Pharmaceuticals

37 pages, 3499 KB

Open AccessArticle

Crystal Engineering as an Efficient Medicinal Chemistry Tool for Animal PK Bioavailability Enhancement in Early Pre-Clinical Research

by Axel Becker, Carolina von Essen, Lars Burgdorf, Marc Lecomte and Daniel Bischof

Pharmaceuticals 2026, 19(5), 803; https://doi.org/10.3390/ph19050803 - 21 May 2026

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Abstract

Background: A lean crystal engineering study was performed on the early pre-clinical POLθ inhibitor MSC178 to enable sufficient exposure for high-dose PK studies. Methods: COSMOquick-derived excess enthalpies in combination with a toxicological assessment of co-formers were used for the selection of four co-formers. [...] Read more.

Background: A lean crystal engineering study was performed on the early pre-clinical POLθ inhibitor MSC178 to enable sufficient exposure for high-dose PK studies. Methods: COSMOquick-derived excess enthalpies in combination with a toxicological assessment of co-formers were used for the selection of four co-formers. Experimental crystallization trials were performed in a staged approach from a 15 mg scale, over a 50 mg upscale, to a final g-scale upscale of the most promising co-crystal form with 2,4-DHBA. Results: The 2,4-DHBA co-crystal form revealed more enhanced and sustained supersaturation plateaus in FaSSIF compared to the amorphous free base form, the 3,4-DHBA co-crystal form, and the 1,2-EDSA salt form. Moreover, the 2,4-DHBA co-crystal form was shown to be physically stable in the suspension vehicle for the PK study. The high physical stability toward physical-form conversion in the suspension vehicle as well as the more sustained supersaturation plateau in the non-sink dissolution profile could be attributed to the intrinsic features of the crystal structure as well as the assessed surface hydrophilicity of the co-crystal particles, both suggesting that rather hydrophobic surfaces are present that help preferentially attract stabilizing surfactants from the dissolution medium (taurocholate) and from the suspension vehicle (polysorbate, methocel), respectively. Successful upscale of the 2,4-DHBA co-crystal form was achieved in the small g-scale, revealing mainly isotropic crystal growth in primary particles as well as a pronounced tendency toward isotropically shaped dendrite-like secondary particles, both favored by a multi-dimensional hydrogen bonding network being present. Excellent agreement was shown for the extent of in vitro supersaturation behavior and in vivo exposure gain in the high-dose PK study for the 2,4-DHBA co-crystal form versus the amorphous free form. Conclusions: The co-crystal strategy can be successfully developed in early pre-clinical industrial research with lean methodologies to optimize sub-optimal phys.-chem. properties of a free base compound to achieve improved and less variable in vivo exposure between animals in high-dose PK studies. Full article

(This article belongs to the Special Issue Crystal Engineering in the Pharmaceutical Sciences)

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25 pages, 4157 KB

Open AccessArticle

Phosphate-Surface-Modified Silica Nanoparticles for 5-Fluorouracil as a Prolonged Drug Delivery System

by Aleksandra Lis, Arkadiusz Surażyński, Przemysław Koźmiński and Paweł Szymański

Pharmaceuticals 2026, 19(5), 802; https://doi.org/10.3390/ph19050802 - 21 May 2026

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Abstract

Background/Objectives: This paper describes the synthesis of silica nanoparticles (SiNPs) and their surface modification with amino and phosphate groups (SiNPs-NH₂-PO₃). The functionalized nanoparticles were subsequently loaded with the anticancer drug 5-fluorouracil (SiNPs-NH₂-PO₃-5-FLU) and further modified [...] Read more.

Background/Objectives: This paper describes the synthesis of silica nanoparticles (SiNPs) and their surface modification with amino and phosphate groups (SiNPs-NH₂-PO₃). The functionalized nanoparticles were subsequently loaded with the anticancer drug 5-fluorouracil (SiNPs-NH₂-PO₃-5-FLU) and further modified with PEG2000 (SiNPs-NH₂-PO₃-5-FLU-PEG2000). Methods: In this study, a one-step, two-phase, sol–gel method carried out at room temperature was used to synthesize the nanoparticles. The size and surface zeta potential of the created SiNPs were determined by DLS measurements. HPLC was used to determine the amount of drug loaded into silica nanoparticles and the drug release profile in two different pH environments (slightly acidic and physiological). Based on physicochemical characteristics, the SiNPs-NH₂-PO₃-5-FLU and SiNPs-NH₂-PO₃-5-FLU-PEG2000 formulations were chosen for comprehensive characterization. The cytotoxicity of the studied complexes was assessed in MCF7 breast cancer cells, while their ability to induce apoptosis in those cells was examined using specific immunofluorescence markers: active caspase-7, active poly(ADP-ribose) polymerase (PARP), and p53 protein. Results: Our findings demonstrate that SiNPs-NH₂-PO₃-5-FLU can induce a stronger apoptotic response than free 5-FLU at equivalent concentrations. We observed that drug release occurs not only under physiological conditions but is further enhanced in a mildly acidic environment (pH 5.0), characteristic of the tumor microenvironment. Conclusions: Most 5-fluorouracil formulations are administered as injectable solutions, resulting in systemic exposure and significant adverse effects. However, their encapsulation within nanoparticles could favor preferential drug release in the acidic tumor microenvironment, thus supporting targeted therapy and reducing toxicity to healthy tissues. Moreover, PEGylation of the nanoformulation allows prolonged and controlled release. Full article

(This article belongs to the Section Pharmaceutical Technology)

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16 pages, 2647 KB

Open AccessArticle

Triazole-Functionalized Jatrophone Derivatives as Antiprotozoal Agents Against Trypanosoma cruzi: Synthesis, Biological Evaluation and Structure—Activity Relationships

by Mariano Walter Pertino, Patricio Carreño Gonzalez, Camila Venegas González, Guillermo Schmeda-Hirschmann, Celeste Vega Gómez, Miriam Rolón and Antonieta Rojas de Arias

Pharmaceuticals 2026, 19(5), 801; https://doi.org/10.3390/ph19050801 - 21 May 2026

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Abstract

Background/Objectives: Jatrophone is a bioactive diterpenoid with reported antitrypanosomal activity; however, its development as a lead compound is limited by pronounced cytotoxicity toward mammalian cells. This study aimed to explore the structural modification of jatrophone through triazole functionalization to modulate its antiparasitic [...] Read more.

Background/Objectives: Jatrophone is a bioactive diterpenoid with reported antitrypanosomal activity; however, its development as a lead compound is limited by pronounced cytotoxicity toward mammalian cells. This study aimed to explore the structural modification of jatrophone through triazole functionalization to modulate its antiparasitic activity and improve selectivity against Trypanosoma cruzi. Methods: A series of mono- and bis-triazole jatrophone derivatives was semi-synthesized via Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) from a stereoselectively prepared diazido intermediate. Jatrophone, its azido precursor, and the synthesized triazole derivatives were evaluated in vitro against T. cruzi epimastigotes and intracellular amastigotes. Cytotoxicity toward mammalian host cells was assessed in parallel to determine selectivity indices. Results: Jatrophone exhibited potent activity against epimastigotes but showed poor selectivity due to significant mammalian cell toxicity. Introduction of azide and triazole functionalities altered the biological profile of the parent scaffold, leading to derivatives with reduced cytotoxicity and improved selectivity in extracellular assays. Among the evaluated compounds, a mono-triazole derivative bearing a methylene-linked cycloalkyl substituent retained antiparasitic activity while displaying markedly lower toxicity toward mammalian cells. However, in the intracellular amastigote model, most derivatives demonstrated a substantial reduction in selectivity, indicating limited translation of extracellular activity to the intracellular parasite stage. Conclusions: Triazole functionalization of the jatrophone scaffold represents a viable strategy to modulate its biological properties and reduce host-cell toxicity. Nevertheless, the reduced efficacy observed in intracellular assays underscores the limitations of epimastigote-based screening and highlights the challenges in developing selective intracellular antitrypanosomal agents from the jatrophone scaffold. Full article

(This article belongs to the Section Medicinal Chemistry)

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29 pages, 6026 KB

Open AccessArticle

Core Substances and Related Bio-Activities on Anti-Lung Cancer Cell A549 of Pleione Pseudobulb

by Chao Huang, Ge Li, Surong Li, Ruyu Yao, Angkhana Inta, Lu Gao and Lixin Yang

Pharmaceuticals 2026, 19(5), 800; https://doi.org/10.3390/ph19050800 - 20 May 2026

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Abstract

Background/Objectives: The Naxi people in Northwest Yunnan of China have used alcohol-soaked Pleione Pseudobulbus, which is the Pseudobulbus of Pleione bulbocodioides Rolfe (PBR), for lung diseases and tumors for a long period of time. This study aims to explore underlying mechanisms of [...] Read more.

Background/Objectives: The Naxi people in Northwest Yunnan of China have used alcohol-soaked Pleione Pseudobulbus, which is the Pseudobulbus of Pleione bulbocodioides Rolfe (PBR), for lung diseases and tumors for a long period of time. This study aims to explore underlying mechanisms of bioactive ingredients in PBR, as well as to underscore the synergy between traditional medicine and modern pharmacological research. Methods: We verified the anti-tumor effects of the PBR extract through in vitro cell experiments, and explored its underlying mechanisms by combining untargeted metabolomics with network pharmacology to predict the related targets. Results: The anti-tumor potential of PBR extracts was systematically evaluated by integrating chemical profiling with in vitro cell-based assays. Untargeted metabolomics tentatively annotated metabolites spanning 12 major chemical classes, several of which have been previously reported to possess anti-tumor activity. To validate these annotations, prioritized candidates were further examined by LC-MS/MS against authentic reference standards at the nanogram scale, which confirmed the presence of sclareol—a naturally occurring diterpene with documented anti-tumor properties—as a constituent of PBR. Consistent with this chemical evidence, the PBR extract exerted multi-faceted anti-tumor effects in A549 lung cancer cells: it significantly suppressed proliferation, migration, and invasion; induced G0/G1-phase cell-cycle arrest; disrupted mitochondrial membrane potential; and modulated the expression of apoptosis-related proteins. Conclusions: By highlighting the pharmacological properties of cultivated PBR, we identified 118 overlapping targets between PBR compounds and lung disease-related targets, and we further selected 25 core lung cancer targets with high topological importance. This study suggests that the primary active compounds of Pleione bulbocodioides (Franch.) Rolfe may exert anti-lung cancer activity, potentially through targeting the EGFR tyrosine kinase inhibitor resistance pathway and the PI3K-Akt signaling pathway. Furthermore, in silico molecular docking suggested that the two major active compounds exhibited favorable predicted binding affinities with four core targets, particularly EGFR and AKT1, providing a basis for further experimental validation. These results support the potential value of Naxi traditional medicine and the need to further research onthese medicinal plants, thereby promoting Chinese herb medicine conservation efforts in the Naxi region. Full article

(This article belongs to the Section Natural Products)

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9 pages, 242 KB

Open AccessOpinion

Reframing Buprenorphine as a Pharmacologic Modifier of Opioid-Induced Respiratory Depression in the Fentanyl Era

by Anees Bahji, Imran Ghauri, Nickie Mathew, Nathaniel Day and Robert Tanguay

Pharmaceuticals 2026, 19(5), 799; https://doi.org/10.3390/ph19050799 - 20 May 2026

Viewed by 473

Abstract

The overdose crisis in North America is increasingly driven by illicitly manufactured fentanyl and other high-potency synthetic opioids, which are associated with severe and unpredictable opioid-induced respiratory depression (OIRD). Current pharmacologic strategies to prevent fatal overdose have largely emphasized downstream rescue through opioid [...] Read more.

The overdose crisis in North America is increasingly driven by illicitly manufactured fentanyl and other high-potency synthetic opioids, which are associated with severe and unpredictable opioid-induced respiratory depression (OIRD). Current pharmacologic strategies to prevent fatal overdose have largely emphasized downstream rescue through opioid antagonism (e.g., naloxone), leaving limited attention to upstream pharmacologic modification of respiratory risk. In this Opinion article, we argue that buprenorphine should be reframed not only as a treatment for opioid use disorder (OUD), but also as a pharmacologic modifier of OIRD risk in fentanyl-dominant drug markets. Drawing on its partial μ opioid receptor agonism, ceiling effect on respiratory depression, and exceptionally high receptor affinity, we describe how buprenorphine can displace full agonists while limiting respiratory suppression. We further situate this pharmacology within emerging population-level observations from North American fentanyl contexts, suggesting reduced overdose mortality among individuals receiving opioid agonist therapy, particularly buprenorphine. In fentanyl-dominant drug markets, reframing buprenorphine as a modifier of respiratory risk has direct implications for clinical messaging about overdose protection, medication selection for individuals with ongoing illicit opioid use, and policy approaches aimed at reducing opioid-related mortality. Full article

(This article belongs to the Special Issue Pharmacological Interventions for Opioid-Induced Respiratory Depression)

23 pages, 5212 KB

Open AccessArticle

Ambrisentan Exhibits Hepatoprotective Effects Against NASH-Associated Hepatic Injury in Dexamethasone-Treated Rats Through Regulation of Inflammation, Ferroptosis and Autophagy

by Naif S. Alharbi, Manar A. Nader, Marwa S. Serrya and Marwa E. Abdelmageed

Pharmaceuticals 2026, 19(5), 798; https://doi.org/10.3390/ph19050798 - 20 May 2026

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Abstract

Background/Objectives: Non-alcoholic steatohepatitis (NASH) represents a worldwide health challenge with limited currently available effective treatment. The present analysis was designed to examine possible therapeutic advances of Ambrisentan (AMB) targeting multiple features of hepatic damage in dexamethasone (DEXA)-provoked nonalcoholic steatohepatitis (NASH) in rats. Methods: [...] Read more.

Background/Objectives: Non-alcoholic steatohepatitis (NASH) represents a worldwide health challenge with limited currently available effective treatment. The present analysis was designed to examine possible therapeutic advances of Ambrisentan (AMB) targeting multiple features of hepatic damage in dexamethasone (DEXA)-provoked nonalcoholic steatohepatitis (NASH) in rats. Methods: Rats were randomly divided into four groups: a control group; a DEXA group; and two AMB-treated groups that received AMB (5 or 10 mg/kg/day orally for a week) before and concomitantly with DEXA (8 mg/kg/day, i.p.) for 6 days. After completion of the experiment, serum markers of liver function and lipid profile were assessed, and hepatic histopathological alterations were examined. Results: AMB (mainly at 10 mg/kg/day) markedly ameliorated liver-function parameters, the lipid profile, and hepatic histopathological characteristics in DEXA-treated rats. MDA was reduced, whereas GSH, GPX4 and Nrf2 were heightened, indicating elevated oxidative damage. Moreover, AMB efficiently reinstated iron homeostasis and aggravated iron overload by altering serum iron, hepatic ferritin, transferrin and hepcidin. AMB decreased serum calcium and hepatic calcineurin A levels, followed by a reduction in hepatic autophagy biomarker Beclin-1. AMB downregulated pro-inflammatory biomarkers NF-κB, IL-6 and TGF-β1. Moreover, it notably repressed the hepatic gene expression of ferritinophagy biomarker NCOA4, with elevated FTH1 hepatic gene expression. Moreover, AMB ameliorated DEXA-induced changes in endothelial and vascular function by increasing hepatic PGI2 and cGMP and lowering ET-1 and iNOS. Conclusions: AMB improved DEXA-induced NASH, primarily through its action on endothelin pathways, with associated reductions in inflammation and the downstream processes of ferroptosis, ferritinophagy, lipophagy, and autophagy. Full article

(This article belongs to the Section Pharmacology)

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31 pages, 11267 KB

Open AccessArticle

Synthesis, Antidepressant-like and Anxiolytic-like Effects of Novel Thiadiazole Derivatives: Behavioral Assessment and Mechanistic Investigation

by Ümmühan Kandemir, Gizem Türkoğlu Sağlık, Derya Osmaniye, Zafer Asım Kaplancıklı, Özgür Devrim Can and Ümide Demir Özkay

Pharmaceuticals 2026, 19(5), 797; https://doi.org/10.3390/ph19050797 - 19 May 2026

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Abstract

Background/Objectives: Based on the central nervous system-related activity potential of 1,3,4-thiadiazole derivatives, novel 1,3,4-thiadiazole compounds were synthesized, and their possible antidepressant-like and anxiolytic-like effects were investigated. Methods: The chemical structures of the compounds were elucidated using several spectroscopic techniques. Antidepressant-like effects [...] Read more.

Background/Objectives: Based on the central nervous system-related activity potential of 1,3,4-thiadiazole derivatives, novel 1,3,4-thiadiazole compounds were synthesized, and their possible antidepressant-like and anxiolytic-like effects were investigated. Methods: The chemical structures of the compounds were elucidated using several spectroscopic techniques. Antidepressant-like effects of compounds were evaluated using the tail suspension and the modified forced swimming tests, while anxiolytic-like effects were assessed using the hole board, elevated plus maze, and open field tests in male Balb/c mice. Motor activities of the animals were examined using the activity-meter device. Mechanistic and computational in silico studies were also performed. Results: The results demonstrated that compounds 4e–4i exhibited antidepressant-like effects, whereas only compound 4e showed an anxiolytic-like effect. None of the compounds produced significant alterations in motor activities of animals, indicating that the observed behavioral effects were specific. The antidepressant-like effects of compounds 4e–4i were abolished by p-chlorophenylalanine methyl ester (PCPA) and α-methyl-para-tyrosine methyl ester (AMPT) pre-administration indicating that the antidepressant-like effects of these test compounds are related to both serotonergic and catecholaminergic mechanisms. Furthermore, the anxiolytic-like effect of compound 4e was reversed by flumazenil and NAN-190 pre-administrations, indicating the participation of the GABA-A benzodiazepine receptor complex and 5-HT_1A receptors in its pharmacological activity. Computational in silico studies revealed that compounds have good ADME profiles; compounds 4e–4i interact with the serotonin transporter; compound 4e shows affinity for GABA-A and 5-HT_1A receptors; and all interactions remain stable under dynamic conditions. Conclusions: These findings supported the previous papers reporting the antidepressant-like and anxiolytic-like effects of 1,3,4-thiadiazole derivatives. Full article

(This article belongs to the Section Medicinal Chemistry)

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15 pages, 567 KB

Open AccessReview

New Technique for Tramadol Dose Accuracy: Are Dosing Pumps the Solution?

by César Alas-Pineda, Carlos Coto-Tejeda, Dennis J. Pavón-Varela, Kristhel Gaitán-Zambrano, Jhacely Medina-Mejía and Gustavo Ferrer

Pharmaceuticals 2026, 19(5), 796; https://doi.org/10.3390/ph19050796 - 19 May 2026

Viewed by 277

Abstract

Background/Objectives: Chronic pain represents a core global health burden and remains a leading cause of disability and reduced quality of life. Tramadol is a widely prescribed analgesic with a dual-opioid and non-opioid mechanism of action; however, safety concerns persist. This scoping review [...] Read more.

Background/Objectives: Chronic pain represents a core global health burden and remains a leading cause of disability and reduced quality of life. Tramadol is a widely prescribed analgesic with a dual-opioid and non-opioid mechanism of action; however, safety concerns persist. This scoping review summarizes current evidence on tramadol pharmacology, dosing, and safety. Methods: A systematic literature search was conducted across main scientific databases to identify preclinical and clinical studies evaluating tramadol pharmacokinetics, safety, and dosing. Results: The same tramadol presentations have been used for several years, with a high overdose risk due to incorrect dosing measurements. Dosing pump devices represent a viable solution to improve dosing accuracy and minimize this risk. Conclusions: Tramadol drops seem like an easier administration pathway but require careful handling when taking the prescribed dose. A dosing pump in the medication bottle will improve dosing accuracy. Full article

(This article belongs to the Section Pharmaceutical Technology)

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26 pages, 3598 KB

Open AccessArticle

Development and Application of an UPLC–MS/MS Method for Simultaneous Quantification of Abemaciclib and Tamoxifen with Their Active Metabolites in Rat Plasma: Application to a Pharmacokinetic Study

by Yahya Alshehri, Abdulrhman Al-Majed, Ahmad Obaidullah, Yousef Bin Jardan, Ahmed Bakheit and Mohamed Hefnawy

Pharmaceuticals 2026, 19(5), 795; https://doi.org/10.3390/ph19050795 - 19 May 2026

Viewed by 230

Abstract

Background: Abemaciclib (ABM) in combination with tamoxifen (TAM) is an extremely significant treatment regimen for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. It is approved for patients to reduce the risk of cancer recurrence. A bioanalytical method for [...] Read more.

Background: Abemaciclib (ABM) in combination with tamoxifen (TAM) is an extremely significant treatment regimen for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. It is approved for patients to reduce the risk of cancer recurrence. A bioanalytical method for the simultaneous determination of this new anti-breast cancer combination and its pharmacokinetic application has not yet been reported. Methods: An ultra-performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) method was developed for quantifying ABM, TAM, and its metabolites, including abemaciclib active metabolites M2, M18, and M20 and tamoxifen active metabolite N-desmethyl tamoxifen (NDTAM), in rat plasma using econazole as the internal standard (IS). Chromatographic separation was achieved on a Kinetex C18 column (100 × 2.1 mm ID, 2.6 µm) using gradient elution with 5 mM ammonium formate in water (eluent A) and 5 mM ammonium formate in water/methanol (1:9, v/v, eluent B) at a flow rate of 0.4 mL/min. Detection was performed on a TSQ Fortis Plus mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization. Results: The developed method was validated according to the guidance of the FDA. Linearity in rat plasma (ng/mL) was achieved from 1 to 1000 for ABM, TAM, and M20; 3 to 1000 for M2; 5 to 500 for M18; and 1 to 500 for NDTAM; with correlation coefficients ranging from 0.9991 to 0.9931 for all analytes using a weighting factor of 1/X². The lower limit of detection (LLOD) ranged between 0.3 and 1.5 ng/mL for all drugs. The accuracy ranged from 96 to 108% and the precision was less than 7.6% RSD for all analytes. For the first time, the newly developed approach was effectively used in a pharmacokinetic study on the simultaneous oral administration of ABM and TAM in rats that received 30.0 mg/kg of ABM and 8.0 mg/kg of TAM. Conclusions: To the best of our knowledge, this is the first reported UPLC–MS/MS method for the assay of ABM, TAM, and its active metabolites in plasma. This method offers a bioanalytical tool for assessing the pharmacokinetics of ABM and TAM. Therefore, this study makes a definite significant contribution to the field of bioanalytical research. Further validation in human plasma is required for future clinical or therapeutic drug monitoring applications, as the approach was developed in an animal model. Full article

(This article belongs to the Special Issue Advances in Hybrid Anticancer Drugs: Innovations and Therapeutic Potential)

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16 pages, 725 KB

Open AccessArticle

Clinical and Biomarker Predictors of Adverse Left Ventricular Remodeling After First STEMI: Insights into Phenotype Variability Using CMR

by Agneta Virbickiene, Vacis Tatarunas, Ieva Ciapiene, Neda Jonaitiene, Justina Jureviciute, Paulius Bucius, Arnoldas Leleika, Ieva Jonauskiene, Liepa Kleizaite, Tomas Lapinskas and Olivija Dobiliene

Pharmaceuticals 2026, 19(5), 794; https://doi.org/10.3390/ph19050794 - 19 May 2026

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Abstract

Background: Adverse left ventricular remodeling (ALVR) remains an important complication after ST-segment elevation myocardial infarction (STEMI) despite timely reperfusion therapy. Early circulating biomarkers reflecting thromboinflammatory and eicosanoid-related pathways may improve identification of patients at risk of unfavorable remodeling. Objectives: To investigate whether platelet [...] Read more.

Background: Adverse left ventricular remodeling (ALVR) remains an important complication after ST-segment elevation myocardial infarction (STEMI) despite timely reperfusion therapy. Early circulating biomarkers reflecting thromboinflammatory and eicosanoid-related pathways may improve identification of patients at risk of unfavorable remodeling. Objectives: To investigate whether platelet count, 20-hydroxyeicosatetraenoic acid (20-HETE), 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], and NETosis activity measured on the morning after reperfusion therapy are associated with serial cardiac magnetic resonance (CMR)-defined ALVR after first STEMI. Methods: In this prospective single-center study, 93 patients with first STEMI treated with reperfusion therapy, including primary percutaneous coronary intervention (PCI) in 87 patients and thrombolysis followed by PCI underwent baseline CMR at a median of 4 days after PCI and repeat CMR at 6 months. ALVR was defined as a ≥12% increase in both left ventricular end-diastolic volume and left ventricular end-systolic volume at follow-up. Fasting blood samples obtained on the morning after PCI were used to measure platelet count, 20-HETE, 15(S)-HETE, and NETosis activity. Univariable and multivariable logistic regression and receiver operating characteristic analyses were performed. A secondary exploratory analysis evaluated predictors of absolute improvement in left ventricular ejection fraction (LVEF) of ≥10%. Results: ALVR occurred in 19 of 93 patients (20.4%). Patients with ALVR had lower platelet count and lower 20-HETE levels at baseline. In the multivariable model, lower platelet count (OR 0.981, 95% CI 0.965–0.996; p = 0.015) and lower 20-HETE (OR 0.985, 95% CI 0.970–1.000; p = 0.047) were independently associated with ALVR, whereas urea was not significant. In receiver operating characteristic analysis, 20-HETE showed the highest discriminatory ability for ALVR (AUC 0.713, 95% CI 0.594–0.833; p < 0.001), followed by platelet count (AUC 0.670, 95% CI 0.546–0.794; p = 0.007). By contrast, 15(S)-HETE and NETosis activity were not significant discriminators in the primary analyses. Overall LV function improved during follow-up, with LVEF increasing from 49.0% to 56.0% (p < 0.001). In secondary exploratory analysis, higher HDL was independently associated with LVEF improvement of ≥10% (OR 7.84, 95% CI 1.26–48.99; p = 0.028). Conclusions: Lower platelet count and lower 20-HETE measured on the morning after PCI were independently associated with subsequent CMR-defined ALVR after first STEMI. Platelet count may serve as a simple, clinically accessible marker of risk, while 20-HETE suggests a potential role of eicosanoid-related pathways in remodeling process. Full article

(This article belongs to the Special Issue Pharmacogenomics for Precision Medicine, 2nd Edition)

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29 pages, 5208 KB

Open AccessArticle

Bioactive Constituents and Therapeutic Mechanisms of Shenfu Decoction in a Rat Model of Seawater-Immersion-Induced Accidental Hypothermia

by Yanrong Gong, Zhibo Wang, Yiwen Ben, Hongzhi Chen, Yajing Wang, Chaoyue Sun, Huifang Deng, Huiqing Zhang, Zifei Yin and Wei Gu

Pharmaceuticals 2026, 19(5), 793; https://doi.org/10.3390/ph19050793 - 19 May 2026

Viewed by 329

Abstract

Background/Objectives: Shenfu Decoction (SFD) is a traditional Chinese herbal formula composed of Panax ginseng and Aconitum carmichaelii that can revive and counteract shock. However, how SFD can mitigate hypothermia caused by seawater immersion is poorly understood. Methods: Three commonly used ratios [...] Read more.

Background/Objectives: Shenfu Decoction (SFD) is a traditional Chinese herbal formula composed of Panax ginseng and Aconitum carmichaelii that can revive and counteract shock. However, how SFD can mitigate hypothermia caused by seawater immersion is poorly understood. Methods: Three commonly used ratios of SFD (Panax ginseng:Aconitum carmichaelii = 1:1, 1:2, 2:1) were prepared, and their chemical properties were analyzed with UPLC-Q-TOF-MS. A rat model of hypothermia caused by seawater immersion at 15 °C was utilized. Survival analysis was used to evaluate the prophylactic effect of single intragastric administration of SFD with different ratios and doses on the survival time of rats, and to identify the optimal intervention conditions. Network pharmacology analysis based on the absorbed constituents of SFD was performed to preliminarily predict the underlying mechanisms, which were subsequently validated using RT-PCR, Western blotting, ELISA, and H&E staining. Results: SFD contained 54 compounds, including ginsenosides and aconitine alkaloids, whose relative concentrations varied across different ratios of SFD. Animal studies showed that pretreatment of SFD (1:1) administered at a dose of 1.35 g/kg was very effective in increasing rats’ survival time in hypothermia and slowed down core body temperature decline. Based on the 28 plasma-absorbed compounds of SFD, network pharmacology identified 503 targets, enriched in cAMP and MAPK signaling pathways. SFD (1:1, 1.35 g/kg) resulted in larger lipid droplets in brown adipose tissue (BAT) and enhanced the respiratory metabolic rate in seawater-immersion-induced hypothermia rats. Furthermore, its thermogenic effect is likely associated with the upregulation of uncoupling protein 1 (UCP1) via activating p38 MAPK/PGC1α/PPARγ and NE-(β3-AR)-cAMP-PKA pathways. Conclusions: The results of this study demonstrate that a single prophylactic administration of the traditional Chinese medicine formula SFD prior to cold seawater exposure significantly prolongs the survival time of rats. This effect is associated with the upregulation of UCP1 and the subsequent enhancement of thermogenesis in BAT. These findings highlight the great potential of SFD as a promising intervention for the management of hypothermia. Full article

(This article belongs to the Section Natural Products)

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24 pages, 3402 KB

Open AccessReview

Rhizomes as Multi-Target Pharmacological Platforms Against Tauopathy: Neuro-Metabolic Crosstalk, Drug-Likeness, and Translational Challenges

by Andreas Wilson Setiawan, Jinwon Choi, Sohyun Park, Min Choi, Raymond Rubianto Tjandrawinata, Edwin Hadinata, Moon Nyeo Park, Taruna Ikrar, Fahrul Nurkolis and Bonglee Kim

Pharmaceuticals 2026, 19(5), 792; https://doi.org/10.3390/ph19050792 - 19 May 2026

Viewed by 375

Abstract

Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one [...] Read more.

Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse “multi-target platforms” whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from “single-compound optimism” to network pharmacology with translational discipline. Full article

(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease, 2nd Edition)

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30 pages, 804 KB

Open AccessReview

Multidimensional Predictors of Tirzepatide Efficacy: Clinical, Genetic, and Molecular Biomarkers for Glycemic, Weight, and Organ Protection

by Min Hyeok Shin, Jin Woo Jeong, Se Eun Ha, Rajan Singh, Moon Young Lee, Seungil Ro and Tae Yang Yu

Pharmaceuticals 2026, 19(5), 791; https://doi.org/10.3390/ph19050791 - 19 May 2026

Viewed by 712

Abstract

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates robust efficacy in glycemic control and weight reduction. However, substantial interindividual variability in treatment response is observed in clinical practice. In this narrative review, we summarize current evidence on [...] Read more.

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates robust efficacy in glycemic control and weight reduction. However, substantial interindividual variability in treatment response is observed in clinical practice. In this narrative review, we summarize current evidence on clinical, genetic, and molecular predictors of tirzepatide response and discuss their implications for a precision medicine framework. Data from pivotal clinical trials, post hoc analyses, and relevant preclinical and clinical studies were evaluated to identify determinants of glycemic and weight loss responses, as well as hepatic and renal protective effects. Key clinical predictors include tirzepatide dose, duration of diabetes, β-cell function, baseline glycated hemoglobin, sex, age, race, concomitant therapies, and early treatment response. Genetic factors implicated in treatment variability include variants in GLP-1 receptor, GIP receptor, β-arrestin 1, transcription factor 7-like 2, fat mass and obesity-associated protein, and melanocortin 4 receptor, although tirzepatide-specific validation remains limited. Molecular biomarkers such as branched-chain amino acids, insulin-like growth factor–binding protein-1 and -2, the adiponectin-to-leptin ratio, high-sensitivity C-reactive protein, and interleukin-6 show potential as pharmacodynamic indicators of metabolic response. For organ-specific outcomes, procollagen type III N-terminal peptide and magnetic resonance imaging–proton density fat fraction are supported for assessing hepatoprotective effects, while cystatin C–based estimated glomerular filtration rate and urine albumin-to-creatinine ratio are validated markers of renoprotection. Additional candidates—including tumor necrosis factor receptor 1/2, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin—are promising but require prospective validation. Overall, predicting response to tirzepatide’s multifaceted therapeutic effects necessitates an integrated, multidimensional approach that incorporates clinical characteristics, genetic variation, and molecular profiling. Ongoing validation and harmonization of these predictors may help establish a precision medicine framework for optimizing tirzepatide therapy. Full article

(This article belongs to the Special Issue Pharmacotherapy and Molecular Biomarkers of Metabolic Diseases)

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18 pages, 3833 KB

Open AccessReview

NIS-Centered Reporter Gene Imaging and Radionuclide-Integrated Nanoplatforms for Quantitative Tracking of Immune Cell Therapy in Oncology and Inflammatory Disease Models

by Sang Bong Lee

Pharmaceuticals 2026, 19(5), 790; https://doi.org/10.3390/ph19050790 - 18 May 2026

Viewed by 407

Abstract

Cell-based immunotherapies require noninvasive tools that can quantify the migration, biodistribution, and persistence of administered immune cells. This review focuses primarily on oncologic immune cell therapy, while also considering selected inflammatory disease models in which immune-cell trafficking is biologically relevant. We critically compare [...] Read more.

Cell-based immunotherapies require noninvasive tools that can quantify the migration, biodistribution, and persistence of administered immune cells. This review focuses primarily on oncologic immune cell therapy, while also considering selected inflammatory disease models in which immune-cell trafficking is biologically relevant. We critically compare direct radionuclide labeling, sodium iodide symporter (NIS)-based reporter gene imaging, radionuclide-integrated nanoplatforms, and Cerenkov-based hybrid optical conversion strategies. Direct labeling with agents such as [⁸⁹Zr]Zr-oxine, [¹¹¹In]In-oxine, and [⁹⁹ᵐTc]Tc-HMPAO enables early positron emission tomography (PET)/single-photon emission computed tomography (SPECT) biodistribution assessment, usually within hours to several days after cell administration. NIS reporter imaging with [¹²⁴I]NaI, [¹²³I]NaI, [⁹⁹ᵐTc]TcO₄⁻, or [¹⁸F]TFB supports repeated viability-dependent imaging, because signal generation depends on active transporter expression in living engineered cells. Radionuclide-integrated gold nanoplatforms can improve intracellular retention and offer theranostic potential through combined imaging, photothermal, radiotherapeutic, or immunomodulatory functions. We further discuss PET/SPECT balance, radiopharmaceutical nomenclature, nanoparticle stabilization, ethical aspects of genetic modification, tumor-on-a-chip systems for preclinical testing, and limitations of narrative evidence synthesis. Together, these platforms provide complementary strategies for image-guided immune cell therapy, with translational relevance for patient selection, treatment optimization, safety monitoring, and oncology practice. In conclusion, NIS-centered nuclear imaging and radionuclide-integrated nanoplatforms represent complementary, clinically actionable tools for quantitative immune-cell tracking, therapeutic optimization, and safety monitoring in translational oncology and inflammatory disease research. Full article

(This article belongs to the Special Issue Nanoplatforms for Enhanced Cancer Therapy)

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29 pages, 3759 KB

Open AccessArticle

Assessing the Safety of Carbon Dioxide Extracts of Acorus calamus Rhizomes and Calendula officinalis Flowers and the Antitussive Activity of the Tablet Dosage Form ‘Exkair’ and Granules ‘Zerp-Ak-Broncho’ Developed on Their Basis

by Galiya Ibadullayeva, Maigul Kizatova, Karlygash Raganina, Meruyert Tleubayeva, Aliya Mamatova, Rauan Botabayeva, Aigerim Karaubaeva, Aktolkyn Ibadullayeva, Aruzhan Darbassova, Lashyn Kiyekbayeva and Rizvangul Ayupova

Pharmaceuticals 2026, 19(5), 789; https://doi.org/10.3390/ph19050789 - 18 May 2026

Viewed by 306

Abstract

Background: The growing demand for safe and effective phytopharmaceuticals underscores the importance of studying regionally available medicinal plants. Acorus calamus L. and Calendula officinalis L., widely distributed in the Republic of Kazakhstan, are promising sources of biologically active compounds with significant pharmacological potential. [...] Read more.

Background: The growing demand for safe and effective phytopharmaceuticals underscores the importance of studying regionally available medicinal plants. Acorus calamus L. and Calendula officinalis L., widely distributed in the Republic of Kazakhstan, are promising sources of biologically active compounds with significant pharmacological potential. However, the combined use of their CO₂ extracts remains insufficiently characterised, particularly regarding possible synergistic interactions. Therefore, the development of new dosage forms and their comprehensive pharmacological and toxicological evaluation is a priority in modern pharmaceutical research. Methods: Concentrated extracts from Acorus calamus rhizomes and Calendula officinalis flowers were obtained using precritical CO₂ extraction. Safety was assessed through acute and chronic toxicity studies in laboratory animals according to standard non-clinical guidelines. Animals received graded doses of the extracts and developed formulations (‘Exkair’ tablets and ‘Zerp-Ak-Broncho’ granules). Clinical condition, mortality, body weight, and behaviour were monitored. Biochemical, haematological, and histopathological analyses were performed. Antitussive activity was evaluated in vivo by measuring oedema inhibition relative to reference drugs. Results: The CO₂ extracts and formulations demonstrated low toxicity and good tolerability, with no mortality or significant adverse effects observed even at high doses. Biochemical and haematological parameters remained within physiological ranges, and histopathological examination revealed no structural alterations in internal organs. Both ‘Exkair’ and ‘Zerp-Ak-Broncho’ exhibited pronounced antitussive activity, confirmed by significant suppression of oedema. This effect is likely associated with the synergistic action of flavonoids, terpenoids, and phenolic compounds. Conclusions: The findings indicate that CO₂ extracts of Acorus calamus L. and Calendula officinalis L., as well as the developed formulations, possess a favourable safety profile and significant antitussive activity. These results support their further development as phytotherapeutic agents in Kazakhstan. Full article

(This article belongs to the Section Pharmacology)

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18 pages, 949 KB

Open AccessReview

The Snakin Family of Antimicrobial Peptides: Promising Alternatives to Conventional Antibiotics

by Tuğba Teker and Gülruh Albayrak

Pharmaceuticals 2026, 19(5), 788; https://doi.org/10.3390/ph19050788 - 18 May 2026

Viewed by 239

Abstract

Antibiotic resistance has become a significant challenge for global health. Exploring novel antimicrobial compounds as alternatives to antibiotics is increasingly prominent in combating resistant pathogens. Antimicrobial peptides (AMPs), produced by various organisms, are considered natural antibiotic candidates that can be used against multidrug-resistant [...] Read more.

Antibiotic resistance has become a significant challenge for global health. Exploring novel antimicrobial compounds as alternatives to antibiotics is increasingly prominent in combating resistant pathogens. Antimicrobial peptides (AMPs), produced by various organisms, are considered natural antibiotic candidates that can be used against multidrug-resistant microorganisms. The snakin family of plant-based AMPs is a promising candidate for use in the agriculture, food and pharmaceutical industries due to its antimicrobial activity against both phytopathogenic and clinical species. This review summarizes current AMP databases and the snakin family of plant AMPs deposited in the Universal Protein Resource, UniProt. It also provides knowledge about potential uses of this family in biotechnology. Full article

(This article belongs to the Section Natural Products)

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20 pages, 3700 KB

Open AccessArticle

Fat Browning Effects of Catalpol and Rhoifolin from Rehmannia glutinosa (Gaertn.) and Lonicera japonica (Thunb.) in 3T3-L1 Adipocytes via the β3-AR Signaling Pathway

by Seung Min Choi, Sung Ho Lim, Ho Seon Lee, Gayoung Choi, Myeong Ji Kim, Hyunwoo Kim and Chang-Ik Choi

Pharmaceuticals 2026, 19(5), 787; https://doi.org/10.3390/ph19050787 - 18 May 2026

Viewed by 351

Abstract

Background/Objectives: Promoting white adipose tissue (WAT) browning into thermogenic beige adipocytes is a promising anti-obesity strategy. Yanggyeoksanhwa-tang (YST) has been used traditionally to alleviate obesity-related conditions. Catalpol and rhoifolin are major bioactive components of Rehmannia glutinosa (Gaertn.) and Lonicera japonica (Thunb.) with [...] Read more.

Background/Objectives: Promoting white adipose tissue (WAT) browning into thermogenic beige adipocytes is a promising anti-obesity strategy. Yanggyeoksanhwa-tang (YST) has been used traditionally to alleviate obesity-related conditions. Catalpol and rhoifolin are major bioactive components of Rehmannia glutinosa (Gaertn.) and Lonicera japonica (Thunb.) with known metabolic or anti-inflammatory effects. However, their direct roles in adipocyte browning and the mechanisms via β3-adrenergic receptor (β3-AR) signaling are not well defined, and this study addresses this gap. Methods: To evaluate browning potential, 3T3-L1 adipocytes were treated with catalpol and rhoifolin during differentiation. The expression of browning markers and lipid metabolism or catabolism transcription factors was analyzed using Western blotting and quantitative real-time polymerase chain reaction. The involvement of the β3-AR and adenosine monophosphate–activated protein kinase (AMPK) signaling pathways was further validated using specific agonists and antagonists. Results: Both compound treatments significantly upregulated beige-specific (Cd137, Cited, Tbx1, Cidea, Fgf21, Tmem26) and mitochondrial biogenesis markers (Cox4, Nrf1, Tfam), accompanied by a marked increase in thermogenic markers (UCP1, PGC-1α, Prdm16). Concurrently, lipolysis-related genes such as Atgl, Hsl, and Plin1 were elevated, while lipogenesis targets (Fasn, Lpl, Srebf1, Acaca) were downregulated through activation of the β3-AR signaling pathway. Conclusions: These findings suggest that catalpol and rhoifolin, key phytochemicals of YST, promote WAT browning and lipolysis. Our findings indicate that these compounds induce browning and modulate metabolism via the β3-AR pathway. These results serve as a cornerstone for natural anti-obesity therapy, pending further validation in vivo and clinical studies. Full article

(This article belongs to the Special Issue Plant-Derived Products in the Treatment of Internal Diseases: 2nd Edition)

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33 pages, 1508 KB

Open AccessReview

New Adjuvant Therapies for Obesity-Related Disorders Associated with Meta-Neuroinflammation

by Flaminia Coluzzi, Kevin Cornali, Maria Sole Scerpa and Annalisa Noce

Pharmaceuticals 2026, 19(5), 786; https://doi.org/10.3390/ph19050786 - 17 May 2026

Viewed by 588

Abstract

Obesity is a complex, heterogeneous, chronic, and progressive disease, which correlates with an augmented risk of developing several comorbidities, including painful conditions, such as osteoarthritis. In this review, authors present for the first time the term meta-neuroinflammation for describing how the chronic, low-grade [...] Read more.

Obesity is a complex, heterogeneous, chronic, and progressive disease, which correlates with an augmented risk of developing several comorbidities, including painful conditions, such as osteoarthritis. In this review, authors present for the first time the term meta-neuroinflammation for describing how the chronic, low-grade systemic inflammation, that occurs in obesity, may trigger oxidative stress and neuroinflammatory processes. Both the peripheral and the central nervous system are involved in neuroinflammation, leading to central sensitization and pain chronification, which leads to the observed increased incidence in obese patients of chronic pain syndromes, particularly osteoarthritis, low back pain, fibromyalgia, headache, and diabetic peripheral neuropathy. Possible mechanisms by which obesity may cause meta-neuroinflammation include adiposopathy, gut microbiota dysbiosis, and compromised integrity of blood–brain barrier, which could explain obesity-related depressive and neurodegenerative disorders. Preclinical data suggest the meta-neuroinflammation as a potential target of treatment in obese patients with degenerative joint disease. Based on these observations, targeted therapeutic strategies may include systemic administration of ultramicronized palmitoylethanolamide (um-PEA), well known for its neuroprotective, anti-neuroinflammatory, and analgesic actions, and comicronized PEA–rutin and hydroxytyrosol to restore intestinal eubiosis, with beneficial effects on body weight and mental disorders. Finally, Adelmidrol, as a PEA congener, could be considered for mitigating intra-articular meta-neuroinflammation in knee osteoarthritis. Full article

(This article belongs to the Special Issue Advances in Natural Products: Basic, Therapeutic, and Computational Approaches in Chronic and Infectious Diseases)

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20 pages, 6016 KB

Open AccessArticle

Liquiritigenin Ameliorates Rheumatoid Arthritis by Modulating the Nrf2/NF-κB/NLRP3 Pathway in Fibroblast-like Synoviocytes

by Zhuoxi Chen, Nana Chen, Limin Liu, Yingrui Wang, Lejian Zhu, Hui Yang, Zhuqi Han, Xiaoyu Zhang, Shuo Yan, Yuan Du and Leiming Zhang

Pharmaceuticals 2026, 19(5), 785; https://doi.org/10.3390/ph19050785 - 17 May 2026

Viewed by 339

Abstract

Background/Objectives: Rheumatoid arthritis (RA) is an autoimmune disorder manifesting as joint destruction and synovial inflammation, with the aberrant activation of fibroblast-like synoviocytes (FLSs) functioning as a critical pathological mechanism. Liquiritigenin (LIQ), a natural flavonoid extracted from licorice root, possesses anti-inflammatory and antioxidant activities; [...] Read more.

Background/Objectives: Rheumatoid arthritis (RA) is an autoimmune disorder manifesting as joint destruction and synovial inflammation, with the aberrant activation of fibroblast-like synoviocytes (FLSs) functioning as a critical pathological mechanism. Liquiritigenin (LIQ), a natural flavonoid extracted from licorice root, possesses anti-inflammatory and antioxidant activities; however, its efficacy and mechanism in RA pathological models remain unclear. This study aimed to investigate the anti-RA effects of LIQ mediated through FLSs and its underlying mechanisms. Methods: Complete Freund’s adjuvant (CFA)-induced rat model and TNF-α-stimulated MH7A cell model were employed to assess the anti-RA effects and underlying mechanisms. In vivo experiments examined the effects of LIQ on RA manifestations, joint damage, and inflammatory responses in CFA-induced rats, while in vitro experiments explored its effects on aberrant activation, oxidative stress, and inflammation in TNF-α-stimulated MH7A cells. The regulatory effects of LIQ on the Nrf2/NF-κB/NLRP3 signaling pathway were validated by immunofluorescence and Western blotting in vivo and in vitro. Results: LIQ alleviated joint swelling and bone damage, reducing synovial cellular infiltration and hyperplastic changes in CFA-induced rats. Furthermore, LIQ inhibited proliferation, migration, and invasion while reducing reactive oxygen species levels in TNF-α-stimulated MH7A cells, and decreased IL-1β and IL-18 levels in rat serum and MH7A cell supernatants. Moreover, LIQ activated Nrf2 and inhibited NF-κB and NLRP3, thereby attenuating inflammatory responses and alleviating oxidative stress. Administration of the Nrf2 inhibitor ML385 partially reversed its suppressive effects on inflammatory responses and oxidative stress in vivo and in vitro. Conclusions: LIQ exerted anti-RA effects in FLSs by suppressing inflammation and aberrant activation. Its mechanism may involve modulation of the Nrf2/NF-κB/NLRP3 signaling pathway. Full article

(This article belongs to the Special Issue Plant Extracts with Biological Activity and Potential Antioxidant Action)

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45 pages, 4123 KB

Open AccessReview

Guanidines: Privileged Scaffolds Against Neglected Tropical Diseases: A Review

by Luana Ribeiro dos Anjos, Rodrigo Santos Aquino de Araújo, Malu Maria Lucas dos Reis, Natalia C. S. Costa, Vitória Gaspar Bernardo, Eduardo Henrique Zampieri, Klinger Antonio da Franca Rodrigues, Eduardo Maffud Cilli, Eduardo René Pérez González and Francisco Jaime Bezerra Mendonça-Junior

Pharmaceuticals 2026, 19(5), 784; https://doi.org/10.3390/ph19050784 - 17 May 2026

Viewed by 470

Abstract

Background: Neglected diseases caused by protozoan parasites remain a major public health burden, particularly in low- and middle-income countries. Among the chemical motifs explored in antiparasitic drug discovery, guanidine-containing compounds have attracted considerable attention due to their strong cationic character, high capacity for [...] Read more.

Background: Neglected diseases caused by protozoan parasites remain a major public health burden, particularly in low- and middle-income countries. Among the chemical motifs explored in antiparasitic drug discovery, guanidine-containing compounds have attracted considerable attention due to their strong cationic character, high capacity for hydrogen bonding, and versatility in interacting with biological targets. Methodology: This review summarizes advances reported in the last decade regarding guanidine derivatives with activity against pathogens associated with Chagas disease, human African trypanosomiasis, Leishmaniasis, tuberculosis, toxoplasmosis, dengue and schistosomiasis. Results: Evidence gathered from synthetic, natural, and drug-repurposing studies indicates that the guanidine, guanidine-containing and guanidine-related compounds contribute to modulating biological activity by changing electrostatic interactions, hydrogen-bonding networks, and physicochemical properties, with enzymes, nucleic acids, and membrane-associated targets essential for parasite survival. Across the analyzed studies, several emerging structure–activity relationship trends were identified, including the contribution of polycationic or dicationic architectures, the influence of halogenated or lipophilic substituents, and the dependence of biological activity on the complete molecular framework, including heterocyclic systems, macrocycles, peptide conjugates, hybrid scaffolds, and repurposed drugs. In addition to direct antiparasitic effects, certain guanidine-containing and guanidine-related compounds demonstrate immunomodulatory or host-protective properties, expanding the therapeutic relevance of this class. Despite promising in vitro results, protonation trapping, efflux pump susceptibility, and pharmacokinetic limitations such as poor oral absorption, high polarity, plasma protein binding and limited membrane permeability remain significant challenges for clinical translation. Nonetheless, the integration of medicinal chemistry, computational modeling, and biological screening continues to accelerate the identification of optimized scaffolds. Conclusions: Overall, guanidine-based compounds constitute a promising scaffold for the development of new therapeutic strategies targeting neglected parasitic diseases, and further structural optimization may enable the emergence of candidates with improved efficacy, selectivity, and drug-like properties. Full article

(This article belongs to the Section Medicinal Chemistry)

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21 pages, 3571 KB

Open AccessReview

Gut Microbiota in Irritable Bowel Syndrome and Inflammatory Bowel Disease: Differences in Pathophysiology, Biomarkers, and Treatment Implications

by Ploutarchos Pastras, Ioanna Aggeletopoulou, Vasiliki Psalti and Christos Triantos

Pharmaceuticals 2026, 19(5), 783; https://doi.org/10.3390/ph19050783 - 17 May 2026

Viewed by 682

Abstract

Alterations in the intestinal microbiota have been implicated in both irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). However, their biological significance and therapeutic implications differ substantially between the two conditions. Although dysbiosis is a common feature, the mechanisms by which alterations [...] Read more.

Alterations in the intestinal microbiota have been implicated in both irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). However, their biological significance and therapeutic implications differ substantially between the two conditions. Although dysbiosis is a common feature, the mechanisms by which alterations in the microbiota contribute to disease pathophysiology and clinical expression are distinct. Some pathways are more prominent in IBS (e.g., the gut–brain axis), whereas others are more prominent in IBD (e.g., reduced microbial diversity). Equally important are pathways that appear to play a role exclusively in IBD [e.g., Adherent-invasive Escherichia coli (AIEC) and Paneth cells], as well as others that seem to be specific to IBS (e.g., mast cell activation). In IBD, microbiota changes are primarily linked to immune dysregulation, mucosal barrier impairment, and inflammation-driven pathways, whereas in IBS, they are mainly associated with functional disturbances mediated by neuroimmune signaling and microbial metabolites. Furthermore, several microbiome-associated biomarkers differ between these two diseases, and some are already assessed by international guidelines. Although the microbiota plays a key role in IBS and IBD pathophysiology, microbiome-based treatments remain limited, especially in IBD. There are clinically available treatments in IBS (e.g., rifaximin, low-FODMAP diet), but in IBD, only the probiotic VSL#3 is guideline-approved in ulcerative colitis pouchitis prophylaxis. Nevertheless, the dynamic nature of the microbiota continues to support the investigation of already studied (e.g., probiotics, fecal microbiota transplantation) and potential novel therapeutic approaches at the research level. The aim of this review is to compare the gut-microbiota-related pathophysiological pathways and biomarkers between IBS and IBD, to summarize the microbiome-related medications that have already been studied in both diseases, and to suggest new potential therapeutic options based on the gut microbiota. Full article

(This article belongs to the Special Issue Research on Diagnosis, Treatment and Related Microbiota in Gastrointestinal Diseases)

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23 pages, 1380 KB

Open AccessReview

Traditional Chinese Medicine-Derived Active Ingredient and Formulation Therapy for Glioma: Multi-Target Mechanisms, Drug Delivery Systems, and Advances in Clinical Translational Research

by Xiaoting Shen, Yueling Wang, Yating Lin, Lirong Chen, Hao Wu, Jiaxin Jiang, Lisong Chen, Ying Chen, Desen Li, Wenyi Wang and Shuisheng Wu

Pharmaceuticals 2026, 19(5), 782; https://doi.org/10.3390/ph19050782 - 16 May 2026

Viewed by 594

Abstract

Glioma, the most common and aggressive primary brain tumor, presents significant clinical management challenges due to difficulties in blood–brain barrier penetration, high tumor heterogeneity, and susceptibility to drug resistance and recurrence, leading to an extremely poor prognosis. Traditional Chinese Medicine (TCM), particularly its [...] Read more.

Glioma, the most common and aggressive primary brain tumor, presents significant clinical management challenges due to difficulties in blood–brain barrier penetration, high tumor heterogeneity, and susceptibility to drug resistance and recurrence, leading to an extremely poor prognosis. Traditional Chinese Medicine (TCM), particularly its derived active ingredients and herbal formulations, with its advantages of multi-component, multi-target, and holistic regulation, demonstrates significant potential in the comprehensive treatment of this disease. This review systematically outlines the research progress in TCM for combating glioma. Regarding mechanisms of action, active TCM components not only directly inhibit tumors by inducing cell apoptosis but also exert synergistic therapeutic effects via multiple pathways. These include remodeling the immunosuppressive microenvironment, activating novel cell death programs such as ferroptosis and immunogenic cell death, intervening in tumor metabolic reprogramming, and reversing chemotherapy resistance. In terms of overcoming delivery barriers, drug delivery systems represented by nanocarriers, liposomes, and extracellular vesicles, combined with the penetration-enhancing effects of aromatic orifice-opening herbs (a class of TCM medicinals traditionally used to “open the orifices” and awaken the mind, now recognized to transiently enhance BBB permeability), have significantly improved the brain-targeting efficiency and bioavailability of TCM components. For clinical translation, a number of innovative drugs derived from TCM, such as elemene, cinobufagin, and ACT001, are currently under clinical investigation, with initial results showing efficacy in prolonging survival and improving quality of life. In the future, by integrating the analysis of multi-target synergistic mechanisms, promoting the clinical translation of intelligent drug delivery systems, and conducting high-quality clinical research on integrated Chinese and Western medicine, TCM is expected to provide a new generation of integrated treatment strategies for glioma that combines holistic and precision medicine. Full article

(This article belongs to the Section Biopharmaceuticals)

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28 pages, 5713 KB

Open AccessArticle

Baicalein-Cyclodextrin Inclusion Complexes Nasal Thermosensitive Hydrogel: Bioavailability Improvement and Pharmacokinetic Evaluation in Rats

by Xinyu Ji, Xiali Wei, Zixuan Guo, Ziyang Li, Yuxian Li, Rui Yang and Qingri Jin

Pharmaceuticals 2026, 19(5), 781; https://doi.org/10.3390/ph19050781 - 16 May 2026

Viewed by 321

Abstract

Background: Baicalein (BA) is a poorly soluble flavonoid with limited oral bioavailability. This study aimed to enhance the solubility and nasal absorption of the compound using a dual-carrier system that combines cyclodextrin inclusion complexes and thermosensitive hydrogels. Methods: The inclusion complexes [...] Read more.

Background: Baicalein (BA) is a poorly soluble flavonoid with limited oral bioavailability. This study aimed to enhance the solubility and nasal absorption of the compound using a dual-carrier system that combines cyclodextrin inclusion complexes and thermosensitive hydrogels. Methods: The inclusion complexes of BA with hydroxypropyl-β-cyclodextrin (HP-β-CD) or sulfobutyl-β-cyclodextrin (SBE-β-CD), namely BA-HP-β-CD and BA-SBE-β-CD, were prepared via solution stirring and characterized by solubility, dissolution, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis-differential scanning calorimetry (TG-DSC), and Madin-Darby canine kidney (MDCK) cell permeation. The optimal complexes were incorporated into chitosan/β-glycerophosphate thermosensitive hydrogels (BA/HP-Gel and BA/SBE-Gel), followed by evaluations of gelation properties, in vitro release, and in vivo pharmacokinetics in rats. Results: The water solubility of BA-HP-β-CD and BA-SBE-β-CD increased 572 and 582 times, with MDCK permeability enhanced by 5.3 and 2.9 times, respectively. Both hydrogels showed rapid solution-gel transition at nasal temperature and sustained release. Following intranasal administration, BA/HP-Gel and BA/SBE-Gel achieved relative bioavailabilities of 623.5% and 697.8%, respectively, compared with BA-Gel. Conclusions: The dual-carrier platform effectively improved BA solubility, permeability, and nasal bioavailability, offering a promising strategy for nasal delivery of poorly soluble drugs. Full article

(This article belongs to the Section Pharmaceutical Technology)

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12 pages, 757 KB

Open AccessArticle

Metformin Treatment Potentially Modifies Genetically Driven Metabolite-HbA1c Associations: A Gene–Environment Interaction Mendelian Randomization Study

by Najeha Anwardeen, Aleem Razzaq, Asma A. Elashi, Gaurav Thareja, Ilhame Diboun, Khaled Naja, Karsten Suhre and Mohamed A. Elrayess

Pharmaceuticals 2026, 19(5), 780; https://doi.org/10.3390/ph19050780 - 15 May 2026

Viewed by 414

Abstract

Introduction/Background: Metformin is the first-line therapy for type 2 diabetes (T2D); however, a considerable inter-individual variability in glycemic response is observed among patients. This heterogeneity suggests that metformin’s effects depend not only on drug exposure but also on the underlying metabolic and [...] Read more.

Introduction/Background: Metformin is the first-line therapy for type 2 diabetes (T2D); however, a considerable inter-individual variability in glycemic response is observed among patients. This heterogeneity suggests that metformin’s effects depend not only on drug exposure but also on the underlying metabolic and genetic factors. Methods: We applied a Gene–Environment interaction Mendelian Randomization (MR-G×E) in a cohort of 2743 individuals to investigate whether genetically influenced metabolite-HbA1c associations differ by metformin use. Metabolites associated with metformin response were used to establish metabolite-specific polygenic risk scores (PRSs) using metabolome-wide association study (mGWAS) variants. Generated PRS were used as genetic instruments within a one-sample, modified two-stage least squares model. An interaction term between PRS and metformin use was included to assess treatment-dependent genetic effects, adjusting for age, sex, body mass index, and genetic ancestry (principal components). Results: Metformin use significantly modified genetically influenced associations between 18 metabolites and HbA1c. Positive and negative PRS-metformin interaction effects indicated attenuation, strengthening or reversal of baseline genetic associations under treatment. Several amino acid metabolites, palmitoyl sphingomyelin (d18:1/16:0), and carbohydrate-related metabolite 1,5-anhydroglucitol showed specific patterns under metformin use. Interestingly, several metabolites (creatinine, gamma glutamylcitrulline, N-acetylthreonine, 3-methyl-2-oxovalerate, glycerol-3-phosphate, 1-(1-enyl-palmitoyl)-GPC (P-16:0), 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2), sphingomyelin (d18:1/22:1, d18:2/22:0, d16:1/24:1), fructose, and methyl-glucopyranoside (alpha + beta)) showed no basal causal association with HbA1c but exhibited significant interaction effect with metformin use, suggesting metabolic association only in the presence of metformin. Conclusions: These findings indicate that metformin modifies the genetically influenced metabolite-HbA1c relationships, exhibiting treatment-dependent metabolic effects that are not detectable with standard MR approaches. Incorporating pharmacological context into causal inference provides new insights into the metabolic basis for the variable metformin response and helps inform precision strategies for T2D management. Full article

(This article belongs to the Section Pharmacology)

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16 pages, 419 KB

Open AccessReview

Progressive Sensorineural Hearing Loss Following Cisplatin Chemotherapy: Mechanisms Underlying Cochlear Retention and Long-Term Ototoxicity

by Antonio Ruggiero, Pasqualina Maria Picciotti, Stefano Mastrangelo, Alberto Romano, Dario Talloa, Jacopo Galli and Giorgio Attinà

Pharmaceuticals 2026, 19(5), 779; https://doi.org/10.3390/ph19050779 - 15 May 2026

Viewed by 324

Abstract

Cisplatin-induced ototoxicity is a permanent, bilateral sensorineural hearing loss occurring in up to 80% of treated patients. Its defining and clinically challenging feature is the progressive worsening of auditory function that continues well after chemotherapy has ended, a trajectory that cannot be explained [...] Read more.

Cisplatin-induced ototoxicity is a permanent, bilateral sensorineural hearing loss occurring in up to 80% of treated patients. Its defining and clinically challenging feature is the progressive worsening of auditory function that continues well after chemotherapy has ended, a trajectory that cannot be explained by cumulative dose alone. This article is a comprehensive review of the present research studies on mechanisms that are responsible for this post-treatment progression. The cochlea, unlike other organs, appears to be unable to eliminate platinum (the active divalent metal ion released from cisplatin and responsible for its cytotoxic and ototoxic effects): traces of it can be found in human temporal bone tissue even more than 18 months after last infusion, and bone might serve as a long-term systemic reservoir. Within the inner ear, platinum accumulates preferentially in the stria vascularis, impairing endocochlear potential and outer hair cell function. Retained platinum sustains cascading effects including sustained NOX3-dependent oxidative stress, mitochondrial dysfunction, ongoing genotoxic injury to non-regenerative cells, and the early loss of ribbon synapses that precipitates delayed spiral ganglion neurodegeneration. Pharmacogenetic variability in platinum transport and antioxidant metabolism further modulates individual susceptibility. These findings support lifelong audiological surveillance and provide a basis for designing strategies that can protect hearing without compromising the essential anticancer efficacy of cisplatin therapy. Full article

(This article belongs to the Section Pharmacology)

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37 pages, 3337 KB

Open AccessArticle

Interpretable QSAR, External PubChem Validation, and Coordination-Aware Docking Enable Tiered Prioritization of Carbonic Anhydrase I Inhibitors

by Alaa M. Elsayad and Khaled A. Elsayad

Pharmaceuticals 2026, 19(5), 778; https://doi.org/10.3390/ph19050778 - 15 May 2026

Viewed by 248

Abstract

Background/Objectives: Carbonic anhydrase I (CAI) is a zinc-dependent metalloenzyme whose inhibitor discovery requires both effective navigation of chemical space and explicit evaluation of coordination-credible binding hypotheses. We aimed to develop an interpretable and reproducible QSAR-to-structure workflow for CAI inhibitor discovery. The workflow links [...] Read more.

Background/Objectives: Carbonic anhydrase I (CAI) is a zinc-dependent metalloenzyme whose inhibitor discovery requires both effective navigation of chemical space and explicit evaluation of coordination-credible binding hypotheses. We aimed to develop an interpretable and reproducible QSAR-to-structure workflow for CAI inhibitor discovery. The workflow links potency prediction with zinc-site plausibility and early developability to support decision-oriented prioritization of new CAI inhibitor candidates. Methods: CAI inhibitors were retrieved from ChEMBL (CHEMBL261) and modeled as

p K_{i} = 9 - {l o g}_{10} (K_{i} [n M])

. AlvaDesc v3.0.8 generated 4224 2D descriptors, which were reduced using train-only preprocessing, variance filtering, correlation pruning, and bagged-tree ranking to a top-100 panel. Five regressors (elastic net, CART, bagging, GB, and XGB) were benchmarked on a held-out test set. Potent ChEMBL seeds (K_i ≤ 10 nM) were used for a 90% 2D similarity PubChem expansion. Predicted hits were then externally validated using independently available PubChem CAI

K_{i}

records. Ten novel candidates lacking CAI

K_{i}

data were docked to CAI (PDB: 1AZM) via SwissDock AutoDock Vina in neutral and relevant anionic states, with pose selection constrained by a Zn-donor filter (Zn-N/O

\leq 2.6

Å). SwissADME was used to profile physicochemical space, alerts, and absorption/distribution proxies. Results: The bagging model showed the best test generalization (

R^{2} = 0.646

; RMSE = 0.61; MAE = 0.45). PFI and SHAP converged on sulfur/heteroatom connectivity and polar–lipophilic organization as dominant potency drivers. PubChem expansion yielded 25,315 analogs and 233 candidates at predicted

p K_{i} \geq 8.0

; external validation on 145 CAI-measured hits gave

R^{2} = 0.358

(RMSE = 0.456; MAE = 0.320). Across 20 ligand/protomer docking runs, 12 produced canonical Zn-anchored poses (10 Zn-N; 2 Zn-O). SwissADME indicated consensus logP values from −0.65 to 3.21, 0/10 PAINS alerts, and predominantly favorable drug-likeness (8/10 with zero Lipinski violations), supporting tiered advancement. Conclusions: Integrating interpretable QSAR, external PubChem validation, coordination-aware docking, and SwissADME yields a practical triage framework for CAI inhibitor discovery. The resulting tiered shortlist identifies two Zn-N-anchored N-alkyl sulfamides (CIDs 103935964 and 112684680) and one Zn-O-anchored carboxylate control (CID 122367674) as highest-priority computational hypotheses for staged biochemical evaluation. Full article

(This article belongs to the Section Medicinal Chemistry)

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22 pages, 18874 KB

Open AccessArticle

MSC-Derived Apoptotic Vesicles Restore Bone Marrow Niche Homeostasis in Postmenopausal Osteoporosis by miRNA-Mediated Suppression of MAPK and NF-κB Signaling Nodes

by Zhiwen Tu, Haolin Wu, Youxi Jiang, Xinxin Li, Zhiqing Huang, Songtao Shi and Ruibao Ren

Pharmaceuticals 2026, 19(5), 777; https://doi.org/10.3390/ph19050777 - 15 May 2026

Viewed by 318

Abstract

Background: Postmenopausal osteoporosis is associated with cellular senescence and the accumulation of the senescence-associated secretory phenotype (SASP). While mesenchymal stem cell (MSC)-derived exosomes show tissue repair potential, the efficacy and mechanisms of MSC-derived apoptotic vesicles (apoVs) remain unclear. This study compared MSC-apoVs [...] Read more.

Background: Postmenopausal osteoporosis is associated with cellular senescence and the accumulation of the senescence-associated secretory phenotype (SASP). While mesenchymal stem cell (MSC)-derived exosomes show tissue repair potential, the efficacy and mechanisms of MSC-derived apoptotic vesicles (apoVs) remain unclear. This study compared MSC-apoVs and exosomes in postmenopausal osteoporosis and investigated the underlying epigenetic mechanisms. Methods: Therapeutic efficacy was evaluated in an ovariectomized (OVX) mouse model and senescent human bone marrow mesenchymal stem cells (hBMMSCs). Small RNA sequencing identified differential microRNA (miRNA) cargos between vesicle types. SASP-related cytokine expression (IL-6, TNF-α, MCP-1) and pathway activation were assessed by RT-qPCR, ELISA, and Western blot. Results: MSC-apoV treatment attenuated bone loss in OVX mice and reduced SASP expression in senescent hBMMSCs to a greater extent than exosomes. Small RNA sequencing revealed that apoVs were enriched with a specific miRNA cluster, including hsa-let-7b-5p, hsa-miR-92a-3p, and hsa-miR-98-5p. Bioinformatic analyses identified BRAF and CRKL as downstream targets of this miRNA cluster, supported by reduced protein levels after apoV treatment. Subsequent molecular assays showed that apoV treatment inhibited the phosphorylation of both the MAPK (p38 and JNK) and NF-κB (p65) signaling pathways, which correlated with reduced local inflammation in the bone marrow microenvironment and preserved osteogenic differentiation capacity. Conclusions: MSC-apoVs attenuate postmenopausal osteoporosis more effectively than exosomes. This enhanced efficacy is associated with the delivery of an enriched miRNA cluster that inhibits MAPK and NF-κB signaling, together with suppression of BRAF and CRKL protein expression. ApoVs may represent a cell-free therapeutic strategy for age-related bone loss. Full article

(This article belongs to the Section Biopharmaceuticals)

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28 pages, 6281 KB

Open AccessSystematic Review

Effectiveness and Safety of Liuwei Dihuang as an Adjunctive Therapy for Cognitive Impairment: A Systematic Review, Meta-Analysis, and Network Pharmacology Analysis

by Jihyun Hwang, Mi Hye Kim, Jeongrim Bak, Jong-Min Yun and Jungtae Leem

Pharmaceuticals 2026, 19(5), 776; https://doi.org/10.3390/ph19050776 - 15 May 2026

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Abstract

Background/Objectives: Liuwei Dihuang (LWDH) is a classical plant-derived herbal formula widely used for cognitive decline. This study aimed to evaluate its efficacy and safety in cognitive disorders and to explore its potential pharmacological mechanisms using network pharmacology. Methods: We searched 11 [...] Read more.

Background/Objectives: Liuwei Dihuang (LWDH) is a classical plant-derived herbal formula widely used for cognitive decline. This study aimed to evaluate its efficacy and safety in cognitive disorders and to explore its potential pharmacological mechanisms using network pharmacology. Methods: We searched 11 databases through November 2024 for randomized controlled trials comparing LWDH plus conventional therapy with conventional therapy alone in cognitive disorders. Meta-analysis was performed for clinical outcomes, and herb–compound–target and disease-target datasets were integrated to identify core molecular modules. Results: Twelve randomized controlled trials involving 1137 participants were included. Adjunctive LWDH was associated with improvements in Mini-Mental State Examination scores (MD = 2.34, 95% CI 0.88–3.79), activities of daily living, and quality of life. However, substantial heterogeneity and methodological limitations, including unclear randomization and blinding, were observed across studies, indicating a potential risk of bias. Fewer adverse events were reported in the LWDH plus conventional treatment group, although reporting quality was limited. The overall risk of bias was judged as “some concerns”. Network pharmacology analysis identified a broad set of overlapping genes between LWDH-associated targets and cognitive disorder-related genes, which were further refined through filtering procedures. Subsequent analyses suggested associations with pathways related to neurodegeneration, apoptosis, and central nervous system function; however, these findings are exploratory and based on in silico predictions. Conclusions: LWDH may be associated with potential adjunctive benefits in cognitive disorders. However, given the methodological limitations and clinical heterogeneity of the included studies, the findings should be interpreted with caution. The proposed pharmacological mechanisms are exploratory and require further validation. Well-designed randomized controlled trials are needed to establish more robust evidence. Full article

(This article belongs to the Special Issue Plant-Derived Products in the Treatment of Internal Diseases: 2nd Edition)

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31 pages, 6619 KB

Open AccessArticle

Anti-Inflammatory Evaluation of Pyrazino[2,1-b]quinazoline-3,6-dione Derivatives Inspired by Fiscalin B

by Márcia S. Martins, Madalena M. M. Pinto, Isabel F. Almeida, Maria T. Cruz and Emília Sousa

Pharmaceuticals 2026, 19(5), 775; https://doi.org/10.3390/ph19050775 - 15 May 2026

Viewed by 217

Abstract

Background/Objectives: Chronic inflammatory skin diseases are frequently associated with pruritus, in which the neurokinin-1 receptor (NK₁R) and its ligand substance P (SP) play a central role. The development of compounds combining anti-inflammatory and antipruritic effects represents a promising therapeutic strategy. This [...] Read more.

Background/Objectives: Chronic inflammatory skin diseases are frequently associated with pruritus, in which the neurokinin-1 receptor (NK₁R) and its ligand substance P (SP) play a central role. The development of compounds combining anti-inflammatory and antipruritic effects represents a promising therapeutic strategy. This study aims to identify fiscalin B derivatives as anti-inflammatory agents with high affinity to NK₁R using an integrated in silico and in vitro approach. Methods: A library of fiscalin B derivatives was screened through molecular docking against NK₁R to identify high-affinity ligands. Selected compounds were further evaluated using in silico ADMET and toxicity predictions. In vitro assays were conducted in HaCaT keratinocytes, RAW264.7 macrophages, and NIH/3T3 fibroblasts to assess cytotoxicity, nitric oxide production, inflammatory proteins expression, and cell migration. Results: Docking studies identified several derivatives with predicted binding affinities comparable to or exceeding those of aprepitant, a well-established NK₁R antagonist. Several compounds, particularly 2, 3, 4, 6, and 7, reduced lipopolysaccharide-induced nitric oxide production to 41–51% without relevant cytotoxicity. This effect was associated with reduced iNOS protein levels, suggesting modulation of inflammatory pathways rather than direct nitric oxide scavenging. Most compounds showed positive safety profiles, although in silico analysis indicated limited biodegradability and potential aquatic toxicity. Conclusions: The fiscalin B derivatives, 2, 3, and 4, demonstrate potential as anti-inflammatory agents, in vitro, and as NK₁R high affinity ligands, in silico. These findings support their potential as lead compounds for topical therapies for inflammatory skin disorders associated with pruritus, although further optimization and validation are required. Full article

(This article belongs to the Section Medicinal Chemistry)

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16 pages, 2765 KB

Open AccessArticle

Biological Sex Influences the Pharmacokinetics and Organ Dosimetry of ¹⁷⁷Lu-DOTATATE: A Systematic Preclinical Evaluation

by Xiangsheng Kong, Peishang Li, Zhiqian Wang, Chenchen Cai, Mingjie Zhang, Chunmiao Qu, Chunlei Jin, Hongzhang Zhang, Yeqing Dong, Kai Lv and Fei Han

Pharmaceuticals 2026, 19(5), 774; https://doi.org/10.3390/ph19050774 - 15 May 2026

Viewed by 360

Abstract

Background/Objectives: While ¹⁷⁷Lu-DOTATATE has demonstrated clinical efficacy in peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs), current dosing regimens do not account for potential sex-based pharmacokinetic differences. Our study systematically characterizes sex-dependent pharmacokinetic variations of ¹⁷⁷Lu-DOTATATE in preclinical models to [...] Read more.

Background/Objectives: While ¹⁷⁷Lu-DOTATATE has demonstrated clinical efficacy in peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs), current dosing regimens do not account for potential sex-based pharmacokinetic differences. Our study systematically characterizes sex-dependent pharmacokinetic variations of ¹⁷⁷Lu-DOTATATE in preclinical models to provide the first preclinical evidence base informing future sex-stratified clinical investigations. Methods: Sex-stratified pharmacokinetic and biodistribution studies were conducted in male and female SD rats following intravenous administration of ¹⁷⁷Lu-DOTATATE at multiple dose levels: 2.86, 5.71, and 11.43 mCi/kg. Metabolic stability and renal excretion patterns were characterized. Safety assessments included acute toxicity, vascular irritation, hemolysis, and allergenicity testing. Therapeutic efficacy was evaluated exclusively in female AR42J xenograft-bearing CB-17 SCID mice. Results: Significant sex-dependent pharmacokinetic differences were observed at high (11.43 mCi/kg) and low (2.86 mCi/kg) dose levels, with females exhibiting 30–40% higher AUC and C_max values compared to males (p < 0.05). Both sexes demonstrated preferential accumulation in SSTR-expressing tissues, particularly the pancreas (females: 10.87 ± 2.51% ID/g; males: 9.10 ± 0.76% ID/g) and adrenal glands, with rapid clearance from non-target organs. Radio-HPLC analysis confirmed high metabolic stability with no detectable radiolabeled metabolites, and over 90% of radioactivity was recovered through renal excretion. Safety assessments demonstrated excellent tolerability across dose levels. In female xenograft models, treatment achieved tumor growth inhibition of 92.35–96.44% and 100% survival rate versus 10% in controls, though mid/high doses caused weight loss. Conclusions: Our study provides systematic preclinical evidence of sex-dependent pharmacokinetic differences in ¹⁷⁷Lu-DOTATATE, with females demonstrating significantly higher systemic exposure than males at specific dose levels. These findings establish the systematic preclinical evidence base for sex-dependent pharmacokinetic differences in ¹⁷⁷Lu-DOTATATE, providing a scientific rationale for incorporating sex as a stratification variable in future dosimetry-guided clinical studies. Full article

(This article belongs to the Section Pharmacology)

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