccessEditor’s ChoiceArticle

A Multi-Laboratory, Multi-Platform Analysis of the Multi-Attribute Method

by Joshua Shipman, Mercy Oyugi, Tim Andres Marzan, Ilan Geerlof-Vidavsky, Douglas Kirkpatrick, Hongbin Zhu, Milani Rasangika and Sarah Rogstad

Pharmaceuticals 2025, 18(11), 1613; https://doi.org/10.3390/ph18111613 - 25 Oct 2025

Cited by 3 | Viewed by 1481

Abstract

Background/Objectives: The multi-attribute method (MAM) has found diverse use in the analytical characterization of therapeutic protein products during their development and production. As the MAM matures it has the potential to enter quality control (QC) laboratories, consolidating and replacing many less informative [...] Read more.

Background/Objectives: The multi-attribute method (MAM) has found diverse use in the analytical characterization of therapeutic protein products during their development and production. As the MAM matures it has the potential to enter quality control (QC) laboratories, consolidating and replacing many less informative chromatographic techniques; however, this requires an appropriate risk assessment and understanding of method capability. Methods: A validated MAM approach was used to quantify product quality attributes (PQAs) using three different mass spectrometers across two laboratories; the results were compared to conventional hydrophilic interaction chromatography–fluorescence detection (HILIC-FLD) and cation exchange chromatography–ultraviolet (CEX-UV) techniques. Results: Stressed, long-term, and accelerated stability studies were performed, and their effects on glycosylation, deamidation, oxidation and N- and C-termini were quantified. Conclusions: Overall, the inter-instrument inter-laboratory data provided here showed important considerations for transferring methods between laboratories and establishing the correlation between the MAM and conventional data, elements which are necessary to transition the MAM to the QC environment and ultimately achieving the goal of replacing orthogonal QC methods. Full article

(This article belongs to the Special Issue Characterization and Quality Control of Biopharmaceuticals Using the Multi-Attribute Method (MAM): Advantages and Challenges)

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22 pages, 955 KB

Open AccessEditor’s ChoiceReview

Targeting Inflammatory Pathways in Chronic Low Back Pain: Opportunities for Novel Therapeutics

by Panagiota Anyfanti, Paschalis Evangelidis, Konstantinos Tragiannidis, Christina Antza, Dimitrios Poulis, Theodoros Dimitroulas and Vasilios Kotsis

Pharmaceuticals 2025, 18(11), 1612; https://doi.org/10.3390/ph18111612 - 24 Oct 2025

Cited by 1 | Viewed by 3403

Abstract

Low back pain (LBP) is a highly prevalent musculoskeletal problem and a leading cause of disability worldwide. From a pathophysiological perspective, the contribution of inflammation to LBP is being increasingly recognized. In this literature review, we aim to provide an overview of the [...] Read more.

Low back pain (LBP) is a highly prevalent musculoskeletal problem and a leading cause of disability worldwide. From a pathophysiological perspective, the contribution of inflammation to LBP is being increasingly recognized. In this literature review, we aim to provide an overview of the role of inflammation as a mediator of LBP while summarizing clinical studies investigating the potential role of anti-inflammatory treatments in the management of LBP. Although often controversial, the available evidence suggests an important role of inflammation in the pathogenesis of LBP, which can be further translated into novel therapeutic targets. Both anti-tumor necrosis factor (anti-TNF) and anti-nerve growth factor (anti-NGF) agents hold the potential of blocking inflammation and pain pathways in patients with chronic LBP. TNF inhibitors have been tested mostly in small trials with mixed results, and their long-term efficacy remains to be proven. Anti-NGF agents have demonstrated stronger and consistent efficacy in randomized controlled trials, but safety concerns compromise their widespread use. The potential role of other anti-inflammatory molecules is currently under investigation. Presently, the routine use of TNF or NGF inhibitors is not supported in radiculopathy or chronic LBP. However, novel anti-inflammatory therapies introduced in the rheumatology field appear to be promising for specific subsets of patients suffering from chronic, refractory LBP, with a complementary role as therapeutic tools, after the unsuccessful outcome of the conservative approach. Full article

(This article belongs to the Section Pharmacology)

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22 pages, 1723 KB

Open AccessEditor’s ChoiceReview

Clinical Experience with Targeted Alpha-Emitter Peptide Receptor Radionuclide Therapy (α-PRRT) for Somatostatin Receptor-Positive Neuroendocrine Tumors

by Hannes Leupe, Merel Cauwenbergh, Frederik Cleeren, Jeroen Dekervel, Chris Verslype and Christophe M. Deroose

Pharmaceuticals 2025, 18(11), 1608; https://doi.org/10.3390/ph18111608 - 24 Oct 2025

Cited by 4 | Viewed by 3983

Abstract

Background: α-emitting Peptide Receptor Radionuclide Therapy (α-PRRT) is emerging as a promising new generation of PRRT for neuroendocrine tumors (NETs), providing enhanced tumor cell cytotoxicity and reduced irradiation of adjacent healthy tissues due to its high linear energy transfer (LET) and short particle [...] Read more.

Background: α-emitting Peptide Receptor Radionuclide Therapy (α-PRRT) is emerging as a promising new generation of PRRT for neuroendocrine tumors (NETs), providing enhanced tumor cell cytotoxicity and reduced irradiation of adjacent healthy tissues due to its high linear energy transfer (LET) and short particle range. This review summarizes available clinical evidence on α-PRRT using different α-emitting isotopes, including actinium-225, lead-212, and bismuth-213, in somatostatin receptor (SSTR)-positive NETs. Methods: A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov, as well as major oncology congress abstracts (ENETS, ESMO, ASCO). Eligible studies included clinical trials evaluating α-PRRT in patients with advanced SSTR-positive NETs, reporting therapeutic response and adverse events. The primary endpoint was the objective response rate (ORR); secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Seven studies encompassing 150 patients were included. Treatment with [²²⁵Ac]Ac-DOTATATE yielded a pooled ORR of 50% and a DCR of 81.3% across 121 evaluable patients. The best responses were observed in patients who had previously responded to β-PRRT (ORR 70.4%, DCR 96.3%), while one-third of β-PRRT–refractory patients achieved partial or complete responses. [²¹²Pb]Pb-DOTAMTATE demonstrated an ORR of 56.8% and DCR of 100% in preliminary phase II results, though dysphagia was noted in 34% of patients. [²¹³Bi]Bi-DOTATOC and [²¹²Pb]Pb-VMT-α-NET studies also showed promising disease control with minimal grade ≥ 3 hematologic or renal toxicities. Across all studies, α-PRRT was well tolerated, with predominantly low-grade hematologic adverse events and no significant hepatic or renal toxicity. Conclusions: Clinical data to date indicate that α-PRRT offers meaningful therapeutic benefit in patients with metastatic or treatment-refractory NETs, achieving favorable response rates with manageable toxicity. Early results support α-PRRT as a potential first- or second-line therapeutic option. Ongoing phase III trials will be critical to confirm its long-term safety, survival outcomes, and role in routine clinical practice. Full article

(This article belongs to the Collection Will (Radio)Theranostics Hold Up in the 21st Century—and Why?)

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32 pages, 1046 KB

Open AccessEditor’s ChoiceReview

Solidification Materials and Technology for Solid Self-Emulsifying Drug Delivery Systems

by Kyungho Baek and Sung Giu Jin

Pharmaceuticals 2025, 18(10), 1550; https://doi.org/10.3390/ph18101550 - 15 Oct 2025

Cited by 5 | Viewed by 2599

Abstract

The low aqueous solubility of many new drug candidates, a key challenge in oral drug development, has been effectively addressed by liquid self-emulsifying drug delivery systems (SEDDS). However, the inherent instability and manufacturing limitations of liquid formulations have prompted significant research into solid [...] Read more.

The low aqueous solubility of many new drug candidates, a key challenge in oral drug development, has been effectively addressed by liquid self-emulsifying drug delivery systems (SEDDS). However, the inherent instability and manufacturing limitations of liquid formulations have prompted significant research into solid SEDDS. This review provides a comprehensive analysis of the recent advancements in solid SEDDS, focusing on the pivotal roles of solid carriers and solidification techniques. We examine a wide range of carrier materials, including mesoporous silica, polymers, mesoporous carbon, porous carbonate salts, and clay-based materials, highlighting how their physicochemical properties can be leveraged to control drug loading, release kinetics, and in vivo performance. We also detail the various solidification methods, such as spray drying, hot melt extrusion, adsorption, and 3D printing, and their impact on the final product’s quality and scalability. Furthermore, this review explores applications of solid SEDDS, including controlled release, mucoadhesive technology, and targeted drug delivery, as well as the key commercial challenges and future perspectives. By synthesizing these diverse aspects, this paper serves as a valuable resource for designing high-performance solid SEDDS with enhanced stability, bioavailability, and functional versatility. Full article

(This article belongs to the Collection Feature Review Collection in Pharmaceutical Technology)

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32 pages, 1390 KB

Open AccessEditor’s ChoiceReview

Discovery of Personalized Treatment for Immuno-Metabolic Depression—Focus on 11beta Hydroxysteroid Dehydrogenase Type 2 (11betaHSD2) and Toll-like Receptor 4 (TLR4) Inhibition with Enoxolone

by Harald Murck

Pharmaceuticals 2025, 18(10), 1517; https://doi.org/10.3390/ph18101517 - 10 Oct 2025

Viewed by 2768

Abstract

Treatment options for major depression are limited: only about one-third of patients achieve remission with first line treatments with no established predictive markers. Parameters associated with treatment refractory depression, including metabolic markers (increased BMI, increased triglyceride levels), inflammation markers (C-reactive protein, CRP), autonomic [...] Read more.

Treatment options for major depression are limited: only about one-third of patients achieve remission with first line treatments with no established predictive markers. Parameters associated with treatment refractory depression, including metabolic markers (increased BMI, increased triglyceride levels), inflammation markers (C-reactive protein, CRP), autonomic disturbances (reduced blood pressure, reduced heart rate variability), and brain morphology changes (increased volume of the choroid plexus and brain ventricle volumes), may serve such purpose. These features can be linked mechanistically to an increase in aldosterone plasma concentration due to a reduced mineralocorticoid receptor (MR) sensitivity. The primary CNS target of aldosterone is the nucleus of the solitary tract (NTS), which is also the entry point of the vagus nerve. This nucleus integrates signals from endocrine, inflammatory, chemoreceptive, and physiological parameters, including blood pressure. In search of a mechanism to overcome this pathology, we identified a molecule which is derived from the licorice plant glycyrrhiza glabra, namely glycyrrhizin and its biologically active metabolite enoxolone. These molecules potentially reverse the above-described pathology. They inhibit the enzyme 11beta hydroxysteroid-dehydrogenase type 2 (11betaHSD2) and the toll-like receptor 4 (TLR4). 11betaHSD2 regulates the activity of the mineralocorticoid receptor (MR) by degrading cortisol/corticosterone, which allows aldosterone to bind to the MR. TLR4 is the ligand for lipopolysaccharide (LPS, endotoxin) and trigger of innate immunity. Consequently, patients with increased inflammation markers, increased aldosterone, or low blood pressure may preferentially benefit from the treatment with glycyrrhizin/enoxolone. Importantly, these patients can be identified BEFORE treatment is initiated. Clinically, patients sharing these biological indicators are primarily young females or patients with a history of childhood trauma. A combination of enoxolone with standard antidepressants may therefore avoid a trial-and-error approach and allow to achieve recovery faster. Full article

(This article belongs to the Special Issue Discovery of Novel Antidepressants and Anxiolytics)

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24 pages, 2042 KB

Open AccessEditor’s ChoiceReview

Thermogenic Targets for Obesity Management in the Era of Incretin-Based Therapies

by Sahar Soliman, Rebecca Andrews-Dickert, Petra Rocic and Mihail Mitov

Pharmaceuticals 2025, 18(10), 1519; https://doi.org/10.3390/ph18101519 - 10 Oct 2025

Cited by 1 | Viewed by 4281

Abstract

The global rise in obesity continues to outpace advances in pharmacologic treatment. While incretin-based therapies have demonstrated significant efficacy in promoting weight loss, their widespread use remains limited by gastrointestinal side effects, long-term tolerability concerns, and access issues. Additionally, sustaining weight loss over [...] Read more.

The global rise in obesity continues to outpace advances in pharmacologic treatment. While incretin-based therapies have demonstrated significant efficacy in promoting weight loss, their widespread use remains limited by gastrointestinal side effects, long-term tolerability concerns, and access issues. Additionally, sustaining weight loss over time poses an ongoing clinical challenge. These limitations highlight the need for alternative or complementary pharmacologic strategies. One such approach involves stimulating thermogenesis, particularly through the activation of brown and beige adipose tissue. This narrative review focuses on β3 adrenergic receptors as key mediators of browning and thermogenic energy expenditure. We review preclinical and clinical data, address pharmacokinetic and delivery challenges, and assess the translational potential of targeting thermogenesis in the management of obesity. Future directions are proposed to guide the development of safe and effective therapies that utilize this underexplored pharmacologic pathway. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Obesity, 2nd Edition)

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22 pages, 5125 KB

Open AccessEditor’s ChoiceReview

Ivermectin as an Alternative Anticancer Agent: A Review of Its Chemical Properties and Therapeutic Potential

by Kimberly Naula Robalino, Oscar Vivanco-Galván, Juan Carlos Romero-Benavides and Yuliana Jiménez-Gaona

Pharmaceuticals 2025, 18(10), 1459; https://doi.org/10.3390/ph18101459 - 28 Sep 2025

Cited by 3 | Viewed by 63011

Abstract

Background: Ivermectin has recently garnered significant scientific attention for its potential anticancer properties. Objective: This research aims a comprehensive literature review to evaluate IVM’s chemical characteristics and assess its applicability as an alternative therapeutic strategy in oncology. Methods: The methodology involved a systematic [...] Read more.

Background: Ivermectin has recently garnered significant scientific attention for its potential anticancer properties. Objective: This research aims a comprehensive literature review to evaluate IVM’s chemical characteristics and assess its applicability as an alternative therapeutic strategy in oncology. Methods: The methodology involved a systematic search and critical appraisal of data from peer-reviewed scientific databases, focusing on structural analyses, such as nuclear magnetic resonance (NMR), crystallography, and in silico modeling, as well as preclinical experimental studies. Results: The review highlights IVM’s distinct physicochemical profile, including high lipophilicity, poor aqueous solubility, and moderate acid stability, which collectively affect its bioavailability and pharmacokinetic behavior. Mechanistically, IVM has been shown to modulate multiple oncogenic signaling pathways, including Wnt/β-catenin, PI3K/Akt/mTOR, and STAT3. These interactions contribute to the induction of apoptosis, inhibition of tumor cell proliferation, and modulation of the tumor microenvironment across a range of malignancies. Despite encouraging preclinical evidence, clinical validation remains limited. Conclusions: Further investigation is needed to optimize IVM’s formulation for enhanced solubility and targeted delivery, as well as to design robust clinical trials assessing its safety and efficacy in oncology settings. This review provides a foundational framework for future interdisciplinary research on drug repurposing and highlights the potential of IVM as a cost-effective and accessible adjunct or alternative to modern cancer therapy. Full article

(This article belongs to the Special Issue Adjuvant Therapies for Cancer Treatment: 2nd Edition)

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17 pages, 808 KB

Open AccessEditor’s ChoiceArticle

Development of Orally Disintegrating Tablets of Standardized Rhodiola rosea Extract

by Oxana Brante, Rihards Talivaldis Bagons, Santa Niedra, Austris Mazurs, Baiba Mauriņa, Jurga Bernatoniene and Konstantins Logviss

Pharmaceuticals 2025, 18(9), 1328; https://doi.org/10.3390/ph18091328 - 4 Sep 2025

Cited by 1 | Viewed by 4741

Abstract

Background/Objectives: Rhodiola rosea L. (Crassulaceae), a perennial adaptogenic herb native to Northern Europe, Asia, and North America, is renowned for its therapeutic properties attributed to phenolic compounds including flavonoids, phenylethanoids, phenylpropanoids, and cinnamyl alcohol glycosides. The plant’s antioxidant and anti-inflammatory [...] Read more.

Background/Objectives: Rhodiola rosea L. (Crassulaceae), a perennial adaptogenic herb native to Northern Europe, Asia, and North America, is renowned for its therapeutic properties attributed to phenolic compounds including flavonoids, phenylethanoids, phenylpropanoids, and cinnamyl alcohol glycosides. The plant’s antioxidant and anti-inflammatory activities align with its traditional use in boosting physical and cognitive performance, reducing fatigue, and improving stress resilience. However, conventional dosage forms present compliance challenges, particularly for vulnerable populations with swallowing difficulties. This study aimed to develop and optimize orally disintegrating tablets (ODTs) containing standardized Rhodiola rosea root and rhizome (RR) dry extract to ensure rapid disintegration and acceptable taste, thereby improving patient compliance. Methods: Dried Rhodiola rosea root and rhizome (particle size 2–3 mm) were extracted using 70% m/m ethanol using the fractionated maceration methodology. The resulting dry RR extract was standardized to 3.0% m/m rosavin content by blending batches of the extract and analyzed using validated chromatographic methods. The standardized dry extract was formulated into ODTs via direct compression technology. Various excipients were evaluated to achieve rapid disintegration while masking the characteristic bitter taste of RR extract. Results: The optimized ODT formulation (500 mg, 11 mm ø, 20% standardized RR dry extract) disintegrated within 3 min and effectively masking the characteristic bitterness of the RR extract. The formulation maintained content uniformity and did not exhibit loss of active compounds during processing, meeting European Pharmacopoeia requirements for ODTs. Conclusions: The developed ODTs containing standardized Rhodiola rosea extract offer a patient-friendly alternative for oro-mucosal administration, supporting improved compliance in populations with swallowing difficulties while retaining the extract’s phytochemical integrity and sensory acceptability. Full article

(This article belongs to the Special Issue Orodispersible and Innovative Dosage Forms: Advances in Preparation Technologies, Direct Compression, and Co-Processed Excipients)

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28 pages, 1361 KB

Open AccessEditor’s ChoiceReview

Artificial Intelligence in Small-Molecule Drug Discovery: A Critical Review of Methods, Applications, and Real-World Outcomes

by Sarfaraz K. Niazi

Pharmaceuticals 2025, 18(9), 1271; https://doi.org/10.3390/ph18091271 - 26 Aug 2025

Cited by 20 | Viewed by 11487

Abstract

Artificial intelligence (AI) is emerging as a valuable complementary tool in small-molecule drug discovery, augmenting traditional methodologies rather than replacing them. This review examines the evolution of AI from early rule-based systems to advanced deep learning, generative models, diffusion models, and autonomous agentic [...] Read more.

Artificial intelligence (AI) is emerging as a valuable complementary tool in small-molecule drug discovery, augmenting traditional methodologies rather than replacing them. This review examines the evolution of AI from early rule-based systems to advanced deep learning, generative models, diffusion models, and autonomous agentic AI systems, highlighting their applications in target identification, hit discovery, lead optimization, and safety prediction. We present both successes and failures to provide a balanced perspective. Notable achievements include baricitinib (BenevolentAI/Eli Lilly, an existing drug repurposed through AI-assisted analysis for COVID-19 and rheumatoid arthritis), halicin (MIT, preclinical antibiotic), DSP-1181 (Exscientia, discontinued after Phase I), and ISM001-055/rentosertib (Insilico Medicine, positive Phase IIa results). However, several AI-assisted compounds have also faced challenges in clinical development. DSP-1181 was discontinued after Phase I, despite a favorable safety profile, highlighting that the acceleration of discovery timelines by AI does not guarantee clinical success. Despite progress, challenges such as data quality, model interpretability, regulatory hurdles, and ethical concerns persist. We provide practical insights for integrating AI into drug discovery workflows, emphasizing hybrid human-AI approaches and the emergence of agentic AI systems that can autonomously navigate discovery pipelines. A critical evaluation of current limitations and future opportunities reveals that while AI offers significant potential as a complementary technology, realistic expectations and careful implementation are crucial for delivering innovative therapeutics. Full article

(This article belongs to the Section Medicinal Chemistry)

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43 pages, 4354 KB

Open AccessEditor’s ChoiceReview

A Comprehensive Review of Azelaic Acid Pharmacological Properties, Clinical Applications, and Innovative Topical Formulations

by Andreea-Georgiana Petrovici, Mariachiara Spennato, Ioan Bîtcan, Francisc Péter, Livius Cotarcă, Anamaria Todea and Valentin Laurențiu Ordodi

Pharmaceuticals 2025, 18(9), 1273; https://doi.org/10.3390/ph18091273 - 26 Aug 2025

Cited by 12 | Viewed by 24343

Abstract

Azelaic acid (AzA), a saturated dicarboxylic acid, is indicated for the treatment of acne vulgaris, rosacea, melasma, and post-inflammatory hyperpigmentation. Its antimicrobial, anti-inflammatory, and antimelanogenic properties support its use; however, its poor aqueous solubility and limited skin permeability constrain its optimal topical delivery. [...] Read more.

Azelaic acid (AzA), a saturated dicarboxylic acid, is indicated for the treatment of acne vulgaris, rosacea, melasma, and post-inflammatory hyperpigmentation. Its antimicrobial, anti-inflammatory, and antimelanogenic properties support its use; however, its poor aqueous solubility and limited skin permeability constrain its optimal topical delivery. This review summarizes clinical evidence and advances in formulations—including conventional vehicles, polymeric/lipid nanocarriers, and deep eutectic solvent (DES) systems—to promote more effective and well-tolerated use. Across indications, 15–20% azelaic acid (AzA) formulations produced clinically meaningful improvements with mild, transient local irritation. For acne vulgaris, reductions in inflammatory and noninflammatory lesions were comparable to those of topical retinoids/adapalene, and tolerability was superior in some studies. For rosacea, the 15% gel formulation was comparable to metronidazole in reducing papules, pustules, and erythema while maintaining negligible systemic exposure. In melasma and other dyschromias, 20% cream demonstrated efficacy similar to hydroquinone, exhibiting a favorable safety profile. Advanced delivery systems, including liposomes, niosomes/ethosomes, nanostructured lipid carriers, microemulsions, nanosponges, and DES platforms, increased AzA solubilization, cutaneous deposition, and stability. This enabled dose-sparing strategies and improved adherence. Data on AzA cocrystals and ionic salts suggest additional control over release and irritation. AzA remains a versatile and well-tolerated dermatologic agent whose performance is strongly vehicle-dependent. Rational selection and engineering of carriers, particularly DES-integrated polymeric and lipid systems, can mitigate solubility and permeability limitations, enhance skin targeting, and reduce irritation in the treatment of acne and rosacea. Full article

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

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16 pages, 1984 KB

Open AccessEditor’s ChoiceArticle

Optimized Automated Cassette-Based Synthesis of [⁶⁸Ga]Ga-DOTATOC

by Anton Amadeus Hörmann, Johannes Neumann, Samuel Nadeje, Gregor Schweighofer-Zwink, Gundula Rendl, Theresa Jung, Teresa Kiener, Ruben Lechner, Sylvia Friedl, Ursula Huber-Schönauer, Martin Wolkersdorfer, Mohsen Beheshti and Christian Pirich

Pharmaceuticals 2025, 18(9), 1274; https://doi.org/10.3390/ph18091274 - 26 Aug 2025

Viewed by 2373

Abstract

Background: [⁶⁸Ga]Ga-DOTATOC is widely used in PET imaging of neuroendocrine tumors (NETs) due to its high affinity for somatostatin receptors. Given the short physical half-life of gallium-68 (~68 min), rapid, reproducible, and GMP-compliant synthesis is essential for clinical application. Methods: An [...] Read more.

Background: [⁶⁸Ga]Ga-DOTATOC is widely used in PET imaging of neuroendocrine tumors (NETs) due to its high affinity for somatostatin receptors. Given the short physical half-life of gallium-68 (~68 min), rapid, reproducible, and GMP-compliant synthesis is essential for clinical application. Methods: An optimized cassette-based automated synthesis protocol was developed using a commercial cassette. Improvements included direct generator elution into the reactor without pre-purification, use of a SepPak^® C18 Plus Light cartridge for purification, replacement of HEPES with 0.3 M sodium acetate buffer (final pH ~3.8), and implementation of a non-vented sterile filter enabling automated pressure-hold integrity testing. Results: Across all batches, the synthesis yielded [⁶⁸Ga]Ga-DOTATOC with high radiochemical purity (> 97%) and reproducible decay-corrected radiochemical yields up to 88.3 ± 0.6%. Total synthesis time was approximately 13 min. The final product remained stable for at least 3 h post-synthesis. The use of acetate buffer eliminated the need for HEPES-specific testing, streamlining the workflow. Automated filter testing improved GMP-compliant documentation and reduced radiation exposure for personnel. Conclusions: This optimized, cassette-based synthesis protocol enables fast, high-yield, and GMP-compliant production of [⁶⁸Ga]Ga-DOTATOC. It supports clinical theranostic workflows by ensuring product quality, process standardization, and regulatory compliance. Full article

(This article belongs to the Special Issue Radiopharmaceuticals in Cancer Disorders: Clinical and Pharmaceutical Perspectives)

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17 pages, 3151 KB

Open AccessEditor’s ChoiceArticle

Towards a Consensus for the Analysis and Exchange of TFA as a Counterion in Synthetic Peptides and Its Influence on Membrane Permeation

by Vanessa Erckes, Alessandro Streuli, Laura Chamera Rendueles, Stefanie Dorothea Krämer and Christian Steuer

Pharmaceuticals 2025, 18(8), 1163; https://doi.org/10.3390/ph18081163 - 5 Aug 2025

Cited by 2 | Viewed by 4151

Abstract

Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as [...] Read more.

Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as a cleavage agent and ion-pairing reagent, respectively, resulting in peptides being obtained as TFA salts. Although TFA has excellent properties for peptide production, numerous studies highlight the negative impact of using peptides from TFA⁻ salts in biological assays. Methods: Investigated peptides were synthesized via SPPS and the TFA⁻ counterion was exchanged for Cl⁻ via freeze-drying in different concentrations of HCl. Detection and quantification of residual TFA⁻ were carried out via FT-IR, ¹⁹F-NMR, and HPLC using an evaporative light-scattering detector (ELSD). A liposomal fluorescence assay was used to test for the influence of the counterion on the peptides’ passive membrane permeability. Results: All TFA⁻ detection methods were successfully validated according to ICH guidelines. TFA⁻ removal with 10 mM HCl was determined to be the optimal condition. No impact on peptide purity was observed at all HCl concentrations. Influences on permeability coefficients depending on peptide sequence and salt form were found. Conclusions: This study presents a systematic investigation of the removal of TFA⁻ counterions from synthetic peptides and their replacement with Cl⁻ counterions. Detected counterion contents were used to understand the impact of sequence differences, especially positive charges, on the amount and potential localization of counterions. Our findings emphasize the importance of counterion quantification and specification in assays with synthetic peptides. Full article

(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)

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43 pages, 3721 KB

Open AccessEditor’s ChoiceReview

Novel Strategies for the Formulation of Poorly Water-Soluble Drug Substances by Different Physical Modification Strategies with a Focus on Peroral Applications

by Julian Quodbach, Eduard Preis, Frank Karkossa, Judith Winck, Jan Henrik Finke and Denise Steiner

Pharmaceuticals 2025, 18(8), 1089; https://doi.org/10.3390/ph18081089 - 23 Jul 2025

Cited by 11 | Viewed by 9492

Abstract

The number of newly developed substances with poor water solubility continually increases. Therefore, specialized formulation strategies are required to overcome the low bioavailability often associated with this property. This review provides an overview of novel physical modification strategies discussed in the literature over [...] Read more.

The number of newly developed substances with poor water solubility continually increases. Therefore, specialized formulation strategies are required to overcome the low bioavailability often associated with this property. This review provides an overview of novel physical modification strategies discussed in the literature over the past decades and focuses on oral dosage forms. A distinction is made between ‘brick-dust’ molecules, which are characterized by high melting points due to the solid-state properties of the substances, and ‘grease-ball’ molecules with high lipophilicity. In general, the discussed strategies are divided into the following three main categories: drug nanoparticles, solid dispersions, and lipid-based formulations. Full article

(This article belongs to the Collection Feature Review Collection in Pharmaceutical Technology)

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26 pages, 1310 KB

Open AccessEditor’s ChoiceReview

Combination Strategies with HSP90 Inhibitors in Cancer Therapy: Mechanisms, Challenges, and Future Perspectives

by Yeongbeom Kim, Su Yeon Lim, Hyun-Ouk Kim, Suk-Jin Ha, Jeong-Ann Park, Young-Wook Won, Sehyun Chae and Kwang Suk Lim

Pharmaceuticals 2025, 18(8), 1083; https://doi.org/10.3390/ph18081083 - 22 Jul 2025

Cited by 5 | Viewed by 6097

Abstract

Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, [...] Read more.

Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, their therapeutic potential as monotherapies has been limited by suboptimal efficacy, dose-limiting toxicity, and the emergence of drug resistance. Recent studies have demonstrated that combination therapies involving HSP90 inhibitors and other anticancer agents such as chemotherapeutics, targeted therapies, and immune checkpoint inhibitors can enhance anticancer activity, overcome resistance mechanisms, and modulate the tumor microenvironment. These synergistic effects are mediated by the concurrent degradation of client proteins, the disruption of signaling pathways, and the enhancement of antitumor immunity. However, the successful clinical implementation of such combination strategies requires the careful optimization of dosage, administration schedules, toxicity management, and patient selection based on predictive biomarkers. In this review, we provide a comprehensive overview of the mechanistic rationale, preclinical and clinical evidence, and therapeutic challenges associated with HSP90 inhibitor-based combination therapies. We also discuss future directions leveraging emerging technologies including multi-omics profiling, artificial intelligence, and nanoparticle-mediated delivery for the development of personalized and effective combination regimens in oncology. Full article

(This article belongs to the Special Issue Hsp90 Inhibitors: Progress, Challenges, and Opportunities in Drug Discovery and Development)

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10 pages, 721 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 6 | Viewed by 3866

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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27 pages, 891 KB

Open AccessEditor’s ChoiceReview

The Antidiabetic Activity of Wild-Growing and Cultivated Medicinal Plants Used in Romania for Diabetes Mellitus Management: A Phytochemical and Pharmacological Review

by Diana Maria Trasca, Dalia Dop, George-Alin Stoica, Niculescu Stefan Adrian, Niculescu Elena Carmen, Renata Maria Văruț and Cristina Elena Singer

Pharmaceuticals 2025, 18(7), 1035; https://doi.org/10.3390/ph18071035 - 11 Jul 2025

Cited by 4 | Viewed by 4392

Abstract

Diabetes mellitus is a chronic metabolic disease that has a significant impact on public health and is becoming more and more common worldwide. Although effective, conventional therapies are often limited by high cost, adverse effects, and issues with patient compliance. As a result, [...] Read more.

Diabetes mellitus is a chronic metabolic disease that has a significant impact on public health and is becoming more and more common worldwide. Although effective, conventional therapies are often limited by high cost, adverse effects, and issues with patient compliance. As a result, there is growing interest in complementary and alternative therapies. Medicinal plants have played an essential role in diabetes treatment, especially in regions such as Romania, where biodiversity is high and traditional knowledge is well preserved. The pathophysiology, risk factors, and worldwide burden of diabetes are examined in this review, with an emphasis on the traditional use of medicinal plants for glycemic control. A total of 47 plant species were identified based on ethnopharmacological records and recent biomedical research, including both native flora and widely cultivated species. The bioactive compounds identified, such as flavonoids, triterpenic saponins, polyphenols, and alkaloids, have hypoglycemic effects through diverse mechanisms, including β-cell regeneration, insulin-mimetic action, inhibition of α-glucosidase and α-amylase, and oxidative stress reduction. A systematic literature search was conducted, including in vitro, in vivo, and clinical studies relevant to antidiabetic activity. Among the species reviewed, Urtica dioica, Silybum marianum, and Momordica charantia exhibited the most promising antidiabetic activity based on both preclinical and clinical evidence. Despite promising preclinical results, clinical evidence remains limited, and variability in phytochemical content poses challenges to reproducibility. This review highlights the potential of Romanian medicinal flora as a source of adjunctive therapies in diabetes care and underscores the need for standardization and clinical validation. Full article

(This article belongs to the Section Natural Products)

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29 pages, 1953 KB

Open AccessEditor’s ChoiceReview

Targeted Biologic Therapies in Severe Asthma: Mechanisms, Biomarkers, and Clinical Applications

by Renata Maria Văruț, Dop Dalia, Kristina Radivojevic, Diana Maria Trasca, George-Alin Stoica, Niculescu Stefan Adrian, Niculescu Elena Carmen and Cristina Elena Singer

Pharmaceuticals 2025, 18(7), 1021; https://doi.org/10.3390/ph18071021 - 10 Jul 2025

Cited by 10 | Viewed by 7916

Abstract

Asthma represents a heterogeneous disorder characterized by a dynamic balance between pro-inflammatory and anti-inflammatory forces, with allergic sensitization contributing substantially to airway hyperresponsiveness and remodeling. Central to its pathogenesis are cytokines such as IL-4, IL-5, IL-13, IL-17, and IL-33, which drive recruitment of [...] Read more.

Asthma represents a heterogeneous disorder characterized by a dynamic balance between pro-inflammatory and anti-inflammatory forces, with allergic sensitization contributing substantially to airway hyperresponsiveness and remodeling. Central to its pathogenesis are cytokines such as IL-4, IL-5, IL-13, IL-17, and IL-33, which drive recruitment of eosinophils, neutrophils, and other effector cells, thereby precipitating episodic exacerbations in response to viral and environmental triggers. Conventional biomarkers, including blood and sputum eosinophil counts, IgE levels, and fractional exhaled nitric oxide, facilitate phenotypic classification and guide the emerging biologic era. Monoclonal antibodies targeting IgE (omalizumab) and IL-5 (mepolizumab, benralizumab, reslizumab, depemokimab) have demonstrated the ability to reduce exacerbation frequency and improve lung function, with newer agents such as depemokimab offering extended dosing intervals. Itepekimab, an anti-IL-33 antibody, effectively engages its target and mitigates tissue eosinophilia, while CM310-stapokibart, tralokinumab, and lebrikizumab inhibit IL-4/IL-13 signaling with variable efficacy depending on patient biomarkers. Comparative analyses of these biologics, encompassing affinity, dosing regimens, and trial outcomes, underscore the imperative of personalized therapy to optimize disease control in severe asthma. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation with Potential Anti-inflammatory Activity)

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29 pages, 2844 KB

Open AccessEditor’s ChoiceReview

Hsp90 pan and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy

by Shiying Jia, Neeraj Maurya, Brian S. J. Blagg and Xin Lu

Pharmaceuticals 2025, 18(7), 1025; https://doi.org/10.3390/ph18071025 - 10 Jul 2025

Cited by 5 | Viewed by 4671

Abstract

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of pan-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered [...] Read more.

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of pan-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered by on-target toxicities, particularly ocular and cardiotoxic effects, as well as the induction of pro-survival, compensatory heat shock responses. Together, these and other complications have prompted the development of isoform-selective Hsp90 inhibitors. In this review, we discuss the molecular bases for Hsp90 function and inhibition and emphasize recent advances in isoform-selective targeting. Importantly, we highlight how Hsp90 inhibition can sensitize tumors to cancer immunotherapy by enhancing antigen presentation, reducing immune checkpoint expression, remodeling the tumor microenvironment, and promoting innate immune activation. Special focus is given to Hsp90β-selective inhibitors, which modulate immunoregulatory pathways without eliciting the deleterious effects observed with pan-inhibition. Preclinical and early clinical data support the integration of Hsp90 inhibitors with immune checkpoint blockade and other immunotherapeutic modalities to overcome resistance mechanisms in immunologically cold tumors. Therefore, the continued development of isoform-selective Hsp90 inhibitors offers a promising avenue to potentiate cancer immunotherapy with improved efficacy. Full article

(This article belongs to the Special Issue Hsp90 Inhibitors: Progress, Challenges, and Opportunities in Drug Discovery and Development)

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12 pages, 1077 KB

Open AccessEditor’s ChoiceSystematic Review

Hawthorn (Crataegus spp.) Clinically Significantly Reduces Blood Pressure in Hypertension: A Meta-Analysis of Randomized Placebo-Controlled Clinical Trials

by Zsóka Szikora, Rebeka Olga Mátyus, Bettina Vargáné Szabó, Dezső Csupor and Barbara Tóth

Pharmaceuticals 2025, 18(7), 1027; https://doi.org/10.3390/ph18071027 - 10 Jul 2025

Cited by 5 | Viewed by 14576

Abstract

Background/Objectives: Hypertension affects over 1.3 billion people globally, and inadequate therapy is reported in 80% of cases. Patients increasingly turn to complementary therapies, including hawthorn (Crataegus spp.), a traditional remedy for cardiovascular diseases. Hawthorn has long been used in folk medicine [...] Read more.

Background/Objectives: Hypertension affects over 1.3 billion people globally, and inadequate therapy is reported in 80% of cases. Patients increasingly turn to complementary therapies, including hawthorn (Crataegus spp.), a traditional remedy for cardiovascular diseases. Hawthorn has long been used in folk medicine to lower blood pressure; however, its efficacy has not been fully established. This meta-analysis aimed to evaluate the antihypertensive effects and safety of hawthorn in randomized, placebo-controlled trials. Methods: A systematic review and meta-analysis were conducted, including six studies with a total of 428 participants. The trials focused on systolic (SBP) and diastolic blood pressure (DBP) changes over treatment periods of 10 weeks to 6 months. Literature searches were conducted in the Embase, PubMed, Cochrane, and Web of Science databases. Studies that met the predefined PICO criteria were included. Data analysis was performed using a random-effects model, and the risk of bias was assessed using the Cochrane Risk of Bias Tool. Results: Hawthorn statistically significantly decreased SBP (MD: −6.65 mmHg; 95% CI [−11.72; 1.59]) and non-significantly reduced DBP (MD: −7.19 mmHg; 95% CI [−15.17; 0.79]) after 2–6 months of treatment. Variations in dosage (250–1200 mg/day) and study protocols contributed to this heterogeneity. Conclusions: The effect of hawthorn on blood pressure is clinically significant. However, larger, well-designed trials are needed to establish optimal dosing, duration, and efficacy with greater reliability. Full article

(This article belongs to the Special Issue Advances in the Mechanism of Action and the Therapeutic Role of Phytopharmaceuticals)

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29 pages, 2035 KB

Open AccessEditor’s ChoiceSystematic Review

Dopamine Partial Agonists in Pregnancy and Lactation: A Systematic Review

by Alexia Koukopoulos, Delfina Janiri, Miriam Milintenda, Sara Barbonetti, Georgios D. Kotzalidis, Tommaso Callovini, Lorenzo Moccia, Silvia Montanari, Marianna Mazza, Lucio Rinaldi, Alessio Simonetti, Mario Pinto, Giovanni Camardese and Gabriele Sani

Pharmaceuticals 2025, 18(7), 1010; https://doi.org/10.3390/ph18071010 - 6 Jul 2025

Cited by 2 | Viewed by 4419

Abstract

Background/Objectives: Dopamine partial agonists are drugs initially developed to treat schizophrenia, seeking a double effect of increased dopaminergic transmission in the prefrontal cortex and decrease in the accumbens/striatum. Of these drugs, aripiprazole, brexpiprazole, and cariprazine are currently marketed and used in schizophrenia [...] Read more.

Background/Objectives: Dopamine partial agonists are drugs initially developed to treat schizophrenia, seeking a double effect of increased dopaminergic transmission in the prefrontal cortex and decrease in the accumbens/striatum. Of these drugs, aripiprazole, brexpiprazole, and cariprazine are currently marketed and used in schizophrenia spectrum and mood disorders. It is debated whether patients with psychiatric disorders becoming pregnant should discontinue or continue their antipsychotic treatment despite some risks for the fetus, i.e., whether it is worse to have an untreated disorder or treating it with drugs. The safety of drugs for mother and baby extend from pregnancy to the postpartum, when breastfeeding assumes great importance. We set to investigate the use of dopamine partial agonists in pregnancy and lactation. Methods: On 23 June 2025, we used suitable strategies for identifying cases and studies of cariprazine, aripiprazole, brexpiprazole, dopamine partial agonists in pregnancy, perinatal period, and/or lactation on PubMed, CINAHL, PsycInfo/PsycArticles, Scopus, and ClinicalTrials.gov. We used the PRISMA Statement in developing our review. We included case reports and clinical studies. We excluded reports without pregnancy or focused on other drugs than the above. We reached consensus on eligibility with Delphi rounds among all authors. Results: Our searches produced 386 results on the above databases. We included 24 case reports/series and 15 studies. Most studies showed no negative pregnancy outcomes. There were serious concerns about the use of dopamine D₂/D₃ partial agonists during lactation. Conclusions: The use of dopamine partial agonists during pregnancy appears to be safe, but during breastfeeding they should be better avoided. Full article

(This article belongs to the Special Issue Pharmaceutical Strategy for Mood Disorders)

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37 pages, 4016 KB

Open AccessEditor’s ChoiceReview

Recent Trends in Bioinspired Metal Nanoparticles for Targeting Drug-Resistant Biofilms

by Devaraj Bharathi and Jintae Lee

Pharmaceuticals 2025, 18(7), 1006; https://doi.org/10.3390/ph18071006 - 5 Jul 2025

Cited by 5 | Viewed by 3064

Abstract

Multidrug-resistant (MDR) biofilm infections characterized by densely packed microbial communities encased in protective extracellular matrices pose a formidable challenge to conventional antimicrobial therapies and are a major contributor to chronic, recurrent and device-associated infections. These biofilms significantly reduce antibiotic penetration, facilitate the survival [...] Read more.

Multidrug-resistant (MDR) biofilm infections characterized by densely packed microbial communities encased in protective extracellular matrices pose a formidable challenge to conventional antimicrobial therapies and are a major contributor to chronic, recurrent and device-associated infections. These biofilms significantly reduce antibiotic penetration, facilitate the survival of dormant persister cells and promote horizontal gene transfer, all of which contribute to the emergence and persistence of MDR pathogens. Metal nanoparticles (MNPs) have emerged as promising alternatives due to their potent antibiofilm properties. However, conventional synthesis methods are associated with high costs, complexity, inefficiency and negative environmental impacts. To overcome these limitations there has been a global push toward the development of sustainable and eco-friendly synthesis approaches. Recent advancements have demonstrated the successful use of various plant extracts, microbial cultures, and biomolecules for the green synthesis of MNPs, which offers biocompatibility, scalability, and environmental safety. This review provides a comprehensive overview of recent trends and the latest progress in the green synthesis of MNPs including silver (Ag), gold (Au), platinum (Pt), and selenium (Se), and also explores the mechanistic pathways and characterization techniques. Furthermore, it highlights the antibiofilm applications of these MNPs emphasizing their roles in disrupting biofilms and restoring the efficacy of existing antimicrobial strategies. Full article

(This article belongs to the Special Issue Challenges in Discovering Innovations Related to Biofilms: Virulence, Spread, Control Strategies and Treatment)

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25 pages, 4259 KB

Open AccessEditor’s ChoiceArticle

Towards Dual-Tracer SPECT for Prostate Cancer Imaging Using [^99mTc]Tc-PSMA-I&S and [¹¹¹In]In-RM2

by Carolina Giammei, Theresa Balber, Veronika Felber, Thomas Dillinger, Jens Cardinale, Marie R. Brandt, Anna Stingeder, Markus Mitterhauser, Gerda Egger and Thomas L. Mindt

Pharmaceuticals 2025, 18(7), 1002; https://doi.org/10.3390/ph18071002 - 3 Jul 2025

Viewed by 2583

Abstract

Background/Objectives: Radiolabeled biomolecules specifically targeting overexpressed structures on tumor cells hold great potential for prostate cancer (PCa) imaging and therapy. Due to heterogeneous target expression, single radiopharmaceuticals may not detect or treat all lesions, while simultaneously applying two or more radiotracers potentially [...] Read more.

Background/Objectives: Radiolabeled biomolecules specifically targeting overexpressed structures on tumor cells hold great potential for prostate cancer (PCa) imaging and therapy. Due to heterogeneous target expression, single radiopharmaceuticals may not detect or treat all lesions, while simultaneously applying two or more radiotracers potentially improves staging, stratification, and therapy of cancer patients. This study explores a dual-tracer SPECT approach using [¹¹¹In]In-RM2 (targeting the gastrin-releasing peptide receptor, GRPR) and [^99mTc]Tc-PSMA-I&S (targeting the prostate-specific membrane antigen, PSMA) as a proof of concept. To mimic heterogeneous tumor lesions in the same individual, we aimed to establish a dual xenograft mouse model for preclinical evaluation. Methods: CHO-K1 cells underwent lentiviral transduction for human GRPR or human PSMA overexpression. Six-to-eight-week-old female immunodeficient mice (NOD SCID) were subsequently inoculated with transduced CHO-K1 cells in both flanks, enabling a dual xenograft with similar target density and growth of both xenografts. Respective dual-isotope imaging and γ-counting protocols were established. Target expression was analyzed ex vivo by Western blotting. Results: In vitro studies showed similar target-specific binding and internalization of [¹¹¹In]In-RM2 and [^99mTc]Tc-PSMA-I&S in transduced CHO-K1 cells compared to reference lines PC-3 and LNCaP. However, in vivo imaging showed negligible tumor uptake in xenografts of the transduced cell lines. Ex vivo analysis indicated a loss of the respective biomarkers in the xenografts. Conclusions: Although the technical feasibility of a dual-tracer SPECT imaging approach using ¹¹¹In and ^99mTc has been demonstrated, the potential of [^99mTc]Tc-PSMA-I&S and [¹¹¹In]In-RM2 in a dual-tracer cocktail to improve PCa diagnosis could not be verified. The animal model, and in particular the transduced cell lines developed exclusively for this project, proved to be unsuitable for this purpose. The in/ex vivo experiments indicated that results from an in vitro model may not necessarily be successfully transferred to an in vivo setting. To assess the potential of this dual-tracer concept to improve PCa diagnosis, optimized in vivo models are needed. Nevertheless, our strategies address key challenges in dual-tracer applications, aiming to optimize future SPECT imaging approaches. Full article

(This article belongs to the Special Issue Challenges in the Development of PET and SPECT Radiotracers: Innovative Ideas with Negative Outcomes)

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27 pages, 1110 KB

Open AccessEditor’s ChoiceSystematic Review

Transdiagnostic Efficacy of Cariprazine: A Systematic Review and Meta-Analysis of Efficacy Across Ten Symptom Domains

by Agota Barabassy, Réka Csehi, Zsófia Borbála Dombi, Balázs Szatmári, Thomas Brevig and György Németh

Pharmaceuticals 2025, 18(7), 995; https://doi.org/10.3390/ph18070995 - 2 Jul 2025

Cited by 2 | Viewed by 7183

Abstract

Introduction: The introduction of the transdiagnostic approach in psychiatry shifts the focus from discrete diagnoses to shared symptoms across various disorders. The Transdiagnostic Global Impression—Psychopathology (TGI-P) scale is a newly developed tool designed to assess psychiatric symptoms across diagnostic boundaries. It evaluates [...] Read more.

Introduction: The introduction of the transdiagnostic approach in psychiatry shifts the focus from discrete diagnoses to shared symptoms across various disorders. The Transdiagnostic Global Impression—Psychopathology (TGI-P) scale is a newly developed tool designed to assess psychiatric symptoms across diagnostic boundaries. It evaluates ten core symptom domains—positive, negative, cognitive, manic, depressive, addiction, anxiety, sleep, hostility, and self-harm—regardless of specific diagnoses. Objective: This study aims to evaluate the efficacy of cariprazine across these ten transdiagnostic symptom domains. Methods: A systematic literature review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were performed on EMBASE and clinicaltrials.gov. Efficacy measures such as the Positive and Negative Syndrome Scale (PANSS), Montgomery–Åsberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), Hamilton Anxiety Rating Scale (HAM-A), and Columbia-Suicide Severity Rating Scale (C-SSRS) were used to assess cariprazine’s effect on the ten transdiagnostic symptoms. Multilevel random-effects meta-analyses were conducted to evaluate the efficacy of cariprazine versus placebo in alleviating depressive and anxiety symptoms across clinical trials. Results: A total of 30 studies were included in the review. Cariprazine showed therapeutic benefits on positive, negative, manic, and depressive symptoms in specifically designed trials. Preliminary positive effects were seen on anxiety, hostility, and cognitive symptoms across disorders. However, specific trials have not been conducted for anxiety disorders or cognitive impairment. Meta-analyses demonstrated that cariprazine significantly reduces both depressive and anxiety symptoms compared to placebo. Cariprazine significantly improved sleep-related symptoms in both mania and depression trials. Suicidality was evaluated in non-suicidal populations, and no increase was observed. Addiction symptoms were part of the exclusion criteria in the RCTs, so they could not be assessed. Previous reports of cariprazine’s anti-craving and anti-abuse effects come from real-world evidence rather than RCT data. Conclusions: Cariprazine appears to be promising in addressing a broad range of symptom domains across psychiatric conditions. Full article

(This article belongs to the Special Issue Recent Advances in Psychopharmacology)

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14 pages, 1527 KB

Open AccessEditor’s ChoiceReview

Stem Cells and Organoids: A Paradigm Shift in Preclinical Models Toward Personalized Medicine

by Eleanor Luce and Jean-Charles Duclos-Vallee

Pharmaceuticals 2025, 18(7), 992; https://doi.org/10.3390/ph18070992 - 1 Jul 2025

Cited by 10 | Viewed by 4423

Abstract

Background/Objectives: Human pluripotent stem cells (hPSCs) and organoid technologies are transforming pharmaceutical research by providing models that more accurately reflect human physiology, genetic variability, and disease mechanisms. This review aims to assess how these systems improve the predictive power of preclinical drug [...] Read more.

Background/Objectives: Human pluripotent stem cells (hPSCs) and organoid technologies are transforming pharmaceutical research by providing models that more accurately reflect human physiology, genetic variability, and disease mechanisms. This review aims to assess how these systems improve the predictive power of preclinical drug development while addressing ethical concerns and supporting the advancement of precision medicine. Methods: We conducted a comprehensive review of the recent literature focusing on the biological principles, technological developments, and pharmaceutical applications of hPSC- and organoid-based systems. Particular attention was given to patient-derived models, integration of omics approaches, bioengineering advances, and artificial intelligence applications in drug screening workflows. Results: hPSC- and organoid-based platforms outperform traditional 2D cultures and animal models in replicating human-specific pathophysiology, enabling personalized drug testing and improving predictions of therapeutic efficacy and safety. These technologies also align with the ethical principles of the 3Rs (replacement, reduction, and refinement) by reducing reliance on animal experimentation. However, challenges persist, including standardization of protocols, batch-to-batch variability, and scalability. Promising solutions involve automation, high-throughput screening, and multi-omics integration, which collectively enhance reproducibility and translational relevance. Conclusions: Stem cell- and organoid-based systems offer a more human-relevant, ethical, and individualized approach to biomedical research. Despite current limitations, ongoing interdisciplinary innovations are expected to accelerate their clinical and industrial adoption. Collaborative efforts will be essential to standardize methodologies and fully realize the potential of these models in bridging preclinical and clinical drug development. Full article

(This article belongs to the Special Issue Stem Cells and Organoids as Tools for Drug Development)

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30 pages, 1334 KB

Open AccessEditor’s ChoiceReview

Revolutionizing Prostate Cancer Detection: The Role of Approved PSMA-PET Imaging Agents

by Ute Hennrich, Laurène Wagner, Harun Taş, Luciana Kovacs and Martina Benešová-Schäfer

Pharmaceuticals 2025, 18(6), 906; https://doi.org/10.3390/ph18060906 - 17 Jun 2025

Cited by 3 | Viewed by 8513

Abstract

Locametz^®/Illuccix^®/Gozellix^TM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [⁶⁸Ga]Ga-PSMA-11), Pylarify^®/Pylclari^® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [¹⁸F]DCFPyL), Radelumin [...] Read more.

Locametz^®/Illuccix^®/Gozellix^TM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [⁶⁸Ga]Ga-PSMA-11), Pylarify^®/Pylclari^® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [¹⁸F]DCFPyL), Radelumin^® (ABX GmbH (Radeberg, Germany), [¹⁸F]PSMA-1007), and Posluma^® (Blue Earth Diagnostics, Ltd. (Oxford, UK), [¹⁸F]rhPSMA-7.3) are four approved PSMA-PET imaging agents that have significantly advanced the diagnosis and management of prostate cancer. These agents offer a new level of precision and accuracy, enabling clinicians to detect prostate cancer with enhanced sensitivity. As a result, they play a critical role in improving detection, staging, and management, ultimately enhancing clinical outcomes for patients. Their use in routine clinical practice is expected to increase diagnostic precision and provide clearer pathways for personalized therapy. This review offers a comprehensive chemical, pharmaceutical, and medicinal overview, discusses comparative studies, and highlights additional highly relevant candidates for prostate cancer detection. Full article

(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)

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19 pages, 3876 KB

Open AccessEditor’s ChoiceArticle

Improving Ex Vivo Nasal Mucosa Experimental Design for Drug Permeability Assessments: Correcting Mucosal Thickness Interference and Reevaluating Fluorescein Sodium as an Integrity Marker for Chemically Induced Mucosal Injury

by Shengnan Zhao, Jieyu Zuo, Marlon C. Mallillin III, Ruikun Tang, Michael R. Doschak, Neal M. Davies and Raimar Löbenberg

Pharmaceuticals 2025, 18(6), 889; https://doi.org/10.3390/ph18060889 - 13 Jun 2025

Cited by 5 | Viewed by 3482

Abstract

Objectives: Ex vivo nasal mucosa models provide physiologically relevant platforms for evaluating nasal drug permeability; however, their application is often limited by high experimental variability and the absence of standardized methodologies. This study aimed to improve experimental design by addressing two major [...] Read more.

Objectives: Ex vivo nasal mucosa models provide physiologically relevant platforms for evaluating nasal drug permeability; however, their application is often limited by high experimental variability and the absence of standardized methodologies. This study aimed to improve experimental design by addressing two major limitations: the confounding effects of mucosal thickness and the questionable reliability of fluorescein sodium (Flu-Na) as an integrity marker for chemically induced mucosal injury. Methods: Permeability experiments were conducted using porcine nasal tissues mounted in Franz diffusion cells, with melatonin and Flu-Na as model compounds. Tissues of varying thickness were collected from both intra- and inter-individual sources, and a numerical simulation-based method was employed to normalize apparent permeability coefficients (Papp) to a standardized mucosal thickness of 0.80 mm. The effects of thickness normalization and chemically induced damage were systematically evaluated. Results: Thickness normalization substantially reduced variability in melatonin Papp, particularly within same-animal comparisons, thereby improving statistical power and data reliability. In contrast, Flu-Na exhibited inconsistent correlations across different pigs and failed to reflect the expected increase in permeability following isopropyl alcohol (IPA)-induced epithelial damage. These results suggest that the relationship between epithelial injury and paracellular transport may be non-linear and not universally applicable under ex vivo conditions, limiting the suitability of Flu-Na as a standalone marker of mucosal integrity. Conclusions: The findings highlight the importance of integrating mucosal thickness correction into standardized experimental protocols and call for a critical reassessment of Flu-Na in nasal drug delivery research. Full article

(This article belongs to the Section Pharmaceutical Technology)

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15 pages, 970 KB

Open AccessEditor’s ChoiceArticle

Potential Natural Blend Hydrosol TGLON Suppresses the Proliferation of Five Cancer Cell Lines and Also Ameliorates Idiopathic Pulmonary Fibrosis in a Mouse Model

by Wei-Hsiang Huang, Mei-Lin Chang, Ching-Che Lin, Chih-Peng Wang, Feng-Jie Tsai and Chih-Chien Lin

Pharmaceuticals 2025, 18(6), 872; https://doi.org/10.3390/ph18060872 - 11 Jun 2025

Viewed by 3674

Abstract

Background: Cancer and fibrotic diseases represent major global health challenges, underscoring the need for safe, multifunctional natural therapies. Although natural products possess notable anticancer properties, their clinical translation is often hindered by non-selective cytotoxicity toward normal cells. Moreover, their therapeutic potential against chronic [...] Read more.

Background: Cancer and fibrotic diseases represent major global health challenges, underscoring the need for safe, multifunctional natural therapies. Although natural products possess notable anticancer properties, their clinical translation is often hindered by non-selective cytotoxicity toward normal cells. Moreover, their therapeutic potential against chronic conditions such as idiopathic pulmonary fibrosis (IPF) remains insufficiently explored. This study aimed to evaluate the efficacy and safety of a natural hydrosol blend, The Greatest Love of Nature (TGLON), in inhibiting cancer cell proliferation and mitigating IPF. Methods: TGLON, composed of 12 steam-distilled plant hydrosols, was chemically characterized by gas chromatography–mass spectrometry (GC-MS). Its cytotoxicity was assessed using the MTT assay against five human cancer cell lines (A-549, HepG2, MCF-7, MKN-45, and MOLT-4) and normal human lung fibroblasts (MRC-5). In vivo safety and therapeutic efficacy were evaluated in Sprague Dawley rats and a bleomycin-induced IPF mouse model, following protocols approved by the Institutional Animal Care and Use Committee (IACUC). Results: TGLON maintained >90% viability in MRC-5 cells at an 80-fold dilution and significantly inhibited the proliferation of A-549 (41%), HepG2 (84%), MCF-7 (50%), MKN-45 (38%), and MOLT-4 (52%) cells. No signs of toxicity were observed in rats administered TGLON orally at 50% (v/v), 10 mL/kg. In mice, TGLON alleviated bleomycin-induced pulmonary inflammation and fibrosis. Conclusions: TGLON exhibited selective anticancer and anti-fibrotic activities under non-toxic conditions, supporting its potential as a bioactive agent for early-stage disease prevention and non-clinical health maintenance. Full article

(This article belongs to the Special Issue Advances in the Chemical-Biological Knowledge of Essential Oils)

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23 pages, 834 KB

Open AccessEditor’s ChoiceReview

Metabolic Reprogramming in Melanoma: An Epigenetic Point of View

by Stefano Giuliani, Celeste Accetta, Simona di Martino, Claudia De Vitis, Elena Messina, Edoardo Pescarmona, Maurizio Fanciulli, Gennaro Ciliberto, Rita Mancini and Italia Falcone

Pharmaceuticals 2025, 18(6), 853; https://doi.org/10.3390/ph18060853 - 6 Jun 2025

Cited by 7 | Viewed by 6430

Abstract

Metabolic reprogramming and epigenetic alterations are fundamental hallmarks of cancer cells, contributing to adaptation, progression, and resistance. In melanoma, high metabolic-epigenetic plasticity enables the rapid modulation of cell states in response to environmental and therapeutic pressures. Recent studies have highlighted a bidirectional crosstalk [...] Read more.

Metabolic reprogramming and epigenetic alterations are fundamental hallmarks of cancer cells, contributing to adaptation, progression, and resistance. In melanoma, high metabolic-epigenetic plasticity enables the rapid modulation of cell states in response to environmental and therapeutic pressures. Recent studies have highlighted a bidirectional crosstalk between cellular metabolism and epigenetic regulation. Epigenetic modifications influence the transcriptional control of metabolic genes, thereby shaping metabolic phenotypes. Conversely, specific metabolites are essential cofactors or substrates for epigenetic enzymes, directly modulating the epigenome. Understanding the intricate mechanisms of this interaction offers opportunities for the development of innovative tumor management that combines epigenetic, metabolic, and therapy interventions. In this review, we summarize the latest evidence on the role of the metabolism–epigenetics axis in melanoma and discuss its potential clinical implications, aiming to provide a comprehensive overview of metabolic/epigenetic interconnections. Full article

(This article belongs to the Section Biopharmaceuticals)

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13 pages, 3110 KB

Open AccessEditor’s ChoiceArticle

Intraoperative Confocal Laser Endomicroscopy Detects Prostate Cancer at the Single-Cell Level with High Specificity and in Real Time: A Preclinical Proof of Concept

by Ann-Christin Eder, Jessica Matthias, Francois Lacombe, Lisa-Charlotte Domogalla, Antoine Jacques, Nils Steinacker, Gaetan Christien, Elodie Martin, Aline Criton and Matthias Eder

Pharmaceuticals 2025, 18(6), 841; https://doi.org/10.3390/ph18060841 - 4 Jun 2025

Viewed by 1559

Abstract

In prostate cancer (PCa) surgery, precise tumor margin identification remains challenging despite advances in surgical techniques. This study evaluates the combination of tumor-specific near-infrared imaging with the PSMA-targeting molecule PSMA-914 and optical endomicroscopy (NIR-pCLE) for single-cell-level tumor identification in a preclinical proof of [...] Read more.

In prostate cancer (PCa) surgery, precise tumor margin identification remains challenging despite advances in surgical techniques. This study evaluates the combination of tumor-specific near-infrared imaging with the PSMA-targeting molecule PSMA-914 and optical endomicroscopy (NIR-pCLE) for single-cell-level tumor identification in a preclinical proof of concept. Methods: NIR-pCLE imaging of varying PSMA-914 concentrations was performed on PSMA-positive LNCaP and PSMA-negative PC-3 cells using Cellvizio^® 100 with pCLE Confocal Miniprobes™. To identify optimal PSMA-914 dosing for in vivo imaging, different doses (0–10 nmol) were evaluated using NIR-pCLE, Odyssey CLx imaging, and confocal microscopy in an LNCaP tumor-bearing xenograft model. A proof of concept mimicking a clinical workflow was performed using 5 nmol [⁶⁸Ga]Ga-PSMA-914 in LNCaP and PC-3 tumor xenografts, including PET/MRI, in/ex vivo NIR-pCLE imaging, and microscopic/macroscopic imaging. Results: NIR-pCLE detected PSMA-specific fluorescence at concentrations above 30 nM in vitro. The optimal dose was identified as 5 nmol PSMA-914 for NIR-pCLE imaging with cellular resolution in LNCaP xenografts. PET/MRI confirmed high tumor uptake and a favorable distribution profile of PSMA-914. NIR-pCLE imaging enabled real-time, single-cell-level detection of PSMA-positive tissue, visualizing tumor heterogeneity, confirmed by ex vivo microscopy and imaging. Conclusions: This preclinical proof of concept demonstrates the potential of intraoperative PSMA-specific NIR-pCLE imaging to visualize tissue structures in real time at cellular resolution. Clinical implementation could provide surgeons with valuable additional information, potentially advancing PCa patient care through improved surgical precision. Full article

(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)

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30 pages, 2081 KB

Open AccessEditor’s ChoiceReview

The Potential of Artificial Intelligence in Pharmaceutical Innovation: From Drug Discovery to Clinical Trials

by Vera Malheiro, Beatriz Santos, Ana Figueiras and Filipa Mascarenhas-Melo

Pharmaceuticals 2025, 18(6), 788; https://doi.org/10.3390/ph18060788 - 25 May 2025

Cited by 31 | Viewed by 14621

Abstract

Artificial intelligence (AI) is a subfield of computer science focused on developing systems that can execute tasks traditionally associated with human intelligence. AI systems work through algorithms based on rules or instructions that enable the machine to make decisions. With the advancement of [...] Read more.

Artificial intelligence (AI) is a subfield of computer science focused on developing systems that can execute tasks traditionally associated with human intelligence. AI systems work through algorithms based on rules or instructions that enable the machine to make decisions. With the advancement of science, more sophisticated AI techniques, such as machine learning and deep learning, have been developed, allowing machines to learn from large amounts of data and improve their performance over time. The pharmaceutical industry has greatly benefited from the development of this technology. AI has revolutionized drug discovery and development by enabling rapid and effective analysis of vast volumes of biological and chemical data during the identification of new therapeutic compounds. The algorithms developed can predict the efficacy, toxicity, and possible adverse effects of new drugs, optimize the steps involved in clinical trials, reduce associated time and costs, and facilitate the implementation of innovative drugs in the market, making it easier to develop precise therapies tailored to the individual genetic profile of patients. Despite significant advancements, there are still gaps in the application of AI, particularly due to the lack of comprehensive regulation. The constant evolution of this technology requires ongoing and in-depth legislative oversight to ensure its use remains safe, ethical, and free from bias. This review explores the role of AI in drug development, assessing its potential to enhance formulation, accelerate discovery, and repurpose existing medications. It highlights AI’s impact across all stages, from initial research to clinical trials, emphasizing its ability to optimize processes, drive innovation, and improve therapeutic outcomes. Full article

(This article belongs to the Special Issue Computational Methods in Drug Development)

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19 pages, 1294 KB

Open AccessEditor’s ChoiceReview

Interferon Lambda: The Next Frontier in Antiviral Therapy?

by Sofia Chronopoulou and Ilias Tsochantaridis

Pharmaceuticals 2025, 18(6), 785; https://doi.org/10.3390/ph18060785 - 24 May 2025

Cited by 5 | Viewed by 6989

Abstract

Type III interferons (IFN-λ) are the most recently identified members of the interferon family, distantly related to type I interferons and members of the interleukin-10 (IL-10). Unlike type I interferons, which have broadly distributed cellular receptors, IFN-λ signals through a heterodimeric receptor complex [...] Read more.

Type III interferons (IFN-λ) are the most recently identified members of the interferon family, distantly related to type I interferons and members of the interleukin-10 (IL-10). Unlike type I interferons, which have broadly distributed cellular receptors, IFN-λ signals through a heterodimeric receptor complex with primary expression on epithelial cells. This restricted receptor distribution makes IFN-λ a favorable candidate for therapeutic and antiviral applications with reduced side effects. In this review, we describe the molecular structure, signaling mechanisms, and the role of IFN-λ in the innate immunity of epithelial tissue, which are its primary sites of action. Moreover, this review will summarize and critically examine the antiviral potential of IFN-λ based on all published clinical trials conducted for the treatment of COVID-19, and hepatitis B, C and D virus. Furthermore, this review suggests IFN-λ as a promising therapeutic recombinant protein, with special emphasis on its potential for production using alternative expression and advanced drug delivery systems. To emphasize its potential as a therapeutic intervention, the design and engineering of recombinant IFN-λ will be presented, with a focus on its lower side-effect profile compared to Type I interferons. Full article

(This article belongs to the Section Biopharmaceuticals)

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13 pages, 1642 KB

Open AccessEditor’s ChoiceArticle

Efficacy and Safety of a Single Ivy Extract Versus Two Herbal Extract Combinations in Patients with Acute Bronchitis: A Multi-Center, Randomized, Open-Label Clinical Trial

by Peter Kardos, Justus de Zeeuw, Inga Trompetter, Simon Braun and Yuliya Ilieva

Pharmaceuticals 2025, 18(5), 754; https://doi.org/10.3390/ph18050754 - 20 May 2025

Cited by 5 | Viewed by 9798

Abstract

Background: The combination therapy for acute bronchitis with several plant extracts, such as Ivy and Thyme or Primrose and Thyme, is assumed to offer added benefit over single extract preparations. However, no clinical trials have yet demonstrated such a therapeutic advantage. Methods [...] Read more.

Background: The combination therapy for acute bronchitis with several plant extracts, such as Ivy and Thyme or Primrose and Thyme, is assumed to offer added benefit over single extract preparations. However, no clinical trials have yet demonstrated such a therapeutic advantage. Methods: In this three-arm, open-label, randomized clinical trial, patients with acute bronchitis were assigned to groups receiving Ivy extract EA 575 (Prospan^® Cough Drops), Ivy/Thyme extract combination (Bronchipret^® Drops), or Thyme/Primrose extract combination (Bronchicum^® Drops) according to their respective labels. The primary endpoint was the assessment of non-inferiority, and the second endpoint was the assessment of superiority of Ivy vs. each of the two comparators (Ivy/Thyme and Thyme/Primrose) regarding the change in Bronchitis Severity Score between baseline and day 7. In total, 325 adult patients were considered for evaluation. Results: Non-inferiority of Ivy extract was statistically significant against both comparators (both p < 0.0001). Superiority of Ivy extract was statistically significant against Ivy/Thyme extract (p < 0.0001) but missed statistical significance against Thyme/Primrose extract (p < 0.0607). The incidence of adverse events was low and comparable between the groups. All adverse events were non-serious. Conclusions: these data revealed that Ivy extract EA 575 is non-inferior in acute bronchitis treatment compared to both comparators and superior to Ivy/Thyme. Full article

(This article belongs to the Section Natural Products)

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27 pages, 550 KB

Open AccessEditor’s ChoiceSystematic Review

Anti-Suicidal Effects of Lithium, Ketamine, and Clozapine—A 10-Year Systematic Review

by Przemyslaw M. Waszak, Jan Opalko, Natalia Olszańska and Paweł Zagożdżon

Pharmaceuticals 2025, 18(5), 742; https://doi.org/10.3390/ph18050742 - 18 May 2025

Cited by 9 | Viewed by 10839

Abstract

Background/Objectives: Suicide is a complex issue resulting in approximately 700,000 deaths annually. Individuals with mood disorders or schizophrenia are at an increased risk. Pharmacological interventions, such as lithium, clozapine, and ketamine, show promise in reducing suicidality. Methods: A systematic search was conducted across [...] Read more.

Background/Objectives: Suicide is a complex issue resulting in approximately 700,000 deaths annually. Individuals with mood disorders or schizophrenia are at an increased risk. Pharmacological interventions, such as lithium, clozapine, and ketamine, show promise in reducing suicidality. Methods: A systematic search was conducted across Google Scholar, Scopus, and PubMed to identify studies evaluating the effects of lithium, clozapine, and ketamine on suicidality. Peer-reviewed articles published between 2014 and 2024 that focused on adult populations were included. After screening 1297 records, 49 studies met the eligibility criteria: 14 on lithium, 23 on ketamine, and 12 on clozapine. Results: Multiple studies highlight lithium’s significant anti-suicidal effects in patients with bipolar disorder, showing superior suicide risk reduction compared to valproate and other mood stabilizers. Ketamine has been shown to rapidly reduce suicidal ideation, with effects observable within hours and lasting up to a week. While most studies support its short-term efficacy, findings regarding its long-term benefits and the impact of repeated dosing remain inconsistent. Clozapine has consistently demonstrated a reduction in suicide risk for individuals with schizophrenia. Large-scale cohort studies report a significant decrease in suicide attempts and mortality when compared to other antipsychotics. Conclusions: Lithium, ketamine, and clozapine were proven to be effective in reducing suicidality. However, limited data, adherence challenges, and methodological differences across studies highlight the need for more robust, large-scale experimental research. Effective suicide prevention is an extremely complex topic and also requires consideration of healthcare and social system factors. Full article

(This article belongs to the Special Issue Recent Advances in Psychiatric Medications)

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13 pages, 544 KB

Open AccessEditor’s ChoiceSystematic Review

The Impact of Methylphenidate on Sexual Functions: A Systematic Review of Benefits and Risks

by Rafał Bieś, Zuzanna Szewczyk, Anna Warchala, Ewa Martyniak and Marek Krzystanek

Pharmaceuticals 2025, 18(5), 718; https://doi.org/10.3390/ph18050718 - 14 May 2025

Viewed by 34022

Abstract

Background: Methylphenidate is a psychostimulant that enhances dopamine and norepinephrine neurotransmission through the mechanism of reuptake inhibition at the synaptic cleft. Studies indicate that sexual dysfunction is prevalent among psychiatric patients. The objective of our study was to assess the impact of methylphenidate [...] Read more.

Background: Methylphenidate is a psychostimulant that enhances dopamine and norepinephrine neurotransmission through the mechanism of reuptake inhibition at the synaptic cleft. Studies indicate that sexual dysfunction is prevalent among psychiatric patients. The objective of our study was to assess the impact of methylphenidate on patients’ sexual health, identify specific types of sexual dysfunction, and analyse the correlations between psychiatric disorders, treatment dosages and durations, and the presence of sexual dysfunction. Additionally, we aimed to evaluate the prevalence of improved sexual function resulting from methylphenidate use. Methods: A systematic literature review was performed using the PubMed database in accordance with PRISMA guidelines. The initial search yielded 186 articles, of which 14 met the inclusion criteria and were analyzed. Clinical studies involving changes in libido, erectile function, ejaculation, semen quality, and sexual behavior due to methylphenidate were reviewed. Results: The findings indicate that methylphenidate can have both negative and positive effects on sexual function. In some patients, particularly those with psychiatric comorbidities, methylphenidate was associated with decreased libido and ejaculation disorders. In other cases, especially in individuals with preexisting dysfunctions or on low doses, it appeared to enhance sexual arousal and performance. Conclusions: Methylphenidate may influence sexual function in complex ways depending on individual patient profiles and treatment variables. Clinicians should be aware of these potential outcomes and consider sexual health as part of the therapeutic discussion when prescribing methylphenidate. Full article

(This article belongs to the Special Issue Toxicological Effects of Drug Abuse and Its Consequences on Health)

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44 pages, 18795 KB

Open AccessEditor’s ChoiceArticle

Citicoline and Coenzyme Q10: Therapeutic Agents for Glial Activation Reduction in Ocular Hypertension

by José A. Matamoros, Sara Rubio-Casado, José A. Fernández-Albarral, Miguel A. Martínez-López, Ana I. Ramírez, Elena Salobrar-García, Eva M. Marco, Victor Paleo-García, Rosa de Hoz, Inés López-Cuenca, Lorena Elvira-Hurtado, Lidia Sánchez-Puebla, José M. Ramírez, Meritxell López-Gallardo and Juan J. Salazar

Pharmaceuticals 2025, 18(5), 694; https://doi.org/10.3390/ph18050694 - 8 May 2025

Cited by 4 | Viewed by 5486

Abstract

Background/Objectives: The loss of retinal ganglion cells (RGCs) is a hallmark of glaucoma, a major cause of blindness. Glial cell activation due to increased intraocular pressure (IOP) significantly contributes to RGC death. Therefore, substances with anti-inflammatory properties could help prevent that process. [...] Read more.

Background/Objectives: The loss of retinal ganglion cells (RGCs) is a hallmark of glaucoma, a major cause of blindness. Glial cell activation due to increased intraocular pressure (IOP) significantly contributes to RGC death. Therefore, substances with anti-inflammatory properties could help prevent that process. This study investigated whether combining Citicoline and Coenzyme Q10 (CoQ10) can reduce glial activation in the retina and the rest of the visual pathway, potentially preventing neurodegeneration in a mouse model of unilateral laser-induced ocular hypertension (OHT). Methods: Four groups of mice were used: vehicle (n = 12), CitiQ10 (n = 12), OHT–vehicle (n = 18), and OHT–CitiQ10 (n = 18). The administration of Citicoline and CoQ10 was performed orally once a day, initiated 15 days prior to the laser treatment and maintained post-treatment until sacrifice (3 days for retina or 7 days for the rest of the visual pathway). The retina, dorsolateral geniculate nucleus, superior colliculus, and visual cortex (V1) were immunohistochemically stained and analyzed. Results: In the laser–CitiQ10 group, the Citicoline + CoQ10 compound revealed (1) an IOP decrease at 24 h and 3 days post-laser; and (2) reduced signs of macroglial (decreased GFAP area) and microglial (soma size, arbor area, microglia number, P2RY12 expression) activation in the retina and in the rest of the visual pathway (reduced activated microglial phenotypes and lower GFAP expression). Conclusions: This study shows that oral administration of Citicoline and CoQ10 can reduce glial activation caused by increased IOP in retina and visual pathway in a mouse model of OHT, potentially protecting RGCs from OHT-induced inflammation. Full article

(This article belongs to the Section Pharmacology)

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