Gene and Protein Profiles of CHI3L1 and CHI3L2 in Patients with Rheumatoid Arthritis
CopperNostics—Here We Are Now, Entertain Us!
Benzimidazole-Quinoline Hybrids: Synthesis and Antimicrobial Properties
Puberty Starts in the Gut: Intestinal Clues to Early Puberty-Rethinking Biomarkers in Pediatric Endocrinology
Hybrid Cooperative Complexes of Low- and High-Molecular-Weight Hyaluronic Acid in Aesthetic Medicine

Journal Description

Pharmaceuticals

Pharmaceuticals is a peer-reviewed, open access journal of medicinal chemistry and related drug sciences, published monthly online by MDPI. The Academy of Pharmaceutical Sciences (APS) is affiliated with Pharmaceuticals and its members receive discounts on the article processing charges.

Open Access free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q1 (Pharmacology and Pharmacy) / CiteScore - Q1 (Pharmaceutical Science)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 16 days after submission; acceptance to publication is undertaken in 3.4 days (median values for papers published in this journal in the second half of 2025).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Testimonials: See what our editors and authors say about Pharmaceuticals.
International Electronic Conference on Medicinal Chemistry (https://sciforum.net/series/ecmc/latest)
Companion journals for Pharmaceuticals include: Pharmacoepidemiology, Psychoactives and Drugs and Drug Candidates.
Journal Clusters-Pharmaceutical Science: Scientia Pharmaceutica, Marine Drugs, Pharmaceuticals, Pharmaceutics, Pharmacy, Future Pharmacology, Pharmacoepidemiology, Drugs and Drug Candidates and Journal of Pharmaceutical and BioTech Industry.

Impact Factor: 4.8 (2024); 5-Year Impact Factor: 4.9 (2024)

Imprint Information Journal Flyer Open Access ISSN: 1424-8247

Latest Articles

50 pages, 5401 KB

Open AccessReview

CDK4/6 Inhibitors for Breast Cancer Therapy—A Review of Clinical Trials, Structural and Computational Approaches

by Adela Avdičević, Samo Lešnik, Urban Bren and Luka Čavka

Pharmaceuticals 2026, 19(4), 610; https://doi.org/10.3390/ph19040610 - 10 Apr 2026

Abstract

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a central role in the regulation of cell cycle progression and represent important therapeutic targets in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. The introduction of selective CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, in combination with endocrine therapy, has significantly improved clinical outcomes and has become a standard treatment strategy in both metastatic and high-risk early-stage disease. Nevertheless, treatment resistance and disease progression remain major clinical challenges. A deeper understanding of the structural characteristics of CDK4/6 and the molecular basis of inhibitor binding is therefore essential for improving therapeutic strategies and guiding the development of new targeted agents. This review provides an integrated overview of the structural features of CDK4/6 and their role in cell cycle regulation, summarizes the clinical development and major clinical trials of currently approved CDK4/6 inhibitors, and discusses recent computational studies investigating inhibitor binding and conformational dynamics. Particular attention is given to the application of in silico approaches, including molecular docking, molecular dynamics simulations, and binding free-energy calculations, which provide insights into mechanisms of therapy resistance and potential strategies to overcome them and support the identification and optimization of novel CDK4/6-targeted therapeutic candidates. By integrating structural, clinical, and computational perspectives, this review highlights current knowledge and emerging directions in CDK4/6 research that may advance the development of more personalized therapies for HR+/HER2− breast cancer, while accounting for both intrinsic and de novo resistance mechanisms. Full article

(This article belongs to the Special Issue Structural Insights into Protein Kinases-Targeted Therapies: Overcoming Resistance and Advancing Precision Oncology)

21 pages, 4314 KB

Open AccessArticle

Effects of Chaenomeles japonica Fruit Juice on Energy Balance and Biochemical and Histological Parameters in a Model of Diet-Induced Metabolic Syndrome in Rats

by Klementina Moneva-Marinova, Silvia Gancheva, Miroslav Eftimov, Maria Tzaneva, Milena Todorova, Mehmed Reyzov, Elis Rafailova, Maria Zhelyazkova-Savova and Stefka Valcheva-Kuzmanova

Pharmaceuticals 2026, 19(4), 609; https://doi.org/10.3390/ph19040609 - 10 Apr 2026

Abstract

Background/Objectives: Metabolic syndrome (MS) is associated with an increased cardiovascular risk. The aim of this study was to reveal the effects of Chaenomeles japonica fruit juice (CJFJ) on energy balance and biochemical and histological parameters in rats with diet-induced MS. Methods: Fifty Wistar rats were allocated into five groups. For ten weeks, the Control group received a standard laboratory diet and tap water, while the other groups were given a high-fat high-fructose (HFHF) diet. The Control and MS groups were treated with distilled water, while the other three groups were treated with CJFJ at increasing doses. Results: Rats on an HFHF diet consumed less food and more liquids and had a higher caloric intake than the Control group. Among the CJFJ-treated animals, an increased food consumption, as well as an increased total caloric intake, and no difference in body weight gain were observed in comparison with the MS group. CJFJ did not affect glucose tolerance or the triglyceride and total cholesterol levels. CJFJ prevented an HFHF-induced decrease in superoxide dismutase and caused a decrease in thiobarbituric acid-reactive substances in serum. The medium CJFJ dose prevented an HFHF-induced increase in adipose tissue indices. Liver and adipose tissue histology revealed a protective effect of CJFJ. Conclusions: CJFJ may exert beneficial effects on visceral adiposity, oxidative status, and histopathological changes in the liver and adipose tissue in rats with diet-induced MS. Full article

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

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13 pages, 505 KB

Open AccessArticle

Development of an Empirical Approach for the Prediction of Cytochrome P450-Based Drug–Drug Interactions in Pediatric Patients

by Veronica Di Paolo, Francesco Maria Ferrari, Italo Poggesi and Luigi Quintieri

Pharmaceuticals 2026, 19(4), 608; https://doi.org/10.3390/ph19040608 - 10 Apr 2026

Abstract

Background and Objective: Predicting drug–drug interactions (DDIs) in pediatric patients remains a major challenge in clinical pharmacology. This study aimed to evaluate and compare three empirical approaches for extrapolating adult cytochrome P450 (CYP)-mediated DDI pharmacokinetics (PK) data to predict the extent of the corresponding DDIs in children across different age groups. Methods: The approaches assessed were: (A) the direct use of adult area under the plasma concentration–time curve ratios (AUCRs) as estimators of pediatric values; (B) the application of a correction accounting for the ontogeny of the involved CYP enzyme; and (C) the application of corrections for both enzyme ontogeny and allometric scaling. Twenty-five pediatric AUCRs were predicted from adult AUCR data. Predictive performance was evaluated by comparing predicted AUCR_pediatric values with observed values, using a 50–200% acceptability range. Results: Approach C demonstrated superior predictive capability, with only one out of 25 predictions falling outside the acceptability range. In contrast, both approaches A and B resulted in three values each outside this range. Further visual exploration and detailed performance analyses confirmed the enhanced accuracy of approach C in predicting pediatric DDIs compared with the other approaches. Conclusions: This study demonstrates that the proposed approach of considering both ontogeny and allometric scaling represents a robust and reasonable method to anticipate the extent of pediatric CYP-based DDIs when adult PK data are available. Full article

(This article belongs to the Special Issue Pediatric Drug Therapy: Safety, Efficacy, and Personalized Medicine)

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23 pages, 8228 KB

Open AccessArticle

Danggui Buxue Tang, a Traditional Chinese Herbal Formula, Potentiates Paclitaxel Efficacy in Non-Small-Cell Lung Cancer by Inducing Ferroptosis via the Nrf2/GPX4 Axis

by Guowei Gong, Tianpeng Yin, Zhenxia Zhang, Kumar Ganesan and Yuzhong Zheng

Pharmaceuticals 2026, 19(4), 607; https://doi.org/10.3390/ph19040607 - 10 Apr 2026

Abstract

Background/Objectives: Non-small-cell lung cancer (NSCLC) involves oxidative stress and inflammation, driving chemoresistance. Paclitaxel (PTX), a first-line chemotherapy, is limited by these factors. Danggui Buxue Tang (DBT), a polyphenolic-rich traditional Chinese herbal formula, was investigated for its ability to potentiate PTX efficacy by inducing ferroptosis via the Nrf2/GPX4 axis. Methods: Effects of DBT + PTX on cell viability, lipid peroxidation, iron accumulation, and Nrf2/GPX4/SLC7A11 expression were evaluated in A549/HCC827 cells with/without ferrostatin-1 (Fer-1). Findings were validated in an A549 xenograft model. Results: DBT significantly enhanced PTX’s anti-tumor effects in vitro and in vivo, an effect reversed by Fer-1. Combination therapy increased ROS, MDA, and iron while suppressing GPX4/SLC7A11 and promoting Nrf2 nuclear translocation. DBT + PTX synergistically reduced tumor volume and proliferation markers (Ki67/PCNA). Crucially, DBT attenuated PTX-induced hepatotoxicity and nephrotoxicity. Conclusions: DBT potentiates PTX efficacy in NSCLC by disrupting the Nrf2/GPX4 axis to induce ferroptosis while mitigating chemotherapy-related toxicity, supporting its potential as an adjuvant strategy targeting oxidative stress pathways. Full article

(This article belongs to the Special Issue Interdisciplinary Approaches to Preventing and Treating Inflammatory and Oxidative Diseases with Medicinal Plants and Bioactive Compounds)

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22 pages, 3091 KB

Open AccessArticle

Polysaccharides and Glycosides from Aralia echinocaulis Modulate Succinate Levels in the Gut to Target Intestinal Dendritic Cells via the Receptor GPR91 in the Treatment of Rheumatoid Arthritis

by Mengqiang Gao, Shanshan Ma and Yunzhi Li

Pharmaceuticals 2026, 19(4), 606; https://doi.org/10.3390/ph19040606 - 9 Apr 2026

Abstract

Background: Aralia echinocaulis has therapeutic effects on rheumatoid arthritis (RA), with total polysaccharide and glycoside (TPGs) as main active components. RA pathogenesis involves gut microbiota dysbiosis and immune–metabolic crosstalk, but the role of microbiota-derived succinate in RA remains unclear. Objective: This study explored the role of succinate-GPR91 signaling in intestinal dendritic cells (DCs) in the context of RA and the therapeutic mechanism of A. echinocaulis TPGs. Methods: Collagen-induced arthritis (CIA) mice were treated with TPGs or exogenous succinate. Paw edema, inflammation, gut succinate levels, the Th17/regulatory T (Treg) balance, and DC activation via succinate-GPR91 were detected, and GPR91-targeting siRNA and CD4+ T-cell coculture assays for verification. Results: TPGs alleviated symptoms in CIA mice and restored the Th17/Treg balance by reducing intestinal succinate levels. Succinate activated DCs via GPR91 to promote Th17 differentiation, while TPGs suppressed DC maturation and Th17-driven inflammation, supporting the involvement of a gut-centric immunometabolic axis in RA. Conclusions: TPGs ameliorate RA by targeting the succinate-GPR91-Th17 pathway, identifying succinate as a novel RA target and TPGs as a potential microbiota-modulating agent. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 469 KB

Open AccessArticle

Evidence-Based Management of MASLD: GRADE Evaluation of Pharmacological Therapies

by Eleni A. Karavia, Andreas Pittaras, Ourania Andreopoulou, Aikaterini Hatziri, Amalia Makrydimitri, Dimitrios Anagnostopoulos, Patroklos Vareltzis and Kyriakos E. Kypreos

Pharmaceuticals 2026, 19(4), 605; https://doi.org/10.3390/ph19040605 - 9 Apr 2026

Abstract

Background/Objectives: Non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic dysfunction-associated steatotic liver disease (MASLD), represents a growing global health burden closely linked to obesity, insulin resistance, and dietary patterns. Despite intense drug-development efforts, effective and widely approved pharmacological therapies remain limited. Methods: In this work, we systematically evaluated the quality of clinical evidence supporting currently proposed pharmacological treatments for MASLD/MASLD using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, focusing on phase III and IV clinical trials. Results: Our analysis demonstrates that overall quality of evidence for most pharmacological agents ranges from very low to moderate, primarily due to imprecision and suspected publication bias. Conclusions: Overall, our findings reinforce that, in the current therapeutic landscape, pharmacological therapies should be reserved for carefully selected patients and interpreted in the context of limited evidence certainty. Full article

(This article belongs to the Special Issue Pharmacotherapy of Liver Fibrosis and Hepatitis: Recent Advances, 2nd Edition)

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12 pages, 5778 KB

Open AccessArticle

Sodium Rutin Ameliorates Non-Alcoholic Fatty Liver Disease and Alleviates Insulin Resistance by Promoting Lipophagy

by Xue Zhang, Shuoshuo Li, Ping Zhang, Chenggang Zhang and Zengqiang Yuan

Pharmaceuticals 2026, 19(4), 604; https://doi.org/10.3390/ph19040604 - 9 Apr 2026

Abstract

Background/Objectives: Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder for which there are limited pharmacotherapies. Sodium rutin (NaR), a soluble flavonoid derivative, has shown beneficial metabolic effects, but its role in NAFLD remains unclear. This study investigates whether NaR ameliorates high-fat diet (HFD)-induced NAFLD and insulin resistance through promoting hepatic lipophagy. Methods: Male mice aged 8 weeks old were fed a HFD for 12 weeks with/without NaR supplementation. Body weight was measured every week. After 12 weeks of treatment, GTT and ITT were performed to assess insulin resistance. Then, the tissues were collected and hepatic histology, serum biochemistry, and markers of autophagy and senescence were assessed. Results: NaR treatment significantly attenuated HFD-induced weight gain, reduced visceral fat and liver weights, and ameliorated hepatic steatosis and vacuolization. NaR improved serum lipid profiles; lowered alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels; and reduced hepatic cellular senescence. NaR enhanced hepatic autophagy, evidenced by decreased p62 levels, increased LC3-II/LC3-I ratio, and enhanced colocalization of lipid droplets with LC3 and LAMP1 in vivo and in vitro. These changes were accompanied by improved glucose tolerance and insulin sensitivity. Conclusions: NaR effectively alleviates HFD-induced NAFLD and insulin resistance by activating hepatic lipophagy. These findings support NaR as a promising multi-targeted therapeutic candidate for NAFLD. Full article

(This article belongs to the Special Issue Medicinal Plants: Exploring Plant-Based Bioactive Compounds for Cancer and Metabolic Diseases Prevention and Intervention)

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24 pages, 2445 KB

Open AccessArticle

Resveratrol Induces Proteasomal Degradation of PTPN1 to Enhance Cisplatin Sensitivity in Epstein–Barr Virus-Associated Malignancies

by Na Liu, Yueshuo Li, Min Tang, Ya Cao, Li Shang and Feng Shi

Pharmaceuticals 2026, 19(4), 603; https://doi.org/10.3390/ph19040603 - 9 Apr 2026

Abstract

Background/Objectives: EBV is an oncogenic virus linked to NPC and GC, driving cisplatin resistance. Resveratrol has anticancer activity, but its targets and mechanisms against EBV-positive cancers remain unclear. Methods: We assessed resveratrol’s cytotoxicity in EBV-positive cells via functional assays, identified targets by chemical similarity search and molecular docking, and validated PTPN1 via in vitro experiments and nude mouse xenograft models. Results: Resveratrol inhibited EBV-positive cell viability in a time- and concentration- dependent manner, with IC50 values ranging from 35.85 to 145.7 μM across different cell lines at 24–72 h. Apoptosis rates increased by approximately 2- to 4-fold after 80 μM resveratrol treatment for 24 h. Resveratrol directly targeted PTPN1 (docking score = −4.89) and promoted its degradation via the proteasome pathway, as MG132 reversed this effect. Notably, resveratrol synergized with cisplatin (combination index < 1) to reverse cisplatin resistance in both in vitro and in vivo models. Furthermore, resveratrol induced EBV lytic reactivation through ROS production, as evidenced by the increased expression of BZLF1, BMRF1, and BALF2, which was attenuated by the ROS scavenger NAC. Conclusions: Our findings identify PTPN1 as a direct anticancer target of resveratrol in EBV-positive cancers. Resveratrol enhances the therapeutic efficacy of cisplatin via PTPN1 proteasomal degradation and induces EBV lytic reactivation through ROS accumulation. These findings provide a mechanistic basis for the development of novel combination therapies targeting EBV-associated malignancies. Full article

(This article belongs to the Special Issue Exploring Natural Products with Antioxidant and Anticancer Properties, 2nd Edition)

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13 pages, 2796 KB

Open AccessArticle

Bromelain and Curcumin Oral Supplementation for Refractory Inherited Retinal Dystrophy-Related Macular Oedema: Changes in Macular Thickness and Visual Acuity over 12 Months

by Mattia D’Andrea, Carmen Dell’Aquila, Lucilla Barbano, Feliciana Menna, Antonio Di Renzo, Gaspare Colacino, Marco Marenco, Roberto Dell’Omo, Vincenzo Parisi and Lucia Ziccardi

Pharmaceuticals 2026, 19(4), 602; https://doi.org/10.3390/ph19040602 - 9 Apr 2026

Abstract

Objectives: To evaluate the long-term effects on retinal structure and visual function of oral bromelain and curcumin supplementation in patients with inherited retinal dystrophies (IRD) complicated by persistent cystoid macular oedema (CMO). Methods: We retrospectively studied 20 eyes with genetically confirmed IRD complicated by CMO, with refractory to systemic or local treatments performed for 6 months. We collected baseline (V1) and follow-up (V2) data from these IRD-CMO patients, who were continuously supplemented with oral bromelain and curcumin for 12 months. Outcome measures were the Snellen best-corrected visual acuity (BCVA) and central macular thickness (CMT) values, collected by spectral-domain optical coherence tomography (OCT). Based on OCT scans, we classified IRD-CMO as microcystic or macrocystic, performing this sub-grouping in two eye cohorts (n = 10). Baseline median BCVA and CMT differences in both groups were verified (Mann–Whitney test). For both CMO groups, changes from V1 to V2 in median BCVA and CMT values were evaluated (Friedman test). Results: At baseline, both the median BCVA and CMT values were significantly different in both groups (p < 0.01 and p < 0.001). Between V1 and V2, in the microcystic CMO group, a slightly improved median BCVA was found, whereas the median CMT was reduced; however, this did not reach statistical significance (p = 0.6 and p = 0.2, respectively). In the macrocystic CMO group, a significant stable median BCVA was found from V1 to V2, with concomitant significant reduction in median CMT (p < 0.05 for both comparisons). Conclusions: Retinal structural improvement and visual function preservation were observed after oral bromelain and curcumin supplementation in macrocystic IRD-CMO. It is likely that the vasogenic component in macrocystic CMO is more responsive to nutraceutical molecules than the degenerative microcystic component. Full article

(This article belongs to the Special Issue Application of Natural Products in Retinal Disorders Therapy)

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27 pages, 2894 KB

Open AccessArticle

Shengmai San Ameliorates High-Glucose-Induced Calcium Homeostasis Imbalance via Improving Energy Metabolism in Neonatal Rat Cardiomyocytes

by Shixi Shang, Qu Zhai, Yuguo Huang, Junsong Yin, Jingju Wang and Xiaolu Shi

Pharmaceuticals 2026, 19(4), 601; https://doi.org/10.3390/ph19040601 - 8 Apr 2026

Abstract

Objective: This study aims to investigate the protective effect of Shengmai San (SMS) against high-glucose (HG)-induced injury in neonatal rat ventricular myocytes (NRVMs) and to elucidate the underlying pharmacological molecular mechanisms. We hypothesize that SMS ameliorates HG-induced calcium homeostasis imbalance in NRVMs by improving mitochondrial energy metabolism disorder, and this protective effect is associated with the downregulation of oxidized and phosphorylated CaMKII expression to inhibit CaMKII signaling pathway overactivation. Herein, we verify this hypothesis by assessing mitochondrial function, calcium transients, sarcoplasmic reticulum (SR) calcium handling and CaMKII phosphorylation levels in NRVMs. Methods: First, ultra-high performance liquid chromatography–high resolution mass spectrometry was used to identify the chemical components of SMS to clarify its material basis. Primary NRVMs were then cultured under low-glucose (LG) or HG conditions, with 2% SMS-medicated serum (SMS-MS) as the experimental intervention, and NAC (ROS scavenger) and KN93 (CaMKII inhibitor) as positive controls. Following intervention, we sequentially detected key indicators corresponding to the proposed pathological pathway: intracellular reactive oxygen species (ROS) levels (oxidative stress), mitochondrial ROS, mitochondrial function indices including oxygen consumption rate (OCR) (energy metabolism), calcium transients and diastolic intracellular free calcium concentration (global calcium homeostasis), sarcoplasmic reticulum (SR) calcium leak (calcium handling disorder), and, finally, the phosphorylation, oxidation levels of CaMKII and RyR2 phosphorylation (Ser2814) (p-RyR2) (key regulatory pathway) via Western blot to systematically elucidate the mechanistic link between SMS intervention and HG-induced NRVM injury. Results: Quantitative analysis revealed that high-glucose (HG) induction significantly reduced calcium transient amplitude and prolonged the decay time constant (tau) in NRVMs at 72 h (p < 0.01 vs. LG), with these parameters normalizing by 120 h—an effect indicative of a compensatory adaptive response. The 2%SMS-MS markedly ameliorated HG-induced calcium transient abnormalities at 72 h (p < 0.01 vs. HG). Additionally, 2%SMS-MS significantly enhanced mitochondrial basal oxygen consumption rate, spare respiratory capacity, ATP production, and maximal respiration in HG-exposed NRVMs (p < 0.01 vs. HG). SMS also significantly reduced intracellular reactive oxygen species (ROS) levels (p < 0.01 vs. HG), mitochondrial ROS levels (p < 0.01 vs. HG), diastolic intracellular free calcium concentration (p < 0.01 vs. HG), and SR calcium leak (p < 0.05 vs. HG). Western blot analysis revealed that 2%SMS-MS intervention effectively downregulated the expression of oxidized CaMKII (Ox-CaMKII) (p < 0.01 vs. HG), phosphorylated CaMKII (p-CaMKII) (p < 0.01 vs. HG), and RyR2 phosphorylation (Ser2814) (p < 0.05 vs. HG), which may be the potential mechanism in maintaining calcium homeostasis in HG-induced NRVMs. Conclusions: This study suggests that SMS enhances mitochondrial energy metabolism and exerts a protective effect against high-glucose-induced calcium homeostasis imbalance in NRVMs, which supports our proposed hypothesis. Its potential mechanism indicates that the protective effects of SMS are associated with its ability to downregulate the expression of oxidized and phosphorylated CaMKII. These findings highlight SMS as a potential therapeutic candidate for alleviating HG-related myocardial injury and provide evidence for its application in the prevention of early diabetic cardiomyopathy. Full article

(This article belongs to the Section Pharmacology)

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47 pages, 19016 KB

Open AccessArticle

Integrated QSAR, Molecular Docking, ADMET Profiling, and Antioxidant Evaluation of Substituted Chromone and Aryloxyalkanoic Acid Derivatives as Potential CysLT₁ Receptor Antagonists

by Mahboob Alam

Pharmaceuticals 2026, 19(4), 600; https://doi.org/10.3390/ph19040600 - 8 Apr 2026

Abstract

Background: Cysteinyl leukotrienes are components of slow-reacting substances of anaphylactic shock (SRS-A) and play a key role in asthma and inflammatory responses. Although chromone-2-carboxylic acids and substituted (aryloxy)alkanoic acids have the potential to be SRS-A antagonists, their comprehensive structure–activity relationships and pharmacokinetic characteristics remain understudied. Objective: This study integrated computational and experimental approaches, including QSAR modeling, molecular docking, ADMET analysis, molecular dynamics (MD) simulations, and antioxidant evaluation to identify and prioritize bifunctional compounds with anti-inflammatory and free radical-scavenging properties. Methods: A set of 68 compounds was analyzed using 2D and 3D quantitative structure–activity relationships (QSAR) (MLR, MNLR, SVR, ANN, and atom-based partial least squares). Molecular docking and 100 ns MD simulations were performed against the CysLT₁ receptor (PDB ID: 6RZ5). ADMET and drug-like properties of the compounds were predicted using ADMETlab 2.0 and SwissADME, and the in vitro antioxidant activity of the top-ranked compounds was evaluated using the DPPH method. Results: The atom-based 3D-QSAR model showed strong predictive power (R² = 0.9524, Q² = 0.5382). Compounds 25, 41, and 47 stood out with the most significant binding energies: −9.5 kcal/mol for 25, −10.0 kcal/mol for 41, and −9.4 kcal/mol for 47. MD simulations confirmed the structural stability and consistent interactions of the protein-compound 47 complex. ADMET analysis showed that compounds 25 and 41 had good pharmacokinetic properties, and in vitro antioxidant assays verified their free radical-scavenging efficacy. Conclusion: Our results highlight the utility of an integrated computational–experimental strategy for the discovery of dual-acting SRS-A antagonists. Compound 25 is highlighted as a promising lead compound for further preclinical development, which effectively combines leukotriene receptor antagonism and antioxidant activity. This framework provides an effective strategy for prioritizing lead compounds in anti-inflammatory drug development. Full article

(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)

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2 pages, 140 KB

Open AccessRetraction

RETRACTED: Badr et al. Design and Evaluation of S-Protected Thiolated-Based Itopride Hydrochloride Polymeric Nanocrystals for Functional Dyspepsia: QbD-Driven Optimization, In Situ, In Vitro, and In Vivo Investigation. Pharmaceuticals 2023, 16, 925

by Moutaz Y. Badr, Pratap Basim, Khaled M. Hosny, Waleed Y. Rizg, N. Raghavendra Naveen, Mallesh Kurakula, Fayez Alsulaimani, Awaji Y. Safhi, Fahad Y. Sabei, Mohammed Alissa and Abdulmohsin J. Alamoudi

Pharmaceuticals 2026, 19(4), 599; https://doi.org/10.3390/ph19040599 - 8 Apr 2026

Abstract

The journal retracts the article cited above, titled “Design and Evaluation of S-Protected Thiolated-Based Itopride Hydrochloride Polymeric Nanocrystals for Functional Dyspepsia: QbD-Driven Optimization, In Situ, In Vitro, and In Vivo Investigation” [...] Full article

(This article belongs to the Section Pharmaceutical Technology)

47 pages, 1207 KB

Open AccessReview

Amorphous Solid Dispersions of Polyphenols: Current State of the Art (Part I)

by Natalia Rosiak, Miłosz Ignacyk, Aleksandra Kryszak, Jakub Piontek and Judyta Cielecka-Piontek

Pharmaceuticals 2026, 19(4), 598; https://doi.org/10.3390/ph19040598 - 8 Apr 2026

Abstract

Polyphenols have attracted considerable scientific interest over recent years due to their broad spectrum of biological activities, including antioxidant, cardioprotective, anti-inflammatory, antidiabetic, and anticancer properties. However, their practical application is often limited by unfavorable physicochemical characteristics, particularly low aqueous solubility. Consequently, amorphous solid dispersions (ASDs) have been extensively investigated as a formulation strategy to overcome these limitations. This article represents the first part of a two-part review and presents the current state of the art in amorphous solid dispersions of polyphenols. The available literature is systematically summarized with respect to the investigated polyphenolic compounds, the employed carriers (with particular emphasis on polymeric systems), the preparation methods, and the solid-state characterization techniques used to confirm amorphization. Both single-component systems and binary combinations of polyphenols reported in the literature are considered. The collected data are presented in tabular form and complemented by a heat map illustrating the frequency of reported polyphenol–carrier combinations. The aim of this review is to organize the available knowledge, identify the most extensively studied systems, and highlight research areas that remain underexplored. A detailed discussion of the pharmaceutical benefits and mechanistic aspects of polyphenols in ASD systems will be provided in Part II. Full article

(This article belongs to the Special Issue Innovations in Solid Dispersions for Drug Delivery)

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24 pages, 564 KB

Open AccessArticle

Flavonoid Composition and Molecular Basis of the Potential Sexual-Enhancing Properties of a Turnera diffusa Extract (Liboost^®)

by Iván Benito-Vázquez, María Inés Morán-Valero, Marina Díez-Municio and Adal Mena-García

Pharmaceuticals 2026, 19(4), 597; https://doi.org/10.3390/ph19040597 - 8 Apr 2026

Abstract

Background/Objectives: Sexual dysfunction is a prevalent and multifactorial condition affecting a large proportion of the global population, with limited therapeutic options beyond pharmacological approaches primarily targeting erectile dysfunction. This has increased interest in botanical supplements for sexual health, although mechanistic evidence and clear links between phytochemical composition and biological activity remain scarce. The present study provides an integrative evaluation of a commercial Turnera diffusa extract (Liboost^®) formulated to support sexual health by combining detailed phytochemical characterization with targeted in vitro mechanistic assays. Methods: The extract was characterized by HPLC-DAD-HRMS, enabling the identification and semi-quantification of its major constituents. A total of 49 compounds were detected, predominantly flavonoids, including luteolin- and apigenin-derived glycosides, flavonols, methoxyflavones, flavanones, and coumaroyl derivatives, with a total quantified flavonoid content of 15.9 mg·g⁻¹. Biological activity was evaluated in human cell models without cytotoxic effects at the tested concentrations. Results: Liboost^® significantly reduced PDE5 expression, inhibited aromatase activity, and moderately increased nitric oxide production. These complementary effects suggest a multi-target modulation of pathways involved in sexual function, integrating vascular, endocrine, and nitrergic mechanisms. Conclusions: Although limited to in vitro models, the findings provide mechanistic support for the biological activity of T. diffusa extracts and highlight the importance of linking phytochemical composition with functional evidence when evaluating botanical supplements. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals—4th Edition)

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19 pages, 5675 KB

Open AccessArticle

A Moderate-Affinity Antibody–Drug Conjugate Targeting B7-H3 Exerts Potent Antitumor Efficacy

by Ziyu Zhang, Huifang Zong, Zhen Li, Shusheng Wang, Xiaodong Xiao, Yueqing Xie and Jianwei Zhu

Pharmaceuticals 2026, 19(4), 596; https://doi.org/10.3390/ph19040596 - 8 Apr 2026

Abstract

Background: B7-H3, a type I transmembrane glycoprotein belonging to the B7 superfamily, is an attractive target for antitumor therapies. B7-H3 demonstrates aberrant overexpression in various types of solid tumors while showing limited and low expression in normal human organs. Various types of treatment targeting B7-H3 have been reported. Among these treatments, antibody–drug conjugates (ADCs) have shown potent activity, and several clinical trials, including DS7300a and MGC018, are currently ongoing. Methods: Here, we constructed CD276-8 ADC, composed of the anti-B7-H3 antibody CD276-8 with moderate affinity, an enzymatically cleavable tetra-peptide-based linker and DXd. Characteristics, including in vitro binding affinity and internalization activity, were assessed by bio-layer interferometry (BLI), flow cytometry and high content analysis (HCA). The cytotoxicity of CD276-8 ADC was evaluated in cell lines expressing B7-H3. Pharmacokinetic profiles and antitumor activity were evaluated in mouse models in vivo. Finally, the developability of CD276-8 ADC was assessed with plasma stability, accelerated stability and freeze–thaw studies using LC-MS and HPLC. Results: Characterization in vitro demonstrated the moderate affinity and acceptable internalization activity of CD276-8 ADC. In addition, CD276-8 ADC exhibited potent antitumor activities in B7-H3-positive cell line-derived xenograft (CDX) models with acceptable pharmacokinetic profiles, although it showed less potent cytotoxicity in various cell lines in vitro, indicating acceptable developability. Conclusions: We developed CD276-8 ADC, a B7-H3-targeting ADC with moderate affinity, which delivers the TOP1 inhibitor DXd. This design combined moderate affinity and acceptable pharmacokinetics, resulting in potent antitumor efficacy in vivo. Our study suggests that affinity optimization could be a useful consideration for enhancing ADC efficacy, positioning CD276-8 ADC as a promising therapeutic for B7-H3-expressing solid tumors. Full article

(This article belongs to the Special Issue Tumor Immunopharmacology, 2nd Edition)

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15 pages, 1103 KB

Open AccessArticle

Multi-Output Probabilistic Prediction of Drug Side Effects Using Classical Machine Learning Algorithms

by Diego Quiguango Farias, Juan Sarasti Espejo, Marlene Arce Salcedo and Byron Velasquez Ron

Pharmaceuticals 2026, 19(4), 595; https://doi.org/10.3390/ph19040595 - 8 Apr 2026

Abstract

Introduction: Drug side effects are a relevant problem for patient safety and public health, and traditional methods have limitations in capturing complex patterns between clinical and pharmacological variables. Objective: To evaluate machine learning models to probabilistically predict multiple side effects associated with drug use. Materials and methods: A cross-sectional computational study was carried out with data from 1000 medications that included clinical condition, dosage and duration of treatment. Random Forest, Decision Tree, Support Vector Classifier and KNN were trained and optimized using Grid Search and an 80:20 split for training and testing. Chi-square tests and Principal Component Analysis were applied to explore associations and overlap between categories. Results: Significant associations were found between side effects and clinical condition (p < 0.05) and the drug administered (p < 0.05). The PCA showed a high overlap between categories, which justified a probabilistic approach. Tree-based models showed better performance (accuracy ≈ 0.35). Conclusions: Prediction of side effects is a multifactorial and non-deterministic problem; probabilistic machine learning models allow for estimating several plausible adverse events and can support clinical decision-making and pharmacovigilance. Full article

(This article belongs to the Section Biopharmaceuticals)

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13 pages, 2172 KB

Open AccessArticle

Bridging Research and Clinical Practice: Automated [⁶⁸Ga]Ga-FAPi-46 Synthesis and Quality Control for Oncological PET Imaging

by Caiubi Rodrigues de Paula Santos, Luciana Malavolta, Jorge Mejia, Leonardo Lima Fuscaldi, Lilian Yuri Itaya Yamaga and Marycel Figols de Barboza

Pharmaceuticals 2026, 19(4), 594; https://doi.org/10.3390/ph19040594 - 8 Apr 2026

Abstract

Background/Objectives: Fibroblast activation protein (FAP) has emerged as a promising target for oncologic molecular imaging due to its high expression in cancer-associated fibroblasts and low presence in healthy tissues. Among available FAP ligands, [⁶⁸Ga]Ga-FAPi-46 has shown rapid tumor accumulation, low background uptake, and broad tumor applicability. This study reports the successful translation of [⁶⁸Ga]Ga-FAPi-46 from preclinical development to routine clinical radiopharmacy practice, detailing automated synthesis, quality control performance, radiochemical stability, and the first clinical imaging results. Methods: Automated radiolabeling of FAPi-46 with gallium-68 was performed using a synthesis module. Quality control included radiochemical purity assessments by iTLC, SPE, and RP-HPLC (pH, appearance, endotoxin levels, and membrane integrity testing). Radiochemical stability was evaluated in saline (up to 6 h) and human serum (up to 90 min). In vitro characterization included the partition coefficient and serum protein binding determination. A clinical evaluation was conducted in a woman with newly diagnosed lung adenocarcinoma who underwent both [¹⁸F]FDG PET/CT and [⁶⁸Ga]Ga-FAPi-46 PET/CT. Results: Automated synthesis of [⁶⁸Ga]Ga-FAPi-46 achieved a high radiochemical yield (87.9 ± 1.3%) and radiochemical purity greater than 98%. All batches met release specifications for sterility, apyrogenicity, and physicochemical parameters. The radiotracer demonstrated high stability in saline and human serum, with radiochemical purity consistently above 95% at all evaluated time points. The compound showed a hydrophilic profile (LogP = −3.32 ± 0.14) and 40–60% serum protein binding. Clinically, [⁶⁸Ga]Ga-FAPi-46 PET/CT provided superior lesion delineation compared to [¹⁸F]FDG, revealing additional mediastinal, supraclavicular, and brain metastases. Conclusions: [⁶⁸Ga]Ga-FAPi-46 can be reliably synthesized using automated procedures under routine radiopharmacy conditions, meeting regulatory quality standards and demonstrating excellent stability. Its enhanced lesion detectability compared with [¹⁸F]FDG in the first patient case supports its potential value for oncological staging and clinical implementation. Full article

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

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4 pages, 179 KB

Open AccessReply

Reply to Cho, P.S.P. Comment on “Kardos et al. Efficacy and Safety of a Single Ivy Extract Versus Two Herbal Extract Combinations in Patients with Acute Bronchitis: A Multi-Center, Randomized, Open-Label Clinical Trial. Pharmaceuticals 2025, 18, 754”

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

Pharmaceuticals 2026, 19(4), 593; https://doi.org/10.3390/ph19040593 - 8 Apr 2026

Abstract

Firstly, we would like to thank the author of the letter [...] Full article

4 pages, 162 KB

Open AccessComment

Comment on Kardos et al. Efficacy and Safety of a Single Ivy Extract Versus Two Herbal Extract Combinations in Patients with Acute Bronchitis: A Multi-Center, Randomized, Open-Label Clinical Trial. Pharmaceuticals 2025, 18, 754

by Peter S. P. Cho

Pharmaceuticals 2026, 19(4), 592; https://doi.org/10.3390/ph19040592 - 8 Apr 2026

Abstract

I read with interest the recently published open-label randomized trial comparing a single ivy extract with two herbal combination therapies (ivy/thyme and thyme/primrose) for the treatment of acute bronchitis [...] Full article

33 pages, 3967 KB

Open AccessReview

Radiation Biology of Radiopharmaceuticals: Beyond External Beam Radiation Therapy

by Aeli P. Olson, Jonathan W. Engle and Mukesh K. Pandey

Pharmaceuticals 2026, 19(4), 591; https://doi.org/10.3390/ph19040591 - 7 Apr 2026

Abstract

The dynamic field of radiopharmaceuticals is currently experiencing an explosion of growth due in part to excitement over the emerging field of theranostics (therapy and diagnostics). Radiopharmaceuticals use physiological targeting methods to deliver radionuclides with medically relevant decay properties to disease biomarkers for diagnosis and treatment, offering opportunities for early disease imaging and radiation therapy treatment in disease pathologies that are inoperable or refractory to other forms of radiotherapy. Sustaining this rapidly growing field depends heavily on the continued design and production of novel, effective radiopharmaceuticals. Effective therapeutic radiopharmaceuticals cause complex and varied cellular responses, and to choose radionuclides that maximize therapeutic response, researchers must understand radiation biology. Cellular radiation response depends heavily on factors including linear energy transfer (LET), dose, dose rate, targeted location, direct or indirect energy deposition mechanisms, the broader cellular matrix, cellular stress signaling pathways, and endogenous radiation protection mechanisms. Because of the extensive application of low-LET external beam radiation on clinical cancer treatments, biological responses to low-LET form the basis of radiation biology and are generally considered transferable to high-LET radiopharmaceuticals. However, increased focus on high-LET, radiopharmaceutical therapy-specific radiation biology is motivated by differences between low- and high-LET radiation, external beam versus radiopharmaceutical therapy-induced biological response, and the observed varied clinical responses to radiopharmaceutical therapies. This review article summarizes historical understanding of low- and high-LET radiation responses within cells, with emphasis on radiopharmaceutical-specific responses when available, and discusses current gaps in understanding in the radiation biology of radiotheranostic pharmaceuticals. Full article

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

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