Pharmaceuticals

13 pages, 4295 KiB

Open AccessArticle

Chelerythrine Inhibits TGF-β-Induced Epithelial–Mesenchymal Transition in A549 Cells via RRM2

by Jinlong Liu, Mengran Xu, Liu Han, Yuxuan Rao, Haoming Han, Haoran Zheng, Jinying Wu and Xin Sun

Pharmaceuticals 2025, 18(7), 1036; https://doi.org/10.3390/ph18071036 (registering DOI) - 12 Jul 2025

Abstract

Background: The mechanisms underlying the metastasis of non-small-cell lung cancer (NSCLC) have long been a focal point of medical research. The anti-tumor effects of chelerythrine (CHE) have been confirmed; however, its ability to inhibit tumor metastasis and the underlying mechanisms remain unknown. The [...] Read more.

Background: The mechanisms underlying the metastasis of non-small-cell lung cancer (NSCLC) have long been a focal point of medical research. The anti-tumor effects of chelerythrine (CHE) have been confirmed; however, its ability to inhibit tumor metastasis and the underlying mechanisms remain unknown. The aim of this study was to investigate the inhibitory effects and molecular mechanisms of CHE on transforming growth factor-beta (TGF-β)-induced epithelial–mesenchymal transition (EMT). Methods: Wound healing and Transwell assays were employed to evaluate TGF-β-induced migration in A549 cells and the inhibitory effects of CHE. Ribonucleotide reductase subunit M2 (RRM2) expression levels were detected via Western blot and immunofluorescence staining. Western blot and RT-qPCR were used to examine the expression levels of EMT-related markers. Animal experiments were conducted to analyze the role of RRM2 in the CHE inhibition of TGF-β-induced lung cancer metastasis. Results: This study found that TGF-β treatment enhanced the metastasis of A549 cells, while CHE inhibited the expression of TGF-β-induced EMT-related transcription factors by RRM2, thereby suppressing tumor cell migration (p < 0.05). Furthermore, the oral administration of CHE inhibited the metastasis of A549 cells to the lungs from the tail vein in mice, consistent with in vitro findings. Despite the high doses of CHE used, there was no evidence of toxicity. Conclusions: Our data reveal the mechanism of the anti-metastatic effects of CHE on TGF-β-induced EMT and indicate that CHE can be used as an effective anti-tumor treatment. Full article

(This article belongs to the Section Natural Products)

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27 pages, 891 KiB

Open AccessReview

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

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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3 pages, 149 KiB

Open AccessEditorial

From Management to Cure: The Shifting Paradigm in HIV and Chronic Viral Hepatitis

by Daniel Sepúlveda-Crespo and Salvador Resino

Pharmaceuticals 2025, 18(7), 1034; https://doi.org/10.3390/ph18071034 - 11 Jul 2025

Abstract

The management of human immunodeficiency virus (HIV) and chronic viral hepatitis (HBV, HCV, and HDV) infections continues to pose a significant global health challenge [...] Full article

(This article belongs to the Special Issue HIV and Viral Hepatitis: Prevention, Treatment and Coinfection)

14 pages, 1524 KiB

Open AccessReview

Scale-Agnostic Models Based on Dimensionless Quality by Design as Pharmaceutical Development Accelerator

by Miquel Romero-Obon, Virginia Sancho-Ochoa, Khadija Rouaz-El-Hajoui, Pilar Pérez-Lozano, Marc Suñé-Pou, Josep María Suñé-Negre and Encarna García-Montoya

Pharmaceuticals 2025, 18(7), 1033; https://doi.org/10.3390/ph18071033 - 11 Jul 2025

Abstract

This comprehensive review of the synergistic use of Quality by Design (QbD) and the Pi–Buckingham theorem explores an innovative approach to enhancing product development and process optimization within the pharmaceutical industry. QbD is a systematic, proactive methodology that integrates quality considerations throughout the [...] Read more.

This comprehensive review of the synergistic use of Quality by Design (QbD) and the Pi–Buckingham theorem explores an innovative approach to enhancing product development and process optimization within the pharmaceutical industry. QbD is a systematic, proactive methodology that integrates quality considerations throughout the product lifecycle to ensure that pharmaceutical products meet regulatory standards for safety and efficacy from the outset of development. The Pi–Buckingham theorem serves as a foundational principle in dimensional analysis, facilitating the simplification of complex models by transforming physical variables into dimensionless parameters. This synergy enables researchers to better understand and control the factors affecting critical quality attributes (CQAs), thereby improving manufacturing outcomes and minimizing variability. Full article

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

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17 pages, 2136 KiB

Open AccessArticle

Charged Thienobenzo-1,2,3-Triazoles as Especially Potent Non-Selective Cholinesterase Inhibitors: Design, Anti-Inflammatory Activity, and Computational Study

by Antonija Jelčić, Anamarija Raspudić, Danijela Barić, Ana Ratković, Ivana Šagud, Paula Pongrac, Dora Štefok, Martina Bosnar, Sunčica Roca, Zlata Lasić, Ilijana Odak and Irena Škorić

Pharmaceuticals 2025, 18(7), 1032; https://doi.org/10.3390/ph18071032 - 11 Jul 2025

Abstract

Background/Objectives: This research reports the synthesis and evaluation of novel charged thienobenzo-triazoles as non-selective cholinesterase inhibitors (AChEs and BChEs), their anti-inflammatory properties, and a computational study. Methods: Fifteen derivatives were created through photochemical cyclization and quaternization of the triazole core. The [...] Read more.

Background/Objectives: This research reports the synthesis and evaluation of novel charged thienobenzo-triazoles as non-selective cholinesterase inhibitors (AChEs and BChEs), their anti-inflammatory properties, and a computational study. Methods: Fifteen derivatives were created through photochemical cyclization and quaternization of the triazole core. The compounds were tested for AChE and BChE inhibition. They showed greater potency and selectivity toward BChE. Results: The most potent compound, derivative 14, inhibited BChE with an IC₅₀ of 98 nM, while derivative 9 also displayed significant anti-inflammatory activity by inhibiting LPS-induced TNF-α production (IC₅₀ = 0.66 µM). Molecular docking revealed that triazolinium salts form key π-π and electrostatic interactions within enzyme active sites. In silico predictions indicated favorable ADME-Tox properties for compounds 9 and 11, including low mutagenicity and moderate CNS permeability. Conclusions: These findings highlight the potential of new charged triazolinium salts as peripherally selective cholinesterase inhibitors with additional anti-inflammatory potential. Full article

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

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18 pages, 2001 KiB

Open AccessArticle

In Vivo Evaluation of the Analgesic and Anti-Inflammatory Activity of Thymus numidicus Essential Oil

by Ouardia Chaouchi, Velislava Todorova, Stanislava Ivanova, Elizabet Dzhambazova, Farida Fernane, Nacira Daoudi Zerrouki, Lyudmil Peychev, Kremena Saracheva, Michaela Shishmanova-Doseva and Zhivko Peychev

Pharmaceuticals 2025, 18(7), 1031; https://doi.org/10.3390/ph18071031 - 11 Jul 2025

Abstract

Background: Thymus numidicus Poiret. (Lamiaceae) is an endemic plant with well-known antibacterial properties. It has been largely used in traditional Algerian medicine. This study aimed to compare the chemical composition of essential oils (EOs) extracted from leaves and flowers using the gas [...] Read more.

Background: Thymus numidicus Poiret. (Lamiaceae) is an endemic plant with well-known antibacterial properties. It has been largely used in traditional Algerian medicine. This study aimed to compare the chemical composition of essential oils (EOs) extracted from leaves and flowers using the gas chromatography–mass spectrometry method, as well as to investigate its analgesic and anti-inflammatory activities. Results: The EOs were rich in monoterpenes and classified as a thymol chemotype. In vivo experiments revealed that acute treatment with T. numidicus EO (20 and 80 mg/kg) significantly increased the thermal threshold on the hot-plate at all tested hours compared to the control animals (p < 0.001, respectively), while only the higher dose had a similar effect to the metamizole group at 2 and 3 h. In the mechanical stimulus test, both doses of the EO led to a late analgesic effect presented with increased paw withdrawal threshold only during the third hour compared to the control group (p < 0.05, respectively). In the plethysmometer test both doses of the EO dose-dependently reduced paw volume with nearly 10% and 15% compared to the control animals at all tested hours (p < 0.001, respectively), with a more pronounced volume reduction in the higher dose. In a neuropathic pain model, the EO (20 mg/kg and 80 mg/kg) dose-dependently increased the withdrawal latency time towards thermal stimuli and enhanced the paw withdrawal threshold in response to mechanical pressure at all tested hours compared to the CCI-group (p < 0.001, respectively). These findings demonstrate the potent analgesic and anti-inflammatory effects of T. numidicus EO in models of acute and neuropathic pain. Full article

(This article belongs to the Special Issue Pharmaceutical Applications and Therapeutic Mechanisms of Substances from Plant Origin)

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24 pages, 4420 KiB

Open AccessArticle

Herbal Extract-Induced DNA Damage, Apoptosis, and Antioxidant Effects of C. elegans: A Comparative Study of Mentha longifolia, Scrophularia orientalis, and Echium biebersteinii

by Anna Hu, Qinghao Meng, Robert P. Borris and Hyun-Min Kim

Pharmaceuticals 2025, 18(7), 1030; https://doi.org/10.3390/ph18071030 - 11 Jul 2025

Abstract

Background: Herbal medicine represents a rich yet complex source of bioactive compounds, offering both therapeutic potential and toxicological risks. Methods: In this study, we systematically evaluated the biological effects of three traditional herbal extracts—Mentha longifolia, Scrophularia orientalis, and Echium biebersteinii [...] Read more.

Background: Herbal medicine represents a rich yet complex source of bioactive compounds, offering both therapeutic potential and toxicological risks. Methods: In this study, we systematically evaluated the biological effects of three traditional herbal extracts—Mentha longifolia, Scrophularia orientalis, and Echium biebersteinii—using Caenorhabditis elegans as an in vivo model. Results: All three extracts significantly reduced worm survival, induced larval arrest, and triggered a high incidence of males (HIM) phenotypes, indicative of mitotic failure and meiotic chromosome missegregation. Detailed analysis of germline architecture revealed extract-specific abnormalities, including nuclear disorganization, ectopic crescent-shaped nuclei, altered meiotic progression, and reduced bivalent formation. These defects were accompanied by activation of the DNA damage response, as evidenced by upregulation of checkpoint genes (atm-1, atl-1), increased pCHK-1 foci, and elevated germline apoptosis. LC-MS profiling identified 21 major compounds across the extracts, with four compounds—thymol, carvyl acetate, luteolin-7-O-rutinoside, and menthyl acetate—shared by all three herbs. Among them, thymol and carvyl acetate significantly upregulated DNA damage checkpoint genes and promoted apoptosis, whereas thymol and luteolin-7-O-rutinoside contributed to antioxidant activity. Notably, S. orientalis and E. biebersteinii shared 11 of 14 major constituents (79%), correlating with their similar phenotypic outcomes, while M. longifolia exhibited a more distinct chemical profile, possessing seven unique compounds. Conclusions: These findings highlight the complex biological effects of traditional herbal extracts, demonstrating that both beneficial and harmful outcomes can arise from specific phytochemicals within a mixture. By deconstructing these extracts into their active components, such as thymol, carvyl acetate, and luteolin-7-O-rutinoside, we gain critical insight into the mechanisms driving reproductive toxicity and antioxidant activity. This approach underscores the importance of component-level analysis for accurately assessing the therapeutic value and safety profile of medicinal plants, particularly those used in foods and dietary supplements. Full article

(This article belongs to the Section Natural Products)

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18 pages, 1121 KiB

Open AccessReview

The Cellular and Mitochondrial Consequences of Mevalonate Pathway Inhibition by Nitrogen-Containing Bisphosphonates: A Narrative Review

by Adrianna Budzinska and Wieslawa Jarmuszkiewicz

Pharmaceuticals 2025, 18(7), 1029; https://doi.org/10.3390/ph18071029 - 11 Jul 2025

Abstract

Nitrogen-containing bisphosphonates (N-BPs) are commonly used drugs in the treatment of bone diseases due to their potent inhibition of the mevalonate pathway, leading to disrupted protein prenylation and reduced osteoclast activity. Although N-BPs are effective in reducing bone resorption, increasing evidence indicates their [...] Read more.

Nitrogen-containing bisphosphonates (N-BPs) are commonly used drugs in the treatment of bone diseases due to their potent inhibition of the mevalonate pathway, leading to disrupted protein prenylation and reduced osteoclast activity. Although N-BPs are effective in reducing bone resorption, increasing evidence indicates their side effects on various non-skeletal cells. The aim of this review is to synthesize the current knowledge on the cellular and molecular effects of N-BPs outside the skeletal system, with particular emphasis on their impact on mitochondrial function and energy metabolism. At the cellular level, N-BPs may reduce viability, modulate inflammatory responses, trigger apoptosis, disrupt cytoskeletal organization, and influence signaling and energy metabolism. N-BPs may also impair the prenylation of proteins essential for mitochondrial dynamics and quality control, and may disrupt Ca²⁺ homeostasis. As we have shown in endothelial cells, by inhibiting the mevalonate pathway, N-BPs may lead to a reduction in key components of the mitochondrial respiratory chain, such as coenzyme Q (CoQ) and a-heme. These effects can contribute to impaired mitochondrial respiratory function, increased oxidative stress, and mitochondria-dependent apoptosis, affecting cellular energy metabolism and viability. These findings underscore the multifaceted impact of N-BPs beyond bone, emphasizing the importance of mitochondrial health and energy metabolism in understanding their broader biological effects and potential adverse outcomes. Full article

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

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24 pages, 1814 KiB

Open AccessArticle

Development and Validation of a New LC-MS/MS Method for Simultaneous Quantification of Ivacaftor, Tezacaftor and Elexacaftor Plasma Levels in Pediatric Cystic Fibrosis Patients

by Alessandro Mancini, Raffaele Simeoli, Luca Cristiani, Sara Cairoli, Fabiana Ciciriello, Alessandra Boni, Federico Alghisi, Chiara Rossi, Giacomo Antonetti, Carlo Dionisi Vici, Alessandro Giovanni Fiocchi, Renato Cutrera and Bianca Maria Goffredo

Pharmaceuticals 2025, 18(7), 1028; https://doi.org/10.3390/ph18071028 - 10 Jul 2025

Abstract

Background: “CFTR modulators” (also named “caftor”) have been developed and introduced into clinical practice to improve the functionality of defective CFTR protein. Therapeutic drug monitoring (TDM) is not currently used for CFTR modulators in routine clinical practice and there is still much [...] Read more.

Background: “CFTR modulators” (also named “caftor”) have been developed and introduced into clinical practice to improve the functionality of defective CFTR protein. Therapeutic drug monitoring (TDM) is not currently used for CFTR modulators in routine clinical practice and there is still much to learn about the pharmacokinetic/pharmacodynamic (PK/PD) and the safety profiles of these drugs in a real-world setting. Moreover, therapeutic ranges are not yet available for both pediatric and adult cystic fibrosis (CF) patients. Methods: A new and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method for contemporary quantification of ivacaftor (IVA), tezacaftor (TEZ) and elexacaftor (ELX) in plasma samples has been developed and validated. The clinical performance of our method has been tested on samples collected during the routine clinical practice from n = 25 pediatric patients (aged between 7 and 17 years) affected by cystic fibrosis. This LC-MS/MS method has been validated according to ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines for the validation of bioanalytical methods. Results: Our method fulfilled ICH guidelines in terms of accuracy, precision, selectivity, specificity and carry-over. Intra- and inter-day accuracy and precision were ≤15%. The 9-day autosampler stability was 90–100% for TEZ and ELX; meanwhile, it fell to 76% for IVA. An injection volume of 1 µL and a wider quantification range (0.1–20 µg/mL) represent a novelty of our method in terms of sensitivity and fields of application. Finally, the evaluation of PK exposure parameters for IVA revealed strong agreement with previously published reports and with results from the summary of product characteristics (SmPCs). Conclusions: This method could be adopted to contemporarily measure ELX/TEZ/IVA plasma levels for both PK studies and monitor therapy compliance, especially in case of poor or partial responses to treatment, or to evaluate drug–drug interactions when multiple concomitant medications are required. Considering also the high cost burden of these medications to the health system, a TDM-based approach could facilitate more cost-effective patient management. Full article

(This article belongs to the Special Issue Innovative Tools for Drug Analysis and Therapeutic Drug Monitoring (TDM))

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13 pages, 774 KiB

Open AccessSystematic 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

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 to [...] 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)

18 pages, 1575 KiB

Open AccessArticle

Novel 3,19-(N-Phenyl-3-(4-fluorophenyl)-pyrazole) Acetal of Andrographolide Promotes Cell Cycle Arrest and Apoptosis in MDA-MB-231 Breast Cancer Cells

by Siva Kumar Rokkam, Shahjalal Chowdhury, Yashwanth Inabathina, Lakshminath Sripada, Srinivas Nanduri, Balasubramanyam Karanam and Nageswara Rao Golakoti

Pharmaceuticals 2025, 18(7), 1026; https://doi.org/10.3390/ph18071026 - 10 Jul 2025

Abstract

Background: Natural products play a crucial role in cancer treatment due to their ability to selectively target cancer cells. Andrographolide, a major constituent of Andrographis paniculata, exhibits potential anticancer properties. Considering the pharmacological importance of nitrogen-based heteroaromatic scaffolds, particularly pyrazole motifs, this [...] Read more.

Background: Natural products play a crucial role in cancer treatment due to their ability to selectively target cancer cells. Andrographolide, a major constituent of Andrographis paniculata, exhibits potential anticancer properties. Considering the pharmacological importance of nitrogen-based heteroaromatic scaffolds, particularly pyrazole motifs, this study aimed to integrate the pyrazole pharmacophore with the andrographolide scaffold to develop novel therapeutic candidates. Methods: Twenty novel 3,19-(N-phenyl-3-aryl-pyrazole) acetals of andrographolide and isoandrographolide were synthesized and characterized using UV-Vis, FT-IR, NMR, and HRMS. Initial anticancer screening was conducted by the National Cancer Institute (NCI), USA, against 60 human cancer cell lines. The most promising compound, 1f (R = 4-F), was selected for further biological evaluation in the MDA-MB-231 breast cancer cell line. Results: The MTT assay results demonstrated that compound 1f exhibited strong, dose-dependent anti-proliferative effects. The apoptosis analysis of 1f revealed a time-dependent increase in apoptotic cells, and cell cycle studies indicated S phase arrest in MDA-MB-231 cells. Antioxidant activity via the DPPH assay identified compounds 1b (R = 3-NO₂) and 2b (R = 3-NO₂) as the most effective radical scavengers. The most active compounds were also evaluated for drug-likeness using in silico Lipinski’s rule assessments. Conclusions: The synthesized 3,19-(N-phenyl-3-aryl-pyrazole) acetals of andrographolide and isoandrographolide exhibited promising anticancer and antioxidant properties. Among them, compound 1f showed the most significant activity, supporting its potential as a lead candidate for further anticancer drug development. Full article

(This article belongs to the Special Issue Exploring Natural Products with Antioxidant and Anticancer Properties)

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29 pages, 2844 KiB

Open AccessReview

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

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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26 pages, 1431 KiB

Open AccessReview

Bridging the Regulatory Divide: A Dual-Pathway Framework Using SRA Approvals and AI Evaluation to Ensure Drug Quality in Developing Countries

by Sarfaraz K. Niazi

Pharmaceuticals 2025, 18(7), 1024; https://doi.org/10.3390/ph18071024 - 10 Jul 2025

Abstract

Background: Developing countries face significant challenges in accessing high-quality pharmaceutical products due to resource constraints, limited regulatory capacity, and market dynamics that often prioritize cost over quality. This review addresses the critical gap in regulatory frameworks that fail to ensure pharmaceutical quality equity [...] Read more.

Background: Developing countries face significant challenges in accessing high-quality pharmaceutical products due to resource constraints, limited regulatory capacity, and market dynamics that often prioritize cost over quality. This review addresses the critical gap in regulatory frameworks that fail to ensure pharmaceutical quality equity between developed and developing nations. Objective: This comprehensive review examines a novel dual-pathway regulatory framework that leverages stringent regulatory authority (SRA) approvals, artificial intelligence-based evaluation systems, and harmonized pricing mechanisms to ensure pharmaceutical quality equity across global markets. Methods: A comprehensive systematic analysis of current regulatory challenges, proposed solutions, and implementation strategies was conducted through an extensive literature review (202 sources, 2019–2025), expert consultation on regulatory science, AI implementation in healthcare, and pharmaceutical policy development. The methodology included an analysis of regulatory precedents, an economic impact assessment, and a feasibility evaluation based on existing technological implementations. Results: The proposed framework addresses key regulatory capacity gaps through two complementary pathways: Pathway 1 enables same-batch distribution from SRA-approved products with pricing parity mechanisms. At the same time, Pathway 2 provides independent evaluation using AI-enhanced systems for differentiated products. Key components include indigenous AI development, which requires systematic implementation over 4–6 years across three distinct stages, outsourced auditing frameworks that reduce costs by 40–50%, and quality-first principles that categorically reject cost-based quality compromises. Implementation analysis demonstrates a potential for achieving a 90–95% quality standardization, accompanied by a 200–300% increase in regulatory evaluation capability. Conclusions: This framework has the potential to significantly improve pharmaceutical quality and access in developing countries while maintaining rigorous safety and efficacy standards through innovative regulatory approaches. The evidence demonstrates substantial public health benefits with projected improvements in population access (85–95% coverage), treatment success rates (90–95% efficacy), and economic benefits (USD 15–30 billion in system efficiencies), providing a compelling case for implementation that aligns with global scientific consensus and Sustainable Development Goal 3.8. Full article

(This article belongs to the Section Medicinal Chemistry)

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26 pages, 4832 KiB

Open AccessArticle

In Vivo Antidiabetic and Antilipidemic Effect of Thiazolidine-2,4-Dione Linked Heterocyclic Scaffolds in Obesity-Induced Zebrafish Model

by Asmaa Galal-Khallaf, Dawlat Mousa, Aml Atyah, Mohamed El-Bahnsawye, Mona K. Abo Hussein, Ibrahim El Tantawy El Sayed, Elshaymaa I. Elmongy, Reem Binsuwaidan, Abdel Moneim A. K. El-Torgoman, Hamed Abdel-Bary and Khaled Mohammed-Geba

Pharmaceuticals 2025, 18(7), 1023; https://doi.org/10.3390/ph18071023 - 10 Jul 2025

Abstract

Background: Type 2 diabetes mellitus (T2DM) presents a significant global health challenge, with obesity being a major contributing risk factor alongside genetic and non-genetic elements. Current treatments focus on reducing hyperglycemia and preventing T2DM progression, often involving drug combinations for enhanced efficacy. This [...] Read more.

Background: Type 2 diabetes mellitus (T2DM) presents a significant global health challenge, with obesity being a major contributing risk factor alongside genetic and non-genetic elements. Current treatments focus on reducing hyperglycemia and preventing T2DM progression, often involving drug combinations for enhanced efficacy. This study introduces two novel nitrogen-containing heterocyclic scaffolds: neocryptolepine–thiazolidinedione (NC-TZD) 8 and acridine–thiazolidinedione (AC-TZD) 11. Methods: These compounds were synthesized and characterized using various spectroscopic techniques. Their antihyperglycemic and antihyperlipidemic effects were assessed in an obesity-induced zebrafish model. Hyperglycemia was induced by immersing zebrafish in 100 mM glucose monohydrate for two weeks. Fish were then divided into groups receiving either 20 mg or 80 mg of the drugs per kg of body weight, alongside negative and positive control groups. Results: Both doses of hybrids 8 and 11 effectively restored glucose, triglyceride, insulin, and nuclear factor kappa beta (nfκβ) mRNA levels to normal. However, only the lower doses restored peroxisomal acyl-CoA oxidase (acox1) mRNA levels, with higher doses proving less effective. A molecular modeling study supported the antidiabetic potential of hybrids 8 and 11, suggesting interactions with target proteins PPAR-α and acox1. In silico ADMET analysis revealed promising oral bioavailability and drug likeness for both compounds. Conclusions: The findings indicate that both hybrids exhibit significant antihyperglycemic and antihypertriglyceridemic effects, particularly at lower doses. These results highlight the promising therapeutic potential of these novel oral bioavailable compounds in managing T2DM. Further research is warranted to elucidate their mechanisms of action. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Heterocyclic Compounds and Their Application in Therapy)

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13 pages, 735 KiB

Open AccessArticle

Comparing the Impact of Different Antiarrhythmic Classes on Clinical Outcomes Following Atrial Fibrillation Catheter Ablation

by Andrej Belančić, Yusuf Ziya Sener, Metin Oksul, Cansu Ozturk, Serdar Soner, Adnan Duha Comert, Gamze Yeter Arslan, Dinko Vitezić, Bojan Jelaković and Erkan Baysal

Pharmaceuticals 2025, 18(7), 1022; https://doi.org/10.3390/ph18071022 - 10 Jul 2025

Abstract

Background/Objectives: Catheter ablation has become the standard of care for patients with symptomatic and drug-refractory atrial fibrillation (AF). Both Class IC and Class III antiarrhythmic drugs (AADs) are effective in preventing early recurrences of AF, but not late recurrences, compared with the [...] Read more.

Background/Objectives: Catheter ablation has become the standard of care for patients with symptomatic and drug-refractory atrial fibrillation (AF). Both Class IC and Class III antiarrhythmic drugs (AADs) are effective in preventing early recurrences of AF, but not late recurrences, compared with the usual care. We aimed to compare the effects of two months of Class IC versus Class III AADs following AF catheter ablation on clinical outcomes, including arrhythmia recurrence and safety endpoints. Methods: All patients undergoing AF catheter ablation between January 2015 and November 2024 were screened, and cases meeting the inclusion criteria were included. Primary outcome was defined as atrial tachycardia recurrence-free survival. Results: A total of 98 patients (mean age 54.2 ± 14.0 years; 55.1% male) were enrolled, with 66.3% presenting with paroxysmal atrial fibrillation (AF). The mean left atrial diameter was 38.7 ± 5.1 mm, and 78.6% underwent cryoballoon ablation. Class IC AADs were administered to 62 cases, while the remaining 36 patients received amiodarone following catheter ablation. The rate of atrial tachycardia (ATa) recurrence was comparable between the patients treated with Class IC and Class III AADs (9.7% vs. 19.4%; p = 0.169). Predictors of ATa recurrence were identified as history of direct current cardioversion—DCCV (HR: 5.86; 95%CI: 1.44–23.82)—and LA diameter (HR: 1.17; 95%CI: 1.04–1.31). The most frequent AAD-related adverse event was symptomatic bradycardia (6.1%), which resolved in all cases following dose reduction. Conclusions: Class IC and Class III antiarrhythmics show comparable efficacy in terms of preventing ATa recurrence following AF catheter ablation. AAD-related adverse event rates are negligible for short-term use. Full article

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29 pages, 1953 KiB

Open AccessReview

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

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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21 pages, 4681 KiB

Open AccessArticle

Spray-Dried Polymeric Microspheres for Lipophilic Drugs: Formulation Design, Physicochemical Characterization, and In Vitro Release Evaluation

by Felipe Nataren-Rodríguez, Jorge Pacheco-Molina, Sandra Leticia Gracia-Vásquez, Isaías Balderas-Rentería, Mónica A. Ramírez-Cabrera, Eder Arredondo-Espinoza, Karla J. Santamaría and Patricia González-Barranco

Pharmaceuticals 2025, 18(7), 1020; https://doi.org/10.3390/ph18071020 - 9 Jul 2025

Abstract

Background/Objectives: The formulation of microspheres for lipophilic drugs using aqueous methods, such as spray drying, faces significant challenges. The main objective of this study was to evaluate the effect of the process parameters and polymer selection on the production of microspheres by [...] Read more.

Background/Objectives: The formulation of microspheres for lipophilic drugs using aqueous methods, such as spray drying, faces significant challenges. The main objective of this study was to evaluate the effect of the process parameters and polymer selection on the production of microspheres by spray drying for a lipophilic drug. Methods: Lipophilic drug-loaded microspheres were developed using various polymers via the aqueous spray drying method. The effects of the factors on the yield percentage and encapsulation efficiency were analyzed. Microspheres preparation included Agave inulin, guar gum, hydroxypropyl methylcellulose, and Eudragit^® S100. A 2³ factorial design was performed, and the parameters were optimized. Results: Inlet temperature, feed flow, and polymer percentage showed a significant effect (p < 0.05) on the yield percentage of guar gum microspheres and encapsulation efficiency of the inulin microspheres. Inulin and guar gum microspheres showed the best yield percentage (75.41%) and encapsulation efficiency (100%), respectively. In addition, guar gum microspheres had the best morphology, and hydroxypropyl methylcellulose microspheres were smaller and had an irregular surface. Eudragit did not maintain its delayed release property due to limitations of the aqueous method; inulin released the drug immediately, and guar gum and hydroxypropyl methylcellulose microspheres prolonged release only by a few additional hours. Conclusions: The experimental design showed that optimizing the parameters (inlet temperature, feed flow, and the type and percentage of polymer) can regulate the microsphere development process to obtain improved product yield and encapsulation efficiency results. Full article

(This article belongs to the Section Pharmaceutical Technology)

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12 pages, 1766 KiB

Open AccessArticle

Negative Impact of Olanzapine on ICU Delirium Resolution: An Emulated Clinical Trial

by Ajna Hamidovic and John Davis

Pharmaceuticals 2025, 18(7), 1019; https://doi.org/10.3390/ph18071019 - 9 Jul 2025

Abstract

Introduction: Delirium is a common and debilitating clinical complication among ICU patients. Despite the prevalence of this condition, there are insufficient data to support or refute the routine use of atypical antipsychotics since the existing evidence remains sparse and inconclusive. The objective [...] Read more.

Introduction: Delirium is a common and debilitating clinical complication among ICU patients. Despite the prevalence of this condition, there are insufficient data to support or refute the routine use of atypical antipsychotics since the existing evidence remains sparse and inconclusive. The objective of the present study was to evaluate whether pre-ICU administration of the atypical antipsychotic olanzapine is associated with a differential time to delirium resolution relative to the control condition. Methods: In this emulated clinical trial, we utilized the MIMIC-IV v3.1 database, which contains deidentified health records from approximately 65,000 ICU patients, to derive a cohort of patients with a positive delirium screening within 24 h of ICU admission. We exluded patients who received any antipsychotic other than olanzapine prior to ICU admission. We performed propensity score matching using logistic regression and nearest-neighbor matching (1:1, caliper = 0.2) to balance covariates between the olanzapine and control groups. The primary outcome was time to delirium resolution, defined as the first negative delirium assessment. A Cox proportional hazards model, adjusted for multiple covariates and incorporating age as a time-dependent variable, was used to examine the association between olanzapine use and delirium resolution. Interaction terms were included to evaluate effect modification by age and gender. Results: A total of 5070 patients with a positive delirium screening within 24 h and no exposure to other antipsychotics met the eligibility criteria; 421 olanzapine users were matched to 421 controls using propensity score matching. Covariate balance was achieved (all standardized mean differences < 0.1), and no multicollinearity was detected (all VIFs < 2). Pre-ICU olanzapine use was associated with a 27% decrease in the likelihood of delirium resolution (HR = 0.73; 95% CI: 0.63–0.86; p < 0.001). A significant interaction with age indicated that the negative impact of olanzapine on delirium resolution increased with advancing age (HR = 1.0024 per unit of age × log(time), p = 0.023), translating to a 2.4% increase in the risk of prolonged delirium resolution for every 10-year increase in age per log(time). There was no modification of the association according to gender. Discussion: The negative effect of olanzapine on ICU delirium resolution, particularly among the elderly, presented in this study is in line with the results of our earlier study showing a negative effect (i.e., prolonged ICU stay) among patients receiving quetiapine relative to both control and haloperidol conditions. Distinctly strong anticholinergic effects of both olanzapine and quetiapine relative to the other antipsychotic agents may be driving the identified negative outcomes. Conclusions: Results of this emulated clinical trial do not support the use of olanzapine for the treatment of ICU delirium because the agent prolongs time to resolution of the condition. Full article

(This article belongs to the Section Pharmacology)

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25 pages, 947 KiB

Open AccessArticle

Synthetic Analogs of the Alkaloid Cassiarin A with Enhanced Antimalarial Activity

by Thomas Klaßmüller, Timo Reiß, Florian Lengauer, Che Julius Ngwa, Karin Bartel, Gabriele Pradel and Franz Bracher

Pharmaceuticals 2025, 18(7), 1018; https://doi.org/10.3390/ph18071018 - 9 Jul 2025

Abstract

Background: Among the alkaloids from Cassia siamea, cassiarin A has outstanding antiprotozoal activity, but structure–activity relationships for this chemotype were only poorly understood until now. Methods: We worked out efficient approaches to hitherto underexplored analogs (12 examples) on three synthesis routes which [...] Read more.

Background: Among the alkaloids from Cassia siamea, cassiarin A has outstanding antiprotozoal activity, but structure–activity relationships for this chemotype were only poorly understood until now. Methods: We worked out efficient approaches to hitherto underexplored analogs (12 examples) on three synthesis routes which mainly comprised variations in the methyl groups at C-2 and C-5. The new compounds were tested for antiprotozoal and cytotoxic activities. Results: Introduction of a (substituted) benzene ring at C-2 led to a significant enhancement of activity against Plasmodium falciparum, while modifications of the methyl group at C-5 and the phenolic group had detrimental effects. Two of the 2-phenyl analogs further showed a resistance index comparable to the one of the reference drug chloroquine. Although the novel derivatives did not show hemolytic effects, investigation on human endothelial (HUVEC) cells at relevant concentrations indicated strong cytotoxic effects on human cells. Conclusions: Systematic structure modifications of cassiarin A led to a significant enhancement of antiplasmodial activity, but the observed strong cytotoxicity to human cells renders this library of cassiarin A derivatives inadequate for drug development. Full article

(This article belongs to the Special Issue Natural Products-Assisted Organic Synthesis in Medicinal Chemistry)

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20 pages, 6229 KiB

Open AccessArticle

Integrating Network Pharmacology and Experimental Validation to Explore the Effect and Mechanism of Inonotus obliquus Polysaccharide in the Treatment of Rheumatoid Arthritis

by Yuan Fu, Tianyi Jiang, Xizhu Fang, Yifang Chen, Jiawei Li, Shengnan Huang, Fangfang Li and Dan Jin

Pharmaceuticals 2025, 18(7), 1017; https://doi.org/10.3390/ph18071017 - 8 Jul 2025

Abstract

Background/Objectives: Rheumatoid arthritis (RA) is a chronic, systemic, and progressive autoimmune–inflammatory disease primarily affecting small joints. Inonotus obliquus polysaccharide (IOP) is the main component of the parasitic fungus obliquus, which has anti-tumor, anti-inflammatory, and antioxidant effects. However, whether IOP has a therapeutic effect [...] Read more.

Background/Objectives: Rheumatoid arthritis (RA) is a chronic, systemic, and progressive autoimmune–inflammatory disease primarily affecting small joints. Inonotus obliquus polysaccharide (IOP) is the main component of the parasitic fungus obliquus, which has anti-tumor, anti-inflammatory, and antioxidant effects. However, whether IOP has a therapeutic effect on RA is still unclear. Thus, this study aimed to reveal the effect of IOP on MH7A cells and collagen-induced arthritis (CIA) rats and to investigate the molecular mechanism of IOP in RA. Methods: In this study, network pharmacology was used to identify the key signaling pathways in IOP treatment of RA. The effect of IOP was verified in rats with CIA. We performed CCK-8, EdU, colony formation assay, cell apoptosis, cell migration and invasion, Western blot analysis, and immunofluorescence to elucidate the effect of IOP on the proliferation, apoptosis, migration and invasion of MH7A cells and revealed its modulation of the NF-κB and NLRP3 inflammasome signaling pathways. Results: IOP treatment of CIA rats significantly alleviated joint swelling, synovial tissue proliferation and erosion, and reduced the expression of inflammatory factors TNF-α, IL-6, IL-1β and IL-18. In vitro, IOP significantly inhibited the proliferation, migration, and invasion abilities of TNF-α-stimulated MH7A cells and promoted their apoptosis. Mechanistically, IOP inhibited the NF-κB and NLRP3 inflammasome activation. Conclusions: This study revealed that IOP exerts anti-RA effects by downregulating the NF-κB and NLRP3 inflammasome signaling pathways, promoting cell apoptosis, and inhibiting the expression of inflammatory cytokines, representing a promising therapeutic option for RA. Full article

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

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23 pages, 10678 KiB

Open AccessArticle

Effects of Angiotensin II Receptor 1 Inhibition by LCZ696 on the Acquisition and Relapse of Methamphetamine-Associated Contextual Memory

by Xiaofang Li, Zhiting Zou, Xiangdong Yang, Jinnan Lü, Xiaoyu Zhang, Jiahui Zhou, Dan Zhu, Xinshuang Gong, Shujun Lin, Zhaoying Yu, Zizhen Si, Wenting Wei, Yakai Xie and Yu Liu

Pharmaceuticals 2025, 18(7), 1016; https://doi.org/10.3390/ph18071016 - 8 Jul 2025

Abstract

Background/Objectives: Contextual memory associated with methamphetamine (METH) use contributes to relapse and persistence of addiction. Angiotensin II type 1 receptor (AT1R) signaling has been implicated in drug reinforcement. LCZ696, a clinically used combination of sacubitril (a neprilysin inhibitor) and valsartan (an AT1R antagonist), [...] Read more.

Background/Objectives: Contextual memory associated with methamphetamine (METH) use contributes to relapse and persistence of addiction. Angiotensin II type 1 receptor (AT1R) signaling has been implicated in drug reinforcement. LCZ696, a clinically used combination of sacubitril (a neprilysin inhibitor) and valsartan (an AT1R antagonist), may interfere with METH-associated memory through the modulation of dopaminergic pathways. Methods: Male C57BL/6J mice were tested in a conditioned place preference (CPP) paradigm to assess the effects of LCZ696, sacubitril (AHU377), and valsartan on METH-induced memory expression and reinstatement. Synaptic plasticity in the nucleus accumbens (NAc) was examined by assessing the levels of synaptophysin (Syp) and postsynaptic density protein 95 (Psd95), as well as dendritic spine density. Dopaminergic signaling in the ventral tegmental area (VTA) was evaluated via ELISA, Western blotting, and chromatin immunoprecipitation (ChIP), targeting cAMP response element-binding protein (Creb) binding to the tyrosine hydroxylase (Th) promoter. To further assess the role of Th, an adeno-associated virus (AAV9) carrying a CRISPR-Cas9-based sgRNA targeting Th (AAV9-Th-sgRNA) was microinjected into the VTA. Results: LCZ696 and valsartan significantly reduced METH-induced CPP and reinstatement. LCZ696 reversed METH-induced synaptic and dopaminergic alterations and suppressed Creb-mediated Th transcription. Th knockdown attenuated both CPP acquisition and relapse. Conclusions: LCZ696 disrupts METH-associated contextual memory by modulating dopaminergic signaling and Creb-dependent Th expression, supporting its potential as a treatment for METH use disorder. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 1875 KiB

Open AccessSystematic Review

PARP Inhibitors for Metastatic CRPC: More Answers than Questions, a Systematic Review and Meta-Analysis

by Ray Manneh, Javier Molina-Cerrillo, Guillermo de Velasco, Linda Ibatá, Susan Martínez, Álvaro Ruiz-Granados and Teresa Alonso-Gordoa

Pharmaceuticals 2025, 18(7), 1015; https://doi.org/10.3390/ph18071015 - 8 Jul 2025

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Abstract

PARP inhibitors (PARPi), alone or in combination with androgen receptor signaling inhibitors (ARSi), have shown clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors with homologous recombination repair (HRR) gene alterations. Recent data from the TALAPRO-2 trial complete the current evidence [...] Read more.

PARP inhibitors (PARPi), alone or in combination with androgen receptor signaling inhibitors (ARSi), have shown clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors with homologous recombination repair (HRR) gene alterations. Recent data from the TALAPRO-2 trial complete the current evidence on PARPi–ARSi combination strategies in this setting. Background/Objectives: To evaluate the efficacy and safety of PARPi-based therapies—monotherapy and combination with ARSi—in patients with mCRPC, focusing on molecular subgroups defined by DNA repair alterations. Methods: We conducted a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) assessing PARPi as monotherapy or in combination with ARSi. Searches were performed in PubMed, EMBASE, the Cochrane Library, and oncology conference proceedings up to February 2025. Outcomes included radiographic progression-free survival (rPFS), overall survival (OS), second progression-free survival (PFS2), and grade ≥3 adverse events (AEs). Data were pooled using a random-effects model, with subgroup analyses by DNA repair status. Results: Five RCTs (n = 2921) were I confirmincluded: three on combination therapy (n = 2271) and two on monotherapy (n = 650). Combination therapy improved rPFS in the ITT (HR = 0.64; 95% CI: 0.56–0.74), HRRm (HR = 0.55; 95% CI: 0.44–0.68), and BRCAm (HR = 0.33; 95% CI: 0.18–0.58) subgroups. OS was also improved in the ITT (HR = 0.80; 95% CI: 0.70–0.92), HRRm (HR = 0.68; 95% CI: 0.55–0.83), and BRCAm (HR = 0.54; 95% CI: 0.34–0.85) groups. No benefit was observed in non-HRRm patients. PFS2 favored combination therapy (HR = 0.77; 95% CI: 0.64–0.91). Grade ≥3 AEs were more frequent (RR = 1.44; 95% CI: 1.20–1.73). Monotherapy improved rPFS in ITT (HR = 0.46; 95% CI: 0.20–0.81) and BRCAm (HR = 0.33; 95% CI: 0.15–0.75); OS benefit was seen only in BRCAm (HR = 0.73; 95% CI: 0.57–0.95). Conclusions: PARPi therapies improve outcomes mainly in HRR- and BRCA-mutated mCRPC. Molecular selection is key to optimizing benefit and minimizing toxicity. Further research on the activity of PARPi combinations in non-HRR mutated mCRPC is needed to better understand the underlying mechanisms of efficacy. Full article

(This article belongs to the Special Issue Advances in Prostate Cancer Therapeutics)

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19 pages, 2326 KiB

Open AccessArticle

N-Acetylcysteine Treatment Restores the Protective Effect of Heart Ischemic Postconditioning in a Murine Model in the Early Stages of Atherosclerosis

by Tamara Zaobornyj, Virginia Perez, Georgina Ossani, Tamara Mazo, Eugenia Godoy, Jorge Godoy, Yohana Yanaje, Camila Musci-Ferrari, Mario Contin, Valeria Tripodi, Magali Barchuk, Gabriela Berg, Ricardo J. Gelpi, Martin Donato and Veronica D’Annunzio

Pharmaceuticals 2025, 18(7), 1014; https://doi.org/10.3390/ph18071014 - 8 Jul 2025

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Abstract

Background/Objectives: Ischemic postconditioning (IP) is a well-established intervention that mitigates this damage by activating endogenous cardioprotective pathways. However, the presence of comorbidities such as dyslipidemia can disrupt these protective mechanisms and abolish the infarct-sparing effect typically induced by IP. In this context, identifying [...] Read more.

Background/Objectives: Ischemic postconditioning (IP) is a well-established intervention that mitigates this damage by activating endogenous cardioprotective pathways. However, the presence of comorbidities such as dyslipidemia can disrupt these protective mechanisms and abolish the infarct-sparing effect typically induced by IP. In this context, identifying pharmacological strategies to restore cardioprotection is of clinical relevance. This study aimed to evaluate whether N-acetylcysteine (NAC), a glutathione precursor with antioxidant properties, can restore the infarct-limiting effect of IP compromised by HFD-induced oxidative stress. Methods: Male mice were fed a control diet (CD) or HFD for 12 weeks. NAC (10 mM) was administered in drinking water for 3 weeks before ex vivo myocardial ischemia/reperfusion (I/R) injury (30 min ischemia/60 min reperfusion). In IP groups, six cycles of brief I/R were applied at the onset of reperfusion. Infarct size, ventricular function, redox status (GSH/GSSG), lipid profile, and histology were evaluated. Results: NAC improved the lipid profile (HDL/non-HDL ratio) and enhanced the infarct-sparing effect of IP in CD-fed mice. In HFD-fed mice, NAC restored the efficacy of IP, significantly reducing infarct size (HFD-I/R-NAC: 39.7 ± 4.5% vs. HFD-IP-NAC: 26.4 ± 2.0%, p < 0.05) without changes in ventricular function. The ratio of oxidized/reduced glutathione (GSSG/GSH) is depicted. Under basal conditions, the hearts of mice fed an HFD exhibited a shift towards a more oxidized state compared to the control diet CD group. In the I/R protocol, a significant shift towards a more oxidized state was observed in both CD and HFD-fed animals. In the IP protocol, the GSSG/GSH ratio revealed a tendency to basal values in comparison to the I/R protocol. The analysis indicates that animals subjected to I/R and IP protocols in conjunction with NAC show a tendency to reach basal values, thus suggesting a potential for the reduction in ROS. Conclusions: NAC treatment mitigates oxidative stress and restores the cardioprotective effect of ischemic postconditioning in a model of early-stage atherosclerosis. These findings support NAC as a potential adjunct therapy to improve myocardial resistance to reperfusion injury under dyslipidemic conditions Full article

(This article belongs to the Section Biopharmaceuticals)

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25 pages, 1374 KiB

Open AccessArticle

Investigation into Safety Profiles of Antiepileptic Drugs and Identification of Predictors for Serious Adverse Events: Insights from National Pharmacovigilance Data

by Soo Hyeon Lee, Dae Hyeon Sung, Euna Cho, Jeongah Min, Sooyoung Shin and Yeo Jin Choi

Pharmaceuticals 2025, 18(7), 1013; https://doi.org/10.3390/ph18071013 - 7 Jul 2025

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Abstract

Backgrounds/Objectives: This study aims to comprehensively characterize the prevalence and severity of antiepileptic drug (AED)-induced adverse drug events (ADEs) and to identify predictors strongly associated with serious adverse events (SAEs) in both general and geriatric populations. Methods: This cross-sectional study investigated AED-related ADEs [...] Read more.

Backgrounds/Objectives: This study aims to comprehensively characterize the prevalence and severity of antiepileptic drug (AED)-induced adverse drug events (ADEs) and to identify predictors strongly associated with serious adverse events (SAEs) in both general and geriatric populations. Methods: This cross-sectional study investigated AED-related ADEs reported to the KIDS KAERS DB from January 2014 to December 2023. Disproportionality analysis was performed to detect the association between reported SAEs, and multiple logistic regression was conducted to identify predictors associated with SAEs. Cox’s proportional hazard model was utilized to assess ADE duration in elderly patients aged 60 years and older. Results: More than 50% of 36,809 AED-related ADEs were reported in elderly patients aged 60 years and older, and the prevalence of SAEs was 3.78%. ADEs associated with endocrine disorders had the highest likelihood of SAEs being reported (ROR 15.30), followed by hematological disorders. The predictors associated with elevated SAE risks in the elderly were male sex (OR 1.91; 95% CI 1.62–2.27), aging (OR 1.17; 95% CI 1.04–1.31), and certain AEDs. However, the concomitant administration of acid-suppressive therapy (AST) and opioids was associated with a lower risk of SAEs in the elderly population. Elderly patients not receiving concomitant AST were less likely to experience prolonged ADE duration (HR 0.28, 95% CI 0.07–1.15); however, no substantial differences in ADE duration were observed with the concomitant use of opioids. Conclusions: This study implies significant variability in the frequency, severity, and duration of ADEs depending on the type of AEDs, patient demographics, and concomitant medication use. Full article

(This article belongs to the Special Issue Pharmacoepidemiology and Pharmacovigilance in Drug Therapy: New Issues, Challenges, and Applications)

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23 pages, 4204 KiB

Open AccessArticle

Investigation of Bioactive Compounds Extracted from Verbena officinalis and Their Biological Effects in the Extraction by Four Butanol/Ethanol Solvent Combinations

by Dejan Stojković, Nikoleta Đorđevski, Mladen Rajaković, Biljana Filipović, Jelena Božunović, Stefani Bolevich, Gokhan Zengin, Sergey Bolevich, Uroš Gašić and Marina Soković

Pharmaceuticals 2025, 18(7), 1012; https://doi.org/10.3390/ph18071012 - 7 Jul 2025

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Abstract

Background/Objectives: Verbena officinalis L. (common vervain) is a medicinal plant traditionally used and investigated in phytotherapy for its neuroprotective, antioxidant, and anti-inflammatory properties. This study aims to investigate the phytochemical diversity and biological activity of V. officinalis extracts prepared with different ratios [...] Read more.

Background/Objectives: Verbena officinalis L. (common vervain) is a medicinal plant traditionally used and investigated in phytotherapy for its neuroprotective, antioxidant, and anti-inflammatory properties. This study aims to investigate the phytochemical diversity and biological activity of V. officinalis extracts prepared with different ratios of butanol and ethanol. Methods: Aerial parts of V. officinalis were extracted using four solvent systems: 100% butanol (B1), 75:25 (BE7.5), 50:50 (BE5), and 25:75 (BE2.5) butanol:ethanol mixtures. Metabolite profiling was conducted using liquid chromatography–high-resolution tandem mass spectrometry (LC-HRMS/MS). Antioxidant activities were evaluated through six assays: 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), cupric ion-reducing antioxidant capacity (CUPRAC), ferric-reducing antioxidant power (FRAP), metal-chelating ability (MCA), and the phosphomolybdenum assay (PMA). Enzyme inhibition assays targeted acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, and α-amylase. Antibacterial activity against Pseudomonas aeruginosa was tested via microdilution, while dominant phytochemicals were evaluated for binding affinity through molecular docking. Results: Seventy-five compounds, including phenolic acids, flavonoids, iridoids, phenylethanoids, and xanthones, were identified. BE5 extract exhibited the highest total phenolic content and strongest antioxidant capacity, while BE2.5 demonstrated the greatest antibacterial and metal-chelating effects. All extracts showed comparable AChE inhibition, with BE5 achieving the strongest tyrosinase and α-amylase inhibition. Docking studies confirmed high binding affinities of luteolin glucuronides to human and bacterial target enzymes. Conclusions: Solvent composition markedly influenced the chemical and biological profiles of V. officinalis extracts. BE5 and BE2.5 emerged as promising systems for obtaining bioactive fractions with therapeutic potential. Full article

(This article belongs to the Section Natural Products)

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3 pages, 5950 KiB

Open AccessCorrection

Correction: Mohammed et al. Alvespimycin Exhibits Potential Anti-TGF-β Signaling in the Setting of a Proteasome Activator in Rats with Bleomycin-Induced Pulmonary Fibrosis: A Promising Novel Approach. Pharmaceuticals 2023, 16, 1123

by Osama A. Mohammed, Mustafa Ahmed Abdel-Reheim, Lobna A. Saleh, Mohannad Mohammad S. Alamri, Jaber Alfaifi, Masoud I. E. Adam, Alshaimaa A. Farrag, AbdulElah Al Jarallah AlQahtani, Waad Fuad BinAfif, Abdullah A. Hashish, Sameh Abdel-Ghany, Elsayed A. Elmorsy, Hend S. El-wakeel, Ahmed S. Doghish, Rabab S. Hamad and Sameh Saber

Pharmaceuticals 2025, 18(7), 1011; https://doi.org/10.3390/ph18071011 - 7 Jul 2025

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Abstract

In the original publication [...] Full article

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29 pages, 2035 KiB

Open AccessSystematic 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

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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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17 pages, 1906 KiB

Open AccessArticle

Effects of Psilocin and Psilocybin on Human 5-HT₄ Serotonin and H₂ Histamine Receptors in Perfused Hearts of Transgenic Mice

by Pauline Braekow, Joachim Neumann, Uwe Kirchhefer and Ulrich Gergs

Pharmaceuticals 2025, 18(7), 1009; https://doi.org/10.3390/ph18071009 - 6 Jul 2025

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Abstract

Background/Objectives: Hallucinogenic substances such as psilocybin, psilocin, ergometrine, ergotamine, and lysergic acid diethylamide (LSD) have been demonstrated to enhance the force of contraction (FOC), in part due to the phosphorylation of phospholamban in human atrial preparations via 5-HT₄ serotonin receptors and/or [...] Read more.

Background/Objectives: Hallucinogenic substances such as psilocybin, psilocin, ergometrine, ergotamine, and lysergic acid diethylamide (LSD) have been demonstrated to enhance the force of contraction (FOC), in part due to the phosphorylation of phospholamban in human atrial preparations via 5-HT₄ serotonin receptors and/or H₂ histamine receptors. However, whether psilocybin or psilocin acts at isolated mammalian ventricular preparations and whether they increase protein phosphorylation in the mammalian ventricle remains to be elucidated. Methods: To this end, the FOC and phospholamban phosphorylation in isolated perfused hearts from transgenic mice with cardiomyocyte-specific overexpression of either human 5-HT₄ receptors (5-HT₄-TG) or human H₂ receptors (H₂-TG) and their wild-type littermates (WT) were examined. Furthermore, the ergot alkaloids ergometrine, ergotamine, and LSD were used as references. Results: Psilocybin and psilocin enhanced the FOC to 137% and to 152%, respectively, and elevated the phospholamban phosphorylation in isolated perfused hearts from 5-HT₄-TG. In H₂-TG hearts, psilocybin and psilocin increased the FOC to a much lesser extent but had no effect on the phospholamban phosphorylation. In contrast, LSD increased the FOC and phosphorylation state of phospholamban in isolated hearts of both 5-HT₄-TG and H₂-TG. On the other hand, ergometrine and ergotamine increased the FOC only in H₂-TG. Ergometrine increased the phosphorylation state of phospholamban in perfused hearts from H₂-TG, but not from 5-HT₄-TG. Ergotamine failed to increase the phospholamban phosphorylation in both H₂-TG and 5-HT₄-TG. Psilocybin, psilocin, ergotamine, ergometrine, and LSD were unable to increase FOC and phospholamban phosphorylation in perfused hearts from WT. Conclusions: The increase in the phosphorylation state of phospholamban could provide a partial explanation for the positive inotropic effects and the relaxant effects of not only psilocybin and psilocin but also ergometrine and LSD in the isolated hearts of the animals used in this study. Full article

(This article belongs to the Special Issue Psychedelics: A New Drug Candidate for Treating Mental Illness)

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Open AccessArticle

Isoliensinine Induces Ferroptosis in Urothelial Carcinoma Cells via the PI3K/AKT/HIF-1α Axis: Molecular Evidence from Next-Generation Sequencing

by Yun-Chen Li, Hsuan-En Huang, Chia-Ying Yu, Ya-Chuan Chang, Shu-Yu Lin, Shao-Chuan Wang and Wen-Wei Sung

Pharmaceuticals 2025, 18(7), 1008; https://doi.org/10.3390/ph18071008 - 6 Jul 2025

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Abstract

Background: Bladder cancer ranks ninth among the most commonly diagnosed cancers, with urothelial carcinoma (UC) accounting for more than 90% of all cases. Given the high recurrence rate and progression risk of bladder cancer, investigating alternative adjunct therapies is imperative. One potential candidate [...] Read more.

Background: Bladder cancer ranks ninth among the most commonly diagnosed cancers, with urothelial carcinoma (UC) accounting for more than 90% of all cases. Given the high recurrence rate and progression risk of bladder cancer, investigating alternative adjunct therapies is imperative. One potential candidate is isoliensinine, which has shown antitumor potential in various cancers; however, the effectiveness of isoliensinine on UC is largely unknown. Methods: In the present study, the effects of isoliensinine on UC cells were examined in a variety of in vitro experiments, including MTT assays, colony formation assays, flow cytometry assays, RNA sequencing analysis, and Western blotting. Results: The isoliensinine-treated T24 and UMUC3 UC cell lines showed cell growth inhibition and proliferation in the MTT and colony formation assays and an apoptotic effect in the flow cytometry assays. RNA sequencing analysis, performed to explain the underlying mechanisms, revealed a significant regulation of cell functions, including apoptosis, the cell cycle, hypoxia-inducible factor 1 (HIF-1) signaling, tumor necrosis factor (TNF) signaling, and ferroptosis. Subsequent Western blotting results verified all these findings. Conclusions: Overall, our data indicate that isoliensinine inhibits UC cell growth and proliferation by inducing apoptosis through alterations in the TNF and HIF1 pathways and ferroptosis. Overall, isoliensinine shows potential for use in new or combined adjunct therapies for the treatment of bladder cancer. Full article

(This article belongs to the Section Biopharmaceuticals)

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26 pages, 1932 KiB

Open AccessArticle

A Machine Learning Platform for Isoform-Specific Identification and Profiling of Human Carbonic Anhydrase Inhibitors

by Lisa Piazza, Miriana Di Stefano, Clarissa Poles, Giulia Bononi, Giulio Poli, Gioele Renzi, Salvatore Galati, Antonio Giordano, Marco Macchia, Fabrizio Carta, Claudiu T. Supuran and Tiziano Tuccinardi

Pharmaceuticals 2025, 18(7), 1007; https://doi.org/10.3390/ph18071007 - 5 Jul 2025

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Abstract

Background/Objectives: Human carbonic anhydrases (hCAs) are metalloenzymes involved in essential physiological processes, and their selective inhibition holds therapeutic potential across a wide range of disorders. However, the high degree of structural similarity among isoforms poses a significant challenge for the design of selective [...] Read more.

Background/Objectives: Human carbonic anhydrases (hCAs) are metalloenzymes involved in essential physiological processes, and their selective inhibition holds therapeutic potential across a wide range of disorders. However, the high degree of structural similarity among isoforms poses a significant challenge for the design of selective inhibitors. In this work, we present a machine learning (ML)-based platform for the isoform-specific prediction and profiling of small molecules targeting hCA I, II, IX, and XII. Methods: By integrating four molecular representations with four ML algorithms, we built 64 classification models, each extensively optimized and validated. The best-performing models for each isoform were applied in a virtual screening campaign for ~2 million compounds. Results: Following a multi-step refinement process, 12 candidates were identified, purchased, and experimentally tested. Several compounds showed potent inhibitory activity in the nanomolar to submicromolar range, with selectivity profiles across the isoforms. To gain mechanistic insights, SHAP-based feature importance analysis and molecular docking supported by molecular dynamics simulations were employed, highlighting the structural determinants of the predicted activity. Conclusions: This study demonstrates the effectiveness of integrating ML, cheminformatics, and experimental validation to accelerate the discovery of selective carbonic anhydrase inhibitors and provides a generalizable framework for activity profiling across enzyme isoforms. Full article

(This article belongs to the Section Medicinal Chemistry)

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Pharmaceuticals, Volume 18, Issue 7 (July 2025) – 105 articles

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