Pharmaceuticals

17 pages, 1541 KiB

Open AccessArticle

Impact of Antiglaucoma Drug Number and Class on Corneal Epithelial Thickness Measured by OCT

by Piotr Miklaszewski, Anna Maria Gadamer, Dominika Janiszewska-Bil, Anita Lyssek-Boroń, Dariusz Dobrowolski, Edward Wylęgała, Beniamin Oskar Grabarek, Michael Janusz Koss and Katarzyna Krysik

Pharmaceuticals 2025, 18(6), 868; https://doi.org/10.3390/ph18060868 - 11 Jun 2025

Abstract

Background/Objectives: The corneal epithelium plays a vital role in maintaining corneal transparency and ocular surface integrity. Chronic topical use of antiglaucoma medications may induce epithelial changes, especially with the concurrent use of multiple agents. This study aimed to evaluate the association between the [...] Read more.

Background/Objectives: The corneal epithelium plays a vital role in maintaining corneal transparency and ocular surface integrity. Chronic topical use of antiglaucoma medications may induce epithelial changes, especially with the concurrent use of multiple agents. This study aimed to evaluate the association between the number and class of antiglaucoma medications and central corneal epithelial thickness (CET), measured using a spectral-domain optical coherence tomography (SD-OCT) device. Methods: This cross-sectional study included 456 eyes from 242 adults (median age 72 years), grouped by the number of antiglaucoma agents used (0–4 medications). All pharmacologically treated participants had received the same regimen for ≥6 months. CET was measured using SD-OCT (SOLIX, Optovue). Generalized estimating equations (GEEs) accounted for inter-eye correlation. Two models were constructed: one evaluating specific medication effects and another assessing CET reduction per additional drug used. Age and sex were included as covariates. Results: CET progressively decreased with the number of medications, ranging from 53 µm in controls to 48 µm with quadruple therapy. Multivariable GEE analysis confirmed a cumulative thinning effect, with each additional medication associated with further CET reduction (β = −2.83 to −9.17 µm, p < 0.001). Latanoprost exerted the most pronounced single-drug effect (β = −3.01 µm, p < 0.001). Age was a modest negative predictor, while sex showed no significant effect. Conclusions: The cumulative number and specific class of antiglaucoma medications have a significant impact on corneal epithelial thickness. These results emphasize the need for vigilant ocular surface evaluation in patients on multi-drug regimens and propose CET as a surrogate marker for the burden of topical therapy. Full article

(This article belongs to the Special Issue Recent Advances in Ocular Pharmacology)

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37 pages, 1218 KiB

Open AccessSystematic Review

Unveiling the Anti-Inflammatory Effects of Antidepressants: A Systematic Review of Human Studies over the Last Decade

by Layla Bleibel, Paulina Sokołowska, Gabriela Henrykowska, Jacek Owczarek and Anna Wiktorowska-Owczarek

Pharmaceuticals 2025, 18(6), 867; https://doi.org/10.3390/ph18060867 - 10 Jun 2025

Abstract

Background/Objectives: Depression ranks among the most prevalent mental health conditions globally, marked by a variety of symptoms that frequently cause significant emotional distress and impairment in individuals, alongside a high recurrence rate. The predominant approach to treating depression revolves around monoamine theory, [...] Read more.

Background/Objectives: Depression ranks among the most prevalent mental health conditions globally, marked by a variety of symptoms that frequently cause significant emotional distress and impairment in individuals, alongside a high recurrence rate. The predominant approach to treating depression revolves around monoamine theory, utilizing SSRIs and SNRIs, with Esketamine emerging as a supplementary option in recent times. Nevertheless, there is a growing focus on exploring the relationship between inflammation and depression, revealing a strong correlation between the two. This insight prompts consideration of the anti-inflammatory properties of current antidepressants in their therapeutic application. Methods: A systematic literature search was conducted using the PubMed database to identify randomized controlled trials (RCTs) and clinical trials (CTs) that assessed the in vivo anti-inflammatory effects of SSRIs (fluoxetine, escitalopram, sertraline, and paroxetine), the SNRI venlafaxine, and esketamine/ketamine in human subjects undergoing treatment for depression. The included studies were evaluated based on changes in levels of pro-inflammatory and anti-inflammatory markers in response to the antidepressant treatments. Results: SSRIs, SNRIs, esketamine, and ketamine (a racemic mixture of S- and R-ketamine not formally approved for the treatment of depression) exhibit anti-inflammatory effects through diverse mechanisms, such as reducing pro-inflammatory cytokines or enhancing anti-inflammatory cytokines in serum or within specific brain regions like the hippocampus and prefrontal cortex. These actions are mediated through various inflammatory pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the brain Nod-like receptor pyrin-containing 3 (NLRP3) inflammasome, the glutamatergic system, the gut–brain axis, the hypothalamic–pituitary axis, impaired neuroplasticity, and the kynurenine pathway. Conclusions: In summary, SSRIs, SNRIs, esketamine, and ketamine exert an anti-inflammatory role alongside their antidepressant effects via these intricate mechanisms. Full article

(This article belongs to the Special Issue Pharmacology of Antidepressants: Recent Advances)

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33 pages, 2003 KiB

Open AccessReview

Acute Compartment Syndrome and Intra-Abdominal Hypertension, Decompression, Current Pharmacotherapy, and Stable Gastric Pentadecapeptide BPC 157 Solution

by Predrag Sikiric, Sven Seiwerth, Anita Skrtic, Mario Staresinic, Sanja Strbe, Antonia Vuksic, Suncana Sikiric, Dinko Bekic, Toni Penovic, Dominik Drazenovic, Tomislav Becejac, Marijan Tepes, Zrinko Madzar, Luka Novosel, Lidija Beketic Oreskovic, Ivana Oreskovic, Mirjana Stupnisek, Alenka Boban Blagaic and Ivan Dobric

Pharmaceuticals 2025, 18(6), 866; https://doi.org/10.3390/ph18060866 - 10 Jun 2025

Abstract

In this study, pharmacotherapies of abdominal compartment syndrome (ACS) and intra-abdominal hypertension (IAH) in animal studies were reviewed from the perspective of ACS/IAH as failed cytoprotection issues, as non-specific injuries, and from the point of view of the cytoprotection concept as resolution. Therefore, [...] Read more.

In this study, pharmacotherapies of abdominal compartment syndrome (ACS) and intra-abdominal hypertension (IAH) in animal studies were reviewed from the perspective of ACS/IAH as failed cytoprotection issues, as non-specific injuries, and from the point of view of the cytoprotection concept as resolution. Therefore, this review challenges the unresolved theoretical and practical issues of severe multiorgan failure, acknowledged significance in clinics, and resolving outcomes (i.e., open abdomen). Generally, the reported agents not aligned with cytoprotection align with current pharmacotherapy limitations and have (non-)confirmed effectiveness, mostly in only one organ, mild/moderate IAH, prophylactic application, and provide only a tentative resolution. Contrarily, stable gastric pentadecapeptide BPC 157 therapy, as a novel and relevant cytoprotective mediator having pleiotropic beneficial effects, simultaneously resolves many targets, resolving established disturbances, specifically compression/ischemia (grade III and grade IV), and decompression/advanced reperfusion. BPC 157 therapy rapidly activates collateral bypassing pathways, and, in ACS and IAH, and later, in reperfusion, there is a “bypassing key” (i.e., azygos vein direct blood flow delivery). This serves to counteract multiorgan and vessel failure, including lesions and hemorrhages in the brain, heart, lung, liver, kidney and gastrointestinal tract, thrombosis, peripherally and centrally, intracranial (superior sagittal sinus), portal and caval hypertension and aortal hypotension, occlusion/occlusion-like syndrome, advanced Virchow triad circumstances, and free radical formation acting as a membrane stabilizer and free radical scavenger. Likewise, not only in ACS/IAH resolving, but also in other occlusion/occlusion-like syndromes, this “bypassing key” could be an effect of the essential endothelial cytoprotective capacity of BPC 157 and a particular modulatory effect on the NO-system, and a rescuing impact on vasomotor tone. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 717 KiB

Open AccessArticle

Pharmacokinetic Equations Applied to Obtain New Topological Models in the Search of Antibacterial Compounds

by Jose I. Bueso-Bordils, Gerardo M. Antón-Fos, Rafael Martín-Algarra and Pedro A. Alemán-López

Pharmaceuticals 2025, 18(6), 865; https://doi.org/10.3390/ph18060865 - 10 Jun 2025

Abstract

Background: QSAR (Quantitative Structure–Activity Relationships) methods have been the basis for the design of new molecules with a certain activity. The great advantage of QSAR methods is that they can predict the pharmacological activity of compounds without the need to obtain or synthesize [...] Read more.

Background: QSAR (Quantitative Structure–Activity Relationships) methods have been the basis for the design of new molecules with a certain activity. The great advantage of QSAR methods is that they can predict the pharmacological activity of compounds without the need to obtain or synthesize them previously. Currently, the development of antibiotic resistance by microorganisms is the most important issue in the treatment of infectious diseases. This elevated resistance is associated with expanded morbidity and mortality, as well as an increase in healthcare costs. The development of new molecules with antibacterial activity is therefore urgently needed. Methods: By means of molecular topology, we developed discriminant functions (DF1 and DF2) capable of predicting antibacterial activity. When applied to a database with 6373 chemicals, they selected 266 molecules as candidates, from which 41% have this activity, according to the bibliography. Regression equations determining pharmacokinetic properties such as mean residence time (MRT), volume of distribution (V_D), and clearance (CL) were applied to the selected molecules. Results: We have observed that most antibacterial compounds have pharmacokinetic theoretical values in the intervals 20 > MRT > 0, 3 > V_D > 0, and 500 > CL > 0. We have applied these intervals to our antibacterial model with the objective of finding new antibacterials with a good pharmacokinetic profile. We show that they are an effective tool for discriminating antibacterial compounds, increasing the bibliographic success rate to 50.8, 59, and 61.5%, respectively. When drug-like filters are applied to these new models, the vast majority (89.9–100%) of the selected molecules present antibacterial activity. Conclusions: Considering these results, these new models could avoid the application of drug-likeness filters when searching for new potential antibacterials. All of this proves the usefulness of these mathematical–topological models. Full article

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

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31 pages, 12094 KiB

Open AccessArticle

Engineering Lipid–Polymer Nanoparticles for siRNA Delivery to Cancer Cells

by Arthur Manda, Abdulelah Alhazza, Hasan Uludağ and Hamidreza Montazeri Aliabadi

Pharmaceuticals 2025, 18(6), 864; https://doi.org/10.3390/ph18060864 - 10 Jun 2025

Abstract

Background: RNA interference (RNAi) is a powerful tool that can target many proteins without the expensive and time-consuming drug development studies. However, due to the challenges in delivering RNA molecules, the potential impact of RNAi approaches is yet to be fully realized [...] Read more.

Background: RNA interference (RNAi) is a powerful tool that can target many proteins without the expensive and time-consuming drug development studies. However, due to the challenges in delivering RNA molecules, the potential impact of RNAi approaches is yet to be fully realized in clinical settings. Lipid nanoparticles (LNPs) have been the most successful delivery system for nucleic acids, but targeted delivery to a solid tumor still eludes the developed LNPs. We hypothesized that specially designed low-molecular-weight PEIs can partially or completely replace the ionizable lipids for more accommodating vehicles due to the structural flexibility offered by polymers, which could lead to safer and more efficient nucleic acid delivery. Methods: To achieve this, we first optimized the LNP formulations as a point of reference for three outcomes: cellular uptake, cytotoxicity, and silencing efficiency. Using a response surface methodology (Design Expert), we optimized siRNA delivery by varying mole fractions of lipid components. Leveraging the optimal LNP formulation, we integrated specifically designed cationic polymers as partial or complete replacements for the ionizable lipid. This methodological approach, incorporating optimal combined designs and response surface methodologies, refined the LPNPs to an optimal efficiency. Results: Our data revealed that DOPE and Dlin-MC3-DMA contributed to higher efficiency in selected breast cancer cells over DSPC and ALC-0315 as neutral and ionizable lipids, respectively, based on the software analysis and direct comparative experiments. Incorporation of selected polymers enhanced the cellular internalization significantly, which in some formulations resulted in higher efficiency. Conclusions: These findings offer a framework for the rational design of LPNPs, that could enhance the passive targeting and silencing efficiency in cancer treatment and broader applications for RNAi-based strategies. Full article

(This article belongs to the Topic Applications of Polymers and Polymer Nanomaterials in Drug Delivery and Nanomedicine)

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21 pages, 2171 KiB

Open AccessArticle

Commiphora leptophloeos Bark Decoction: Phytochemical Composition, Antioxidant Capacity, and Non-Genotoxic Safety Profile

by José Rafael da Silva Araujo, Rafael de Felício, Camila Marinho da Silva, Palloma Lima de Oliveira, Silvany de Sousa Araújo, Laís Roberta Deroldo Sommaggio, Adriana Fabiana Corrêa da Silva, Paulo Henrique Valença Nunes, Bruno Oliveira de Veras, Erwelly Barros de Oliveira, Jaciana dos Santos Aguiar, Maria Aparecida Marin-Morales, Daniela Barretto Barbosa Trivella, Ana Maria Benko-Iseppon, Márcia Vanusa da Silva and Ana Christina Brasileiro-Vidal

Pharmaceuticals 2025, 18(6), 863; https://doi.org/10.3390/ph18060863 - 10 Jun 2025

Abstract

Background: Commiphora leptophloeos has long been used in Latin American folk medicine for the treatment of respiratory and gastrointestinal disorders. Therefore, toxicological and phytochemical investigations are required to assess the safety and support the evidence-based use of its bark in medicinal applications. [...] Read more.

Background: Commiphora leptophloeos has long been used in Latin American folk medicine for the treatment of respiratory and gastrointestinal disorders. Therefore, toxicological and phytochemical investigations are required to assess the safety and support the evidence-based use of its bark in medicinal applications. This study aimed to evaluate the aqueous bark extract of C. leptophloeos, focusing on its chemical composition and its antioxidant, cytotoxic, and genotoxic properties. Methods: The aqueous extract was obtained by decoction of dried bark samples. Phytochemical characterization was conducted using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS), and data were processed using the NP³ MS Workflow 1.1.4 software, allowing for the annotation of key secondary metabolites. Antioxidant activity was assessed through multiple in vitro assays, including DPPH, ABTS, phosphomolybdenum, and reducing power tests. Cytotoxicity was evaluated using the MTT assay, while genotoxicity was investigated through the Ames test and micronucleus assay. Results: Phytochemical analysis revealed several flavonoids, with procyanidin B2 annotated as a major compound. The extract exhibited strong antioxidant activity, with EC₅₀ values of 5.43 μg/mL (DPPH), 12.40 μg/mL (ABTS), 35.20 μg/mL (phosphomolybdenum), and 31.27 μg/mL (reducing power). The MTT assay showed no cytotoxic effects at concentrations up to 6400 μg/mL. Furthermore, both the Ames and micronucleus assays showed the absence of genotoxic effects at concentrations up to 1600 μg/plate and 400 μg/mL, respectively. Conclusions: The aqueous bark extract of C. leptophloeos demonstrates strong antioxidant potential and a favorable safety profile, with no detectable cytotoxicity or genotoxicity at concentrations effective in antioxidant assays. Further studies are recommended to confirm and validate its traditional medicinal properties using appropriate in vivo models, followed by pre-clinical evaluations. Full article

(This article belongs to the Special Issue Pharmacologically Active Compounds from Plants)

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18 pages, 1139 KiB

Open AccessArticle

Designing Novel Antimicrobial Agents from the Synthetic Antimicrobial Peptide (Pep-38) to Combat Antibiotic Resistance

by Yara Al Tall, Yasmeen Alkurdi, Nid’A Alshraiedeh and Salsabeel H. Sabi

Pharmaceuticals 2025, 18(6), 862; https://doi.org/10.3390/ph18060862 - 10 Jun 2025

Abstract

Background/Objectives: The rise of antibiotic-resistant bacteria presents a major global health challenge, highlighting the need for novel antimicrobial agents such as antimicrobial peptides (AMPs). AMPs are promising due to their broad-spectrum activity, membrane-disruptive mechanisms, and low development of resistance. This study aimed to [...] Read more.

Background/Objectives: The rise of antibiotic-resistant bacteria presents a major global health challenge, highlighting the need for novel antimicrobial agents such as antimicrobial peptides (AMPs). AMPs are promising due to their broad-spectrum activity, membrane-disruptive mechanisms, and low development of resistance. This study aimed to design and evaluate novel AMPs derived from a synthetic parent peptide (PEP-38). Methods: Novel peptides were designed using bioinformatics tools, including CAMP_R3 and Peptide Ranker. Their antimicrobial potential was validated through in vitro assays, including bacterial susceptibility, antibiofilm activity, cytotoxicity, hemolysis, and time–kill kinetics. Results: Among the designed peptides, Hel-4K-12K showed potent activity against both Gram-positive and Gram-negative bacteria, with MICs ranging from 3.125 to 6.25 µM. It also effectively eradicated biofilms of resistant Staphylococcus aureus at an MBEC of 6.25 µM. Time–kill assays confirmed rapid bactericidal action, achieving complete bacterial elimination within one hour at its MIC. Moreover, Hel-4K-12K exhibited low toxicity toward mammalian MDCK cells (>82% viability at MIC) and minimal hemolytic activity on human erythrocytes. Conclusions: Hel-4K-12K demonstrates strong antibacterial and antibiofilm activities with a favorable safety profile, indicating its potential as a therapeutic candidate for treating infections caused by resistant bacteria. These findings support further development of this peptide as a basis for new antimicrobial drug strategies. In addition to its promising in vitro profile, future studies will investigate Hel-4K-12K in animal models and evaluate strategies for attaining stable formulations, such as peptide encapsulation or PEGylation. These steps are critical to ensure its therapeutic viability in systemic applications. Full article

(This article belongs to the Section Biopharmaceuticals)

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16 pages, 3198 KiB

Open AccessArticle

Validation of a Traditional Medicine, Achyrocline satureioides Infusion, for the Improvement of Mild Respiratory Infection Symptoms: A Randomized, Placebo-Controlled and Open-Label Clinical Trial

by Catherina Isdra Moszkowicz Bastos, Caroline Dani, Laura Reck Cechinel, Arthur Hipolito da Silva Neves, Fabiana Briato Rasia, Marcelo Lazzaron Lamers, Sara Elis Bianchi, Gabriela Meirelles, Paulo Valdeci Worm, Valquiria Linck Bassani and Ionara Rodrigues Siqueira

Pharmaceuticals 2025, 18(6), 861; https://doi.org/10.3390/ph18060861 - 9 Jun 2025

Abstract

Background/Objectives: The need for the scientific validation of traditional and folk medicine knowledge has emerged lately. Achyrocline satureioides inflorescences have been widely used for the management of mild viral respiratory infection symptoms in South Brazil, Uruguay and Argentina. We intended to assess the [...] Read more.

Background/Objectives: The need for the scientific validation of traditional and folk medicine knowledge has emerged lately. Achyrocline satureioides inflorescences have been widely used for the management of mild viral respiratory infection symptoms in South Brazil, Uruguay and Argentina. We intended to assess the therapeutic efficacy of a 14-day course with A. satureioides for mild viral respiratory infection symptoms. Methods: We conducted a randomized, open-label, placebo-controlled trial. Before COVID-19 (SARS-CoV-2) diagnostic tests, participants were randomly assigned to one of two experimental groups: A. satureioides or Malus domestica infusions, with instructions to use the infusions twice a day for 14 days. Our primary endpoint was the recovery time for respiratory symptoms in the overall analysis; the secondary outcomes were the recovery time for non-respiratory symptoms and for stratified analysis, taking into account the vaccination status against SARS-CoV-2 and COVID-19 infection; and the rate of symptom recovery was also evaluated. Results: The A. satureioides infusion significantly accelerated the resolution of sore throat and sneezing compared with the control group. The participants with COVID-19 who had not been vaccinated and received A. satureioides infusion recovered faster from sore throat, body ache, fever and cough, and showed a shorter median survival time for symptom resolution. The SARS-CoV-2-negative group that received A. satureioides had a faster improvement in the survival analysis of sore throat, earache and loss of appetite. Conclusions: Our findings support the hypothesis that Achyrocline satureioides inflorescence infusions may offer therapeutic benefits in the management of mild viral respiratory infections, as its administration was associated with a significantly accelerated resolution of clinical symptoms. This study was registered in the Brazilian Registry of Clinical Trials (ReBEC; registration number RBR-8g6f2rv) on 27 January 2022. Full article

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24 pages, 7057 KiB

Open AccessArticle

Synergistic Effect of Banaba Leaf Extract and Policosanol (Raydel^®) Ameliorate High Cholesterol and High Galactose-Diet Induced Adverse Events in Zebrafish

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

Pharmaceuticals 2025, 18(6), 860; https://doi.org/10.3390/ph18060860 - 9 Jun 2025

Abstract

Background: This study aimed to explore the therapeutic potential of a dietary regimen of banaba leaf extract (BNB), policosanol (PCO, Raydel^®), and their combination (BNB+PCO), to mitigate high cholesterol (HC) and high galactose (HG) diet-induced dyslipidemia, hyperglycemia, oxidative stress, senescence, [...] Read more.

Background: This study aimed to explore the therapeutic potential of a dietary regimen of banaba leaf extract (BNB), policosanol (PCO, Raydel^®), and their combination (BNB+PCO), to mitigate high cholesterol (HC) and high galactose (HG) diet-induced dyslipidemia, hyperglycemia, oxidative stress, senescence, and organ damage in zebrafish (Danio rerio). Methodology: Zebrafish (n = 28/group) were fed with HC (4% w/w)+HG (30% w/w) or HC+HG supplemented either with BNB (0.1% w/w) or PCO (0.1% w/w) or BNB+PCO (0.1% w/w each). Following 6 weeks of dietary intervention, biochemical and histopathological examinations across the groups were performed. Results: Post 6 weeks of consumption, the BNB+PCO group exhibited a significant 40% decrease in body weight (BW) relative to the BW of the HC+HG group, while the BNB or PCO groups displayed nonsignificant changes in BW. Both BNB and PCO reduced HC+HG-induced dyslipidemia and hyperglycemia; however, co-administration (BNB+PCO) demonstrated a significantly greater therapeutic effect in countering these conditions compared to either BNB or PCO alone. A similar effect of the BNB+PCO combination was observed on the elevation of plasma sulfhydryl content, paraoxonase (PON), and ferric ion reduction activity (FRA), with notably ~1.2-times (p < 0.01) higher levels compared to their corresponding values observed in the BNB or PCO groups. Significantly diminished plasma AST, ALT, hepatic interleukin 6 (IL-6) levels, and fatty liver changes were observed in response to BNB+PCO, compared to either BNB or PCO alone. Also, BNB+PCO displayed a higher curative effect against HC+HG-induced impairment of tissue regeneration than BNB or PCO alone. A notable effect of BNB+PCO was perceived in protecting kidneys, testis, and ovary damage. Consistently, BNB+PCO showed a profound impact on mitigating HC+HG elevated reactive oxygen species (ROS) generation, apoptosis, cellular senescence, and accumulation of brain-binding lipid proteins (BLBPs) and 4-hydroxynoneal (4-HNE) in the brain. Conclusions: The findings highlight the synergistic effects of the BNB and PCO combination to mitigate the adversity posed by the consumption of the HC+HG diet. Full article

(This article belongs to the Special Issue Therapeutic Methods Against Acute and Chronic Diseases and Oxidative Stress)

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17 pages, 4283 KiB

Open AccessArticle

SPHK1-S1p Signaling Drives Fibrocyte-Mediated Pulmonary Fibrosis: Mechanistic Insights and Therapeutic Potential

by Fei Lu, Gaoming Wang, Xiangzhe Yang, Jing Luo, Haitao Ma, Liangbin Pan, Yu Yao and Kai Xie

Pharmaceuticals 2025, 18(6), 859; https://doi.org/10.3390/ph18060859 - 9 Jun 2025

Abstract

Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by chronic inflammation and excessive extracellular matrix deposition, with fibrocytes playing a pivotal role in fibrotic remodeling. This study aimed to identify upstream molecular mechanisms regulating fibrocyte recruitment and activation, focusing on [...] Read more.

Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by chronic inflammation and excessive extracellular matrix deposition, with fibrocytes playing a pivotal role in fibrotic remodeling. This study aimed to identify upstream molecular mechanisms regulating fibrocyte recruitment and activation, focusing on the SPHK1 pathway as a potential therapeutic target. Methods: We utilized Mendelian Randomization and phenome-wide association analyses on genes involved in sphingolipid metabolism to identify potential regulators of idiopathic pulmonary fibrosis (IPF). A bleomycin-induced mouse model was employed to examine the role of the SPHK1-S1P axis in fibrocyte recruitment, using SKI-349 to target SPHK1 and FTY720 to antagonize S1PR1. Results: Our analyses revealed SPHK1 as a significant genetic driver of IPF. Targeting SPHK1 and S1PR1 led to a marked reduction in fibrocyte accumulation, collagen deposition, and histopathological fibrosis. Additionally, PAXX and RBKS were identified as downstream effectors of SPHK1. Our protein–protein interaction mapping indicated potential therapeutic synergies with existing anti-fibrotic drug targets. Conclusions: Our findings establish the SPHK1-S1P-S1PR1 axis as a key regulator of fibrocyte-mediated pulmonary fibrosis and support SPHK1 as a promising therapeutic target. Full article

(This article belongs to the Special Issue Innovative Drug Strategies in Chronic Disease Management: Addressing Non-Adherence and Improving Therapeutic Outcomes)

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2 pages, 136 KiB

Open AccessCorrection

Correction: Sgherza et al. Efficacy and Safety of Isatuximab, Carfilzomib, and Dexamethasone (IsaKd) in Multiple Myeloma Patients at the First Relapse After Autologous Stem Cell Transplantation and Lenalidomide Maintenance: Results from the Multicenter, Real-Life AENEID Study. Pharmaceuticals 2025, 18, 595

by Nicola Sgherza, Olga Battisti, Paola Curci, Concetta Conticello, Salvatore Palmieri, Daniele Derudas, Candida Germano, Enrica Antonia Martino, Giuseppe Mele, Roberta Della Pepa, Francesca Fazio, Anna Mele, Bernardo Rossini, Giulia Palazzo, Daniela Roccotelli, Simona Rasola, Maria Teresa Petrucci, Domenico Pastore, Giuseppe Tarantini, Fabrizio Pane, Massimo Gentile, Francesco Di Raimondo, Emanuela Resta and Pellegrino Musto Show full author list Hide full author list

Pharmaceuticals 2025, 18(6), 858; https://doi.org/10.3390/ph18060858 - 9 Jun 2025

Abstract

In the original publication [...] Full article

28 pages, 727 KiB

Open AccessReview

Potential New Applications of Sodium–Glucose Cotransporter-2 Inhibitors Across the Continuum of Cancer-Related Cardiovascular Toxicity

by Agnieszka Maria Zebrowska and Anna Borowiec

Pharmaceuticals 2025, 18(6), 857; https://doi.org/10.3390/ph18060857 - 9 Jun 2025

Abstract

Sodium–glucose cotransporter-2 inhibitors (SGLT2i), initially developed for the management of type 2 diabetes mellitus, have demonstrated significant nephroprotective and cardioprotective effects. These benefits have led to their inclusion in heart failure (HF) management guidelines, irrespective of glycemic status and left ventricular ejection fraction [...] Read more.

Sodium–glucose cotransporter-2 inhibitors (SGLT2i), initially developed for the management of type 2 diabetes mellitus, have demonstrated significant nephroprotective and cardioprotective effects. These benefits have led to their inclusion in heart failure (HF) management guidelines, irrespective of glycemic status and left ventricular ejection fraction (LVEF). Various anticancer therapies, particularly anthracyclines, are associated with substantial cardiotoxicity risks, resulting in cancer therapy-related cardiovascular toxicity (CTR-CVT). Promising evidence from preclinical and observational studies indicates that SGLT2i may mitigate cardiotoxic effects of cancer therapy by alleviating LVEF decline, reducing HF incidence and hospitalizations, and lowering overall mortality. Moreover, improved survival has been reported in patients with various malignancies. The current review explores the potential applications of SGLT2i in the prevention of CTR-CVT, highlights their possible mechanisms of cardioprotection, discusses the published evidence, and emphasizes the need for the results from ongoing randomized controlled trials to establish SGLT2i efficacy and safety in cardio-oncology patients. Full article

(This article belongs to the Special Issue New Insights of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Biomedical Applications)

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12 pages, 630 KiB

Open AccessArticle

Real-World Analysis of Short-Term Effectiveness of Oral Semaglutide: Impact on Glycometabolic Control and Cardiovascular Risk

by Sara Palazzi, Federica Sentinelli, Antonella Zugaro, Sara Morgante, Livia Santarelli, Sandra Melanzi, Annamaria De Mutiis, Deamaria Piersanti, Barbara Macerola, Marco Iezzi, Pietro Mercuri, Alessandro Ferranti, Daniele Tienforti, Maria Gisella Cavallo, Arcangelo Barbonetti and Marco Giorgio Baroni

Pharmaceuticals 2025, 18(6), 856; https://doi.org/10.3390/ph18060856 - 8 Jun 2025

Abstract

Background: Oral semaglutide, a GLP1-receptor agonist (GLP1-RA), shows promise in efficacy and compliance, especially amid the global shortage of injectable GLP-1 RAs. Its short-term effectiveness remains unexplored. Objective: This real-world observational study assessed the short-term effectiveness of oral semaglutide after three [...] Read more.

Background: Oral semaglutide, a GLP1-receptor agonist (GLP1-RA), shows promise in efficacy and compliance, especially amid the global shortage of injectable GLP-1 RAs. Its short-term effectiveness remains unexplored. Objective: This real-world observational study assessed the short-term effectiveness of oral semaglutide after three months of therapy. Methods: Patients with type 2 diabetes from four Italian diabetes centers, who received an initial prescription of oral semaglutide, were reassessed after three months. Primary outcomes included glycated hemoglobin (HbA1c) and body weight reduction; secondary outcomes involved changes in lipid parameters and cardiovascular risk. Results: Among 167 participants (mean age 66.5 years, mostly obese, baseline HbA1c 8.4% ± 1.5), 83.2% received a 7 mg dose. After three months, HbA1c significantly declined (8.4% to 7.1%, −1.3%, p < 0.001), alongside body mass index (BMI) (30.9 kg/m² to 29.6 kg/m², p < 0.0001). The target HbA1c ≤ 7% was achieved by 54.5%, and 34.7% reached ≤6.5%. Patients losing >5% of their initial weight (30.5%) saw the largest HbA1c drop (−1.9%). Those with newly diagnosed diabetes or a duration < 5 years showed superior responses (p = 0.001), while no significant differences were found based on the timing of drug administration. Oral semaglutide replaced or supplemented prior therapies, allowing discontinuation of dipeptidyl peptidase 4 inhibitors (DPP4i), sulfonylureas, glinides, and acarbose, and deprescription of thiazolidinediones. A significant reduction in cardiovascular risk was observed (p = 0.04), together with a significant reduction in lipid parameters. Conclusions: Oral semaglutide showed significant short-term efficacy, reducing HbA1c, body weight, and cardiovascular risk in three months, making it a valuable therapeutic option. Full article

(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy, 2nd Edition)

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10 pages, 557 KiB

Open AccessArticle

Valproate-Enhanced Protocols for Alcohol Withdrawal Syndrome: A Brief Review and Retrospective Study of Efficacy and the Ability to Reduce Benzodiazepine Use

by Simone Pardossi, Alessandro Cuomo, Giacomo Gualtieri, Mario Pinzi, Giuditta Piumini and Andrea Fagiolini

Pharmaceuticals 2025, 18(6), 855; https://doi.org/10.3390/ph18060855 - 8 Jun 2025

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Abstract

Background: Although benzodiazepines are the first-line treatment for alcohol withdrawal syndrome (AWS), their use may pose significant risks, including oversedation and the potential for misuse, particularly in vulnerable populations such as individuals with alcohol use disorder. Valproate has been investigated as a potential [...] Read more.

Background: Although benzodiazepines are the first-line treatment for alcohol withdrawal syndrome (AWS), their use may pose significant risks, including oversedation and the potential for misuse, particularly in vulnerable populations such as individuals with alcohol use disorder. Valproate has been investigated as a potential adjunctive treatment for AWS. We first conducted a brief narrative review of the existing literature on valproate in AWS, identifying only a few relevant studies. We then performed a retrospective study to evaluate the effectiveness of valproate, administered orally (PO) or intravenously (IV), in combination with benzodiazepines for the treatment of AWS and associated anxiety symptoms. Methods: We retrospectively analyzed 72 inpatients treated for AWS with valproate (IV or PO) combined with benzodiazepines. Dosages of valproate, the type and daily dose of benzodiazepine, and any adverse effects were recorded. Withdrawal symptoms were assessed using the Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised (CIWA-Ar) on days 1, 3, 5, and 7. Anxiety symptoms were evaluated using the Hamilton Anxiety Rating Scale (HAM-A) on days 1, 3, and 7. Results: The median daily benzodiazepine dose was 2.5 mg lorazepam-equivalents (IQR: 2.0–3.81 mg). Significant reductions in both CIWA-Ar and HAM-A scores were observed across all time points. Percentage reductions in both anxiety and withdrawal symptoms were significantly higher in the IV group. No serious adverse events occurred. Conclusions: Valproate appears to be an effective adjunctive treatment for AWS, providing symptom relief and enabling reduced benzodiazepine use. IV administration may offer more rapid clinical improvement. Larger prospective trials are warranted to confirm these findings. Full article

(This article belongs to the Special Issue Advances in Neuropharmacology of Drug Abuse)

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16 pages, 1346 KiB

Open AccessArticle

In Vitro Evaluation of Cytotoxic and Pro-Apoptotic Effects of Hesperidin Alone and in Combination with Cisplatin on Human Malignant Melanoma Cell Line (A431)

by Mehmet Uğur Karabat, Mehmet Cudi Tuncer and İlhan Özdemir

Pharmaceuticals 2025, 18(6), 854; https://doi.org/10.3390/ph18060854 - 7 Jun 2025

Viewed by 142

Abstract

Background/Objectives: Melanoma is an aggressive skin cancer with high metastatic potential and poor prognosis in advanced stages. Hesperidin, a natural flavonoid, has shown anticancer properties across various malignancies. This study aimed to evaluate the antiproliferative and pro-apoptotic effects of Hesperidin, alone and in [...] Read more.

Background/Objectives: Melanoma is an aggressive skin cancer with high metastatic potential and poor prognosis in advanced stages. Hesperidin, a natural flavonoid, has shown anticancer properties across various malignancies. This study aimed to evaluate the antiproliferative and pro-apoptotic effects of Hesperidin, alone and in combination with Cisplatin, on the human epidermoid carcinoma cell line A431. Materials and Methods: A431 cells were cultured under standard conditions and treated with different concentrations of Hesperidin and Cisplatin for 48 h. Cell viability was assessed using the MTT assay. Apoptosis was evaluated by Annexin V-FITC/PI staining and caspase-3/7 activity assays. Expression levels of Bax, caspase-3/7, and survivin were measured by RT-qPCR. Results: Hesperidin significantly reduced cell viability at both 24 and 48 h. Annexin V/PI staining revealed increased apoptosis, with the highest apoptotic ratio in the Hesperidin + Cisplatin group (p < 0.001). Caspase-3/7 activity was markedly elevated in Hesperidin-treated cells. RT-qPCR showed upregulation of Bax and caspase-3/7 and downregulation of survivin. Conclusions: Hesperidin demonstrated significant cytotoxic and pro-apoptotic effects in A431 cells. When combined with Cisplatin, a synergistic enhancement of apoptosis was observed. These findings support the potential of Hesperidin as a complementary agent in carcinoma therapy, pending further in vivo and clinical validation. Full article

(This article belongs to the Special Issue Adjuvant Therapies for Cancer Treatment: 2nd Edition)

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23 pages, 834 KiB

Open AccessReview

Metabolic Reprogramming in Melanoma: An Epigenetic Point of View

by Stefano Giuliani, Celeste Accetta, Simona di Martino, Claudia De Vitis, Elena Messina, Edoardo Pescarmona, Maurizio Fanciulli, Gennaro Ciliberto, Rita Mancini and Italia Falcone

Pharmaceuticals 2025, 18(6), 853; https://doi.org/10.3390/ph18060853 - 6 Jun 2025

Viewed by 313

Abstract

Metabolic reprogramming and epigenetic alterations are fundamental hallmarks of cancer cells, contributing to adaptation, progression, and resistance. In melanoma, high metabolic-epigenetic plasticity enables the rapid modulation of cell states in response to environmental and therapeutic pressures. Recent studies have highlighted a bidirectional crosstalk [...] Read more.

Metabolic reprogramming and epigenetic alterations are fundamental hallmarks of cancer cells, contributing to adaptation, progression, and resistance. In melanoma, high metabolic-epigenetic plasticity enables the rapid modulation of cell states in response to environmental and therapeutic pressures. Recent studies have highlighted a bidirectional crosstalk between cellular metabolism and epigenetic regulation. Epigenetic modifications influence the transcriptional control of metabolic genes, thereby shaping metabolic phenotypes. Conversely, specific metabolites are essential cofactors or substrates for epigenetic enzymes, directly modulating the epigenome. Understanding the intricate mechanisms of this interaction offers opportunities for the development of innovative tumor management that combines epigenetic, metabolic, and therapy interventions. In this review, we summarize the latest evidence on the role of the metabolism–epigenetics axis in melanoma and discuss its potential clinical implications, aiming to provide a comprehensive overview of metabolic/epigenetic interconnections. Full article

(This article belongs to the Section Biopharmaceuticals)

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17 pages, 5124 KiB

Open AccessArticle

Combination Treatment with Free Doxorubicin and Inductive Moderate Hyperthermia for Sarcoma Saos-2 Cells

by Valerii E. Orel, Anatolii G. Diedkov, Vasyl V. Ostafiichuk, Sergii A. Lyalkin, Igor O. Tkachenko, Denys L. Kolesnyk, Valerii B. Orel, Olga Yo. Dasyukevich, Oleksandr Yu. Rykhalskyi, Oleksii V. Movchan, Alexander Yu. Galkin and Anna B. Prosvietova

Pharmaceuticals 2025, 18(6), 852; https://doi.org/10.3390/ph18060852 - 6 Jun 2025

Viewed by 202

Abstract

Background: Osteosarcoma (OS) is the most common primary malignant bone tumor. Doxorubicin (DOX) is extensively used in OS chemotherapy, yet improving patient outcomes remains challenging. This study investigated the effect of free DOX combined with inductive moderate hyperthermia (IMH) on Saos-2 human OS [...] Read more.

Background: Osteosarcoma (OS) is the most common primary malignant bone tumor. Doxorubicin (DOX) is extensively used in OS chemotherapy, yet improving patient outcomes remains challenging. This study investigated the effect of free DOX combined with inductive moderate hyperthermia (IMH) on Saos-2 human OS cells. Methods: Cell viability was assessed by trypan blue exclusion. Flow cytometry analyzed apoptosis, necrosis, and reactive oxygen species (ROS) in cells exposed to control (no treatment), IMH (42 MHz frequency, 500 μT magnetic field induction, 564 V/m electric field strength, 15 W output power, and 30 min duration) alone, DOX (0.06 μg/mL) alone, or DOX combined with IMH. The expression of p14^ARF tumor suppressor and epidermal growth factor receptor (EGFR) was evaluated by immunocytochemistry. Spatial autocorrelation analysis quantified the heterogeneity of p14^ARF and EGFR distributions in acquired images. Results: The half maximal inhibitory concentration (IC₅₀) of DOX in Saos-2 cells had minimal variation between 48 h (0.060 ± 0.01 μg/mL) and 72 h (0.055 ± 0.003 μg/mL). DOX + IMH resulted in a 15% increase in early apoptosis and a 20% elevation in ROS levels compared with DOX alone. Immunocytochemical analysis revealed a 37% increase in p14^ARF and a 32% reduction in EGFR expression following combined treatment in comparison to DOX alone. Image analysis showed that DOX + IMH treatment caused the highest Moran’s index values for p14^ARF and EGFR, reflecting less heterogeneous spatial distributions (p < 0.05). Conclusions: IMH enhanced DOX-induced cytotoxicity in Saos-2 cells by initiating ROS-mediated apoptosis and reducing heterogeneity of cellular responses. Full article

(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies, 2nd Edition)

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20 pages, 1823 KiB

Open AccessArticle

In Vitro and In Silico Assessments of Curcuminoids and Turmerones from Curcuma longa as Novel Inhibitors of Leishmania infantum Arginase

by Flora F. S. Spíndola, Anderson S. Pinheiro, Maria Athana Mpalantinos, Jefferson R. A. Silva, Walter S. M. F. Neto, Raissa A. Conceição, Eduarda M. Barreto, Barbara A. Abrahim-Vieira, Carlos R. Rodrigues, Alessandra M. T. Souza, Dirlei Nico, Ana Claudia F. Amaral, Andreza R. Garcia and Igor A. Rodrigues

Pharmaceuticals 2025, 18(6), 851; https://doi.org/10.3390/ph18060851 - 6 Jun 2025

Viewed by 196

Abstract

Background/Objectives: The anti-Leishmania potential of Curcuma longa and its derivatives, such as curcuminoids, is well-established, yet their mechanisms of action remain underexplored. This study investigates the inhibitory effects of C. longa extracts and curcumin on Leishmania infantum arginase, a key enzyme [...] Read more.

Background/Objectives: The anti-Leishmania potential of Curcuma longa and its derivatives, such as curcuminoids, is well-established, yet their mechanisms of action remain underexplored. This study investigates the inhibitory effects of C. longa extracts and curcumin on Leishmania infantum arginase, a key enzyme in polyamine and trypanothione biosynthesis, and evaluates their antiparasitic activity. Methods: Extracts were prepared via rhizome successive maceration with hexane (HEXCURC), dichloromethane (DCCURC), and ethanol (ETOHCURC) and chemically characterized by a combination of chromatographic and spectrometric methods. The inhibition of recombinant L. infantum arginase (LiARG) was assessed by urea quantification, while molecular docking explored interactions between the main compounds annotated in the extracts and the enzyme’s active site. Biological activity was tested against L. infantum promastigotes, intracellular amastigotes, and mammalian cells. Results: LC-MS and GC-MS revealed curcuminoids and turmerones as main compounds annotated in the extracts. DCCURC, HEXCURC, and curcumin showed the strongest LiARG inhibition (IC₅₀ = 10.04, 14.4, and 17.55 μg/mL, respectively). Docking analysis revealed that curcumin, demethoxycurcumin, and bisdemethoxycurcumin bind near the active site, with binding energies of –3.43, –4.14, and –3.99 kcal/mol, respectively. Curcumin demonstrated superior anti-promastigote activity (IC₅₀ = 15.01 μg/mL) and selectivity (SI = 12.7) compared to the extracts. It also significantly reduced amastigote burden in infected macrophages (IC₅₀ = 13.6 μg/mL). Conclusions: This is the first report demonstrating that C. longa extracts and curcumin inhibit LiARG. These findings support curcumin’s potential as a lead compound for developing multi-target therapies against leishmaniasis, combining enzyme inhibition with direct antiparasitic effects. Full article

(This article belongs to the Section Natural Products)

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17 pages, 875 KiB

Open AccessArticle

Bevacizumab in Platinum-Sensitive Recurrent Epithelial Ovarian Cancer: A Risk-Stratified Analysis

by İrem Öner and Pınar Karaçin

Pharmaceuticals 2025, 18(6), 850; https://doi.org/10.3390/ph18060850 - 6 Jun 2025

Viewed by 157

Abstract

Background and Objectives: Epithelial ovarian cancer (EOC) is a complex disease characterized by heterogeneous clinical, pathological, and molecular features. Diagnosed frequently at advanced stages, it presents significant challenges in treatment due to the risks of resistance and recurrence. While bevacizumab, by inhibiting angiogenesis, [...] Read more.

Background and Objectives: Epithelial ovarian cancer (EOC) is a complex disease characterized by heterogeneous clinical, pathological, and molecular features. Diagnosed frequently at advanced stages, it presents significant challenges in treatment due to the risks of resistance and recurrence. While bevacizumab, by inhibiting angiogenesis, offers a valuable therapeutic option for platinum-sensitive recurrent ovarian cancer (PSROC), its impact on overall survival (OS) remains incompletely understood. This retrospective study aims to compare treatment responses in high- and low-risk groups of patients with PSROC and to evaluate the effects of bevacizumab on survival within these risk strata. Materials and Methods: This retrospective study included patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage III and IV EOC who received chemotherapy or chemotherapy plus bevacizumab for platinum-sensitive recurrence. Patients were classified according to risk groups, and their clinicopathological characteristics were compared. Survival analyses and adverse events regarding risk groups and bevacizumab use were examined. In this study, the effect of bevacizumab on survival in patients with PSROC was evaluated for the first time according to risk stratification, and the relationship between treatment response and survival was investigated according to recurrence localization. Results: Of the 174 patients included in this study, 102 (58.6%) were classified as low risk and 72 (41.4%) were classified as high risk. Significant differences in survival were observed between the risk groups. In the low-risk group, progression-free survival and overall survival were markedly longer compared to the high-risk group. Median PFS was 13.7 months in the low-risk group and 10.8 months in the high-risk group (p = 0.007). Median OS was 36.5 and 23.5 months, respectively (p = 0.003). In low-risk patients, the addition of bevacizumab to chemotherapy significantly increased median PFS (13.5 months vs. 9.7 months, p = 0.029); however, this advantage did not translate into a significant overall survival benefit (39.4 months vs. 33.3 months, p = 0.669). Conversely, in the high-risk group, bevacizumab use provided significant benefits in both PFS and OS. Median PFS was 13.9 months in the bevacizumab group and 8.8 months in the control group (p < 0.001). Median OS was calculated as 36.5 and 23.2 months, respectively (p < 0.001). Conclusions: Our study is among the first to comprehensively compare the effectiveness of bevacizumab treatment in patients with platinum-sensitive recurrent ovarian cancer based on clinical risk groups and recurrence patterns using real-world data. The current literature lacks a comprehensive analysis that simultaneously evaluates these two critical parameters. In this respect, our study aims to contribute to developing more personalized treatment strategies for specific patient subgroups. Full article

(This article belongs to the Special Issue New Targets and Experimental Therapeutic Approaches for Cancers)

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9 pages, 3017 KiB

Open AccessCase Report

Intrascleral Tunnel Clamping of Fluocinolone Acetonide Implant: A Novel Scleral Fixation Technique

by Lucas Sejournet, Laurent Kodjikian, Thibaud Mathis, Alban Comet, Pierre Gascon and Frederic Matonti

Pharmaceuticals 2025, 18(6), 849; https://doi.org/10.3390/ph18060849 - 6 Jun 2025

Viewed by 139

Abstract

Purpose: This retrospective observational study evaluates the efficacy and safety of a novel scleral fixation technique of the fluocinolone acetonide (FAc) implant in four consecutive patients with post-surgical macular edema (PSME). Case Presentation: Four patients with PSME underwent intrascleral tunnel clamping (ITC) of [...] Read more.

Purpose: This retrospective observational study evaluates the efficacy and safety of a novel scleral fixation technique of the fluocinolone acetonide (FAc) implant in four consecutive patients with post-surgical macular edema (PSME). Case Presentation: Four patients with PSME underwent intrascleral tunnel clamping (ITC) of the FAc implant due to lens defects. A 25-gauge sclerotomy was made 3.5 mm from the limbus and the implant was inserted into it until its end reached the edge of the sclera. Then, an 8-0 absorbable suture was passed through the sclera without penetrating the implant, thereby clamping the sclera around the FAc. All the patients showed improvements in best-corrected visual acuity (from a mean of 20/100 at baseline to 20/40) and central retinal thickness (from a mean of 534 µm at baseline to 318 µm) and with no recurrence of macular edema in most cases, without the need for further treatment. In addition, no anterior migration of the FAc implant or ocular hypertension was observed. This procedure effectively reduced the therapeutic burden for these patients. Although scleral fixation of the FAc implant has been described in small series of patients with successful results, this approach remains off-label. Conclusions: Although off-label, ITC of the FAc implant may offer a promising treatment option for patients who would otherwise remain untreated. Full article

(This article belongs to the Special Issue Advances in Ophthalmic Drug Discovery and Delivery: From Targets to Treatments)

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15 pages, 304 KiB

Open AccessReview

Improving the Dosing Schedules of Targeted Anticancer Agents

by Dominique Levêque

Pharmaceuticals 2025, 18(6), 848; https://doi.org/10.3390/ph18060848 - 6 Jun 2025

Viewed by 232

Abstract

Beyond developing new agents, cancer treatment can also be optimized by modifying the dosing regimen of approved drugs. Academic teams have experimented with different ways of improving drug regimens, leading to off-label practices for therapeutic and/or economic purposes, and currently, drug regulatory agencies [...] Read more.

Beyond developing new agents, cancer treatment can also be optimized by modifying the dosing regimen of approved drugs. Academic teams have experimented with different ways of improving drug regimens, leading to off-label practices for therapeutic and/or economic purposes, and currently, drug regulatory agencies have begun to reappraise this often-neglected topic. This concept also considers the patient’s perspective in terms of quality of life and convenience, including the concept of time toxicity. Overall, the optimization of drug dosing of anticancer agents may be viewed on three sides: the improvement of the benefits/risks balance (patient), the improvement of the convenience of the treatment (patient, healthcare professionals), and the mitigation of the financial impact (health insurance, patient). Examples of dose reassessments of targeted therapies (approved since 1997) are chosen to illustrate the context. Suboptimal/overdosed regimens are found for certain molecularly targeted agents, mostly based on the ancient concept of maximum tolerated dose in oncology. This underlines the lack of comparative effective dose trials before approval. Fortunately, dosing regimens of newly approved molecularly targeted agents is going to evolve with the hope of more convenient and better tolerated treatments. This optimization will bring greater benefit to patients and to healthcare professionals but without addressing the economic issue. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Adverse Drug Reactions: 2nd Edition)

12 pages, 1768 KiB

Open AccessArticle

Synthesis and Combination Studies of Novel Dipeptide Nitriles with Curcumin for a Potent Synergistic Action Against Rhodesain, Cysteine Protease of Trypanosoma brucei rhodesiense

by Carla Di Chio, Josè Starvaggi, Santo Previti, Fabiola De Luca, Benito Natale, Sandro Cosconati, Tanja Schirmeister, Maria Zappalà and Roberta Ettari

Pharmaceuticals 2025, 18(6), 847; https://doi.org/10.3390/ph18060847 - 5 Jun 2025

Viewed by 222

Abstract

Background/Objectives: Rhodesain is a cysteine protease crucial for the life cycle of Trypanosoma brucei rhodesiense, a parasite that causes the lethal form of human African trypanosomiasis. For these reasons, rhodesain is considered an important target for the drug discovery process of novel [...] Read more.

Background/Objectives: Rhodesain is a cysteine protease crucial for the life cycle of Trypanosoma brucei rhodesiense, a parasite that causes the lethal form of human African trypanosomiasis. For these reasons, rhodesain is considered an important target for the drug discovery process of novel antitrypanosomal agents. Methods: In the present work, we carried out a combination study of two novel synthetic nitriles, Nitrile 1 and Nitrile 2, with curcumin, the golden multitarget nutraceutical obtained from Curcuma longa L., which we demonstrated to inhibit rhodesain in a non-competitive manner. We calculated the combination index (CI) in both the combination studies by using the Chou and Talalay method. Results: Comparing the CI values of the combinations Nitrile 1 + curcumin and Nitrile 2 + curcumin, we assessed that the inhibitory effect of the combination Nitrile 2 + curcumin against rhodesain was much more potent than that of the other combination. At the IC₅₀ value, in the case of the combination Nitrile 1 + curcumin an additive effect occurred, while in the case of Nitrile 2 + curcumin, we observed a moderate synergism: at 99% of the effect, the synergism induced by the combination Nitrile 2 + curcumin was much stronger than the synergism promoted by the combination Nitrile 1 + curcumin (CI = 0.3843 vs 0.6622, respectively). Conclusions: The co-administration of dipeptide nitriles with curcumin enhances rhodesain inhibition through synergistic effects. Notably, Nitrile 2 + curcumin exhibits a stronger synergy at higher inhibition levels, indicating a greater therapeutic potential. Full article

(This article belongs to the Special Issue Advances in Antiparasitic Drug Research)

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16 pages, 7040 KiB

Open AccessArticle

Exploring the Potential Association Between Inhaled Corticosteroid and Face Aging Risk: A Mendelian Randomization Study

by Junpeng Li, Yaqiong Liu, Gujie Wu, Shanye Yin, Lin Cheng and Wenjun Deng

Pharmaceuticals 2025, 18(6), 846; https://doi.org/10.3390/ph18060846 - 5 Jun 2025

Viewed by 192

Abstract

Background: Asthma is one of the most prevalent chronic diseases, affecting more than 300 million individuals globally. Inhaled corticosteroids (ICSs) are recommended as the primary therapy for managing and preventing asthma symptoms in current treatment guidelines. However, long-term use of ICSs could [...] Read more.

Background: Asthma is one of the most prevalent chronic diseases, affecting more than 300 million individuals globally. Inhaled corticosteroids (ICSs) are recommended as the primary therapy for managing and preventing asthma symptoms in current treatment guidelines. However, long-term use of ICSs could lead to multiple side effects, including skin changes. Methods: We identified ICS target genes using DrugBank and DGIdb databases and derived genetic instruments from cis-eQTL data in whole-blood samples (n = 31,684). GWAS data for facial aging traits (n = 423,999) and plasma metabolites (1400 metabolites, n = 8000) were analyzed. DNA methylation QTL (mQTL) data were used to explore epigenetic regulation. Mendelian randomization (MR) and colocalization analyses were performed to assess causality and shared genetic loci. Results: MR analysis suggested a significant link between genetically proxied ICSs (ORMDL3) and face aging in the European population. Further mediation analysis indicated that 5-Hydroxylysine partially mediates the relationship between ICSs and face aging. In addition, our analysis revealed the pleiotropic association of some novel DNA methylation sites of ORMDL3 with face aging, suggesting the possible regulatory mechanism that are involved in face aging. Conclusions: These findings, while exploratory, raise the hypothesis that ICSs may impact face aging through upregulation of ORMDL3 expression and 5-hydroxylysine metabolism and highlight the need for further pharmacological and clinical research to validate these potential effects. Full article

(This article belongs to the Section Pharmacology)

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23 pages, 7163 KiB

Open AccessArticle

In Silico Investigation of TATA-Binding Protein as a Therapeutic Target for Chagas Disease: Insights into FDA Drug Repositioning

by Carlos Gaona-López, Domingo Méndez-Álvarez, Alonzo Gonzalez-Gonzalez, Guadalupe Avalos-Navarro, Alma D. Paz-González, Adriana Moreno-Rodríguez, Benjamín Nogueda-Torres and Gildardo Rivera

Pharmaceuticals 2025, 18(6), 845; https://doi.org/10.3390/ph18060845 - 4 Jun 2025

Viewed by 178

Abstract

Background: Parasitic diseases, particularly Chagas disease caused by Trypanosoma cruzi, primarily affect developing countries but are now spreading to wealthier nations due to changing migration patterns. With approximately 8 to 9 million cases annually and a rise in drug resistance and side [...] Read more.

Background: Parasitic diseases, particularly Chagas disease caused by Trypanosoma cruzi, primarily affect developing countries but are now spreading to wealthier nations due to changing migration patterns. With approximately 8 to 9 million cases annually and a rise in drug resistance and side effects, there is an urgent need for new therapeutic approaches. Objectives: This study aimed to identify potential pharmacological compounds to target the TATA Binding Protein (TBP) of T. cruzi. Methods: Over eleven thousand FDA-approved pharmacological compounds were analyzed using in silico methods, including homology modeling, molecular docking, and molecular dynamics simulations. In addition, in vitro assays were conducted to assess the trypanocidal activity of promising candidates against T. cruzi epimastigotes and their selectivity toward macrophage J774.2. Results: Two compounds, DB00890 and DB07635, emerged as promising candidates, demonstrating significant potential against T. cruzi TBP. Compound DB00890 had trypanocidal activity against T. cruzi epimastigotes, with IC₅₀ values of 70.4 µM (SI 2.84) and 37.3 µM (SI 5.36) for the NINOA and A1 strains, respectively. Conclusions: Our findings suggest DB00890 is a promising candidate for the development of new agents against Chagas disease, with the potential for targeted therapies that minimize side effects. These results provide a strong foundation for further research into novel treatments for parasitic diseases caused by T. cruzi. Full article

(This article belongs to the Special Issue Drug Discovery and Development for Parasitic Diseases)

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20 pages, 2723 KiB

Open AccessArticle

Natural Nanoparticles for Drug Delivery: Proteomic Insights and Anticancer Potential of Doxorubicin-Loaded Avocado Exosomes

by Dina Salem, Shaimaa Abdel-Ghany, Eman Mohamed, Nada F. Alahmady, Amany Alqosaibi, Ibtesam S. Al-Dhuayan, Mashal Meshal Alnamshan, Rebekka Arneth, Borros Arneth and Hussein Sabit

Pharmaceuticals 2025, 18(6), 844; https://doi.org/10.3390/ph18060844 - 4 Jun 2025

Viewed by 279

Abstract

Background: Exosomes have recently attracted significant attention for their potential in drug delivery. Plant-derived exosomes, in particular, may serve as direct anticancer agents due to their unique characteristics, including immunogenicity, biocompatibility, safety, cell-free nature, and nanoscale structure. Methods: This study characterizes [...] Read more.

Background: Exosomes have recently attracted significant attention for their potential in drug delivery. Plant-derived exosomes, in particular, may serve as direct anticancer agents due to their unique characteristics, including immunogenicity, biocompatibility, safety, cell-free nature, and nanoscale structure. Methods: This study characterizes Persea americana (avocado)-derived exosomes, exploring their anticancer properties, proteomic profile, and therapeutic potential. Results: Isolated exosomes exhibited a diameter of 99.58 ± 5.09 nm (non-loaded) and 151.2 ± 6.36 nm (doxorubicin (DOX)-loaded), with zeta potentials of −17 mV and −28 mV, respectively. Proteomic analysis identified 47 proteins, including conserved exosome markers (GAPDH, tubulin) and stress-response proteins (defensin, endochitinase). Functional enrichment revealed roles in photosynthesis, glycolysis, ATP synthesis, and transmembrane transport, supported by protein–protein interaction networks highlighting energy metabolism and cellular trafficking. DOX encapsulation efficiency was 18%, with sustained release (44.4% at 24 h). In vitro assays demonstrated reduced viability in breast cancer (MCF-7, T47D, 4T1) and endothelial (C166) cells, enhanced synergistically by DOX (Av+DOX). Gene expression analysis revealed cell-specific modulation: Av+DOX upregulated TP53 and STAT in T47D but suppressed both in 4T1/C166, suggesting context-dependent mechanisms. Conclusions: These findings underscore avocado exosomes as promising nanovehicles for drug delivery, combining biocompatibility, metabolic functionality, and tunable cytotoxicity. Their plant-derived origin offers a scalable, low-cost alternative to mammalian exosomes, with potential applications in oncology and targeted therapy. Further optimization of loading efficiency and in vivo validation are warranted to advance translational prospects. Full article

(This article belongs to the Special Issue Recent Advances in Natural Product-Based Nanostructured Systems: 2nd Edition)

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23 pages, 1615 KiB

Open AccessSystematic Review

The Efficacy and Safety Herbal Medicine for Symptom Management After HIFU Treatment in Adenomyosis: A Systematic Review and Meta-Analysis

by Eun-Jin Kim, Young-Shin Shim, Hyun-Kyung Sung and Sang-Yeon Min

Pharmaceuticals 2025, 18(6), 843; https://doi.org/10.3390/ph18060843 - 4 Jun 2025

Viewed by 246

Abstract

Background/Objectives: Adenomyosis (AM) is a hormone-dependent gynecological disorder that negatively impacts the quality of life and fertility of reproductive-age women. This study aimed to evaluate the effectiveness of herbal medicine (HM) as a post-treatment strategy following high-intensity focused ultrasound (HIFU) therapy. Methods: [...] Read more.

Background/Objectives: Adenomyosis (AM) is a hormone-dependent gynecological disorder that negatively impacts the quality of life and fertility of reproductive-age women. This study aimed to evaluate the effectiveness of herbal medicine (HM) as a post-treatment strategy following high-intensity focused ultrasound (HIFU) therapy. Methods: English, Chinese, and Korean databases were systematically searched up to 24 March 2025. Eligible randomized controlled trials (RCTs) compared HM administration after HIFU therapy with HIFU therapy alone. Statistical analyses included mean difference (MD), standardized mean difference (SMD), and risk ratio (RR) with 95% confidence intervals (CIs). Evidence quality was assessed using GRADE approach. The protocol was registered with INPLASY (No.: INPLASY202530088). Results: Fourteen RCTs involving 1259 patients were included in the review. HM administration after HIFU therapy showed superior efficacy over HIFU therapy alone in reducing uterine volume (MD = −11.84, 95% CI: −13.74 to −9.95; p < 0.00001), adenomyotic lesion volume (MD = −2.86, 95% CI: −3.29 to −2.43; p < 0.00001), serum CA125 levels (SMD = −1.49, 95% CI: −2.41 to −0.58; p < 0.00001), serum estradiol (E2) levels (SMD = −1.28, 95% CI: −1.54 to −1.03; p < 0.0001), and improvements in dysmenorrhea (MD = −0.54, 95% CI: −1.06 to −0.02; p < 0.00001) Conclusions: HM may be an effective and safe adjunct to HIFU for managing AM. However, further high-quality RCTs with long-term follow-up are needed to validate these findings. Full article

(This article belongs to the Special Issue Pharmacotherapy of Endometriosis)

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24 pages, 2492 KiB

Open AccessReview

Antioxidant Peptides Derived from Woody Oil Resources: Mechanisms of Redox Protection and Emerging Therapeutic Opportunities

by Jia Tu, Jie Peng, Li Wen, Changzhu Li, Zhihong Xiao, Ying Wu, Zhou Xu, Yuxi Hu, Yan Zhong, Yongjun Miao, Jingjing Xiao and Sisi Liu

Pharmaceuticals 2025, 18(6), 842; https://doi.org/10.3390/ph18060842 - 4 Jun 2025

Viewed by 191

Abstract

Antioxidant peptides derived from woody oil resource by-products exhibit strong free radical scavenging abilities and offer potential applications in functional foods, nutraceuticals, and cosmetics. This review summarizes the latest advances in preparation technologies, including enzymatic hydrolysis, microbial fermentation, chemical synthesis, recombinant expression, and [...] Read more.

Antioxidant peptides derived from woody oil resource by-products exhibit strong free radical scavenging abilities and offer potential applications in functional foods, nutraceuticals, and cosmetics. This review summarizes the latest advances in preparation technologies, including enzymatic hydrolysis, microbial fermentation, chemical synthesis, recombinant expression, and molecular imprinting, each with distinct advantages in yield, selectivity, and scalability. The structure–activity relationships of antioxidant peptides are explored with respect to amino acid composition, molecular weight, and 3D conformation, which collectively determine their bioactivity and stability. Additionally, emerging delivery systems—such as nanoliposomes, microencapsulation, and cell-penetrating peptides—are discussed for their role in enhancing peptide stability, absorption, and targeted release. Mechanistic studies reveal that antioxidant peptides from woody oil resources act through network pharmacology, engaging core signaling pathways, including Nrf2/ARE, PI3K/Akt, AMPK, and JAK/STAT, to regulate oxidative stress, mitochondrial health, and inflammation. Preliminary safety data from in vitro, animal, and early clinical studies suggest low toxicity and favorable tolerability. The integration of omics technologies, molecular docking, and bioinformatics is accelerating the mechanism-driven design and functional validation of peptides. In conclusion, antioxidant peptides derived from woody oil resources represent a sustainable, multifunctional, and scalable solution for improving human health and promoting a circular bioeconomy. Future research should focus on structural optimization, delivery enhancement, and clinical validation to facilitate their industrial translation. Full article

(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)

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13 pages, 3110 KiB

Open AccessArticle

Intraoperative Confocal Laser Endomicroscopy Detects Prostate Cancer at the Single-Cell Level with High Specificity and in Real Time: A Preclinical Proof of Concept

by Ann-Christin Eder, Jessica Matthias, Francois Lacombe, Lisa-Charlotte Domogalla, Antoine Jacques, Nils Steinacker, Gaetan Christien, Elodie Martin, Aline Criton and Matthias Eder

Pharmaceuticals 2025, 18(6), 841; https://doi.org/10.3390/ph18060841 - 4 Jun 2025

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Abstract

In prostate cancer (PCa) surgery, precise tumor margin identification remains challenging despite advances in surgical techniques. This study evaluates the combination of tumor-specific near-infrared imaging with the PSMA-targeting molecule PSMA-914 and optical endomicroscopy (NIR-pCLE) for single-cell-level tumor identification in a preclinical proof of [...] Read more.

In prostate cancer (PCa) surgery, precise tumor margin identification remains challenging despite advances in surgical techniques. This study evaluates the combination of tumor-specific near-infrared imaging with the PSMA-targeting molecule PSMA-914 and optical endomicroscopy (NIR-pCLE) for single-cell-level tumor identification in a preclinical proof of concept. Methods: NIR-pCLE imaging of varying PSMA-914 concentrations was performed on PSMA-positive LNCaP and PSMA-negative PC-3 cells using Cellvizio^® 100 with pCLE Confocal Miniprobes™. To identify optimal PSMA-914 dosing for in vivo imaging, different doses (0–10 nmol) were evaluated using NIR-pCLE, Odyssey CLx imaging, and confocal microscopy in an LNCaP tumor-bearing xenograft model. A proof of concept mimicking a clinical workflow was performed using 5 nmol [⁶⁸Ga]Ga-PSMA-914 in LNCaP and PC-3 tumor xenografts, including PET/MRI, in/ex vivo NIR-pCLE imaging, and microscopic/macroscopic imaging. Results: NIR-pCLE detected PSMA-specific fluorescence at concentrations above 30 nM in vitro. The optimal dose was identified as 5 nmol PSMA-914 for NIR-pCLE imaging with cellular resolution in LNCaP xenografts. PET/MRI confirmed high tumor uptake and a favorable distribution profile of PSMA-914. NIR-pCLE imaging enabled real-time, single-cell-level detection of PSMA-positive tissue, visualizing tumor heterogeneity, confirmed by ex vivo microscopy and imaging. Conclusions: This preclinical proof of concept demonstrates the potential of intraoperative PSMA-specific NIR-pCLE imaging to visualize tissue structures in real time at cellular resolution. Clinical implementation could provide surgeons with valuable additional information, potentially advancing PCa patient care through improved surgical precision. Full article

(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)

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16 pages, 2458 KiB

Open AccessArticle

Evaluating TnP as a Potential Therapeutic Agent for Retinopathy in Zebrafish Models

by João Gabriel Santos Rosa, Jefferson Thiago Gonçalves Bernardo, Yolanda Álvarez, Breandán Kennedy, Carla Lima and Monica Lopes-Ferreira

Pharmaceuticals 2025, 18(6), 840; https://doi.org/10.3390/ph18060840 - 4 Jun 2025

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Abstract

Background: The retina plays a vital role in vision, and its impairment can cause significant visual deficits. Current retinal disease treatments range from conventional anti-inflammatory drugs to advanced anti-VEGF therapies and monoclonal antibodies. TnP, a novel synthetic peptide in preclinical development, has [...] Read more.

Background: The retina plays a vital role in vision, and its impairment can cause significant visual deficits. Current retinal disease treatments range from conventional anti-inflammatory drugs to advanced anti-VEGF therapies and monoclonal antibodies. TnP, a novel synthetic peptide in preclinical development, has demonstrated therapeutic potential in chronic inflammatory conditions such as multiple sclerosis and asthma due to its immunomodulatory properties. Using zebrafish—which share significant genetic homology with humans—we investigated TnP’s effects on retinopathy models mimicking diabetic retinopathy (DR) through either cobalt chloride (CoCl₂)-induced hypoxia or light-induced retinal damage (LIRD). Methods: We employed two retinal injury models (CoCl₂-induced hypoxia and LIRD) and subjected them to TnP treatment, assessing the outcomes through visual–motor response testing and histological examination. Results: CoCl₂ exposure impaired swimming activity, while light damage reduced the movement distance. Both models induced distinct retinal morphological changes. Although TnP failed to reverse most injury effects, it specifically restored the inner plexiform layer (IPL)’s thickness. Conclusions: Our findings suggest that TnP may enhance neuronal plasticity by promoting cell proliferation and synaptic connectivity. While showing promise as a therapeutic candidate for retinal and neurodegenerative disorders, TnP might achieve optimal efficacy when combined with complementary treatments. Full article

(This article belongs to the Special Issue Advances in Ophthalmic Drug Discovery and Delivery: From Targets to Treatments)

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12 pages, 2306 KiB

Open AccessArticle

Rhodococcus rhodochrous IEGM 1362 Immobilized in Macroporous PVA Cryogel as an Effective Biocatalyst for the Production of Bioactive (–)-Isopulegol Compounds

by Polina Y. Maltseva, Natalia A. Plotnitskaya, Alexandra A. Chudinova, Irina V. Ilyina, Konstantin P. Volcho, Nariman F. Salakhutdinov and Irina B. Ivshina

Pharmaceuticals 2025, 18(6), 839; https://doi.org/10.3390/ph18060839 - 3 Jun 2025

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Abstract

Background: This study explored the biotransformation of (–)-isopulegol using immobilized cells of Rhodococcus rhodochrous IEGM 1362 to optimize the production of new bioactive compounds. Methods: An efficient biocatalyst based on R. rhodochrous IEGM 1362 cells immobilized in a macroporous polyvinyl alcohol [...] Read more.

Background: This study explored the biotransformation of (–)-isopulegol using immobilized cells of Rhodococcus rhodochrous IEGM 1362 to optimize the production of new bioactive compounds. Methods: An efficient biocatalyst based on R. rhodochrous IEGM 1362 cells immobilized in a macroporous polyvinyl alcohol (PVA) cryogel matrix was developed for the production of bioactive derivatives of (–)-isopulegol. The biological characteristics of the immobilized cells were investigated using scanning and transmission electron microscopy and energy-dispersive X-ray spectroscopy methods. Results: The use of the biocatalyst increased the overall yield of target products from 54% with free cells to 87% with immobilized cells in a single cycle. Major derivatives identified included (1R,2S,5R)-5-(hydroxymethyl)-2-(prop-1-en-2-yl)cyclohexanol and (1R,3R,4S)-3-hydroxy-4-(prop-1-en-2-yl)cyclohexanecarboxylic acid, both exhibiting potential pharmacological activity. The biocatalyst retained functional activity toward monoterpenoid over 13 exploitation cycles, meeting industrial biotechnology requirements. Immobilized cells were characterized by the absence of endogenous reserve inclusions (in particular lipids) and a high intracellular iron content. Conclusions: The developed immobilized biocatalyst is promising for scaling up the production of biologically active compounds. Full article

(This article belongs to the Section Natural Products)

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Pharmaceuticals, Volume 18, Issue 6 (June 2025) – 104 articles

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