Pharmaceuticals

23 pages, 9320 KiB

Open AccessArticle

Evaluation of the Cytotoxicity, Genotoxicity and Acute Oral Toxicity of Thymus longicaulis subsp. chaubardii (Rchb.f.) Jalas

by Ayfer Beceren, Ayse Nur Hazar-Yavuz, Ozlem Bingol Ozakpinar, Duygu Taskin, Ismail Senkardes, Turgut Taskin, Ozlem Tugçe Cilingir-Kaya, Ahmad Kado, Elif Caliskan Salihi and Hatice Kubra Elcioglu

Pharmaceuticals 2025, 18(7), 1037; https://doi.org/10.3390/ph18071037 (registering DOI) - 12 Jul 2025

Abstract

Background/Objectives: Thymus longicaulis subsp. chaubardii (TL) (Rchb.f.) Jalas is widely used in traditional Turkish medicine for respiratory, digestive and uro-genital disorders. The aim of this study was to determine its phytochemical profile and to evaluate its cytotoxic, genotoxic and acute oral toxicity [...] Read more.

Background/Objectives: Thymus longicaulis subsp. chaubardii (TL) (Rchb.f.) Jalas is widely used in traditional Turkish medicine for respiratory, digestive and uro-genital disorders. The aim of this study was to determine its phytochemical profile and to evaluate its cytotoxic, genotoxic and acute oral toxicity effects. Methods: The phenolic composition of the methanolic extract was determined by HPLC-DAD. Cytotoxicity and genotoxicity were evaluated in NIH3T3 cells using MTT, comet and micronucleus assays. Acute toxicity was evaluated in rats at doses of 300 and 2000 mg/kg body weight according to the OECD Guideline 420. Results: Rosmarinic acid (87.37 ± 5.39 µg/mg) was the major phenolic compound. TL extract showed >90% cell viability at 50–200 µg/mL, indicating no cytotoxicity. Comet assay revealed a slight increase in DNA damage at 100–200 µg/mL (p < 0.001), though significantly lower than the H₂O₂ group (p < 0.001). No significant (p > 0.05) effect was observed in the micronucleus assay between the treated groups. In rats, TL extract caused no mortality or behavioral changes over 14 days. No significant differences were observed in body or organ weights. Hematologically, platelet count increased (p < 0.001) and eosinophils decreased (p < 0.01 and p < 0.001). Biochemical tests showed lower ALT and AST levels (p < 0.01 and p < 0.05, respectively) and significantly decreased triglycerides in the high-dose group (p < 0.001). Histopathological examination showed no organ damage. Conclusions: The results of this study indicate that TL methanol extract is non-toxic up to 2000 mg/kg and exhibits no significant cytotoxic or genotoxic effects. These findings support its safe use and traditional medicinal value. Full article

(This article belongs to the Section Natural Products)

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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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25 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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