Pharmaceuticals

26 pages, 1546 KiB

Open AccessReview

Cellular Epigenetic Targets and Epidrugs in Breast Cancer Therapy: Mechanisms, Challenges, and Future Perspectives

by Ibrahim S. Alalhareth, Saleh M. Alyami, Ali H. Alshareef, Ahmed O. Ajeibi, Manea F. Al Munjem, Ahmad A. Elfifi, Meshal M. Alsharif, Seham A. Alzahrani, Mohammed A. Alqaad, Marwa B. Bakir and Basel A. Abdel-Wahab

Pharmaceuticals 2025, 18(2), 207; https://doi.org/10.3390/ph18020207 (registering DOI) - 3 Feb 2025

Abstract

Breast cancer is the most common malignancy affecting women, manifesting as a heterogeneous disease with diverse molecular characteristics and clinical presentations. Recent studies have elucidated the role of epigenetic modifications in the pathogenesis of breast cancer, including drug resistance and efflux characteristics, offering [...] Read more.

Breast cancer is the most common malignancy affecting women, manifesting as a heterogeneous disease with diverse molecular characteristics and clinical presentations. Recent studies have elucidated the role of epigenetic modifications in the pathogenesis of breast cancer, including drug resistance and efflux characteristics, offering potential new diagnostic and prognostic markers, treatment efficacy predictors, and therapeutic agents. Key modifications include DNA cytosine methylation and the covalent modification of histone proteins. Unlike genetic mutations, reprogramming the epigenetic landscape of the cancer epigenome is a promising targeted therapy for the treatment and reversal of drug resistance. Epidrugs, which target DNA methylation and histone modifications, can provide novel options for the treatment of breast cancer by reversing the acquired resistance to treatment. Currently, the most promising approach involves combination therapies consisting of epidrugs with immune checkpoint inhibitors. This review examines the aberrant epigenetic regulation of breast cancer initiation and progression, focusing on modifications related to estrogen signaling, drug resistance, cancer progression, and the epithelial–mesenchymal transition (EMT). It examines existing epigenetic drugs for treating breast cancer, including agents that modify DNA, inhibitors of histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone demethyltransferases. It also delves into ongoing studies on combining epidrugs with other therapies and addresses the upcoming obstacles in this field. Full article

(This article belongs to the Section Pharmacology)

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18 pages, 505 KiB

Open AccessReview

Breakthrough Advances in Beta-Lactamase Inhibitors: New Synthesized Compounds and Mechanisms of Action Against Drug-Resistant Bacteria

by Ya-Si Huang and Hong Zhou

Pharmaceuticals 2025, 18(2), 206; https://doi.org/10.3390/ph18020206 (registering DOI) - 3 Feb 2025

Abstract

Beta-lactam drugs hold a central place in the antibacterial arsenal, and the production of beta-lactamases by drug-resistant bacteria has severely compromised the effectiveness of nearly all available beta-lactams. Therefore, in the face of the increasing threat of drug resistance, the combined use of [...] Read more.

Beta-lactam drugs hold a central place in the antibacterial arsenal, and the production of beta-lactamases by drug-resistant bacteria has severely compromised the effectiveness of nearly all available beta-lactams. Therefore, in the face of the increasing threat of drug resistance, the combined use of beta-lactamase inhibitors (BLIs) with beta-lactam antibiotics is crucial for treating infections caused by drug-resistant bacteria. Hence, the development of BLIs has always been a hot topic in the field of medicinal chemistry. In recent years, significant progress has been made in screening active drugs by enhancing the affinity of inhibitors for enzymes and the stability of their complexes, based on the design concept of competitive inhibitors. Here, we review the effects and mechanisms of newly synthesized beta-lactamase inhibitors on various BLIs in recent years, to provide ideas for the development of subsequent beta-lactamase inhibitors. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis and Evaluation of Beta-Lactamase Inhibitors)

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27 pages, 4842 KiB

Open AccessArticle

Discovery of a Novel Multitarget Analgesic Through an In Vivo-Guided Approach

by Guo Zhen, Nayeon Do, Nguyen Van Manh, Hee-Jin Ha, Hee Kim, Hyunsoo Kim, Kwanghyun Choi, Jihyae Ann and Jeewoo Lee

Pharmaceuticals 2025, 18(2), 205; https://doi.org/10.3390/ph18020205 - 3 Feb 2025

Abstract

Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget [...] Read more.

Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget analgesic with improved pharmacological properties. Methods: An in vivo-guided screening approach was used to discover a new analgesic compound. Compound 29, derived from a novel scaffold inspired by opiranserin and vilazodone pharmacophores, was identified through analog screening in the formalin test. Its efficacy was further evaluated in the spinal nerve ligation (SNL) model of neuropathic pain. Mechanistic studies explored its interaction with neurotransmitter transporters and receptors, while pharmacokinetic and safety assessments were conducted to determine its stability, brain penetration, and potential toxicity. Results: Compound 29 demonstrated high potency in the formalin test, with an ED50 of 0.78 mg/kg in the second phase and a concentration-dependent effect in the first phase. In the SNL model, it produced dose-dependent analgesic effects, increasing withdrawal thresholds by 24% and 45% maximum possible effect (MPE) at 50 and 100 mg/kg, respectively. Mechanistic studies revealed strong triple uptake inhibition, particularly at dopamine (DAT) and serotonin (SERT) transporters, alongside high-affinity 5-HT2A receptor antagonism. Pharmacokinetic analysis indicated enhanced stability and blood–brain barrier permeability. In vitro studies confirmed its nontoxicity to HT-22 cells but revealed potential hERG inhibition and strong CYP3A4 inhibition. Conclusions: Compound 29 is a promising multitarget analgesic with potent efficacy and favorable pharmacokinetics. Ongoing optimization efforts aim to mitigate side effects and enhance its therapeutic profile for clinical application. Full article

(This article belongs to the Special Issue Discovery and Development of Novel Analgesics)

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18 pages, 933 KiB

Open AccessArticle

Formulation, Quality Control and Stability Study of Pediatric Oral Dextrose Gel

by Edouard Lamy, Caroline Orneto, Oumil Her Abdou Ali, Lyna Kireche, Fanny Mathias, Cyrielle Bouguergour, Florence Peyron, Nicolas Primas, Christophe Sauzet, Philippe Piccerelle, Anne-Marie Maillotte, Veronique Brevaut-Malaty, Pascal Rathelot, Patrice Vanelle and Christophe Curti

Pharmaceuticals 2025, 18(2), 204; https://doi.org/10.3390/ph18020204 - 3 Feb 2025

Viewed by 266

Abstract

Background/Objective: Little information is available on the stability and quality controls of compounded 40% dextrose gel required to ensure its safe use in the treatment and prevention of neonatal hypoglycemia. Whether its efficacy relies on buccal absorption also remains uncertain. This study investigates [...] Read more.

Background/Objective: Little information is available on the stability and quality controls of compounded 40% dextrose gel required to ensure its safe use in the treatment and prevention of neonatal hypoglycemia. Whether its efficacy relies on buccal absorption also remains uncertain. This study investigates the stability, microbiological safety, rheological properties and dextrose diffusion of a compounded 40% oral dextrose gel, ensuring it can be widely compounded and stored for clinical use. Methods: A 40% dextrose gel compounded with anhydrous dextrose, carboxymethylcellulose, citric acid, sorbic acid and sterile water was subjected to quality control measures including a dextrose content assay, degradation product analysis, microbiological testing and preservative efficacy. Stability studies were conducted at refrigerated (4–8 °C) and ambient temperatures for 7 days and 3 months, respectively. Rheological properties were assessed, and dextrose permeation was measured through an artificial membrane model that mimics a biological membrane. Results: The compounded gel demonstrated stability for up to 7 days at ambient temperature and 90 days when refrigerated. The dextrose content remained within the acceptable range (90–110%) and microbiological tests confirmed compliance with safety standards. The gel exhibited the consistent rheological properties and shear-thinning behavior appropriate for oral mucosal administration. In vitro permeation studies showed no evidence of dextrose diffusion with a long lag time followed by a low steady-state permeation flux. Conclusions: This study validates the compounding process of a stable 40% oral dextrose gel formulation for neonatal hypoglycemia management, which meets quality control criteria and can be safely administered in clinical practice, offering a cost-effective and safe alternative for neonatal care. Full article

(This article belongs to the Special Issue Pharmaceutical Formulation Characterization Design)

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7 pages, 847 KiB

Open AccessCase Report

Assessment of Treatment Effects of Aminaphtone by Capillaroscopy in a Patient with Raynaud’s Phenomenon

by Gianluca Screm, Lucrezia Mondini, Francesco Salton, Paola Confalonieri, Chiara Bozzi, Chiara Torregiani, Caterina Antonaglia, Pietro Geri, Mario D’Oria, Giulia Bandini, Michael Hughes, Marco Confalonieri and Barbara Ruaro

Pharmaceuticals 2025, 18(2), 203; https://doi.org/10.3390/ph18020203 - 2 Feb 2025

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Abstract

Background: Aminaphtone is a well-established pharmaceutical agent that has been utilized for over 40 years, primarily due to its effectiveness in treating microvascular disorders. Recent studies have explored its impact on various conditions, including chronic venous insufficiency, diabetic microangiopathy, leg ulcers, systemic sclerosis, [...] Read more.

Background: Aminaphtone is a well-established pharmaceutical agent that has been utilized for over 40 years, primarily due to its effectiveness in treating microvascular disorders. Recent studies have explored its impact on various conditions, including chronic venous insufficiency, diabetic microangiopathy, leg ulcers, systemic sclerosis, and Raynaud’s phenomenon. These investigations have consistently demonstrated that aminaphtone enhances skin blood perfusion and mitigates endothelial damage, all while maintaining a robust safety profile over time. Case Summary: This report highlights the potential of aminaphtone in improving microcirculation in a young patient who experienced spontaneous capillary rupture in her second finger. A 38-year-old woman with undifferentiated connective tissue disease presented to the clinic for periungual videocapillaroscopy (NVC). Given the microangiopathic changes observed during the NVC, she was prescribed aminaphtone. After seven months of treatment, a follow-up NVC revealed significant improvement in the capillaroscopic findings. A comprehensive literature review on aminaphtone was conducted using electronic databases (PUBMED, Google Scholar, ResearchGate, UpToDate), along with manual searches, focusing on articles published until November 2024. Conclusion: Treatment with aminaphtone led to notable improvements in microangiopathic health. Following the introduction of this medication, the nailfold microvascular bed, which previously exhibited severe alterations, showed a remarkable transition to only mild abnormalities. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 7523 KiB

Open AccessArticle

Discovering the Potential of Cannabidiol for Cosmeceutical Development at the Cellular Level

by Natjira Tassaneesuwan, Mattaka Khongkow, Siriyakorn Jansrinual and Pasarat Khongkow

Pharmaceuticals 2025, 18(2), 202; https://doi.org/10.3390/ph18020202 - 2 Feb 2025

Viewed by 331

Abstract

Backgrounds: Cannabidiol (CBD) has been used for the development of extensive cosmeceutical commercial products. However, the safety and unclear bioactivity of CBD are still concerns and need to be examined to assess the impact of CBD on skin cells through cosmeceutical applications, particularly [...] Read more.

Backgrounds: Cannabidiol (CBD) has been used for the development of extensive cosmeceutical commercial products. However, the safety and unclear bioactivity of CBD are still concerns and need to be examined to assess the impact of CBD on skin cells through cosmeceutical applications, particularly its impact on anti-aging and wound healing activities. Methods: In our study, the cytotoxicity of CBD was investigated on keratinocytes and fibroblasts in short-term and long-term treatments using a sulforhodamine B (SRB) assay and a clonogenic assay, respectively. Next, the antioxidant, anti-aging, and wound healing bioactivities of CBD were assessed. Then, we investigated the expression of the related genes. Results: Our results show that CBD at low concentrations (0.625–2.5 µg/mL) was not toxic to cells in the short-term treatment and significantly enhanced the growth of keratinocytes and fibroblasts under long-term exposure. Furthermore, CBD exhibited promising cellular bioactivities, including antioxidant and anti-aging activities in keratinocytes and fibroblasts, and it enhanced wound healing in skin cells. Moreover, CBD has affected the expression of skin regenerative genes in fibroblasts via TGF-β, VEGF, and NF-κB expression. In addition, CBD promoted CO1A2 expression, which is related to collagen production. Conclusions: Altogether, our findings confirm the promising potential of CBD, showing that it can be applied in various topical cosmeceutical products. However, further studies, including in vivo studies and clinical trials, should be conducted to confirm the safety and long-term effectiveness of CBD on the skin. Full article

(This article belongs to the Section Biopharmaceuticals)

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26 pages, 7550 KiB

Open AccessArticle

BuZhong YiQi Formula Alleviates Postprandial Hyperglycemia in T2DM Rats by Inhibiting α-Amylase and α-Glucosidase In Vitro and In Vivo

by Xin-Xin Zeng, Liang Wang, Ming-Yu Wang, Zhen-Ran Hu, Xiang-Ke Li, Guo-Jun Fei, Ling Ling, Yu-Ting Fan and Ze-Min Yang

Pharmaceuticals 2025, 18(2), 201; https://doi.org/10.3390/ph18020201 - 2 Feb 2025

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Abstract

Background/Objectives: BuZhong YiQi Formula (BZYQF) can alleviate type 2 diabetes mellitus (T2DM). However, its efficacy in managing postprandial hyperglycemia in T2DM needs to be further confirmed, and its underlying mechanism and pharmacodynamic material basis have not been sufficiently investigated. Methods: A T2DM rat [...] Read more.

Background/Objectives: BuZhong YiQi Formula (BZYQF) can alleviate type 2 diabetes mellitus (T2DM). However, its efficacy in managing postprandial hyperglycemia in T2DM needs to be further confirmed, and its underlying mechanism and pharmacodynamic material basis have not been sufficiently investigated. Methods: A T2DM rat model was induced to measure postprandial glycemic responses following glucose and starch ingestion. In vitro assays of enzymatic inhibition and the kinetic mode were performed to evaluate the inhibitory effect of BZYQF on α-amylase and α-glucosidase activities. The main constituent contents of BZYQF in a simulated digestion assay were measured to screen the active constituents in BZYQF against α-amylase and α-glucosidase activities via Pearson correlation and multiple linear regression analyses. Finally, the total flavonoids were purified from BZYQF to perform in vitro activity validation, and the flavonoid constituent activity was verified through molecular docking. Results: In vivo assays showed that BZYQF significantly reduced the blood glucose values of CON rats but not T2DM rats after glucose ingestion, while BZYQF significantly reduced the blood glucose levels by 15 min after starch ingestion in CON and T2DM rats, with more significant decreases in blood glucose levels in T2DM rats. In vitro enzymatic assays showed that BZYQF could inhibit the activities of α-amylase and α-glucosidase in competitive and non-competitive modes and in an uncompetitive mode, respectively. Furthermore, BZYQF showed a stronger inhibitory effect on α-glucosidase activity than on α-amylase activity. Simulated digestion showed that simulated gastric fluid and intestinal fluid changed the main constituent contents of BZYQF and their inhibition rates against α-amylase and α-glucosidase activities, and similar results were rarely found in simulated salivary fluid. Pearson correlation and multiple linear regression analyses revealed that the total flavonoids were the active constituents in BZYQF inhibiting α-amylase and α-glycosidase activities. This result was verified by examining the total flavonoids purified from BZYQF. A total of 1909 compounds were identified in BZYQF using UPLC-MS/MS, among which flavones were the most abundant and consisted of 467 flavonoids. Molecular docking showed that flavonoids in BZYQF were bound to the active site of α-amylase, while they were bound to the inactive site of α-glucosidase. This result supported the results of the enzyme kinetic assay. Conclusions: BZYQF significantly alleviated postprandial hyperglycemia in T2DM rats by inhibiting α-amylase and α-glycosidase activities, in which flavonoids in BZYQF were the active constituents. Full article

(This article belongs to the Special Issue Natural Products in Diabetes Mellitus: 2nd Edition)

24 pages, 13252 KiB

Open AccessArticle

A Comparative Effect of 12-Week Dietary Intervention of Policosanol (Raydel^®) and Red Yeast Rice (RYR, Kobayashi) in Managing Dyslipidemia and Organ Damage in Hyperlipidemic Zebrafish

by Kyung-Hyun Cho, Ashutosh Bahuguna, Ji-Eun Kim, Sang Hyuk Lee, Yunki Lee and Cheolmin Jeon

Pharmaceuticals 2025, 18(2), 200; https://doi.org/10.3390/ph18020200 - 1 Feb 2025

Viewed by 439

Abstract

Background: A comparative 12-week dietary intervention of red yeast rice (RYR, Beni-koji, Kobayashi, Japan) and Cuban policosanol (PCO, Raydel^®, Thornleigh, Australia) was assessed for dyslipidemia, antioxidant status, and vital organ functionality in hyperlipidemic zebrafish. Methods: Hyperlipidemic zebrafish were supplemented with [...] Read more.

Background: A comparative 12-week dietary intervention of red yeast rice (RYR, Beni-koji, Kobayashi, Japan) and Cuban policosanol (PCO, Raydel^®, Thornleigh, Australia) was assessed for dyslipidemia, antioxidant status, and vital organ functionality in hyperlipidemic zebrafish. Methods: Hyperlipidemic zebrafish were supplemented with a high-cholesterol diet (HC, final 4%, w/w) infused with either a powdered RYR tablet (final 1.0%, w/w), a PCO tablet (final 1.0%, w/w), or a combination of 0.5% (w/w) each of RYR and PCO powder for 12 weeks. Subsequently, blood and organs were collected and processed for biochemical and histological examination. Results: RYR and PCO consumption showed a substantial effect against HC-induced hyperlipidemia by reducing the total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C). Exclusively, PCO supplementation revealed a significant elevation in the HC-diminished high-density lipoprotein cholesterol (HDL-C). In addition, PCO supplementation showed a significant elevation in plasma ferric ion-reducing ability (FRA) and sulfhydryl content, as well as alleviating the blood glucose level of hyperlipidemic zebrafish. The most noteworthy impact, with a significant two-fold (p < 0.001) augmentation of HC-diminished plasma paraoxonase (PON) activity, was observed in response to PCO. In contrast, the RYR supplementation failed to establish curative effects against HC-disturbed plasma antioxidant variables and blood glucose levels. The histological outcome revealed a severe toxicological impact of the RYR on the liver, reflected by fatty liver changes and three-fold heightened IL-6 production compared to HC control. Contrastingly, PCO exhibited significant hepatoprotection and effectively neutralized the hepatic toxicity triggered by HC and RYR. Also, RYR showed kidney atrophy, intense ROS generation, apoptosis, and senescence. Conversely, the PCO supplementation protected the kidney from HC- and RYR-induced toxicity. Likewise, PCO supplementation notably alleviated histological alterations and oxidative stress in the brain, ovary, and testis of hyperlipidemic zebrafish. Conclusions: This comparative study establishes PCO’s therapeutic effect against the challenges posed by HC, while RYR emerged with serious toxicological concerns towards the liver, kidney, and other organs of hyperlipidemic zebrafish. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 3338 KiB

Open AccessTechnical Note

Chemical Analysis of Plasma-Activated Culture Media by Ion Chromatography

by Marcello Locatelli, Miryam Perrucci, Marwa Balaha, Tirtha-Raj Acharya, Nagendra-Kumar Kaushik, Eun-Ha Choi, Monica Rapino and Vittoria Perrotti

Pharmaceuticals 2025, 18(2), 199; https://doi.org/10.3390/ph18020199 - 1 Feb 2025

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Abstract

Background: Currently, the procedures and methods applied in biological and medical fields for the determination of reactive oxygen and nitrogen species (RONS), primarily rely on spectrophotometric techniques, which involve the use of colorimetric reagents. While these methods are widely accepted, they exhibit [...] Read more.

Background: Currently, the procedures and methods applied in biological and medical fields for the determination of reactive oxygen and nitrogen species (RONS), primarily rely on spectrophotometric techniques, which involve the use of colorimetric reagents. While these methods are widely accepted, they exhibit significant limitations from an analytical standpoint, particularly due to potential inaccuracies, artifacts, and pronounced susceptibility to matrix effects. The purpose of this Technical Note is to demonstrate the application of ion chromatography—a robust and well-established analytical technique—for the quantification of RONS produced in cell culture media through the exposure to cold atmospheric plasma (CAP), an innovative therapeutic approach for cancer treatment, known as CAP indirect treatment. In addition, the present protocol proposes to apply the pharmacokinetics principles to the RONS generated in plasma-treated liquids (PTLs) following CAP exposure. Methods: The strategy involves elucidating the kinetic profiles of certain characteristic species by evaluating their half-life in the specific media used for cell cultures and investigating their “pharmacokinetic” (PK) profile. In this approach the drug dose is represented by the plasma power and the infusion time corresponds to the exposure time of the culture medium to CAP. Volume-dependent results were shown, focusing on nitrites and nitrates activities, justifying cellular inhibition. Results: This methodology enables the correlation of the PTL biological effects on different cell lines with the PK profiles (dose/time) obtained via ion chromatography. Conclusions: In conclusion, being a simple and green method, it could be used as an alternative to toxic reactions and analytical techniques with higher detection limits, while achieving good resolution. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 1081 KiB

Open AccessArticle

Immunomodulatory Effects of Atractylodes lancea in Healthy Volunteers with Dosage Prediction for Cholangiocarcinoma Therapy: A Modelling Approach

by Teerachat Saeheng, Juntra Karbwang and Kesara Na-bangchang

Pharmaceuticals 2025, 18(2), 198; https://doi.org/10.3390/ph18020198 - 31 Jan 2025

Viewed by 376

Abstract

Background and Aims: According to a recent study on the immunomodulatory activity of Atractylodes Lancea (Thunb.) DC. (AL) in healthy Thai subjects, AL significantly inhibited the production of key pro-inflammatory cytokines while stimulating the production of immune cells. However, no maximum tolerated [...] Read more.

Background and Aims: According to a recent study on the immunomodulatory activity of Atractylodes Lancea (Thunb.) DC. (AL) in healthy Thai subjects, AL significantly inhibited the production of key pro-inflammatory cytokines while stimulating the production of immune cells. However, no maximum tolerated dose (MTD) and phase 2A dosage regimens were reported. The study aimed to evaluate the immunomodulatory effects of Atractylodes lancea (Thunb.) DC. (AL) in healthy subjects, and to recommend optimal dose regimens for intrahepatic cholangiocarcinoma (iCCA) based on toxicity criteria. Methods: A physiologically based pharmacokinetic (PBPK) model, combined with the toxicological approach and the immunomodulatory effect, was used for dose-finding. The safety and efficacy of each AL regimen were evaluated based on the previous study. At least a once-daily dose of 1000 mg AL significantly suppressed the production of all pro-inflammatory cytokines while significantly increasing the number of peripheral immune cells. Results: The developed PBPK model predicted the clinically observed data well. No significant differences in SII index values were found, but a difference in the lymphocyte-monocyte ratio was found on day 4. The dosage regimen for phase 2A is a once-daily dose of 1500 or 2000 mg. Preliminary results in phase 2A revealed that a once-daily dose of 2000 mg had a significantly higher median overall survival, progression-free survival, disease control rate, and inhibition of increased tumor size without toxicities compared with control. Conclusions: A PBPK model, in conjunction with a toxicological approach, could assist in finding the potential dosage regimens for a clinical study, including herbal medicine. Full article

(This article belongs to the Section Natural Products)

26 pages, 1040 KiB

Open AccessReview

The Anti-inflammatory Potential of Tricyclic Antidepressants (TCAs): A Novel Therapeutic Approach to Atherosclerosis Pathophysiology

by Majid Eslami, Marzieh Monemi, Mohammad Ali Nazari, Mohammad Hossein Azami, Parand Shariat Rad, Valentyn Oksenych and Ramtin Naderian

Pharmaceuticals 2025, 18(2), 197; https://doi.org/10.3390/ph18020197 - 31 Jan 2025

Viewed by 343

Abstract

Atherosclerosis, a chronic inflammatory disease, is driven by complex molecular mechanisms involving inflammatory cytokines and immune pathways. According to recent research, tricyclic antidepressants (TCAs), which are typically prescribed to treat depressive disorders, have strong anti-inflammatory effects. TCAs, including imipramine and amitriptyline, alter inflammatory [...] Read more.

Atherosclerosis, a chronic inflammatory disease, is driven by complex molecular mechanisms involving inflammatory cytokines and immune pathways. According to recent research, tricyclic antidepressants (TCAs), which are typically prescribed to treat depressive disorders, have strong anti-inflammatory effects. TCAs, including imipramine and amitriptyline, alter inflammatory signaling cascades, which include lowering the levels pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 and inhibiting NF-κB activation. By inhibiting the NLRP3 inflammasome and suppressing pathways including JAK/STAT, MAPK, and PI3K, these effects are produced, improving endothelial function and reducing oxidative stress. The intricacy of TCAs’ anti-inflammatory actions has demonstrated by the existence of contradictory findings about how they alter IL-6 levels. The dependence of the heterogeneity of the reaction on the use of particular TCAs and experimental settings is shown by the fact that some studies show reduced IL-6 production, while others indicate increases or no changes. This review explores the multifaceted mechanisms through which TCAs modulate inflammatory pathways. TCAs inhibit NF-κB activation, reduce oxidative stress, and suppress the production of key inflammatory mediators, including IL-6 and TNF-α. They also regulate Toll-like receptor (TLR) signaling and NOD-, LRR-, and NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome activation, reducing the release of IL-1β and IL-18, critical drivers of endothelial dysfunction and plaque instability. Given their capacity to target critical inflammatory molecules and pathways, TCAs provide great potential in the therapy of atherosclerosis, particularly for individuals with associated depression and cardiovascular risk factors. Nevertheless, further research is essential to clarify the precise molecular mechanisms, resolve inconsistencies in current findings, and establish the clinical applicability of TCAs as anti-inflammatory agents in atherosclerosis management. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

23 pages, 1344 KiB

Open AccessArticle

In Silico Approach for Antibacterial Discovery: PTML Modeling of Virtual Multi-Strain Inhibitors Against Staphylococcus aureus

by Valeria V. Kleandrova, M. Natália D. S. Cordeiro and Alejandro Speck-Planche

Pharmaceuticals 2025, 18(2), 196; https://doi.org/10.3390/ph18020196 - 31 Jan 2025

Viewed by 406

Abstract

Background/Objectives: Infectious diseases caused by Staphylococcus aureus (S. aureus) have become alarming health issues worldwide due to the ever-increasing emergence of multidrug resistance. In silico approaches can accelerate the identification and/or design of versatile antibacterial chemicals with the ability to [...] Read more.

Background/Objectives: Infectious diseases caused by Staphylococcus aureus (S. aureus) have become alarming health issues worldwide due to the ever-increasing emergence of multidrug resistance. In silico approaches can accelerate the identification and/or design of versatile antibacterial chemicals with the ability to target multiple S. aureus strains with varying degrees of drug resistance. Here, we develop a perturbation theory machine learning model based on a multilayer perceptron neural network (PTML-MLP) for the prediction and design of versatile virtual inhibitors against S. aureus strains. Methods: To develop the PTML-MLP model, chemical and biological data associated with antibacterial activity against S. aureus strains were retrieved from the ChEMBL database. We applied the Box–Jenkins approach to convert the topological indices into multi-label graph-theoretical indices; the latter were used as inputs for the creation of the PTML-MLP model. Results: The PTML-MLP model exhibited accuracy higher than 80% in both training and test sets. The physicochemical and structural interpretation of the PTML-MLP model was performed through the fragment-based topological design (FBTD) approach. Such interpretations permitted the analysis of different molecular fragments with favorable contributions to the multi-strain antibacterial activity and the design of four new drug-like molecules using different fragments as building blocks. The designed molecules were predicted/confirmed by our PTML model as multi-strain inhibitors of diverse S. aureus strains, thus representing promising chemotypes to be considered for future synthesis and biological testing of versatile anti-S. aureus agents. Conclusions: This work envisages promising applications of PTML modeling for early antibacterial drug discovery and related antimicrobial research areas. Full article

(This article belongs to the Special Issue Integrating Machine Learning (ML) into Medicinal Chemistry and Cheminformatics)

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51 pages, 1719 KiB

Open AccessReview

Evaluation of Drug Permeation Enhancement by Using In Vitro and Ex Vivo Models

by Johan D. Steyn, Anja Haasbroek-Pheiffer, Wihan Pheiffer, Morné Weyers, Suzanne E. van Niekerk, Josias H. Hamman and Daniélle van Staden

Pharmaceuticals 2025, 18(2), 195; https://doi.org/10.3390/ph18020195 - 31 Jan 2025

Viewed by 228

Abstract

Drugs administered by means of extravascular routes of drug administration must be absorbed into the systemic circulation, which involves the movement of the drug molecules across biological barriers such as epithelial cells that cover mucosal surfaces or the stratum corneum that covers the [...] Read more.

Drugs administered by means of extravascular routes of drug administration must be absorbed into the systemic circulation, which involves the movement of the drug molecules across biological barriers such as epithelial cells that cover mucosal surfaces or the stratum corneum that covers the skin. Some drugs exhibit poor permeation across biological membranes or may experience excessive degradation during first-pass metabolism, which tends to limit their bioavailability. Various strategies have been used to improve drug bioavailability. Absorption enhancement strategies include the co-administration of chemical permeation enhancers, enzymes, and/or efflux transporter inhibitors, chemical changes, and specialized dosage form designs. Models with physiological relevance are needed to evaluate the efficacy of drug absorption enhancement techniques. Various in vitro cell culture models and ex vivo tissue models have been explored to evaluate and quantify the effectiveness of drug permeation enhancement strategies. This review deliberates on the use of in vitro and ex vivo models for the evaluation of drug permeation enhancement strategies for selected extravascular drug administration routes including the nasal, oromucosal, pulmonary, oral, rectal, and transdermal routes of drug administration. Full article

(This article belongs to the Special Issue Using In Vitro and Ex Vivo Models to Evaluate Strategies for Drug Delivery Improvement)

16 pages, 1869 KiB

Open AccessArticle

New UB006 Derivatives With Higher Solubility and Cytotoxic Activity in Ovarian Cancer Cells

by Marc Reina, Xavier Ariza, Dolors Serra, Jordi Garcia and Laura Herrero

Pharmaceuticals 2025, 18(2), 194; https://doi.org/10.3390/ph18020194 - 31 Jan 2025

Viewed by 243

Abstract

Background/Objectives: The compound (±)-UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one) is a promising anti-cancer molecule. The enantiomer (–)-UB006 displays a potent cytotoxic effect in several tumor cell lines, particularly the ovarian cancer OVCAR-3 cell line, with a 40-fold increase in potency compared with the fatty acid [...] Read more.

Background/Objectives: The compound (±)-UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one) is a promising anti-cancer molecule. The enantiomer (–)-UB006 displays a potent cytotoxic effect in several tumor cell lines, particularly the ovarian cancer OVCAR-3 cell line, with a 40-fold increase in potency compared with the fatty acid synthase (FAS) inhibitor C75. Furthermore, in vivo, (–)-UB006 reduced the tumor burden in neuroblastoma xenografts. This effect was attributed to FAS inhibition and upregulation of apoptotic markers. However, CoA adducts of UB006 presented low solubility. Methods: We synthesized several (±)-UB006 derivatives by elongating the carbon chain of the primary alcohol and/or by adding hydroxyl groups with the aim of finding more potent and soluble anti-cancer compounds. Results: Our results showed a decrease in cytotoxicity when the carbon chain was elongated by more than two carbons. However, ethyl or propyl polyhydroxylated four-branched compounds showed an increased or maintained potency and solubility. The most promising compound was (±)-UB035 (IC50: 2.1 ± 0.2 µM), with a 2.5-fold increase in cytotoxicity in the OVCAR-3 cell line and a >4-fold increase in solubility (>2 mM) compared with (±)-UB006. Full article

(This article belongs to the Section Biopharmaceuticals)

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19 pages, 477 KiB

Open AccessReview

Perspectives on Berberine and the Regulation of Gut Microbiota: As an Anti-Inflammatory Agent

by Quintero Vargas Jael Teresa de Jesús, Juan-Carlos Gálvez-Ruíz, Adriana Alejandra Márquez Ibarra and Mario-Alberto Leyva-Peralta

Pharmaceuticals 2025, 18(2), 193; https://doi.org/10.3390/ph18020193 - 31 Jan 2025

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Abstract

Berberine is a promising agent for modulating the intestinal microbiota, playing a crucial role in human health homeostasis. This natural compound promotes the growth of beneficial bacteria such as Bacteroides, Bifidobacterium, and Lactobacillus while reducing harmful bacteria such as Escherichia coli [...] Read more.

Berberine is a promising agent for modulating the intestinal microbiota, playing a crucial role in human health homeostasis. This natural compound promotes the growth of beneficial bacteria such as Bacteroides, Bifidobacterium, and Lactobacillus while reducing harmful bacteria such as Escherichia coli. Clinical and preclinical studies demonstrate that Berberine helps regulate T2D and metabolic disorders, improves blood glucose levels during T2D, and reduces lipid profile and chronic inflammation, especially when combined with probiotics. Berberine represents a promising adjuvant therapy for inflammatory diseases, particularly intestinal disorders, due to its multifaceted actions of inhibiting proinflammatory cytokines and pathways during IBS, IBD, and UC and its modulation of gut microbiota and/or enhancement of the integrity of the intestinal epithelial barrier. This review establishes the basis for future treatment protocols with berberine and fully elucidates its mechanisms. Full article

(This article belongs to the Special Issue Gut Microbiota Modulation: Probiotics, Postbiotics and other Bioactive Compounds)

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16 pages, 591 KiB

Open AccessArticle

Investigating Potential Anti-Bacterial Natural Products Based on Ayurvedic Formulae Using Supervised Network Analysis and Machine Learning Approaches

by Pei Gao, Ahmad Kamal Nasution, Naoaki Ono, Shigehiko Kanaya and Md. Altaf-Ul-Amin

Pharmaceuticals 2025, 18(2), 192; https://doi.org/10.3390/ph18020192 - 30 Jan 2025

Viewed by 367

Abstract

Objectives: This study implements a multi-dimensional methodology to systematically identify potential natural antibiotics derived from the medicinal plants utilized in Ayurvedic practices. Methods: Two primary analytical techniques are employed to explore the antibiotic potential of the medicinal plants. The initial approach [...] Read more.

Objectives: This study implements a multi-dimensional methodology to systematically identify potential natural antibiotics derived from the medicinal plants utilized in Ayurvedic practices. Methods: Two primary analytical techniques are employed to explore the antibiotic potential of the medicinal plants. The initial approach utilizes a supervised network analysis, which involves the application of distance measurement algorithms to scrutinize the interconnectivity and relational patterns within the network derived from Ayurvedic formulae. Results: 39 candidate plants with potential natural antibiotic properties were identified. The second approach leverages advanced machine learning techniques, particularly focusing on feature extraction and pattern recognition. This approach yielded a list of 32 plants exhibiting characteristics indicative of natural antibiotics. A key finding of this research is the identification of 17 plants that were consistently recognized by both analytical methods. These plants are well-documented in existing literature for their antibacterial properties, either directly or through their bioactive compounds, which suggests a strong validation of the study’s methodology. By synergizing network analysis with machine learning, this study provides a rigorous and multi-faceted examination of Ayurvedic medicinal plants, significantly contributing to the identification of natural antibiotic candidates. Conclusions: This research not only reinforces the potential of traditional medicine as a source for new therapeutics but also demonstrates the effectiveness of combining classical and contemporary analytical techniques to explore complex biological datasets. Full article

(This article belongs to the Section Natural Products)

11 pages, 2399 KiB

Open AccessArticle

Aging Reduces ATP-Binding Cassette Transporter Expression in Brain Microvessels of Mice

by Yukiyo Wada, Masaki Inoko, Kanako Ishihara, Karin Fukumoto, Yuya Tsurudome, Michiko Horiguchi, Akio Fujimura and Kentaro Ushijima

Pharmaceuticals 2025, 18(2), 191; https://doi.org/10.3390/ph18020191 - 30 Jan 2025

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Abstract

Background: ATP-binding cassette (ABC) transporters are expressed in the vascular walls of brain capillaries and remove toxic chemicals from the brain. The expression of ABC transporters in peripheral organs is transcriptionally regulated by clock genes and exhibits 24 h periodic fluctuations. In addition, [...] Read more.

Background: ATP-binding cassette (ABC) transporters are expressed in the vascular walls of brain capillaries and remove toxic chemicals from the brain. The expression of ABC transporters in peripheral organs is transcriptionally regulated by clock genes and exhibits 24 h periodic fluctuations. In addition, clock gene outputs diminish with aging. In this study, we evaluated whether the expression of ABC transporters in the blood–brain barrier (BBB) of young mice had a 24 h cycle, and whether the expression of ABC transporters in the BBB decreased with age. Methods: Brain microvascular (BMV) fractions from the cerebral cortex of male C57BL/6J mice were prepared using dextran. BMV fractions from young mice (12 weeks old) were prepared every four hours to evaluate 24 h rhythmicity. BMV fractions from both young and aged mice (85 weeks old) were prepared when protein expression peaked (Zeitgeber Time 5). Protein and mRNA expression of ABC transporters in BMV fractions were measured. Results: In young mice, protein expression of P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein 4 showed time-dependent variations with a peak in the light phase (Zeitgeber Time 5); mRNA expression showed no time-dependent variation. The protein expression of these transporters was lower in the BBB of aged mice than in that of young mice, although mRNA expression did not differ between young and aged mice. Conclusions: ABC transporter protein expression levels in BMV endothelial cells decreased with aging; however, mRNA levels did not change, which suggests changes in protein expression did not result from diminished clock gene output. Further studies are needed to elucidate the mechanisms by which ABC transporter expression in the BBB decreases with aging. Full article

(This article belongs to the Section Pharmacology)

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32 pages, 619 KiB

Open AccessReview

Drug Development in Inflammatory Bowel Diseases: What Is Next?

by Lorenzo Petronio, Arianna Dal Buono, Roberto Gabbiadini, Giulia Migliorisi, Giuseppe Privitera, Matteo Ferraris, Laura Loy, Cristina Bezzio and Alessandro Armuzzi

Pharmaceuticals 2025, 18(2), 190; https://doi.org/10.3390/ph18020190 - 30 Jan 2025

Viewed by 295

Abstract

Background/Objectives: Inflammatory bowel diseases (IBDs), which include Crohn’s disease (CD) and ulcerative colitis (UC), are chronic conditions requiring long-term therapy to maintain remission and improve quality of life. Despite the approval of numerous drugs, IBD continues to present treatment challenges. This review [...] Read more.

Background/Objectives: Inflammatory bowel diseases (IBDs), which include Crohn’s disease (CD) and ulcerative colitis (UC), are chronic conditions requiring long-term therapy to maintain remission and improve quality of life. Despite the approval of numerous drugs, IBD continues to present treatment challenges. This review aims to summarize novel therapeutic target agents in phases II and III of development, including sphingosine-1-phosphate receptor modulators (S1P), anti-interleukin-23 (IL-23), and other small molecules and monoclonal antibodies currently under investigation (e.g., anti-TL1A, obefazimod, NX-13, RIPK-inhibitors). Methods: A comprehensive literature search was conducted up to December 2024 to identify relevant articles published in English over the past three–five years, focusing on phase II/III studies for UC and CD. The search included databases such as PubMed, Google Scholar, and the ClinicalTrials.gov portal. Results: Clinical trials underline the potential of novel immunomodulators, including anti-TL1A, obefazimod, NX-13, RIPK inhibitors, and anti-IL-23p19 agents, as promising therapeutic options for IBD. Anti-IL23p19 therapies, such as risankizumab and mirikizumab, alongside guselkumab, exemplify this class’s growing clinical relevance. While some are already in clinical use, others are nearing approval. Conclusions: Ongoing research into long-term safety and the development of personalized treatment strategies remains pivotal to enhance outcomes. Patient stratification and the strategic positioning of these therapies within the expanding treatment landscape are critical for optimizing their clinical impact. Full article

(This article belongs to the Special Issue Pharmacotherapy of Inflammatory Bowel Disease)

27 pages, 7763 KiB

Open AccessArticle

Alternaria alternata (Fr) Keissl Crude Extract Inhibits HIV Subtypes and Integrase Drug-Resistant Strains at Different Stages of HIV Replication

by Darian Naidu, Ernest Oduro-Kwateng, Mahmoud E. S. Soliman, Sizwe I. Ndlovu and Nompumelelo P. Mkhwanazi

Pharmaceuticals 2025, 18(2), 189; https://doi.org/10.3390/ph18020189 - 30 Jan 2025

Viewed by 544

Abstract

Background/Objectives: The development of HIV drug resistance to current antiretrovirals, and the antiretrovirals’ inability to cure HIV, provides the need of developing novel drugs that inhibit HIV-1 subtypes and drug-resistance strains. Fungal endophytes, including Alternaria alternata, stand out for their potentially antiviral secondary [...] Read more.

Background/Objectives: The development of HIV drug resistance to current antiretrovirals, and the antiretrovirals’ inability to cure HIV, provides the need of developing novel drugs that inhibit HIV-1 subtypes and drug-resistance strains. Fungal endophytes, including Alternaria alternata, stand out for their potentially antiviral secondary metabolites. Hence, this study investigates the anti-HIV activities and mechanism of action of the A. alternata crude extract against different HIV-1 subtypes and integrase-resistant mutant strains. Methods: Cytotoxicity of the A. alternata crude extract on TZM-bl cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was performed. The crude extract antiviral activity against subtypes A, B, C, and D and integrase drug-resistant strain T66K and S230R was determined using a luciferase-based antiviral assay. Luciferase and p24 ELISA-based time-of-addition assays were used to determine the mechanism of action of the crude extract. Docking scores and protein ligand interactions of integrase T66K and S230R strains against the identified bioactive compounds were determined. Results: The crude extract CC₅₀ was 300 μg/mL and not cytotoxic to the TZM-bl cell lines. In HIV-1 subtypes A, B, C, and D, the crude extract exhibited 100% inhibition and therapeutic potential. The A. alternata crude extract had strong anti-HIV-1 activity against integrase strand transfer drug-resistant strains T66K and S230R, with a 0.7265- and 0. 8751-fold increase in susceptibility. The crude extract had antiviral activity during attachment, reverse transcription, integration, and proteolysis. In silico calculations showed compounds 2,3-2H-Benzofuran-2-one, 3,3,4,6-tetramethyl-, 3-Methyl-1,4-diazabicyclo[4.3.0]nonan-2,5-dione, N-acetyl, Coumarin, 3,4-dihydro-4,5,7-trimethyl-, Cyclopropanecarboxamide, N-cycloheptyl, Pyrrolo[1,2-a]pyrazine-1,4-dione, and hexahydro-3-(2-methylpropyl)- crude extract bioactive compounds had strong docking scores and diverse binding mechanisms with integrase. Conclusions: The A. alternata crude extract demonstrates strong antiviral activity against different HIV-1 subtypes and integrase drug-resistance strains. The extract inhibited various stages of the HIV-1 life cycle. The bioactive compounds 2,3-2H-Benzofuran-2-one, 3,3,4,6-tetramethyl-, 3-Methyl-1,4-diazabicyclo[4.3.0]nonan-2,5-dione, N-acetyl, Coumarin, 3,4-dihydro-4,5,7-trimethyl-, Cyclopropanecarboxamide, N-cycloheptyl, Pyrrolo[1,2-a]pyrazine-1,4-dione, and hexahydro-3-(2-methylpropyl)- may be responsible for the antiviral activity of A. alternata. Full article

(This article belongs to the Section Natural Products)

17 pages, 6207 KiB

Open AccessArticle

Prevention and Treatment of Peritoneal Dialysis-Associated Fibrosis with Intraperitoneal Anti-Fibrotic Therapy in Experimental Peritoneal Fibrosis

by Chiao-Yin Sun, Yu-Ting Hsieh, Shang-Chieh Lu and Chi-Ying F. Huang

Pharmaceuticals 2025, 18(2), 188; https://doi.org/10.3390/ph18020188 - 30 Jan 2025

Viewed by 359

Abstract

Background/Objectives: Long-term peritoneal dialysis (PD) often results in peritoneal damage and fibrosis, impairing peritoneal membrane function and leading to ultrafiltration failure. This study aimed to explore the therapeutic potential of nintedanib and pirfenidone in preventing and treating PD-associated peritoneal fibrosis using experimental models. [...] Read more.

Background/Objectives: Long-term peritoneal dialysis (PD) often results in peritoneal damage and fibrosis, impairing peritoneal membrane function and leading to ultrafiltration failure. This study aimed to explore the therapeutic potential of nintedanib and pirfenidone in preventing and treating PD-associated peritoneal fibrosis using experimental models. Methods: An animal model of peritoneal fibrosis and cultured mesothelial cells were utilized to evaluate the effects of nintedanib and pirfenidone. Histological analysis, molecular techniques, and RNA sequencing were employed to assess the fibrosis, inflammation, and gene expression. The key outcomes included changes in the peritoneal structure, inflammatory markers, and transcriptional regulation. Results: Induced peritoneal fibrosis resulted in significant structural and histological changes. Treatment with nintedanib and pirfenidone effectively prevented peritoneal thickening and reduced excessive fibrosis deposition. Both agents ameliorated the inflammatory responses by lowering inflammatory marker expression, inhibiting cytokine activity, and decreasing macrophage infiltration. Molecular analyses revealed the suppression of inflammation-related transcription regulators and cytokine receptors. RNA sequencing identified glucose-induced gene expression changes and demonstrated significant modulation by the treatments. In animal studies with established fibrosis, these agents reduced peritoneal inflammation and slowed fibrosis progression. Conclusions: This study demonstrates that intraperitoneal administration of nintedanib and pirfenidone shows promise as an anti-fibrosis therapy for preventing and treating peritoneal fibrosis associated with PD. These findings highlight the potential of targeted interventions to improve the long-term outcomes for PD patients. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 6920 KiB

Open AccessArticle

Synergistic Interaction Between Justicia spicigera Extract and Analgesics on the Formalin Test in Rats

by Juan Ramón Zapata-Morales, Angel Josabad Alonso-Castro, María Leonor González-Rivera, Hugo Israel González Prado, Juan Carlos Barragán-Gálvez, Araceli Hernández-Flores, María del Carmen Juárez-Vázquez, Fabiola Domínguez, Candy Carranza-Álvarez, Amaury de Jesús Pozos-Guillén, Juan F. López-Rodríguez, Patricia Aguirre-Bañuelos and Marco Antonio Ramírez-Morales

Pharmaceuticals 2025, 18(2), 187; https://doi.org/10.3390/ph18020187 - 30 Jan 2025

Viewed by 358

Abstract

Background: Combining antinociceptive drugs with different mechanisms of action can reduce the doses and the adverse effects, with a possible increase in the antinociceptive effect. This work evaluated the antinociceptive effect of the combination of an ethanol extract of Justicia spicigera (JSE) with [...] Read more.

Background: Combining antinociceptive drugs with different mechanisms of action can reduce the doses and the adverse effects, with a possible increase in the antinociceptive effect. This work evaluated the antinociceptive effect of the combination of an ethanol extract of Justicia spicigera (JSE) with naproxen (NPX) or tramadol (TML) using the formalin test in rats. Methods: Rats received JSE (30–200 mg/kg p.o.), NPX (50–300 mg/kg p.o.), or TML (5–50 mg/kg p.o.) 60 min before paw administration with formalin (5%). Different proportions of the combination between NPX and JSE, as well as TML and JSE, were used in the formalin test to obtain the dose–response curve of each drug and the experimental effective dose 50 (ED₅₀). The levels of IL-1β and COX2 were assessed using a Western blot analysis as a possible mechanism of action for the combination of JSE and analgesics. A pharmacokinetic study was conducted to evaluate the effect of JSE on the pharmacokinetic parameters of NPX. Results: The ED₅₀ values for the proportions NPX:JSE were 107.09 mg/kg (1:1), 102.44 mg/kg (3:1), and 73.82 mg/kg (1:3). The ED₅₀ values for the proportions TML:JSE were 66 mg/kg (1:1), 29.5 mg/kg (1:3), and 78 mg/kg (3:1). The combination NPX:JSE (1:3) showed the best synergistic interaction index (0.501). The pharmacokinetic study revealed that there were no significant changes in the pharmacokinetic parameters of NPX administered individually and the combination NPX:JSE. Conclusions: In this preclinical study, the combination NPX:JSE showed antinociceptive effects by decreasing the levels of COX2 and IL-1β without affecting NPX’s pharmacokinetics. Full article

(This article belongs to the Section Natural Products)

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18 pages, 6122 KiB

Open AccessArticle

GABA_A Receptors Are Involved in the Seizure Blockage Prompted by a Polyphenol-Rich Extract of White Grape Juice in Rodents

by Alessandro Maugeri, Rita Citraro, Antonio Leo, Caterina Russo, Michele Navarra and Giovambattista De Sarro

Pharmaceuticals 2025, 18(2), 186; https://doi.org/10.3390/ph18020186 - 30 Jan 2025

Viewed by 326

Abstract

Background/Objectives: Polyphenols have been suggested to possess anticonvulsant properties, which can be exploited as tools in novel strategies against epilepsy. Along that line, the aim of this study was to investigate the effects of a polyphenol-rich extract of white grape juice (WGJe) in [...] Read more.

Background/Objectives: Polyphenols have been suggested to possess anticonvulsant properties, which can be exploited as tools in novel strategies against epilepsy. Along that line, the aim of this study was to investigate the effects of a polyphenol-rich extract of white grape juice (WGJe) in different rodent models of epilepsy, exploring its putative mechanism of action. Methods: In this study, we employed pentylenetetrazole (PTZ)-injected ICR-CD1 mice, audiogenic seizure (AGS)-susceptible DBA/2 mice and WAG/Rij rats. Seizures were monitored and scored, while absence was assessed by electroencephalogram. The open-field test was employed to assess the anxiolytic effects of WGJe. In order to assess the involvement of the GABA_A receptor, we used the antagonist flumazenil in AGS-susceptible DBA/2 mice. Computational analyses were employed to evaluate the interaction of the main polyphenols of WGJe and GABA_A receptors. Results: Our results showed that the intraperitoneal injection of WGJe hindered tonic seizures in PTZ-injected ICR-CD1 mice. In WAG/Rij rats, WGJe did not elicit any significant effects on spike-wave discharges compared to untreated rats. In AGS-susceptible DBA/2 mice, WGJe significantly hampered both clonic and tonic seizures, as well as induced anxiolytic effects. Interestingly, when administering WGJe with flumazenil to DBA/2 mice, we noted that the observed effects were mediated by the GABA_A receptor. Moreover, docking simulations confirmed that the main polyphenols of WGJe are able to interact with the benzodiazepine sites located in both extracellular and transmembrane domains in the GABA_A receptor. Conclusions: This study outlines the mechanism underlying the anti-epileptic activity of WGJe, thus supporting its potential role in the management of epilepsy. Full article

(This article belongs to the Special Issue Neuroprotective Potential of Natural Products: A Shield against Brain Decay)

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22 pages, 713 KiB

Open AccessReview

Multifunctionality and Possible Medical Application of the BPC 157 Peptide—Literature and Patent Review

by Michalina Józwiak, Marta Bauer, Wojciech Kamysz and Patrycja Kleczkowska

Pharmaceuticals 2025, 18(2), 185; https://doi.org/10.3390/ph18020185 - 30 Jan 2025

Viewed by 353

Abstract

BPC 157, known as the “Body Protection Compound”, is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other [...] Read more.

BPC 157, known as the “Body Protection Compound”, is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other drugs, BPC 157 has a desirable safety profile, since only a few side effects have been reported following its administration. Nevertheless, this compound was temporarily banned by the World Anti-Doping Agency (WADA) in 2022 (it is not currently listed as banned by the WADA). However, it has not been approved for use in standard medicine by the FDA and other global regulatory authorities due to the absence of sufficient and comprehensive clinical studies confirming its health benefits in humans. In this review, we summarize information on the biological activities of BPC 157, with particular reference to its mechanism of action and probable toxicity. This generated the attention of experts, as BPC 157 has been offered for sale on many websites. We also present recent interest in BPC 157 as reflected in a number of patent applications and granted patents. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery and Development of Drugs for Civilization Diseases)

27 pages, 1040 KiB

Open AccessReview

Fluoroquinolone-Mediated Tendinopathy and Tendon Rupture

by Ezgi Duman, Sigrid Müller-Deubert, Girish Pattappa, Ioannis Stratos, Stephan A. Sieber, Hauke Clausen-Schaumann, Victoria Sarafian, Chisa Shukunami, Maximilian Rudert and Denitsa Docheva

Pharmaceuticals 2025, 18(2), 184; https://doi.org/10.3390/ph18020184 - 30 Jan 2025

Viewed by 288

Abstract

The fluoroquinolone (FQ) class of antibiotics includes the world’s most prescribed antibiotics such as ciprofloxacin, levofloxacin, and ofloxacin that are known for their low bacterial resistance. This is despite their potential to trigger severe side effects, such as myopathy, hearing loss, tendinopathy, and [...] Read more.

The fluoroquinolone (FQ) class of antibiotics includes the world’s most prescribed antibiotics such as ciprofloxacin, levofloxacin, and ofloxacin that are known for their low bacterial resistance. This is despite their potential to trigger severe side effects, such as myopathy, hearing loss, tendinopathy, and tendon rupture. Thus, healthcare organizations around the world have recommended limiting the prescription of FQs. Tendinopathy is a common name for maladies that cause pain and degeneration in the tendon tissue, which can result in tendon rupture. Whilst there are several identified effects of FQ on tendons, the exact molecular mechanisms behind FQ-mediated tendon rupture are unclear. Previous research studies indicated that FQ-mediated tendinopathy and tendon rupture can be induced by changes in gene expression, metabolism, and function of tendon resident cells, thus leading to alterations in the extracellular matrix. Hence, this review begins with an update on FQs, their mode of action, and their known side effects, as well as summary information on tendon tissue structure and cellular content. Next, how FQs affect the tendon tissue and trigger tendinopathy and tendon rupture is explored in detail. Lastly, possible preventative measures and promising areas for future research are also discussed. Specifically, follow-up studies should focus on understanding the FQ-mediated tendon changes in a more complex manner and integrating in vitro with in vivo models. With respect to in vitro systems, the field should move towards three-dimensional models that reflect the cellular diversity found in the tissue. Full article

(This article belongs to the Special Issue Fluoroquinolones)

19 pages, 3265 KiB

Open AccessReview

Andrographolide Sulfonates and Xiyanping: A Review of Chemical Composition, Pharmacological Activities, Clinical Applications, and Adverse Reactions

by Zihong Li, Lihao Yao, Zhenjie Liu, Liuping Wang, Huini Ruan, Yuanle Shen, Peng Zhang, Kaitong Li, Honglan Wang, Lili Fan, Liangxing Tu and Jianfang Feng

Pharmaceuticals 2025, 18(2), 183; https://doi.org/10.3390/ph18020183 - 29 Jan 2025

Viewed by 485

Abstract

Andrographis paniculata is a plant of the Acanthaceae family and its primary bioactive constituent, andrographolide, exhibits a broad spectrum of pharmacological activities and notable clinical efficacy. However, its poor solubility and limited bioavailability pose significant challenges for therapeutic applications. To overcome these limitations, [...] Read more.

Andrographis paniculata is a plant of the Acanthaceae family and its primary bioactive constituent, andrographolide, exhibits a broad spectrum of pharmacological activities and notable clinical efficacy. However, its poor solubility and limited bioavailability pose significant challenges for therapeutic applications. To overcome these limitations, researchers have synthesized andrographolide sulfonates by reacting andrographolide with ethanol and sulfuric acid. This sulfonated derivative significantly enhances water solubility and bioavailability while retaining key pharmacological properties such as anti-inflammatory and antiviral activities. As a representative formulation, Xiyanping injection has been widely employed in the treatment of respiratory infections, pneumonia, and related conditions, playing a critical role during the COVID-19 pandemic. Despite its widespread application, there has yet to be a comprehensive review of its chemical composition and pharmacological mechanisms. Additionally, the safety of Xiyanping injection remains a topic of some debate. This review systematically examines the chemical composition, pharmacological activities, clinical applications, and adverse reactions of andrographolide sulfonates and their formulation in Xiyanping injection to provide a scientific basis for further research and applications, while also offering valuable insights for the development of similar sulfonated drugs. Full article

(This article belongs to the Section Pharmaceutical Technology)

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19 pages, 539 KiB

Open AccessReview

The Efficacy of Honey for the Treatment of Perineal Wounds Following Vaginal Birth: A Narrative Review

by Isa S. Schaap, Céline M. J. G. Lardenoije, Senna J. J. M. van Riel and Niels A. J. Cremers

Pharmaceuticals 2025, 18(2), 182; https://doi.org/10.3390/ph18020182 - 29 Jan 2025

Viewed by 332

Abstract

Background/Objectives: During vaginal delivery, the perineum can be damaged either by episiotomy or by a spontaneous perineal tear, leading to several complications. The wound healing process should proceed as quickly and properly as possible without an infection. Medical grade honey (MGH) may [...] Read more.

Background/Objectives: During vaginal delivery, the perineum can be damaged either by episiotomy or by a spontaneous perineal tear, leading to several complications. The wound healing process should proceed as quickly and properly as possible without an infection. Medical grade honey (MGH) may be a potent treatment option due to its antimicrobial and pro-healing activities. This literature study investigated the role of honey in the treatment of vaginal wounds after delivery. Methods: Studies published before 17 July 2024 in the PubMed, Web of Science, Embase, Scopus, EBSCO host/CINAHL, Cochrane Library, and Google Scholar databases about honey, episiotomy wounds, and perineal tears, as well as those investigating wound healing and/or pain, were assessed. Results: Ten studies were included (six RCTs, of which three were double-blind, one was quasi-experimental with a posttest only, and three were observational studies without a control group), with 723 participants in total. Six of the seven controlled studies showed honey significantly improved various outcome measures, such as improved wound healing, and reduced need for pain medication. The three non-controlled studies also had a positive outcome, improving wound healing and decreasing pain intensity and prickling sensation. However, the overall quality of available evidence is limited. Different types of honey concentrations, origins, and additives were used in the included studies. Using a standardized MGH formulation may help to maintain consistent and potent effects. Therefore, additional research is needed to determine the efficacy of MGH in perineal trauma and to establish guidelines for clinical use. Conclusions: Honey potentially has a great effect on wound healing of perineal trauma; however, more research is necessary to substantiate the findings in the current literature. Full article

(This article belongs to the Special Issue Pharmacological Properties and Therapeutic Potential of Honey Bee Products)

19 pages, 2490 KiB

Open AccessArticle

In Vitro and In Vivo Assessment of Pharmacokinetic Profile of Peramivir in the Context of Inhalation Therapy

by Liuhan Dong, Juanwen Hu, Qiannan Zhang, Mengmeng Yang, Wenpeng Zhang and Xiaomei Zhuang

Pharmaceuticals 2025, 18(2), 181; https://doi.org/10.3390/ph18020181 - 29 Jan 2025

Viewed by 392

Abstract

Objective: The aim was to evaluate the pharmacokinetics and underlying mechanisms of peramivir, a clinically approved antiviral agent for severe influenza, subsequent to airway inhalation in rats, thereby surmounting the constraints associated with the sole currently available intravenous formulation. Methods: Pharmacokinetic and tissue [...] Read more.

Objective: The aim was to evaluate the pharmacokinetics and underlying mechanisms of peramivir, a clinically approved antiviral agent for severe influenza, subsequent to airway inhalation in rats, thereby surmounting the constraints associated with the sole currently available intravenous formulation. Methods: Pharmacokinetic and tissue distribution investigations of peramivir were carried out in rats following both intravenous and inhaled administration. In vitro cell models were verified to investigate peramivir’s transmembrane transport and cellular uptake across diverse cell systems. Results: In vivo, peramivir exhibited restricted permeability, predominantly localizing within the alveolar epithelial lining fluid and lung tissue after inhalation, accompanied by minimal systemic dissemination. In vitro, it manifested low permeability across cell models, with no participation of efflux transporters. Despite the low rate of A549 uptake, the underlying uptake transport mechanism was still revealed. Peramivir was verified as an OCTN2 substrate. A robust correlation was observed between the in vitro and in vivo findings. Conclusions: A preclinical pharmacokinetic platform applicable to inhaled medications was established. Inhalation of peramivir augments exposure at the target site while diminishing systemic exposure, presenting potential therapeutic benefits in terms of efficacy and safety and suggesting it as a favorable alternative administration pathway. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 946 KiB

Open AccessReview

Diverse Roles of Antibodies in Antibody–Drug Conjugates

by Aiko Yamaguchi and H. Charles Manning

Pharmaceuticals 2025, 18(2), 180; https://doi.org/10.3390/ph18020180 - 29 Jan 2025

Viewed by 595

Abstract

The emergence of antibody–drug conjugates (ADCs) has transformed the treatment landscape of a variety of cancers. ADCs typically consist of three main components: monoclonal antibody, chemical linker, and cytotoxic payload. These integrated therapeutic modalities harness the benefits of each component to provide a [...] Read more.

The emergence of antibody–drug conjugates (ADCs) has transformed the treatment landscape of a variety of cancers. ADCs typically consist of three main components: monoclonal antibody, chemical linker, and cytotoxic payload. These integrated therapeutic modalities harness the benefits of each component to provide a therapeutic response that cannot be achieved by conventional chemotherapy. Antibodies play roles in determining tumor specificity through target-mediated uptake, prolonging the circulation half-life of cytotoxic payloads, and providing additional mechanisms of action inherent to the original antibody, thus significantly contributing to the overall performance of ADCs. However, ADCs have unique safety concerns, such as drug-induced adverse events related to the target-mediated uptake of the ADC in normal tissues (so-called “on-target, off-tumor toxicity”) and platform toxicity, which are partially derived from limited tumor uptake of antibodies. Identifying suitable target antigens thus impacts the clinical success of ADCs and requires careful consideration, given the multifaceted aspects of this unique treatment modality. This review briefly summarizes the representative roles that antibodies play in determining the efficacy and safety of ADCs. Key considerations for selecting suitable cell surface target antigens for ADC therapy are also highlighted. Full article

(This article belongs to the Special Issue Antibody-Based Imaging and Targeted Therapy in Cancer)

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17 pages, 2708 KiB

Open AccessArticle

HDAC/σ1R Dual-Ligand as a Targeted Melanoma Therapeutic

by Claudia Giovanna Leotta, Carla Barbaraci, Jole Fiorito, Alessandro Coco, Viviana di Giacomo, Emanuele Amata, Agostino Marrazzo and Giovanni Mario Pitari

Pharmaceuticals 2025, 18(2), 179; https://doi.org/10.3390/ph18020179 - 28 Jan 2025

Viewed by 475

Abstract

Background: In melanoma, multiligand drug strategies to disrupt cancer-associated epigenetic alterations and angiogenesis are particularly promising. Here, a novel dual-ligand with a single shared pharmacophore capable of simultaneously targeting histone deacetylases (HDACs) and sigma receptors (σRs) was synthesized and subjected to phenotypic in [...] Read more.

Background: In melanoma, multiligand drug strategies to disrupt cancer-associated epigenetic alterations and angiogenesis are particularly promising. Here, a novel dual-ligand with a single shared pharmacophore capable of simultaneously targeting histone deacetylases (HDACs) and sigma receptors (σRs) was synthesized and subjected to phenotypic in vitro screening. Methods: Tumor cell proliferation and spreading were investigated using immortalized human cancer and normal cell lines. Angiogenesis was also evaluated in mouse endothelial cells using a tube formation assay. Results: The dual-ligand compound exhibited superior potency in suppressing both uveal and cutaneous melanoma cell viability compared to other cancer cell types or normal cells. Melanoma selectivity reflected inhibition of the HDAC-dependent epigenetic regulation of tumor proliferative kinetics, without involvement of σR signaling. In contrast, the bifunctional compound inhibited the formation of capillary-like structures, formed by endothelial cells, and tumor cell spreading through the specific regulation of σ₁R signaling, but not HDAC activity. Conclusions: Together, the present findings suggest that dual-targeted HDAC/σ₁R ligands might efficiently and simultaneously disrupt tumor growth, dissemination and angiogenesis in melanoma, a strategy amenable to future clinical applications in precision cancer treatment. Full article

(This article belongs to the Section Medicinal Chemistry)

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Open AccessSystematic Review

Comparative Efficacy and Safety of JAK Inhibitors in the Management of Rheumatoid Arthritis: A Network Meta-Analysis

by Hani M. Almoallim, Mohammed A. Omair, Sameh A. Ahmed, Kota Vidyasagar, Bisher Sawaf and Mohamed A. Yassin

Pharmaceuticals 2025, 18(2), 178; https://doi.org/10.3390/ph18020178 - 28 Jan 2025

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Abstract

Background/objective: Janus Kinase inhibitors (JAKinibs) are effective and well-tolerated targeted therapies for rheumatoid arthritis (RA). The comparative efficacy and safety of different JAKinibs remains unclear. This network meta-analysis (NMA) aimed to assess the relative efficacy and safety of different available JAKinibs. Methods: Searches [...] Read more.

Background/objective: Janus Kinase inhibitors (JAKinibs) are effective and well-tolerated targeted therapies for rheumatoid arthritis (RA). The comparative efficacy and safety of different JAKinibs remains unclear. This network meta-analysis (NMA) aimed to assess the relative efficacy and safety of different available JAKinibs. Methods: Searches were conducted on PubMed, CENTRAL, and ClinicalTrials.gov for randomized, double-blind, placebo-controlled trials comparing JAKinibs in RA patients. A frequentist NMA using the Netmeta package in R (R.4.3.0) was performed to evaluate both efficacy and safety outcomes. Continuous outcomes were presented as mean differences (MDs) and binary outcomes as relative risks (RR) with 95% confidence intervals (CI). The Cochrane risk of bias tool was used to assess the risk of bias in the included trials. Results: The analysis encompassed 39 trials with a total of 16,894 participants. Six JAKinibs (tofacitinib, baricitinib, upadacitinib, decernotinib, peficitinib, and filgotinib) were compared. Decernotinib at a dose of 300 mg showed a higher ACR50 response than other JAKinibs (RR = 7.55, 95% CI: 3.48 to 16.39, p < 0.01, surface under the cumulative ranking curve (SUCRA): 0.92). Tofacitinib at a dose of 1 mg twice daily had a significantly lower incidence of adverse drug reactions (ADRs) compared to other JAKinibs (RR = 0.80, 95% CI: 0.65 to 0.99, p = 0.04, SUCRA: 0.89), filgotinib 100 mg had a significantly lower infection risk (RR = 0.40, 95% CI: 0.21 to 0.79, p < 0.01, SUCRA: 0.90), whereas baricitinib 4 mg had the significantly highest herpes zoster risk (RR = 4.79, 95% CI: 1.03 to 22.21, p = 0.05, SUCRA: 0.11) compared to other JAKinibs. Conclusions: This NMA’s results indicate that commercially available JAKinibs show superior ACR responses and have comparable tolerability to placebo. Full article

(This article belongs to the Special Issue Pharmacovigilance in Drug Therapy: Drug–Drug Interactions and Safety Evaluation, 2nd Edition)

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Pharmaceuticals, Volume 18, Issue 2 (February 2025) – 73 articles

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