Pharmaceuticals

22 pages, 5125 KB

Open AccessEditor’s ChoiceReview

Ivermectin as an Alternative Anticancer Agent: A Review of Its Chemical Properties and Therapeutic Potential

by Kimberly Naula Robalino, Oscar Vivanco-Galván, Juan Carlos Romero-Benavides and Yuliana Jiménez-Gaona

Pharmaceuticals 2025, 18(10), 1459; https://doi.org/10.3390/ph18101459 - 28 Sep 2025

Viewed by 4620

Abstract

Background: Ivermectin has recently garnered significant scientific attention for its potential anticancer properties. Objective: This research aims a comprehensive literature review to evaluate IVM’s chemical characteristics and assess its applicability as an alternative therapeutic strategy in oncology. Methods: The methodology involved a systematic [...] Read more.

Background: Ivermectin has recently garnered significant scientific attention for its potential anticancer properties. Objective: This research aims a comprehensive literature review to evaluate IVM’s chemical characteristics and assess its applicability as an alternative therapeutic strategy in oncology. Methods: The methodology involved a systematic search and critical appraisal of data from peer-reviewed scientific databases, focusing on structural analyses, such as nuclear magnetic resonance (NMR), crystallography, and in silico modeling, as well as preclinical experimental studies. Results: The review highlights IVM’s distinct physicochemical profile, including high lipophilicity, poor aqueous solubility, and moderate acid stability, which collectively affect its bioavailability and pharmacokinetic behavior. Mechanistically, IVM has been shown to modulate multiple oncogenic signaling pathways, including Wnt/β-catenin, PI3K/Akt/mTOR, and STAT3. These interactions contribute to the induction of apoptosis, inhibition of tumor cell proliferation, and modulation of the tumor microenvironment across a range of malignancies. Despite encouraging preclinical evidence, clinical validation remains limited. Conclusions: Further investigation is needed to optimize IVM’s formulation for enhanced solubility and targeted delivery, as well as to design robust clinical trials assessing its safety and efficacy in oncology settings. This review provides a foundational framework for future interdisciplinary research on drug repurposing and highlights the potential of IVM as a cost-effective and accessible adjunct or alternative to modern cancer therapy. Full article

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

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17 pages, 808 KB

Open AccessEditor’s ChoiceArticle

Development of Orally Disintegrating Tablets of Standardized Rhodiola rosea Extract

by Oxana Brante, Rihards Talivaldis Bagons, Santa Niedra, Austris Mazurs, Baiba Mauriņa, Jurga Bernatoniene and Konstantins Logviss

Pharmaceuticals 2025, 18(9), 1328; https://doi.org/10.3390/ph18091328 - 4 Sep 2025

Viewed by 1959

Abstract

Background/Objectives: Rhodiola rosea L. (Crassulaceae), a perennial adaptogenic herb native to Northern Europe, Asia, and North America, is renowned for its therapeutic properties attributed to phenolic compounds including flavonoids, phenylethanoids, phenylpropanoids, and cinnamyl alcohol glycosides. The plant’s antioxidant and anti-inflammatory [...] Read more.

Background/Objectives: Rhodiola rosea L. (Crassulaceae), a perennial adaptogenic herb native to Northern Europe, Asia, and North America, is renowned for its therapeutic properties attributed to phenolic compounds including flavonoids, phenylethanoids, phenylpropanoids, and cinnamyl alcohol glycosides. The plant’s antioxidant and anti-inflammatory activities align with its traditional use in boosting physical and cognitive performance, reducing fatigue, and improving stress resilience. However, conventional dosage forms present compliance challenges, particularly for vulnerable populations with swallowing difficulties. This study aimed to develop and optimize orally disintegrating tablets (ODTs) containing standardized Rhodiola rosea root and rhizome (RR) dry extract to ensure rapid disintegration and acceptable taste, thereby improving patient compliance. Methods: Dried Rhodiola rosea root and rhizome (particle size 2–3 mm) were extracted using 70% m/m ethanol using the fractionated maceration methodology. The resulting dry RR extract was standardized to 3.0% m/m rosavin content by blending batches of the extract and analyzed using validated chromatographic methods. The standardized dry extract was formulated into ODTs via direct compression technology. Various excipients were evaluated to achieve rapid disintegration while masking the characteristic bitter taste of RR extract. Results: The optimized ODT formulation (500 mg, 11 mm ø, 20% standardized RR dry extract) disintegrated within 3 min and effectively masking the characteristic bitterness of the RR extract. The formulation maintained content uniformity and did not exhibit loss of active compounds during processing, meeting European Pharmacopoeia requirements for ODTs. Conclusions: The developed ODTs containing standardized Rhodiola rosea extract offer a patient-friendly alternative for oro-mucosal administration, supporting improved compliance in populations with swallowing difficulties while retaining the extract’s phytochemical integrity and sensory acceptability. Full article

(This article belongs to the Special Issue Orodispersible and Innovative Dosage Forms: Advances in Preparation Technologies, Direct Compression, and Co-Processed Excipients)

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16 pages, 1984 KB

Open AccessEditor’s ChoiceArticle

Optimized Automated Cassette-Based Synthesis of [⁶⁸Ga]Ga-DOTATOC

by Anton Amadeus Hörmann, Johannes Neumann, Samuel Nadeje, Gregor Schweighofer-Zwink, Gundula Rendl, Theresa Jung, Teresa Kiener, Ruben Lechner, Sylvia Friedl, Ursula Huber-Schönauer, Martin Wolkersdorfer, Mohsen Beheshti and Christian Pirich

Pharmaceuticals 2025, 18(9), 1274; https://doi.org/10.3390/ph18091274 - 26 Aug 2025

Viewed by 1121

Abstract

Background: [⁶⁸Ga]Ga-DOTATOC is widely used in PET imaging of neuroendocrine tumors (NETs) due to its high affinity for somatostatin receptors. Given the short physical half-life of gallium-68 (~68 min), rapid, reproducible, and GMP-compliant synthesis is essential for clinical application. Methods: An [...] Read more.

Background: [⁶⁸Ga]Ga-DOTATOC is widely used in PET imaging of neuroendocrine tumors (NETs) due to its high affinity for somatostatin receptors. Given the short physical half-life of gallium-68 (~68 min), rapid, reproducible, and GMP-compliant synthesis is essential for clinical application. Methods: An optimized cassette-based automated synthesis protocol was developed using a commercial cassette. Improvements included direct generator elution into the reactor without pre-purification, use of a SepPak^® C18 Plus Light cartridge for purification, replacement of HEPES with 0.3 M sodium acetate buffer (final pH ~3.8), and implementation of a non-vented sterile filter enabling automated pressure-hold integrity testing. Results: Across all batches, the synthesis yielded [⁶⁸Ga]Ga-DOTATOC with high radiochemical purity (> 97%) and reproducible decay-corrected radiochemical yields up to 88.3 ± 0.6%. Total synthesis time was approximately 13 min. The final product remained stable for at least 3 h post-synthesis. The use of acetate buffer eliminated the need for HEPES-specific testing, streamlining the workflow. Automated filter testing improved GMP-compliant documentation and reduced radiation exposure for personnel. Conclusions: This optimized, cassette-based synthesis protocol enables fast, high-yield, and GMP-compliant production of [⁶⁸Ga]Ga-DOTATOC. It supports clinical theranostic workflows by ensuring product quality, process standardization, and regulatory compliance. Full article

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

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43 pages, 4354 KB

Open AccessEditor’s ChoiceReview

A Comprehensive Review of Azelaic Acid Pharmacological Properties, Clinical Applications, and Innovative Topical Formulations

by Andreea-Georgiana Petrovici, Mariachiara Spennato, Ioan Bîtcan, Francisc Péter, Livius Cotarcă, Anamaria Todea and Valentin Laurențiu Ordodi

Pharmaceuticals 2025, 18(9), 1273; https://doi.org/10.3390/ph18091273 - 26 Aug 2025

Viewed by 7961

Abstract

Azelaic acid (AzA), a saturated dicarboxylic acid, is indicated for the treatment of acne vulgaris, rosacea, melasma, and post-inflammatory hyperpigmentation. Its antimicrobial, anti-inflammatory, and antimelanogenic properties support its use; however, its poor aqueous solubility and limited skin permeability constrain its optimal topical delivery. [...] Read more.

Azelaic acid (AzA), a saturated dicarboxylic acid, is indicated for the treatment of acne vulgaris, rosacea, melasma, and post-inflammatory hyperpigmentation. Its antimicrobial, anti-inflammatory, and antimelanogenic properties support its use; however, its poor aqueous solubility and limited skin permeability constrain its optimal topical delivery. This review summarizes clinical evidence and advances in formulations—including conventional vehicles, polymeric/lipid nanocarriers, and deep eutectic solvent (DES) systems—to promote more effective and well-tolerated use. Across indications, 15–20% azelaic acid (AzA) formulations produced clinically meaningful improvements with mild, transient local irritation. For acne vulgaris, reductions in inflammatory and noninflammatory lesions were comparable to those of topical retinoids/adapalene, and tolerability was superior in some studies. For rosacea, the 15% gel formulation was comparable to metronidazole in reducing papules, pustules, and erythema while maintaining negligible systemic exposure. In melasma and other dyschromias, 20% cream demonstrated efficacy similar to hydroquinone, exhibiting a favorable safety profile. Advanced delivery systems, including liposomes, niosomes/ethosomes, nanostructured lipid carriers, microemulsions, nanosponges, and DES platforms, increased AzA solubilization, cutaneous deposition, and stability. This enabled dose-sparing strategies and improved adherence. Data on AzA cocrystals and ionic salts suggest additional control over release and irritation. AzA remains a versatile and well-tolerated dermatologic agent whose performance is strongly vehicle-dependent. Rational selection and engineering of carriers, particularly DES-integrated polymeric and lipid systems, can mitigate solubility and permeability limitations, enhance skin targeting, and reduce irritation in the treatment of acne and rosacea. Full article

(This article belongs to the Special Issue Natural Products for Therapeutic Potential)

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28 pages, 1361 KB

Open AccessEditor’s ChoiceReview

Artificial Intelligence in Small-Molecule Drug Discovery: A Critical Review of Methods, Applications, and Real-World Outcomes

by Sarfaraz K. Niazi

Pharmaceuticals 2025, 18(9), 1271; https://doi.org/10.3390/ph18091271 - 26 Aug 2025

Viewed by 3977

Abstract

Artificial intelligence (AI) is emerging as a valuable complementary tool in small-molecule drug discovery, augmenting traditional methodologies rather than replacing them. This review examines the evolution of AI from early rule-based systems to advanced deep learning, generative models, diffusion models, and autonomous agentic [...] Read more.

Artificial intelligence (AI) is emerging as a valuable complementary tool in small-molecule drug discovery, augmenting traditional methodologies rather than replacing them. This review examines the evolution of AI from early rule-based systems to advanced deep learning, generative models, diffusion models, and autonomous agentic AI systems, highlighting their applications in target identification, hit discovery, lead optimization, and safety prediction. We present both successes and failures to provide a balanced perspective. Notable achievements include baricitinib (BenevolentAI/Eli Lilly, an existing drug repurposed through AI-assisted analysis for COVID-19 and rheumatoid arthritis), halicin (MIT, preclinical antibiotic), DSP-1181 (Exscientia, discontinued after Phase I), and ISM001-055/rentosertib (Insilico Medicine, positive Phase IIa results). However, several AI-assisted compounds have also faced challenges in clinical development. DSP-1181 was discontinued after Phase I, despite a favorable safety profile, highlighting that the acceleration of discovery timelines by AI does not guarantee clinical success. Despite progress, challenges such as data quality, model interpretability, regulatory hurdles, and ethical concerns persist. We provide practical insights for integrating AI into drug discovery workflows, emphasizing hybrid human-AI approaches and the emergence of agentic AI systems that can autonomously navigate discovery pipelines. A critical evaluation of current limitations and future opportunities reveals that while AI offers significant potential as a complementary technology, realistic expectations and careful implementation are crucial for delivering innovative therapeutics. Full article

(This article belongs to the Section Medicinal Chemistry)

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17 pages, 3151 KB

Open AccessEditor’s ChoiceArticle

Towards a Consensus for the Analysis and Exchange of TFA as a Counterion in Synthetic Peptides and Its Influence on Membrane Permeation

by Vanessa Erckes, Alessandro Streuli, Laura Chamera Rendueles, Stefanie Dorothea Krämer and Christian Steuer

Pharmaceuticals 2025, 18(8), 1163; https://doi.org/10.3390/ph18081163 - 5 Aug 2025

Viewed by 1931

Abstract

Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as [...] Read more.

Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as a cleavage agent and ion-pairing reagent, respectively, resulting in peptides being obtained as TFA salts. Although TFA has excellent properties for peptide production, numerous studies highlight the negative impact of using peptides from TFA⁻ salts in biological assays. Methods: Investigated peptides were synthesized via SPPS and the TFA⁻ counterion was exchanged for Cl⁻ via freeze-drying in different concentrations of HCl. Detection and quantification of residual TFA⁻ were carried out via FT-IR, ¹⁹F-NMR, and HPLC using an evaporative light-scattering detector (ELSD). A liposomal fluorescence assay was used to test for the influence of the counterion on the peptides’ passive membrane permeability. Results: All TFA⁻ detection methods were successfully validated according to ICH guidelines. TFA⁻ removal with 10 mM HCl was determined to be the optimal condition. No impact on peptide purity was observed at all HCl concentrations. Influences on permeability coefficients depending on peptide sequence and salt form were found. Conclusions: This study presents a systematic investigation of the removal of TFA⁻ counterions from synthetic peptides and their replacement with Cl⁻ counterions. Detected counterion contents were used to understand the impact of sequence differences, especially positive charges, on the amount and potential localization of counterions. Our findings emphasize the importance of counterion quantification and specification in assays with synthetic peptides. Full article

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

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43 pages, 3721 KB

Open AccessEditor’s ChoiceReview

Novel Strategies for the Formulation of Poorly Water-Soluble Drug Substances by Different Physical Modification Strategies with a Focus on Peroral Applications

by Julian Quodbach, Eduard Preis, Frank Karkossa, Judith Winck, Jan Henrik Finke and Denise Steiner

Pharmaceuticals 2025, 18(8), 1089; https://doi.org/10.3390/ph18081089 - 23 Jul 2025

Cited by 2 | Viewed by 4135

Abstract

The number of newly developed substances with poor water solubility continually increases. Therefore, specialized formulation strategies are required to overcome the low bioavailability often associated with this property. This review provides an overview of novel physical modification strategies discussed in the literature over [...] Read more.

The number of newly developed substances with poor water solubility continually increases. Therefore, specialized formulation strategies are required to overcome the low bioavailability often associated with this property. This review provides an overview of novel physical modification strategies discussed in the literature over the past decades and focuses on oral dosage forms. A distinction is made between ‘brick-dust’ molecules, which are characterized by high melting points due to the solid-state properties of the substances, and ‘grease-ball’ molecules with high lipophilicity. In general, the discussed strategies are divided into the following three main categories: drug nanoparticles, solid dispersions, and lipid-based formulations. Full article

(This article belongs to the Collection Feature Review Collection in Pharmaceutical Technology)

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26 pages, 1310 KB

Open AccessEditor’s ChoiceReview

Combination Strategies with HSP90 Inhibitors in Cancer Therapy: Mechanisms, Challenges, and Future Perspectives

by Yeongbeom Kim, Su Yeon Lim, Hyun-Ouk Kim, Suk-Jin Ha, Jeong-Ann Park, Young-Wook Won, Sehyun Chae and Kwang Suk Lim

Pharmaceuticals 2025, 18(8), 1083; https://doi.org/10.3390/ph18081083 - 22 Jul 2025

Cited by 1 | Viewed by 2757

Abstract

Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, [...] Read more.

Heat shock protein 90 (HSP90) is a molecular chaperone that plays a pivotal role in the stabilization and functional activation of numerous oncoproteins and signaling molecules essential for cancer cell survival and proliferation. Despite the extensive development and clinical evaluation of HSP90 inhibitors, their therapeutic potential as monotherapies has been limited by suboptimal efficacy, dose-limiting toxicity, and the emergence of drug resistance. Recent studies have demonstrated that combination therapies involving HSP90 inhibitors and other anticancer agents such as chemotherapeutics, targeted therapies, and immune checkpoint inhibitors can enhance anticancer activity, overcome resistance mechanisms, and modulate the tumor microenvironment. These synergistic effects are mediated by the concurrent degradation of client proteins, the disruption of signaling pathways, and the enhancement of antitumor immunity. However, the successful clinical implementation of such combination strategies requires the careful optimization of dosage, administration schedules, toxicity management, and patient selection based on predictive biomarkers. In this review, we provide a comprehensive overview of the mechanistic rationale, preclinical and clinical evidence, and therapeutic challenges associated with HSP90 inhibitor-based combination therapies. We also discuss future directions leveraging emerging technologies including multi-omics profiling, artificial intelligence, and nanoparticle-mediated delivery for the development of personalized and effective combination regimens in oncology. Full article

(This article belongs to the Special Issue Hsp90 Inhibitors: Progress, Challenges, and Opportunities in Drug Discovery and Development)

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10 pages, 721 KB

Open AccessEditor’s ChoiceArticle

Pharmacokinetic Analysis of the Bioavailability of AQUATURM^®, a Water-Soluble Curcumin Formulation, in Comparison to a Conventional Curcumin Tablet, in Human Subjects

by Lillian Jabur, Rishi Pandey, Meena Mikhael, Garry Niedermayer, Erika Gyengesi, David Mahns and Gerald Münch

Pharmaceuticals 2025, 18(7), 1073; https://doi.org/10.3390/ph18071073 - 21 Jul 2025

Cited by 2 | Viewed by 1545

Abstract

Background/Objectives: Curcumin, the principal bioactive component of Curcuma longa, is known for its anti-inflammatory, antioxidant, and neuroprotective properties. Despite its therapeutic potential, curcumin exhibits poor oral bioavailability due to low solubility, rapid metabolism, and limited gastrointestinal absorption. Various delivery systems have been developed [...] Read more.

Background/Objectives: Curcumin, the principal bioactive component of Curcuma longa, is known for its anti-inflammatory, antioxidant, and neuroprotective properties. Despite its therapeutic potential, curcumin exhibits poor oral bioavailability due to low solubility, rapid metabolism, and limited gastrointestinal absorption. Various delivery systems have been developed to overcome these limitations. This study aimed to evaluate and compare the pharmacokinetic profile of AQUATURM®, a novel, water-soluble curcumin formulation, with that of a widely available commercial curcumin supplement. Methods: A randomized, double-blind, two-period crossover study was conducted in 12 healthy adult participants (6 male, 6 female; aged 20–45 years). Each participant received a single oral dose of either AQUATURM® or the comparator product, followed by a 7-day washout period before receiving the alternate treatment. Blood samples were collected at multiple time points over a 12-h period post-dosing. Plasma curcumin concentrations were quantified using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). Results: AQUATURM® achieved a significantly higher systemic exposure compared to the comparator, with a more than 7-fold increase in area under the curve (AUC_0–12h) and higher peak plasma concentrations (Cmax). AQUATURM® also maintained detectable curcumin levels for the full 12-h observation period, whereas levels from the comparator fell below quantification limits in most participants after 4 h. Conclusions: AQUATURM® significantly enhances curcumin bioavailability in humans compared to a standard curcumin formulation. These pharmacokinetic improvements support its potential for greater clinical efficacy and warrant further evaluation in therapeutic setting Full article

(This article belongs to the Special Issue Phytochemicals and Analogues as Sources of Bioactive Substances of Pharmacological and Industrial Interest)

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27 pages, 891 KB

Open AccessEditor’s ChoiceReview

The Antidiabetic Activity of Wild-Growing and Cultivated Medicinal Plants Used in Romania for Diabetes Mellitus Management: A Phytochemical and Pharmacological Review

by Diana Maria Trasca, Dalia Dop, George-Alin Stoica, Niculescu Stefan Adrian, Niculescu Elena Carmen, Renata Maria Văruț and Cristina Elena Singer

Pharmaceuticals 2025, 18(7), 1035; https://doi.org/10.3390/ph18071035 - 11 Jul 2025

Viewed by 2612

Abstract

Diabetes mellitus is a chronic metabolic disease that has a significant impact on public health and is becoming more and more common worldwide. Although effective, conventional therapies are often limited by high cost, adverse effects, and issues with patient compliance. As a result, [...] Read more.

Diabetes mellitus is a chronic metabolic disease that has a significant impact on public health and is becoming more and more common worldwide. Although effective, conventional therapies are often limited by high cost, adverse effects, and issues with patient compliance. As a result, there is growing interest in complementary and alternative therapies. Medicinal plants have played an essential role in diabetes treatment, especially in regions such as Romania, where biodiversity is high and traditional knowledge is well preserved. The pathophysiology, risk factors, and worldwide burden of diabetes are examined in this review, with an emphasis on the traditional use of medicinal plants for glycemic control. A total of 47 plant species were identified based on ethnopharmacological records and recent biomedical research, including both native flora and widely cultivated species. The bioactive compounds identified, such as flavonoids, triterpenic saponins, polyphenols, and alkaloids, have hypoglycemic effects through diverse mechanisms, including β-cell regeneration, insulin-mimetic action, inhibition of α-glucosidase and α-amylase, and oxidative stress reduction. A systematic literature search was conducted, including in vitro, in vivo, and clinical studies relevant to antidiabetic activity. Among the species reviewed, Urtica dioica, Silybum marianum, and Momordica charantia exhibited the most promising antidiabetic activity based on both preclinical and clinical evidence. Despite promising preclinical results, clinical evidence remains limited, and variability in phytochemical content poses challenges to reproducibility. This review highlights the potential of Romanian medicinal flora as a source of adjunctive therapies in diabetes care and underscores the need for standardization and clinical validation. Full article

(This article belongs to the Section Natural Products)

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12 pages, 1077 KB

Open AccessEditor’s ChoiceSystematic Review

Hawthorn (Crataegus spp.) Clinically Significantly Reduces Blood Pressure in Hypertension: A Meta-Analysis of Randomized Placebo-Controlled Clinical Trials

by Zsóka Szikora, Rebeka Olga Mátyus, Bettina Vargáné Szabó, Dezső Csupor and Barbara Tóth

Pharmaceuticals 2025, 18(7), 1027; https://doi.org/10.3390/ph18071027 - 10 Jul 2025

Cited by 1 | Viewed by 5820

Abstract

Background/Objectives: Hypertension affects over 1.3 billion people globally, and inadequate therapy is reported in 80% of cases. Patients increasingly turn to complementary therapies, including hawthorn (Crataegus spp.), a traditional remedy for cardiovascular diseases. Hawthorn has long been used in folk medicine [...] Read more.

Background/Objectives: Hypertension affects over 1.3 billion people globally, and inadequate therapy is reported in 80% of cases. Patients increasingly turn to complementary therapies, including hawthorn (Crataegus spp.), a traditional remedy for cardiovascular diseases. Hawthorn has long been used in folk medicine to lower blood pressure; however, its efficacy has not been fully established. This meta-analysis aimed to evaluate the antihypertensive effects and safety of hawthorn in randomized, placebo-controlled trials. Methods: A systematic review and meta-analysis were conducted, including six studies with a total of 428 participants. The trials focused on systolic (SBP) and diastolic blood pressure (DBP) changes over treatment periods of 10 weeks to 6 months. Literature searches were conducted in the Embase, PubMed, Cochrane, and Web of Science databases. Studies that met the predefined PICO criteria were included. Data analysis was performed using a random-effects model, and the risk of bias was assessed using the Cochrane Risk of Bias Tool. Results: Hawthorn statistically significantly decreased SBP (MD: −6.65 mmHg; 95% CI [−11.72; 1.59]) and non-significantly reduced DBP (MD: −7.19 mmHg; 95% CI [−15.17; 0.79]) after 2–6 months of treatment. Variations in dosage (250–1200 mg/day) and study protocols contributed to this heterogeneity. Conclusions: The effect of hawthorn on blood pressure is clinically significant. However, larger, well-designed trials are needed to establish optimal dosing, duration, and efficacy with greater reliability. Full article

(This article belongs to the Special Issue Advances in the Mechanism of Action and the Therapeutic Role of Phytopharmaceuticals)

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29 pages, 2844 KB

Open AccessEditor’s ChoiceReview

Hsp90 pan and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy

by Shiying Jia, Neeraj Maurya, Brian S. J. Blagg and Xin Lu

Pharmaceuticals 2025, 18(7), 1025; https://doi.org/10.3390/ph18071025 - 10 Jul 2025

Cited by 1 | Viewed by 2449

Abstract

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of pan-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered [...] Read more.

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of pan-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered by on-target toxicities, particularly ocular and cardiotoxic effects, as well as the induction of pro-survival, compensatory heat shock responses. Together, these and other complications have prompted the development of isoform-selective Hsp90 inhibitors. In this review, we discuss the molecular bases for Hsp90 function and inhibition and emphasize recent advances in isoform-selective targeting. Importantly, we highlight how Hsp90 inhibition can sensitize tumors to cancer immunotherapy by enhancing antigen presentation, reducing immune checkpoint expression, remodeling the tumor microenvironment, and promoting innate immune activation. Special focus is given to Hsp90β-selective inhibitors, which modulate immunoregulatory pathways without eliciting the deleterious effects observed with pan-inhibition. Preclinical and early clinical data support the integration of Hsp90 inhibitors with immune checkpoint blockade and other immunotherapeutic modalities to overcome resistance mechanisms in immunologically cold tumors. Therefore, the continued development of isoform-selective Hsp90 inhibitors offers a promising avenue to potentiate cancer immunotherapy with improved efficacy. Full article

(This article belongs to the Special Issue Hsp90 Inhibitors: Progress, Challenges, and Opportunities in Drug Discovery and Development)

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29 pages, 1953 KB

Open AccessEditor’s ChoiceReview

Targeted Biologic Therapies in Severe Asthma: Mechanisms, Biomarkers, and Clinical Applications

by Renata Maria Văruț, Dop Dalia, Kristina Radivojevic, Diana Maria Trasca, George-Alin Stoica, Niculescu Stefan Adrian, Niculescu Elena Carmen and Cristina Elena Singer

Pharmaceuticals 2025, 18(7), 1021; https://doi.org/10.3390/ph18071021 - 10 Jul 2025

Cited by 3 | Viewed by 3763

Abstract

Asthma represents a heterogeneous disorder characterized by a dynamic balance between pro-inflammatory and anti-inflammatory forces, with allergic sensitization contributing substantially to airway hyperresponsiveness and remodeling. Central to its pathogenesis are cytokines such as IL-4, IL-5, IL-13, IL-17, and IL-33, which drive recruitment of [...] Read more.

Asthma represents a heterogeneous disorder characterized by a dynamic balance between pro-inflammatory and anti-inflammatory forces, with allergic sensitization contributing substantially to airway hyperresponsiveness and remodeling. Central to its pathogenesis are cytokines such as IL-4, IL-5, IL-13, IL-17, and IL-33, which drive recruitment of eosinophils, neutrophils, and other effector cells, thereby precipitating episodic exacerbations in response to viral and environmental triggers. Conventional biomarkers, including blood and sputum eosinophil counts, IgE levels, and fractional exhaled nitric oxide, facilitate phenotypic classification and guide the emerging biologic era. Monoclonal antibodies targeting IgE (omalizumab) and IL-5 (mepolizumab, benralizumab, reslizumab, depemokimab) have demonstrated the ability to reduce exacerbation frequency and improve lung function, with newer agents such as depemokimab offering extended dosing intervals. Itepekimab, an anti-IL-33 antibody, effectively engages its target and mitigates tissue eosinophilia, while CM310-stapokibart, tralokinumab, and lebrikizumab inhibit IL-4/IL-13 signaling with variable efficacy depending on patient biomarkers. Comparative analyses of these biologics, encompassing affinity, dosing regimens, and trial outcomes, underscore the imperative of personalized therapy to optimize disease control in severe asthma. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation with Potential Anti-inflammatory Activity)

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29 pages, 2035 KB

Open AccessEditor’s ChoiceSystematic Review

Dopamine Partial Agonists in Pregnancy and Lactation: A Systematic Review

by Alexia Koukopoulos, Delfina Janiri, Miriam Milintenda, Sara Barbonetti, Georgios D. Kotzalidis, Tommaso Callovini, Lorenzo Moccia, Silvia Montanari, Marianna Mazza, Lucio Rinaldi, Alessio Simonetti, Mario Pinto, Giovanni Camardese and Gabriele Sani

Pharmaceuticals 2025, 18(7), 1010; https://doi.org/10.3390/ph18071010 - 6 Jul 2025

Viewed by 2470

Abstract

Background/Objectives: Dopamine partial agonists are drugs initially developed to treat schizophrenia, seeking a double effect of increased dopaminergic transmission in the prefrontal cortex and decrease in the accumbens/striatum. Of these drugs, aripiprazole, brexpiprazole, and cariprazine are currently marketed and used in schizophrenia [...] Read more.

Background/Objectives: Dopamine partial agonists are drugs initially developed to treat schizophrenia, seeking a double effect of increased dopaminergic transmission in the prefrontal cortex and decrease in the accumbens/striatum. Of these drugs, aripiprazole, brexpiprazole, and cariprazine are currently marketed and used in schizophrenia spectrum and mood disorders. It is debated whether patients with psychiatric disorders becoming pregnant should discontinue or continue their antipsychotic treatment despite some risks for the fetus, i.e., whether it is worse to have an untreated disorder or treating it with drugs. The safety of drugs for mother and baby extend from pregnancy to the postpartum, when breastfeeding assumes great importance. We set to investigate the use of dopamine partial agonists in pregnancy and lactation. Methods: On 23 June 2025, we used suitable strategies for identifying cases and studies of cariprazine, aripiprazole, brexpiprazole, dopamine partial agonists in pregnancy, perinatal period, and/or lactation on PubMed, CINAHL, PsycInfo/PsycArticles, Scopus, and ClinicalTrials.gov. We used the PRISMA Statement in developing our review. We included case reports and clinical studies. We excluded reports without pregnancy or focused on other drugs than the above. We reached consensus on eligibility with Delphi rounds among all authors. Results: Our searches produced 386 results on the above databases. We included 24 case reports/series and 15 studies. Most studies showed no negative pregnancy outcomes. There were serious concerns about the use of dopamine D₂/D₃ partial agonists during lactation. Conclusions: The use of dopamine partial agonists during pregnancy appears to be safe, but during breastfeeding they should be better avoided. Full article

(This article belongs to the Special Issue Pharmaceutical Strategy for Mood Disorders)

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37 pages, 4016 KB

Open AccessEditor’s ChoiceReview

Recent Trends in Bioinspired Metal Nanoparticles for Targeting Drug-Resistant Biofilms

by Devaraj Bharathi and Jintae Lee

Pharmaceuticals 2025, 18(7), 1006; https://doi.org/10.3390/ph18071006 - 5 Jul 2025

Cited by 1 | Viewed by 1678

Abstract

Multidrug-resistant (MDR) biofilm infections characterized by densely packed microbial communities encased in protective extracellular matrices pose a formidable challenge to conventional antimicrobial therapies and are a major contributor to chronic, recurrent and device-associated infections. These biofilms significantly reduce antibiotic penetration, facilitate the survival [...] Read more.

Multidrug-resistant (MDR) biofilm infections characterized by densely packed microbial communities encased in protective extracellular matrices pose a formidable challenge to conventional antimicrobial therapies and are a major contributor to chronic, recurrent and device-associated infections. These biofilms significantly reduce antibiotic penetration, facilitate the survival of dormant persister cells and promote horizontal gene transfer, all of which contribute to the emergence and persistence of MDR pathogens. Metal nanoparticles (MNPs) have emerged as promising alternatives due to their potent antibiofilm properties. However, conventional synthesis methods are associated with high costs, complexity, inefficiency and negative environmental impacts. To overcome these limitations there has been a global push toward the development of sustainable and eco-friendly synthesis approaches. Recent advancements have demonstrated the successful use of various plant extracts, microbial cultures, and biomolecules for the green synthesis of MNPs, which offers biocompatibility, scalability, and environmental safety. This review provides a comprehensive overview of recent trends and the latest progress in the green synthesis of MNPs including silver (Ag), gold (Au), platinum (Pt), and selenium (Se), and also explores the mechanistic pathways and characterization techniques. Furthermore, it highlights the antibiofilm applications of these MNPs emphasizing their roles in disrupting biofilms and restoring the efficacy of existing antimicrobial strategies. Full article

(This article belongs to the Special Issue Challenges in Discovering Innovations Related to Biofilms: Virulence, Spread, Control Strategies and Treatment)

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25 pages, 4259 KB

Open AccessEditor’s ChoiceArticle

Towards Dual-Tracer SPECT for Prostate Cancer Imaging Using [^99mTc]Tc-PSMA-I&S and [¹¹¹In]In-RM2

by Carolina Giammei, Theresa Balber, Veronika Felber, Thomas Dillinger, Jens Cardinale, Marie R. Brandt, Anna Stingeder, Markus Mitterhauser, Gerda Egger and Thomas L. Mindt

Pharmaceuticals 2025, 18(7), 1002; https://doi.org/10.3390/ph18071002 - 3 Jul 2025

Viewed by 1585

Abstract

Background/Objectives: Radiolabeled biomolecules specifically targeting overexpressed structures on tumor cells hold great potential for prostate cancer (PCa) imaging and therapy. Due to heterogeneous target expression, single radiopharmaceuticals may not detect or treat all lesions, while simultaneously applying two or more radiotracers potentially [...] Read more.

Background/Objectives: Radiolabeled biomolecules specifically targeting overexpressed structures on tumor cells hold great potential for prostate cancer (PCa) imaging and therapy. Due to heterogeneous target expression, single radiopharmaceuticals may not detect or treat all lesions, while simultaneously applying two or more radiotracers potentially improves staging, stratification, and therapy of cancer patients. This study explores a dual-tracer SPECT approach using [¹¹¹In]In-RM2 (targeting the gastrin-releasing peptide receptor, GRPR) and [^99mTc]Tc-PSMA-I&S (targeting the prostate-specific membrane antigen, PSMA) as a proof of concept. To mimic heterogeneous tumor lesions in the same individual, we aimed to establish a dual xenograft mouse model for preclinical evaluation. Methods: CHO-K1 cells underwent lentiviral transduction for human GRPR or human PSMA overexpression. Six-to-eight-week-old female immunodeficient mice (NOD SCID) were subsequently inoculated with transduced CHO-K1 cells in both flanks, enabling a dual xenograft with similar target density and growth of both xenografts. Respective dual-isotope imaging and γ-counting protocols were established. Target expression was analyzed ex vivo by Western blotting. Results: In vitro studies showed similar target-specific binding and internalization of [¹¹¹In]In-RM2 and [^99mTc]Tc-PSMA-I&S in transduced CHO-K1 cells compared to reference lines PC-3 and LNCaP. However, in vivo imaging showed negligible tumor uptake in xenografts of the transduced cell lines. Ex vivo analysis indicated a loss of the respective biomarkers in the xenografts. Conclusions: Although the technical feasibility of a dual-tracer SPECT imaging approach using ¹¹¹In and ^99mTc has been demonstrated, the potential of [^99mTc]Tc-PSMA-I&S and [¹¹¹In]In-RM2 in a dual-tracer cocktail to improve PCa diagnosis could not be verified. The animal model, and in particular the transduced cell lines developed exclusively for this project, proved to be unsuitable for this purpose. The in/ex vivo experiments indicated that results from an in vitro model may not necessarily be successfully transferred to an in vivo setting. To assess the potential of this dual-tracer concept to improve PCa diagnosis, optimized in vivo models are needed. Nevertheless, our strategies address key challenges in dual-tracer applications, aiming to optimize future SPECT imaging approaches. Full article

(This article belongs to the Special Issue Challenges in the Development of PET and SPECT Radiotracers: Innovative Ideas with Negative Outcomes)

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27 pages, 1110 KB

Open AccessEditor’s ChoiceSystematic Review

Transdiagnostic Efficacy of Cariprazine: A Systematic Review and Meta-Analysis of Efficacy Across Ten Symptom Domains

by Agota Barabassy, Réka Csehi, Zsófia Borbála Dombi, Balázs Szatmári, Thomas Brevig and György Németh

Pharmaceuticals 2025, 18(7), 995; https://doi.org/10.3390/ph18070995 - 2 Jul 2025

Cited by 1 | Viewed by 3840

Abstract

Introduction: The introduction of the transdiagnostic approach in psychiatry shifts the focus from discrete diagnoses to shared symptoms across various disorders. The Transdiagnostic Global Impression—Psychopathology (TGI-P) scale is a newly developed tool designed to assess psychiatric symptoms across diagnostic boundaries. It evaluates [...] Read more.

Introduction: The introduction of the transdiagnostic approach in psychiatry shifts the focus from discrete diagnoses to shared symptoms across various disorders. The Transdiagnostic Global Impression—Psychopathology (TGI-P) scale is a newly developed tool designed to assess psychiatric symptoms across diagnostic boundaries. It evaluates ten core symptom domains—positive, negative, cognitive, manic, depressive, addiction, anxiety, sleep, hostility, and self-harm—regardless of specific diagnoses. Objective: This study aims to evaluate the efficacy of cariprazine across these ten transdiagnostic symptom domains. Methods: A systematic literature review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were performed on EMBASE and clinicaltrials.gov. Efficacy measures such as the Positive and Negative Syndrome Scale (PANSS), Montgomery–Åsberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), Hamilton Anxiety Rating Scale (HAM-A), and Columbia-Suicide Severity Rating Scale (C-SSRS) were used to assess cariprazine’s effect on the ten transdiagnostic symptoms. Multilevel random-effects meta-analyses were conducted to evaluate the efficacy of cariprazine versus placebo in alleviating depressive and anxiety symptoms across clinical trials. Results: A total of 30 studies were included in the review. Cariprazine showed therapeutic benefits on positive, negative, manic, and depressive symptoms in specifically designed trials. Preliminary positive effects were seen on anxiety, hostility, and cognitive symptoms across disorders. However, specific trials have not been conducted for anxiety disorders or cognitive impairment. Meta-analyses demonstrated that cariprazine significantly reduces both depressive and anxiety symptoms compared to placebo. Cariprazine significantly improved sleep-related symptoms in both mania and depression trials. Suicidality was evaluated in non-suicidal populations, and no increase was observed. Addiction symptoms were part of the exclusion criteria in the RCTs, so they could not be assessed. Previous reports of cariprazine’s anti-craving and anti-abuse effects come from real-world evidence rather than RCT data. Conclusions: Cariprazine appears to be promising in addressing a broad range of symptom domains across psychiatric conditions. Full article

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

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14 pages, 1527 KB

Open AccessEditor’s ChoiceReview

Stem Cells and Organoids: A Paradigm Shift in Preclinical Models Toward Personalized Medicine

by Eleanor Luce and Jean-Charles Duclos-Vallee

Pharmaceuticals 2025, 18(7), 992; https://doi.org/10.3390/ph18070992 - 1 Jul 2025

Cited by 1 | Viewed by 2210

Abstract

Background/Objectives: Human pluripotent stem cells (hPSCs) and organoid technologies are transforming pharmaceutical research by providing models that more accurately reflect human physiology, genetic variability, and disease mechanisms. This review aims to assess how these systems improve the predictive power of preclinical drug [...] Read more.

Background/Objectives: Human pluripotent stem cells (hPSCs) and organoid technologies are transforming pharmaceutical research by providing models that more accurately reflect human physiology, genetic variability, and disease mechanisms. This review aims to assess how these systems improve the predictive power of preclinical drug development while addressing ethical concerns and supporting the advancement of precision medicine. Methods: We conducted a comprehensive review of the recent literature focusing on the biological principles, technological developments, and pharmaceutical applications of hPSC- and organoid-based systems. Particular attention was given to patient-derived models, integration of omics approaches, bioengineering advances, and artificial intelligence applications in drug screening workflows. Results: hPSC- and organoid-based platforms outperform traditional 2D cultures and animal models in replicating human-specific pathophysiology, enabling personalized drug testing and improving predictions of therapeutic efficacy and safety. These technologies also align with the ethical principles of the 3Rs (replacement, reduction, and refinement) by reducing reliance on animal experimentation. However, challenges persist, including standardization of protocols, batch-to-batch variability, and scalability. Promising solutions involve automation, high-throughput screening, and multi-omics integration, which collectively enhance reproducibility and translational relevance. Conclusions: Stem cell- and organoid-based systems offer a more human-relevant, ethical, and individualized approach to biomedical research. Despite current limitations, ongoing interdisciplinary innovations are expected to accelerate their clinical and industrial adoption. Collaborative efforts will be essential to standardize methodologies and fully realize the potential of these models in bridging preclinical and clinical drug development. Full article

(This article belongs to the Special Issue Stem Cells and Organoids as Tools for Drug Development)

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30 pages, 1334 KB

Open AccessEditor’s ChoiceReview

Revolutionizing Prostate Cancer Detection: The Role of Approved PSMA-PET Imaging Agents

by Ute Hennrich, Laurène Wagner, Harun Taş, Luciana Kovacs and Martina Benešová-Schäfer

Pharmaceuticals 2025, 18(6), 906; https://doi.org/10.3390/ph18060906 - 17 Jun 2025

Viewed by 4314

Abstract

Locametz^®/Illuccix^®/Gozellix^TM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [⁶⁸Ga]Ga-PSMA-11), Pylarify^®/Pylclari^® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [¹⁸F]DCFPyL), Radelumin [...] Read more.

Locametz^®/Illuccix^®/Gozellix^TM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [⁶⁸Ga]Ga-PSMA-11), Pylarify^®/Pylclari^® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [¹⁸F]DCFPyL), Radelumin^® (ABX GmbH (Radeberg, Germany), [¹⁸F]PSMA-1007), and Posluma^® (Blue Earth Diagnostics, Ltd. (Oxford, UK), [¹⁸F]rhPSMA-7.3) are four approved PSMA-PET imaging agents that have significantly advanced the diagnosis and management of prostate cancer. These agents offer a new level of precision and accuracy, enabling clinicians to detect prostate cancer with enhanced sensitivity. As a result, they play a critical role in improving detection, staging, and management, ultimately enhancing clinical outcomes for patients. Their use in routine clinical practice is expected to increase diagnostic precision and provide clearer pathways for personalized therapy. This review offers a comprehensive chemical, pharmaceutical, and medicinal overview, discusses comparative studies, and highlights additional highly relevant candidates for prostate cancer detection. Full article

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

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19 pages, 3876 KB

Open AccessEditor’s ChoiceArticle

Improving Ex Vivo Nasal Mucosa Experimental Design for Drug Permeability Assessments: Correcting Mucosal Thickness Interference and Reevaluating Fluorescein Sodium as an Integrity Marker for Chemically Induced Mucosal Injury

by Shengnan Zhao, Jieyu Zuo, Marlon C. Mallillin III, Ruikun Tang, Michael R. Doschak, Neal M. Davies and Raimar Löbenberg

Pharmaceuticals 2025, 18(6), 889; https://doi.org/10.3390/ph18060889 - 13 Jun 2025

Cited by 1 | Viewed by 2281

Abstract

Objectives: Ex vivo nasal mucosa models provide physiologically relevant platforms for evaluating nasal drug permeability; however, their application is often limited by high experimental variability and the absence of standardized methodologies. This study aimed to improve experimental design by addressing two major [...] Read more.

Objectives: Ex vivo nasal mucosa models provide physiologically relevant platforms for evaluating nasal drug permeability; however, their application is often limited by high experimental variability and the absence of standardized methodologies. This study aimed to improve experimental design by addressing two major limitations: the confounding effects of mucosal thickness and the questionable reliability of fluorescein sodium (Flu-Na) as an integrity marker for chemically induced mucosal injury. Methods: Permeability experiments were conducted using porcine nasal tissues mounted in Franz diffusion cells, with melatonin and Flu-Na as model compounds. Tissues of varying thickness were collected from both intra- and inter-individual sources, and a numerical simulation-based method was employed to normalize apparent permeability coefficients (Papp) to a standardized mucosal thickness of 0.80 mm. The effects of thickness normalization and chemically induced damage were systematically evaluated. Results: Thickness normalization substantially reduced variability in melatonin Papp, particularly within same-animal comparisons, thereby improving statistical power and data reliability. In contrast, Flu-Na exhibited inconsistent correlations across different pigs and failed to reflect the expected increase in permeability following isopropyl alcohol (IPA)-induced epithelial damage. These results suggest that the relationship between epithelial injury and paracellular transport may be non-linear and not universally applicable under ex vivo conditions, limiting the suitability of Flu-Na as a standalone marker of mucosal integrity. Conclusions: The findings highlight the importance of integrating mucosal thickness correction into standardized experimental protocols and call for a critical reassessment of Flu-Na in nasal drug delivery research. Full article

(This article belongs to the Section Pharmaceutical Technology)

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15 pages, 970 KB

Open AccessEditor’s ChoiceArticle

Potential Natural Blend Hydrosol TGLON Suppresses the Proliferation of Five Cancer Cell Lines and Also Ameliorates Idiopathic Pulmonary Fibrosis in a Mouse Model

by Wei-Hsiang Huang, Mei-Lin Chang, Ching-Che Lin, Chih-Peng Wang, Feng-Jie Tsai and Chih-Chien Lin

Pharmaceuticals 2025, 18(6), 872; https://doi.org/10.3390/ph18060872 - 11 Jun 2025

Viewed by 2691

Abstract

Background: Cancer and fibrotic diseases represent major global health challenges, underscoring the need for safe, multifunctional natural therapies. Although natural products possess notable anticancer properties, their clinical translation is often hindered by non-selective cytotoxicity toward normal cells. Moreover, their therapeutic potential against chronic [...] Read more.

Background: Cancer and fibrotic diseases represent major global health challenges, underscoring the need for safe, multifunctional natural therapies. Although natural products possess notable anticancer properties, their clinical translation is often hindered by non-selective cytotoxicity toward normal cells. Moreover, their therapeutic potential against chronic conditions such as idiopathic pulmonary fibrosis (IPF) remains insufficiently explored. This study aimed to evaluate the efficacy and safety of a natural hydrosol blend, The Greatest Love of Nature (TGLON), in inhibiting cancer cell proliferation and mitigating IPF. Methods: TGLON, composed of 12 steam-distilled plant hydrosols, was chemically characterized by gas chromatography–mass spectrometry (GC-MS). Its cytotoxicity was assessed using the MTT assay against five human cancer cell lines (A-549, HepG2, MCF-7, MKN-45, and MOLT-4) and normal human lung fibroblasts (MRC-5). In vivo safety and therapeutic efficacy were evaluated in Sprague Dawley rats and a bleomycin-induced IPF mouse model, following protocols approved by the Institutional Animal Care and Use Committee (IACUC). Results: TGLON maintained >90% viability in MRC-5 cells at an 80-fold dilution and significantly inhibited the proliferation of A-549 (41%), HepG2 (84%), MCF-7 (50%), MKN-45 (38%), and MOLT-4 (52%) cells. No signs of toxicity were observed in rats administered TGLON orally at 50% (v/v), 10 mL/kg. In mice, TGLON alleviated bleomycin-induced pulmonary inflammation and fibrosis. Conclusions: TGLON exhibited selective anticancer and anti-fibrotic activities under non-toxic conditions, supporting its potential as a bioactive agent for early-stage disease prevention and non-clinical health maintenance. Full article

(This article belongs to the Special Issue Advances in the Chemical-Biological Knowledge of Essential Oils)

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23 pages, 834 KB

Open AccessEditor’s ChoiceReview

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

Cited by 3 | Viewed by 4686

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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13 pages, 3110 KB

Open AccessEditor’s ChoiceArticle

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

Viewed by 1036

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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30 pages, 2081 KB

Open AccessEditor’s ChoiceReview

The Potential of Artificial Intelligence in Pharmaceutical Innovation: From Drug Discovery to Clinical Trials

by Vera Malheiro, Beatriz Santos, Ana Figueiras and Filipa Mascarenhas-Melo

Pharmaceuticals 2025, 18(6), 788; https://doi.org/10.3390/ph18060788 - 25 May 2025

Cited by 9 | Viewed by 8748

Abstract

Artificial intelligence (AI) is a subfield of computer science focused on developing systems that can execute tasks traditionally associated with human intelligence. AI systems work through algorithms based on rules or instructions that enable the machine to make decisions. With the advancement of [...] Read more.

Artificial intelligence (AI) is a subfield of computer science focused on developing systems that can execute tasks traditionally associated with human intelligence. AI systems work through algorithms based on rules or instructions that enable the machine to make decisions. With the advancement of science, more sophisticated AI techniques, such as machine learning and deep learning, have been developed, allowing machines to learn from large amounts of data and improve their performance over time. The pharmaceutical industry has greatly benefited from the development of this technology. AI has revolutionized drug discovery and development by enabling rapid and effective analysis of vast volumes of biological and chemical data during the identification of new therapeutic compounds. The algorithms developed can predict the efficacy, toxicity, and possible adverse effects of new drugs, optimize the steps involved in clinical trials, reduce associated time and costs, and facilitate the implementation of innovative drugs in the market, making it easier to develop precise therapies tailored to the individual genetic profile of patients. Despite significant advancements, there are still gaps in the application of AI, particularly due to the lack of comprehensive regulation. The constant evolution of this technology requires ongoing and in-depth legislative oversight to ensure its use remains safe, ethical, and free from bias. This review explores the role of AI in drug development, assessing its potential to enhance formulation, accelerate discovery, and repurpose existing medications. It highlights AI’s impact across all stages, from initial research to clinical trials, emphasizing its ability to optimize processes, drive innovation, and improve therapeutic outcomes. Full article

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

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19 pages, 1294 KB

Open AccessEditor’s ChoiceReview

Interferon Lambda: The Next Frontier in Antiviral Therapy?

by Sofia Chronopoulou and Ilias Tsochantaridis

Pharmaceuticals 2025, 18(6), 785; https://doi.org/10.3390/ph18060785 - 24 May 2025

Cited by 4 | Viewed by 4021

Abstract

Type III interferons (IFN-λ) are the most recently identified members of the interferon family, distantly related to type I interferons and members of the interleukin-10 (IL-10). Unlike type I interferons, which have broadly distributed cellular receptors, IFN-λ signals through a heterodimeric receptor complex [...] Read more.

Type III interferons (IFN-λ) are the most recently identified members of the interferon family, distantly related to type I interferons and members of the interleukin-10 (IL-10). Unlike type I interferons, which have broadly distributed cellular receptors, IFN-λ signals through a heterodimeric receptor complex with primary expression on epithelial cells. This restricted receptor distribution makes IFN-λ a favorable candidate for therapeutic and antiviral applications with reduced side effects. In this review, we describe the molecular structure, signaling mechanisms, and the role of IFN-λ in the innate immunity of epithelial tissue, which are its primary sites of action. Moreover, this review will summarize and critically examine the antiviral potential of IFN-λ based on all published clinical trials conducted for the treatment of COVID-19, and hepatitis B, C and D virus. Furthermore, this review suggests IFN-λ as a promising therapeutic recombinant protein, with special emphasis on its potential for production using alternative expression and advanced drug delivery systems. To emphasize its potential as a therapeutic intervention, the design and engineering of recombinant IFN-λ will be presented, with a focus on its lower side-effect profile compared to Type I interferons. Full article

(This article belongs to the Section Biopharmaceuticals)

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13 pages, 1642 KB

Open AccessEditor’s ChoiceArticle

Efficacy and Safety of a Single Ivy Extract Versus Two Herbal Extract Combinations in Patients with Acute Bronchitis: A Multi-Center, Randomized, Open-Label Clinical Trial

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

Pharmaceuticals 2025, 18(5), 754; https://doi.org/10.3390/ph18050754 - 20 May 2025

Cited by 1 | Viewed by 4882

Abstract

Background: The combination therapy for acute bronchitis with several plant extracts, such as Ivy and Thyme or Primrose and Thyme, is assumed to offer added benefit over single extract preparations. However, no clinical trials have yet demonstrated such a therapeutic advantage. Methods [...] Read more.

Background: The combination therapy for acute bronchitis with several plant extracts, such as Ivy and Thyme or Primrose and Thyme, is assumed to offer added benefit over single extract preparations. However, no clinical trials have yet demonstrated such a therapeutic advantage. Methods: In this three-arm, open-label, randomized clinical trial, patients with acute bronchitis were assigned to groups receiving Ivy extract EA 575 (Prospan^® Cough Drops), Ivy/Thyme extract combination (Bronchipret^® Drops), or Thyme/Primrose extract combination (Bronchicum^® Drops) according to their respective labels. The primary endpoint was the assessment of non-inferiority, and the second endpoint was the assessment of superiority of Ivy vs. each of the two comparators (Ivy/Thyme and Thyme/Primrose) regarding the change in Bronchitis Severity Score between baseline and day 7. In total, 325 adult patients were considered for evaluation. Results: Non-inferiority of Ivy extract was statistically significant against both comparators (both p < 0.0001). Superiority of Ivy extract was statistically significant against Ivy/Thyme extract (p < 0.0001) but missed statistical significance against Thyme/Primrose extract (p < 0.0607). The incidence of adverse events was low and comparable between the groups. All adverse events were non-serious. Conclusions: these data revealed that Ivy extract EA 575 is non-inferior in acute bronchitis treatment compared to both comparators and superior to Ivy/Thyme. Full article

(This article belongs to the Section Natural Products)

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27 pages, 550 KB

Open AccessEditor’s ChoiceSystematic Review

Anti-Suicidal Effects of Lithium, Ketamine, and Clozapine—A 10-Year Systematic Review

by Przemyslaw M. Waszak, Jan Opalko, Natalia Olszańska and Paweł Zagożdżon

Pharmaceuticals 2025, 18(5), 742; https://doi.org/10.3390/ph18050742 - 18 May 2025

Cited by 4 | Viewed by 6034

Abstract

Background/Objectives: Suicide is a complex issue resulting in approximately 700,000 deaths annually. Individuals with mood disorders or schizophrenia are at an increased risk. Pharmacological interventions, such as lithium, clozapine, and ketamine, show promise in reducing suicidality. Methods: A systematic search was conducted across [...] Read more.

Background/Objectives: Suicide is a complex issue resulting in approximately 700,000 deaths annually. Individuals with mood disorders or schizophrenia are at an increased risk. Pharmacological interventions, such as lithium, clozapine, and ketamine, show promise in reducing suicidality. Methods: A systematic search was conducted across Google Scholar, Scopus, and PubMed to identify studies evaluating the effects of lithium, clozapine, and ketamine on suicidality. Peer-reviewed articles published between 2014 and 2024 that focused on adult populations were included. After screening 1297 records, 49 studies met the eligibility criteria: 14 on lithium, 23 on ketamine, and 12 on clozapine. Results: Multiple studies highlight lithium’s significant anti-suicidal effects in patients with bipolar disorder, showing superior suicide risk reduction compared to valproate and other mood stabilizers. Ketamine has been shown to rapidly reduce suicidal ideation, with effects observable within hours and lasting up to a week. While most studies support its short-term efficacy, findings regarding its long-term benefits and the impact of repeated dosing remain inconsistent. Clozapine has consistently demonstrated a reduction in suicide risk for individuals with schizophrenia. Large-scale cohort studies report a significant decrease in suicide attempts and mortality when compared to other antipsychotics. Conclusions: Lithium, ketamine, and clozapine were proven to be effective in reducing suicidality. However, limited data, adherence challenges, and methodological differences across studies highlight the need for more robust, large-scale experimental research. Effective suicide prevention is an extremely complex topic and also requires consideration of healthcare and social system factors. Full article

(This article belongs to the Special Issue Recent Advances in Psychiatric Medications)

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13 pages, 544 KB

Open AccessEditor’s ChoiceSystematic Review

The Impact of Methylphenidate on Sexual Functions: A Systematic Review of Benefits and Risks

by Rafał Bieś, Zuzanna Szewczyk, Anna Warchala, Ewa Martyniak and Marek Krzystanek

Pharmaceuticals 2025, 18(5), 718; https://doi.org/10.3390/ph18050718 - 14 May 2025

Viewed by 18958

Abstract

Background: Methylphenidate is a psychostimulant that enhances dopamine and norepinephrine neurotransmission through the mechanism of reuptake inhibition at the synaptic cleft. Studies indicate that sexual dysfunction is prevalent among psychiatric patients. The objective of our study was to assess the impact of methylphenidate [...] Read more.

Background: Methylphenidate is a psychostimulant that enhances dopamine and norepinephrine neurotransmission through the mechanism of reuptake inhibition at the synaptic cleft. Studies indicate that sexual dysfunction is prevalent among psychiatric patients. The objective of our study was to assess the impact of methylphenidate on patients’ sexual health, identify specific types of sexual dysfunction, and analyse the correlations between psychiatric disorders, treatment dosages and durations, and the presence of sexual dysfunction. Additionally, we aimed to evaluate the prevalence of improved sexual function resulting from methylphenidate use. Methods: A systematic literature review was performed using the PubMed database in accordance with PRISMA guidelines. The initial search yielded 186 articles, of which 14 met the inclusion criteria and were analyzed. Clinical studies involving changes in libido, erectile function, ejaculation, semen quality, and sexual behavior due to methylphenidate were reviewed. Results: The findings indicate that methylphenidate can have both negative and positive effects on sexual function. In some patients, particularly those with psychiatric comorbidities, methylphenidate was associated with decreased libido and ejaculation disorders. In other cases, especially in individuals with preexisting dysfunctions or on low doses, it appeared to enhance sexual arousal and performance. Conclusions: Methylphenidate may influence sexual function in complex ways depending on individual patient profiles and treatment variables. Clinicians should be aware of these potential outcomes and consider sexual health as part of the therapeutic discussion when prescribing methylphenidate. Full article

(This article belongs to the Special Issue Toxicological Effects of Drug Abuse and Its Consequences on Health)

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44 pages, 18795 KB

Open AccessEditor’s ChoiceArticle

Citicoline and Coenzyme Q10: Therapeutic Agents for Glial Activation Reduction in Ocular Hypertension

by José A. Matamoros, Sara Rubio-Casado, José A. Fernández-Albarral, Miguel A. Martínez-López, Ana I. Ramírez, Elena Salobrar-García, Eva M. Marco, Victor Paleo-García, Rosa de Hoz, Inés López-Cuenca, Lorena Elvira-Hurtado, Lidia Sánchez-Puebla, José M. Ramírez, Meritxell López-Gallardo and Juan J. Salazar

Pharmaceuticals 2025, 18(5), 694; https://doi.org/10.3390/ph18050694 - 8 May 2025

Cited by 2 | Viewed by 3896

Abstract

Background/Objectives: The loss of retinal ganglion cells (RGCs) is a hallmark of glaucoma, a major cause of blindness. Glial cell activation due to increased intraocular pressure (IOP) significantly contributes to RGC death. Therefore, substances with anti-inflammatory properties could help prevent that process. [...] Read more.

Background/Objectives: The loss of retinal ganglion cells (RGCs) is a hallmark of glaucoma, a major cause of blindness. Glial cell activation due to increased intraocular pressure (IOP) significantly contributes to RGC death. Therefore, substances with anti-inflammatory properties could help prevent that process. This study investigated whether combining Citicoline and Coenzyme Q10 (CoQ10) can reduce glial activation in the retina and the rest of the visual pathway, potentially preventing neurodegeneration in a mouse model of unilateral laser-induced ocular hypertension (OHT). Methods: Four groups of mice were used: vehicle (n = 12), CitiQ10 (n = 12), OHT–vehicle (n = 18), and OHT–CitiQ10 (n = 18). The administration of Citicoline and CoQ10 was performed orally once a day, initiated 15 days prior to the laser treatment and maintained post-treatment until sacrifice (3 days for retina or 7 days for the rest of the visual pathway). The retina, dorsolateral geniculate nucleus, superior colliculus, and visual cortex (V1) were immunohistochemically stained and analyzed. Results: In the laser–CitiQ10 group, the Citicoline + CoQ10 compound revealed (1) an IOP decrease at 24 h and 3 days post-laser; and (2) reduced signs of macroglial (decreased GFAP area) and microglial (soma size, arbor area, microglia number, P2RY12 expression) activation in the retina and in the rest of the visual pathway (reduced activated microglial phenotypes and lower GFAP expression). Conclusions: This study shows that oral administration of Citicoline and CoQ10 can reduce glial activation caused by increased IOP in retina and visual pathway in a mouse model of OHT, potentially protecting RGCs from OHT-induced inflammation. Full article

(This article belongs to the Section Pharmacology)

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22 pages, 3787 KB

Open AccessEditor’s ChoiceArticle

Development of Smart pH-Sensitive Collagen-Hydroxyethylcellulose Films with Naproxen for Burn Wound Healing

by Elena-Emilia Tudoroiu, Mădălina Georgiana Albu Kaya, Cristina Elena Dinu-Pîrvu, Lăcrămioara Popa, Valentina Anuța, Mădălina Ignat, Emilia Visileanu, Durmuș Alpaslan Kaya, Răzvan Mihai Prisada and Mihaela Violeta Ghica

Pharmaceuticals 2025, 18(5), 689; https://doi.org/10.3390/ph18050689 - 7 May 2025

Cited by 2 | Viewed by 1731

Abstract

Background: Developing versatile dressings that offer wound protection, maintain a moist environment, and facilitate healing represents an important therapeutic approach for burn patients. Objectives: This study presents the development of new smart pH-sensitive collagen-hydroxyethylcellulose films, incorporating naproxen and phenol red, designed [...] Read more.

Background: Developing versatile dressings that offer wound protection, maintain a moist environment, and facilitate healing represents an important therapeutic approach for burn patients. Objectives: This study presents the development of new smart pH-sensitive collagen-hydroxyethylcellulose films, incorporating naproxen and phenol red, designed to provide controlled drug release while enabling real-time pH monitoring for burn care. Methods: Biopolymeric films were prepared by the solvent-casting method using ethanol and glycerol as plasticizers. Results: Orange-colored films were thin, flexible, and easily peelable, with uniform, smooth, and nonporous morphology. Tensile strength varied from 0.61 N/mm² to 3.33 N/mm², indicating improved mechanical properties with increasing collagen content, while wetting analysis indicated a hydrophilic surface with contact angle values between 17.61° and 75.51°. Maximum swelling occurred at pH 7.4, ranging from 5.65 g/g to 9.20 g/g and pH 8.5, with values from 4.74 g/g to 7.92 g/g, suggesting effective exudate absorption. In vitro degradation proved structural stability maintenance for at least one day, with more than 40% weight loss. Films presented a biphasic naproxen release profile with more than 75% of the drug released after 24 h, properly managing inflammation and pain on the first-day post-burn. The pH variation mimicking the stages of the healing process demonstrated the color transition from yellow (pH 5.5) to orange (pH 7.4) and finally to bright fuchsia (pH 8.5), enabling easy visual evaluation of the wound environment. Conclusions: New multifunctional films combine diagnostic and therapeutic functions, providing a promising platform for monitoring wound healing, making them suitable for real-time wound assessment. Full article

(This article belongs to the Special Issue Development of Specific Dosage Form: Wound Dressing)

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35 pages, 19345 KB

Open AccessEditor’s ChoiceReview

Natural Antidiabetic Agents: Insights into Ericaceae-Derived Phenolics and Their Role in Metabolic and Oxidative Modulation in Diabetes

by Mihaela Popescu, Kristina Radivojevic, Diana-Maria Trasca, Renata Maria Varut, Irina Enache and Andrei Osman

Pharmaceuticals 2025, 18(5), 682; https://doi.org/10.3390/ph18050682 - 4 May 2025

Cited by 1 | Viewed by 2974

Abstract

Diabetes mellitus (DM) is a chronic disease with a growing prevalence worldwide, leading to severe health complications. Current treatment relies on antidiabetic medications, which may have adverse effects, highlighting the need for alternative approaches. Natural compounds, such as phenolic compounds, have shown promise [...] Read more.

Diabetes mellitus (DM) is a chronic disease with a growing prevalence worldwide, leading to severe health complications. Current treatment relies on antidiabetic medications, which may have adverse effects, highlighting the need for alternative approaches. Natural compounds, such as phenolic compounds, have shown promise in glucose modulation. The Ericaceae family includes several plants with potential antidiabetic properties. This review examines the pathophysiology of diabetes, chemical composition, and specific Ericaceae species that have demonstrated antidiabetic effects. Studies indicate that Vaccinium species and other Ericaceae plants can lower blood glucose levels and improve insulin sensitivity through mechanisms such as enzyme inhibition. These findings suggest that Ericaceae plants may serve as complementary strategies for diabetes management. Full article

(This article belongs to the Section Natural Products)

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27 pages, 764 KB

Open AccessEditor’s ChoiceArticle

Effects of Carnosine Supplementation on Cognitive Outcomes in Prediabetes and Well-Controlled Type 2 Diabetes: A Randomised Placebo-Controlled Clinical Trial

by Rohit Hariharan, Aya Mousa, Kirthi Menon, Jack Feehan, Barbara Ukropcová, Jozef Ukropec, Martin Schön, Arshad Majid, Giancarlo Aldini, Maximilian de Courten, James Cameron, Simon M. Bell and Barbora de Courten

Pharmaceuticals 2025, 18(5), 630; https://doi.org/10.3390/ph18050630 - 26 Apr 2025

Viewed by 3412

Abstract

Background: Trends in global ageing underscore the rising burden of age-related cognitive decline and concomitant cardiometabolic diseases, including type 2 diabetes mellitus (T2DM). Carnosine, a naturally occurring dipeptide with anti-inflammatory, antioxidant and anti-glycating properties, has shown promise in animal models and limited human [...] Read more.

Background: Trends in global ageing underscore the rising burden of age-related cognitive decline and concomitant cardiometabolic diseases, including type 2 diabetes mellitus (T2DM). Carnosine, a naturally occurring dipeptide with anti-inflammatory, antioxidant and anti-glycating properties, has shown promise in animal models and limited human studies for improving cognitive function, insulin resistance and T2DM, but its therapeutic effects on cognition remain unclear. The aim of this study is to assess the effects of carnosine on cognitive function in individuals with prediabetes or well-controlled T2DM. Methods: This is a secondary analysis of a double-blind randomised controlled trial (RCT), whereby 49 adults with prediabetes or early-stage well-controlled T2DM were randomised to receive 2 g of carnosine or identical placebo daily for 14 weeks. At baseline and follow-up, cognitive function was assessed as a secondary outcome using the Digit-Symbol Substitution Test, Stroop test, Trail Making Tests A & B, and the Cambridge Automated Neuropsychological Test Battery (CANTAB). Results: In total, 42 adults (23 males and 19 females) completed the trial. There were no differences in participant anthropometry or cognitive functioning between carnosine and placebo groups at baseline (all p > 0.1). After the 14-week supplementation period, there were no differences between carnosine and placebo groups in change and follow-up values for any cognitive measures including Stroop, Digit Symbol Substitution Sest, Trail Making A/B or CANTAB (all p > 0.05). Adjustments for baseline cognitive scores, diabetic status, level of education, age or interaction effects with participants’ sex did not change the results. Conclusions: Carnosine supplementation did not improve cognitive measures in individuals with prediabetes or T2DM in this study. While larger trials may provide further insights, alternative factors—such as the relatively young and healthy profile of our cohort—may have contributed to the lack of observed effect. Future research should examine individuals with existing cognitive impairment or those at higher risk of cognitive decline to better define the therapeutic potential of carnosine in this context. Full article

(This article belongs to the Special Issue Therapeutic Potential of Natural Products in Internal Diseases)

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23 pages, 8189 KB

Open AccessEditor’s ChoiceReview

Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery

by Taegwan Kim, Eunbee Baek and Jonghoon Kim

Pharmaceuticals 2025, 18(5), 617; https://doi.org/10.3390/ph18050617 - 24 Apr 2025

Cited by 4 | Viewed by 4127

Abstract

Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity to target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein interfaces. However, despite their potential, the synthesis [...] Read more.

Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity to target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein interfaces. However, despite their potential, the synthesis and optimization of macrocyclic compounds present considerable challenges related to structural complexity, synthetic accessibility, and the attainment of favorable drug-like properties, particularly cell permeability and oral bioavailability. Recent advancements in synthetic methodologies have expanded the chemical space accessible to macrocycles, enabling the creation of structurally diverse and pharmacologically active compounds. Concurrent developments in computational strategies have further enhanced macrocycle design, providing valuable insights into structural optimization and predicting molecular properties essential for therapeutic efficacy. Additionally, a deeper understanding of macrocycles’ conformational adaptability, especially their ability to internally shield polar functionalities to improve membrane permeability, has significantly informed their rational design. This review discusses recent innovations in synthetic and computational methodologies that have advanced macrocycle drug discovery over the past five years. It emphasizes the importance of integrating these strategies to overcome existing challenges, illustrating how their synergy expands the therapeutic potential and chemical diversity of macrocycles. Selected case studies underscore the practical impact of these integrated approaches, highlighting promising therapeutic applications across diverse biomedical targets. Full article

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

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40 pages, 1048 KB

Open AccessEditor’s ChoiceReview

Antidiabetic GLP-1 Receptor Agonists Have Neuroprotective Properties in Experimental Animal Models of Alzheimer’s Disease

by Melinda Urkon, Elek Ferencz, József Attila Szász, Monica Iudita Maria Szabo, Károly Orbán-Kis, Szabolcs Szatmári and Előd Ernő Nagy

Pharmaceuticals 2025, 18(5), 614; https://doi.org/10.3390/ph18050614 - 23 Apr 2025

Cited by 7 | Viewed by 6409

Abstract

In addition to the classically accepted pathophysiological features of Alzheimer’s disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The [...] Read more.

In addition to the classically accepted pathophysiological features of Alzheimer’s disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The present review aims to offer a comprehensive overview of the neuroprotective properties of GLP-1R agonists (GLP-1RAs), with a particular focus on experimental animal models of AD. Ameliorated amyloid-β plaque and neurofibrillary tangle formation and deposition following exenatide, liraglutide, and lixisenatide treatment was confirmed in several models. The GLP-1RAs studied alleviated central insulin resistance, as evidenced by the decreased serine phosphorylation of insulin receptor substrate 1 (IRS-1) and restored downstream phosphoinositide 3-kinase/RAC serine/threonine–protein kinase (PI3K/Akt) signaling. Furthermore, the GLP-1RAs influenced multiple mitogen-activated protein kinases (extracellular signal-regulated kinase: ERK; c-Jun N-terminal kinase: JNK, p38) positively and suppressed glycogen synthase kinase 3 (GSK-3β) hyperactivation. A lower proportion of reactive microglia and astrocytes was associated with better neuronal preservation following their administration. Finally, restoration of cognitive functions, particularly spatial memory, was also observed for semaglutide and dulaglutide. GLP-1RAs, therefore, hold promising disease-modifying potential in the management of AD. Full article

(This article belongs to the Special Issue Neurodegenerative Disorders: Computer – Aided Drug Design, Еxperimental Аpproaches and Mechanisms)

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17 pages, 294 KB

Open AccessEditor’s ChoiceReview

Hormonal Treatment of Endometriosis: A Narrative Review

by Elvin Piriyev, Sven Schiermeier and Thomas Römer

Pharmaceuticals 2025, 18(4), 588; https://doi.org/10.3390/ph18040588 - 17 Apr 2025

Cited by 4 | Viewed by 8493

Abstract

Background: Endometriosis is one of the most common gynecological diseases, affecting up to 10–15% of women of reproductive age. It is a chronic, estrogen-dependent condition that often presents with heterogeneous symptoms, complicating diagnosis and delaying treatment. Methods: This is a narrative [...] Read more.

Background: Endometriosis is one of the most common gynecological diseases, affecting up to 10–15% of women of reproductive age. It is a chronic, estrogen-dependent condition that often presents with heterogeneous symptoms, complicating diagnosis and delaying treatment. Methods: This is a narrative review based on a comprehensive analysis of recent literature regarding hormonal treatment options for endometriosis, including primary and adjuvant therapies. Results: Combined oral contraceptives (COCs) are effective in reducing dysmenorrhea, but show limited benefit for other symptoms and may not prevent disease progression. Progestins, particularly dienogest, demonstrate superior long-term efficacy with favorable side-effect profiles. GnRH agonists and antagonists are reserved for second-line treatment due to side effects and hypoestrogenism, but can significantly reduce endometriotic lesions. The levonorgestrel intrauterine system (LNG-IUS) is especially effective in patients with adenomyosis. Conclusions: Hormonal therapies are central to the management of endometriosis. Progestins are considered the most suitable long-term option. Despite promising results, evidence quality varies, and further studies are needed to establish long-term efficacy, patient-specific outcomes, and direct comparisons between agents. Full article

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

31 pages, 3986 KB

Open AccessEditor’s ChoiceArticle

GNNSeq: A Sequence-Based Graph Neural Network for Predicting Protein–Ligand Binding Affinity

by Somanath Dandibhotla, Madhav Samudrala, Arjun Kaneriya and Sivanesan Dakshanamurthy

Pharmaceuticals 2025, 18(3), 329; https://doi.org/10.3390/ph18030329 - 26 Feb 2025

Cited by 5 | Viewed by 5674

Abstract

Background/Objectives: Accurately predicting protein–ligand binding affinity is essential in drug discovery for identifying effective compounds. While existing sequence-based machine learning models for binding affinity prediction have shown potential, they lack accuracy and robustness in pattern recognition, which limits their generalizability across diverse and [...] Read more.

Background/Objectives: Accurately predicting protein–ligand binding affinity is essential in drug discovery for identifying effective compounds. While existing sequence-based machine learning models for binding affinity prediction have shown potential, they lack accuracy and robustness in pattern recognition, which limits their generalizability across diverse and novel binding complexes. To overcome these limitations, we developed GNNSeq, a novel hybrid machine learning model that integrates a Graph Neural Network (GNN) with Random Forest (RF) and XGBoost. Methods: GNNSeq predicts ligand binding affinity by extracting molecular characteristics and sequence patterns from protein and ligand sequences. The fully optimized GNNSeq model was trained and tested on subsets of the PDBbind dataset. The novelty of GNNSeq lies in its exclusive reliance on sequence features, a hybrid GNN framework, and an optimized kernel-based context-switching design. By relying exclusively on sequence features, GNNSeq eliminates the need for pre-docked complexes or high-quality structural data, allowing for accurate binding affinity predictions even when interaction-based or structural information is unavailable. The integration of GNN, XGBoost, and RF improves GNNSeq performance by hierarchical sequence learning, handling complex feature interactions, reducing variance, and forming a robust ensemble that improves predictions and mitigates overfitting. The GNNSeq unique kernel-based context switching scheme optimizes model efficiency and runtime, dynamically adjusts feature weighting between sequence and basic structural information, and improves predictive accuracy and model generalization. Results: In benchmarking, GNNSeq performed comparably to several existing sequence-based models and achieved a Pearson correlation coefficient (PCC) of 0.784 on the PDBbind v.2020 refined set and 0.84 on the PDBbind v.2016 core set. During external validation with the DUDE-Z v.2023.06.20 dataset, GNNSeq attained an average area under the curve (AUC) of 0.74, demonstrating its ability to distinguish active ligands from decoys across diverse ligand–receptor pairs. To further evaluate its performance, we combined GNNSeq with two additional specialized models that integrate structural and protein–ligand interaction features. When tested on a curated set of well-characterized drug–target complexes, the hybrid models achieved an average PCC of 0.89, with the top-performing model reaching a PCC of 0.97. GNNSeq was designed with a strong emphasis on computational efficiency, training on 5000+ complexes in 1 h and 32 min, with real-time affinity predictions for test complexes. Conclusions: GNNSeq provides an efficient and scalable approach for binding affinity prediction, offering improved accuracy and generalizability while enabling large-scale virtual screening and cost-effective hit identification. GNNSeq is publicly available in a server-based graphical user interface (GUI) format. Full article

(This article belongs to the Section Biopharmaceuticals)

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85 pages, 24685 KB

Open AccessEditor’s ChoiceReview

Adaptogens in Long-Lasting Brain Fatigue: An Insight from Systems Biology and Network Pharmacology

by Alexander Panossian, Terrence Lemerond and Thomas Efferth

Pharmaceuticals 2025, 18(2), 261; https://doi.org/10.3390/ph18020261 - 15 Feb 2025

Cited by 4 | Viewed by 11591

Abstract

Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine [...] Read more.

Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine cycle imbalance, glucose metabolism, and ATP energy supply, which are associated with multiple molecular targets and signaling pathways in neuroendocrine-immune and blood circulation systems. Regeneration of damaged brain tissue is a long-lasting multistage process, including spontaneously regulating hypothalamus-pituitary (HPA) axis-controlled anabolic–catabolic homeostasis to recover harmonized sympathoadrenal system (SAS)-mediated function, brain energy supply, and deregulated gene expression in rehabilitation. The driving mechanism of spontaneous recovery and regeneration of brain tissue is a cross-talk of mediators of neuronal, microglia, immunocompetent, and endothelial cells collectively involved in neurogenesis and angiogenesis, which plant adaptogens can target. Adaptogens are small molecules of plant origin that increase the adaptability of cells and organisms to stress by interaction with the HPA axis and SAS of the stress system (neuroendocrine-immune and cardiovascular complex), targeting multiple mediators of adaptive GPCR signaling pathways. Two major groups of adaptogens comprise (i) phenolic phenethyl and phenylpropanoid derivatives and (ii) tetracyclic and pentacyclic glycosides, whose chemical structure can be distinguished as related correspondingly to (i) monoamine neurotransmitters of SAS (epinephrine, norepinephrine, and dopamine) and (ii) steroid hormones (cortisol, testosterone, and estradiol). In this narrative review, we discuss (i) the multitarget mechanism of integrated pharmacological activity of botanical adaptogens in stress overload, ischemic stroke, and long-lasting brain fatigue; (ii) the time-dependent dual response of physiological regulatory systems to adaptogens to support homeostasis in chronic stress and overload; and (iii) the dual dose-dependent reversal (hormetic) effect of botanical adaptogens. This narrative review shows that the adaptogenic concept cannot be reduced and rectified to the various effects of adaptogens on selected molecular targets or specific modes of action without estimating their interactions within the networks of mediators of the neuroendocrine-immune complex that, in turn, regulates other pharmacological systems (cardiovascular, gastrointestinal, reproductive systems) due to numerous intra- and extracellular communications and feedback regulations. These interactions result in polyvalent action and the pleiotropic pharmacological activity of adaptogens, which is essential for characterizing adaptogens as distinct types of botanicals. They trigger the defense adaptive stress response that leads to the extension of the limits of resilience to overload, inducing brain fatigue and mental disorders. For the first time, this review justifies the neurogenesis potential of adaptogens, particularly the botanical hybrid preparation (BHP) of Arctic Root and Ashwagandha, providing a rationale for potential use in individuals experiencing long-lasting brain fatigue. The review provided insight into future research on the network pharmacology of adaptogens in preventing and rehabilitating long-lasting brain fatigue following stroke, trauma, and viral infections. Full article

(This article belongs to the Section Natural Products)

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16 pages, 2977 KB

Open AccessEditor’s ChoiceArticle

Protective Effects of Oleanolic Acid on Human Keratinocytes: A Defense Against Exogenous Damage

by Marzia Vasarri, Maria Camilla Bergonzi, Manuela Leri, Rebecca Castellacci, Monica Bucciantini, Lucia De Marchi and Donatella Degl’Innocenti

Pharmaceuticals 2025, 18(2), 238; https://doi.org/10.3390/ph18020238 - 11 Feb 2025

Cited by 2 | Viewed by 4888

Abstract

Background/objectives: Aging leads to increased oxidative stress and chronic inflammation in the skin, which contribute to various disorders such as dermatitis and cancer. This study explores the cytoprotective effects of oleanolic acid (OA), a natural triterpenoid compound known for its potential in mitigating [...] Read more.

Background/objectives: Aging leads to increased oxidative stress and chronic inflammation in the skin, which contribute to various disorders such as dermatitis and cancer. This study explores the cytoprotective effects of oleanolic acid (OA), a natural triterpenoid compound known for its potential in mitigating oxidative damage, on human keratinocyte (HaCaT) cells exposed to oxidative stress from tert-butyl hydroperoxide (tBHP). Methods: Using in vitro experiments, we assessed cell viability, reactive oxygen species (ROS) levels, nitric oxide (NO) production, and protein expression following OA pre-treatment. Advanced imaging techniques were employed to visualize protein localization. Results: Results demonstrated that OA significantly improved cell viability and reduced intracellular ROS levels compared with those in controls. Additionally, OA inhibited inducible nitric oxide synthase (iNOS) expression and subsequent nitric oxide release, indicating a modulation of inflammatory responses. Notably, while tBHP activated the Nrf2/HO-1 signaling pathway, OA did not enhance this response, suggesting that OA exerts cytoprotective effects through mechanisms independent of Nrf2 activation. Conclusion: OA shows promise in protecting HaCaT cells from tBHP-induced oxidative stress, highlighting its potential role in promoting skin health and addressing aging-related damage. The study proposes that OA operates through pathways distinct from Nrf2 and MAPKs, paving the way for new therapeutic strategies aimed at improving skin health against oxidative stress. Full article

(This article belongs to the Special Issue Natural-Based Skincare Solutions)

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18 pages, 3686 KB

Open AccessEditor’s ChoiceArticle

Drug Repurposing of Voglibose, a Diabetes Medication for Skin Health

by Hyeon-Mi Kim and Chang-Gu Hyun

Pharmaceuticals 2025, 18(2), 224; https://doi.org/10.3390/ph18020224 - 7 Feb 2025

Cited by 1 | Viewed by 3079

Abstract

Background/Objectives: Voglibose, an α-glucosidase inhibitor commonly prescribed to manage postprandial hyperglycemia in diabetes mellitus, demonstrates potential for repurposing as an anti-melanogenic agent. This study aims to explore the inhibitory effects of voglibose on melanogenesis and elucidate its molecular mechanisms, highlighting its possible applications [...] Read more.

Background/Objectives: Voglibose, an α-glucosidase inhibitor commonly prescribed to manage postprandial hyperglycemia in diabetes mellitus, demonstrates potential for repurposing as an anti-melanogenic agent. This study aims to explore the inhibitory effects of voglibose on melanogenesis and elucidate its molecular mechanisms, highlighting its possible applications in treating hyperpigmentation disorders. Methods: The anti-melanogenic effects of voglibose were investigated using B16F10 melanoma cells. Cell viability, melanin content, and tyrosinase activity were assessed following voglibose treatment. Western blot analysis was performed to examine changes in melanogenic proteins and transcription factors. The role of signaling pathways, including PKA/CREB, MAPK, PI3K/AKT, and GSK3β/β-Catenin, was analyzed. Primary human skin irritation tests were conducted to evaluate the topical safety of voglibose. Results: Voglibose significantly reduced melanin synthesis and tyrosinase activity in B16F10 cells in a dose-dependent manner. Western blot analysis revealed decreased expression of MITF, TRP-1, and TRP-2, indicating the inhibition of melanogenesis. Voglibose modulated key signaling pathways, including the suppression of PKA/CREB, MAPK, and AKT activation, while restoring GSK3β activity to inhibit β-catenin stabilization. Human skin irritation tests confirmed voglibose’s safety for topical application, showing no adverse reactions at 50 and 100 μM concentrations. Conclusions: Voglibose demonstrates anti-melanogenic properties through the modulation of multiple signaling pathways and the inhibition of melanin biosynthesis. Its safety profile and efficacy suggest its potential as a repurposed drug for managing hyperpigmentation and advancing cosmeceutical applications. Full article

(This article belongs to the Special Issue Bioactive Substances and Skin Health: The Role of Pharmacy and Nutrition—Properties and Technology)

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19 pages, 2136 KB

Open AccessEditor’s ChoiceReview

Exploring the Therapeutic Potential of Mitragynine and Corynoxeine: Kratom-Derived Indole and Oxindole Alkaloids for Pain Management

by Ahmed S. Alford, Hope L. Moreno, Menny M. Benjamin, Cody F. Dickinson and Mark T. Hamann

Pharmaceuticals 2025, 18(2), 222; https://doi.org/10.3390/ph18020222 - 6 Feb 2025

Cited by 4 | Viewed by 9740

Abstract

The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an [...] Read more.

The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an estimated economic burden of USD 1.5 trillion annually—exceeding the gross domestic product (GDP) of most US industrial sectors. A remarkable breakthrough lies in the discovery that indole and oxindole alkaloids, produced by several genera within the plant Tribe Naucleeae, act on opioid receptors without activating the beta-arrestin-2 pathway, the primary driver of respiratory depression and overdose deaths. This systematic review explores the pharmacological properties, mechanisms of action, dosing considerations, interactions, and long-term effects of mitragynine and corynoxeine, alkaloids from the Southeast Asian plant Mitragyna speciosa (kratom) and others in the Tribe Naucleeae. Mitragynine, a partial opioid receptor agonist, and corynoxeine, known for its anti-inflammatory and neuroprotective effects, demonstrate significant therapeutic potential for managing diverse pain types—including neuropathic, inflammatory, nociceptive, visceral, and central pain syndromes—with a focus on cancer pain. Unlike traditional opioids, these compounds do not recruit beta-arrestin-2, avoiding key adverse effects such as respiratory depression, severe constipation, and rapid tolerance development. Their distinct pharmacological profiles make them innovative candidates for safer, non-lethal pain relief. However, challenges persist, including the unregulated nature of kratom products, inconsistencies in potency due to crude extract variability, potential for misuse, and adverse drug interactions. Addressing these issues requires establishing standardized quality control protocols, such as Good Manufacturing Practices (GMP), to ensure consistent potency and purity. Clear labeling requirements with dosage guidelines and warnings should be mandated to ensure safe use and prevent misuse. Furthermore, the implementation of regulatory oversight to monitor product quality and enforce compliance is essential. This review emphasizes the urgency of focused research to optimize dosing regimens, characterize the pharmacodynamic profiles of these alkaloids, and evaluate long-term safety. By addressing these gaps, the mitragynine- and corynoxeine-related drug classes can transition from promising plant-derived molecules to validated pharmacotherapeutic agents, potentially revolutionizing the field of pain management. Full article

(This article belongs to the Section Natural Products)

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22 pages, 940 KB

Open AccessEditor’s ChoiceReview

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

Cited by 5 | Viewed by 98569

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)

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17 pages, 946 KB

Open AccessEditor’s ChoiceReview

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

Cited by 2 | Viewed by 4402

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 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 3 | Viewed by 2968

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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36 pages, 4971 KB

Open AccessEditor’s ChoiceReview

Coffea arabica: An Emerging Active Ingredient in Dermato-Cosmetic Applications

by Grațiana Ruse, Alex-Robert Jîjie, Elena-Alina Moacă, Dalia Pătrașcu, Florina Ardelean, Alina-Arabela Jojic, Simona Ardelean and Diana-Simona Tchiakpe-Antal

Pharmaceuticals 2025, 18(2), 171; https://doi.org/10.3390/ph18020171 - 27 Jan 2025

Cited by 3 | Viewed by 10422

Abstract

Background: Coffea arabica, commonly known as Arabica coffee, has garnered attention in recent years for its potential applications in dermato-cosmetic formulations. This review aims to critically evaluate the emerging role of Coffea arabica as an active ingredient in skin care products, [...] Read more.

Background: Coffea arabica, commonly known as Arabica coffee, has garnered attention in recent years for its potential applications in dermato-cosmetic formulations. This review aims to critically evaluate the emerging role of Coffea arabica as an active ingredient in skin care products, focusing on its bioactive compounds derived from both the leaves and beans, mechanisms of action, and efficacy in dermatological applications. A comparative analysis between the bioactive profiles of the leaves and beans is also presented to elucidate their respective contributions to dermato-cosmetic efficacy. Results: This review synthesizes findings from various studies that highlight the presence of key bioactive compounds in Coffea arabica, including caffeine, chlorogenic acids, and flavonoids. Notably, the leaves exhibit a higher concentration of certain phenolic compounds compared to the beans, suggesting unique properties that may enhance skin health. These compounds have demonstrated significant anticellulite, anti-inflammatory, antioxidant, photoprotective, anti-aging, antibacterial, and moisturizing properties. Discussion: This article delves into the biochemical pathways through which bioactive compounds derived from both the leaves and beans of Coffea arabica exert their beneficial effects on skin and hair health. Furthermore, this review highlights the growing trend of incorporating natural ingredients in cosmetic formulations and the consumer demand for products with scientifically substantiated benefits. Conclusions: The findings of this review underscore the potential of Coffea arabica as a valuable active ingredient in dermato-cosmetic applications. Its multifaceted bioactivity suggests that it can contribute significantly to skin health and cosmetic efficacy. Future research should focus on clinical trials to further validate these benefits and explore optimal formulation strategies for enhanced delivery and stability in cosmetic products. Full article

(This article belongs to the Special Issue Bioactive Substances and Skin Health: The Role of Pharmacy and Nutrition—Properties and Technology)

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19 pages, 2325 KB

Open AccessEditor’s ChoiceArticle

Development and Blood–Brain Barrier Penetration of Nanovesicles Loaded with Cannabidiol

by Lucia Grifoni, Elisa Landucci, Giuseppe Pieraccini, Costanza Mazzantini, Maria Camilla Bergonzi, Domenico E. Pellegrini-Giampietro and Anna Rita Bilia

Pharmaceuticals 2025, 18(2), 160; https://doi.org/10.3390/ph18020160 - 25 Jan 2025

Cited by 5 | Viewed by 5083

Abstract

Background: Cannabidiol (CBD) is a highly lipophilic compound with potential therapeutic applications in neurological disorders. However, its poor aqueous solubility and bioavailability, coupled with instability in physiological conditions, significantly limit its clinical use. Objectives: This study aimed to develop and characterize nanovesicles [...] Read more.

Background: Cannabidiol (CBD) is a highly lipophilic compound with potential therapeutic applications in neurological disorders. However, its poor aqueous solubility and bioavailability, coupled with instability in physiological conditions, significantly limit its clinical use. Objectives: This study aimed to develop and characterize nanovesicles incorporating Tween 20 to enhance CBD encapsulation, stability, and the performance across the blood–brain barrier (BBB). Methods: Nanovesicles were prepared via thin-film hydration followed by sonication and optimized for size, polydispersity index, and zeta potential. Stability studies were conducted under physiological conditions and during storage at 4 °C. In vitro release studies employed the dialysis bag method, while permeability across the BBB was assessed using PAMPA-BBB and the hCMEC/D3-BBB cell line, characterized for brain endothelial phenotype and largely employed as a model of human blood–brain barrier (BBB) function. Cytotoxicity was evaluated via MTT and LDH assays. Results: The quantification of CBD was carried out by HPLC-DAD and HPLC-MS/MS. Nanovesicles with Tween 20 (VS-CBD) exhibited smaller size (65.27 ± 1.27 nm vs. 90.7 ± 0.2), lower polydispersity (0.230 ± 0.005 vs. 0.295 ± 0.003), and higher stability compared to conventional liposomes (L-CBD). VS-CBD achieved high encapsulation efficiency (96.80 ± 0.96%) and recovery (99.89 ± 0.52%). Release studies showed sustained CBD release with Higuchi model fitting (R² = 0.9901). Both PAMPA-BBB and hCMEC/D3-BBB cell lines demonstrated an improved controlled permeability of the formulation compared to free CBD. Cytotoxicity tests confirmed the good biocompatibility of VS-CBD formulations. The addition of Tween 20 to nanovesicles enhanced CBD encapsulation, stability, and controlled release. Conclusions: These nanovesicles represent a promising strategy to improve CBD delivery to the brain, offering sustained therapeutic effects and reduced dosing frequency, potentially benefiting the treatment of neurological disorders. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabinoid and Its Receptor)

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24 pages, 13681 KB

Open AccessEditor’s ChoiceArticle

Enhancing Tetrahydrocannabinol’s Therapeutic Efficacy in Inflammatory Bowel Disease: The Roles of Cannabidiol and the Cannabinoid 1 Receptor Allosteric Modulator ZCZ011

by Dinesh Thapa, Mohan Patil, Leon N Warne, Rodrigo Carlessi and Marco Falasca

Pharmaceuticals 2025, 18(2), 148; https://doi.org/10.3390/ph18020148 - 23 Jan 2025

Cited by 4 | Viewed by 5079

Abstract

Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic [...] Read more.

Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic effects limit clinical use. ZCZ011, a CB1R allosteric modulator, and cannabidiol (CBD), a non-psychoactive cannabinoid, offer alternatives. This study investigated combining sub-therapeutic THC doses with ZCZ011 or CBD in a murine model of dextran sodium sulphate (DSS)-induced colitis. Methods: Acute colitis was induced with 4% DSS for 7 days, followed by 3 days of water. Chronic colitis was modelled over 24 days with alternating DSS concentrations. The combination of 2.5 mg/kg THC with 20 mg/kg ZCZ011 or 10 mg/kg CBD was evaluated. Key markers were assessed to determine efficacy and safety, including disease activity index (DAI), inflammation, cytokine levels, GLP-1, and organ health. Results: DSS-induced colitis resulted in increased DAI scores, cytokines, organ inflammation and dysregulation of GLP-1 and ammonia. THC at 10 mg/kg significantly improved colitis markers but was ineffective at 2.5 and 5 mg/kg. ZCZ011 alone showed transient effects. However, combining 2.5 mg/kg THC with either 20 mg/kg ZCZ011 or 10 mg/kg CBD significantly alleviated colitis markers, restored colon integrity and reestablished GLP-1 homeostasis. This combination also maintained favourable haematological and biochemical profiles, including a notable reduction in colitis-induced elevated ammonia levels. Conclusions: This study demonstrates the synergistic potential of low-dose THC combined with CBD or ZCZ011 as a novel, effective and safer therapeutic strategy for ulcerative colitis. Full article

(This article belongs to the Special Issue Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success)

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22 pages, 2130 KB

Open AccessEditor’s ChoiceReview

Dual-Labeled Small Peptides in Cancer Imaging and Fluorescence-Guided Surgery: Progress and Future Perspectives

by Paul Minges, Matthias Eder and Ann-Christin Eder

Pharmaceuticals 2025, 18(2), 143; https://doi.org/10.3390/ph18020143 - 22 Jan 2025

Cited by 4 | Viewed by 4833

Abstract

Dual-labeled compounds that combine radiolabeling and fluorescence labeling represent a significant advancement in precision oncology. Their clinical implementation enhances patient care and outcomes by leveraging the high sensitivity of radioimaging for tumor detection and taking advantage of fluorescence-based optical visualization for surgical guidance. [...] Read more.

Dual-labeled compounds that combine radiolabeling and fluorescence labeling represent a significant advancement in precision oncology. Their clinical implementation enhances patient care and outcomes by leveraging the high sensitivity of radioimaging for tumor detection and taking advantage of fluorescence-based optical visualization for surgical guidance. Non-invasive radioimaging facilitates immediate identification of both primary tumors and metastases, while fluorescence imaging assists in decision-making during surgery by offering a spatial distinction between malignant and non-malignant tissue. These advancements hold promise for enhancing patient outcomes and personalization of cancer treatment. The development of dual-labeled molecular probes targeting various cancer biomarkers is crucial in addressing the heterogeneity inherent in cancer pathology and recent studies had already demonstrated the impact of dual-labeled compounds in surgical decision-making (NCT03699332, NCT03407781). This review focuses on the development and application of small dual-labeled peptides in the imaging and treatment of various cancer types. It summarizes the biomarkers targeted to date, tracing their development from initial discovery to the latest advancements in peptidomimetics. Through comprehensive analysis of recent preclinical and clinical studies, the review demonstrates the potential of these dual-labeled peptides to improve tumor detection, localization, and resection. Additionally, it highlights the evolving landscape of dual-modality imaging, emphasizing its critical role in advancing personalized and effective cancer therapy. This synthesis of current research underscores the promise of dual-labeled peptides in enhancing diagnostic accuracy and therapeutic outcomes in oncology. Full article

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

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24 pages, 5476 KB

Open AccessEditor’s ChoiceArticle

Sustainable Skincare Innovation: Cork Powder Extracts as Active Ingredients for Skin Aging

by Ana Silva, Cláudia Pinto, Sara Cravo, Sandra Mota, Liliana Rego, Smeera Ratanji, Clara Quintas, Joana Rocha e Silva, Carlos Afonso, Maria Elizabeth Tiritan, Honorina Cidade, Teresa Cruz and Isabel F. Almeida

Pharmaceuticals 2025, 18(1), 121; https://doi.org/10.3390/ph18010121 - 17 Jan 2025

Cited by 2 | Viewed by 3924

Abstract

Background: An emerging practice within the concept of circular beauty involves the upcycling of agro-industrial by-products. Cork processing, for instance, yields by-products like cork powder, which presents an opportunity to create value-added cosmetic ingredients. Building upon our previous research, demonstrating the antioxidant [...] Read more.

Background: An emerging practice within the concept of circular beauty involves the upcycling of agro-industrial by-products. Cork processing, for instance, yields by-products like cork powder, which presents an opportunity to create value-added cosmetic ingredients. Building upon our previous research, demonstrating the antioxidant potential of hydroalcoholic extracts derived from two distinct cork powders (P0 and P1), in this work, aqueous extracts were prepared and analyzed. The safety and bioactivities of the newly obtained aqueous extracts, as well as the 30% ethanol extracts, previously reported to be the most promising for skin application, were also evaluated. Methods: Aqueous extracts were obtained from cork powders (P0 and P1) and the identification and quantification of some polyphenols was achieved by liquid chromatography (LC). Antioxidant potential was screened by DPPH method and the bioactivity and safety of extracts were further explored using cell-based assays. Results: All extracts exhibited a reduction in age-related markers, including senescence-associated beta-galactosidase (SA-β-gal) activity. Additionally, they demonstrated a pronounced anti-inflammatory effect by suppressing the production of several pro-inflammatory mediators in macrophages upon lipopolysaccharide stimulation. Moreover, the extracts upregulated genes and proteins associated with antioxidant activity, such as heme oxygenase 1. The aqueous extract from P1 powder was especially active in reducing pro-inflammatory mediators, namely the Nos2 gene, inducible nitric oxide protein levels, and nitric oxide production. Moreover, it did not induce skin irritation, as assessed by the EpiSkin test, in compliance with the OECD Test Guidelines. Conclusions: Overall, our findings underscore the potential of aqueous extracts derived from cork waste streams to mitigate various hallmarks of skin aging, including senescence and inflammaging, and their suitability for incorporation into cosmetics formulations. These results warrant further exploration for their application in the pharmaceutical and cosmetic industries and could foster a sustainable and circular bioeconomy. Full article

(This article belongs to the Special Issue Natural-Based Skincare Solutions)

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54 pages, 6031 KB

Open AccessEditor’s ChoiceArticle

(E)-1-(3-(3-Hydroxy-4-Methoxyphenyl)-1-(3,4,5-Trimethoxyphenyl)allyl)-1H-1,2,4-Triazole and Related Compounds: Their Synthesis and Biological Evaluation as Novel Antimitotic Agents Targeting Breast Cancer

by Gloria Ana, Azizah M. Malebari, Sara Noorani, Darren Fayne, Niamh M. O’Boyle, Daniela M. Zisterer, Elisangela Flavia Pimentel, Denise Coutinho Endringer and Mary J. Meegan

Pharmaceuticals 2025, 18(1), 118; https://doi.org/10.3390/ph18010118 - 17 Jan 2025

Cited by 4 | Viewed by 4771

Abstract

Background/Objectives: The synthesis of (E)-1-(1,3-diphenylallyl)-1H-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. Methods: A panel of [...] Read more.

Background/Objectives: The synthesis of (E)-1-(1,3-diphenylallyl)-1H-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. Methods: A panel of 29 compounds was synthesized and examined by a preliminary screening in estrogen receptor (ER) and progesterone receptor (PR)-positive MCF-7 breast cancer cells together with cell cycle analysis and tubulin polymerization inhibition. Results: (E)-5-(3-(1H-1,2,4-triazol-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2-methoxyphenol 22b was identified as a potent antiproliferative compound with an IC₅₀ value of 0.39 mM in MCF-7 breast cancer cells, 0.77 mM in triple-negative MDA-MB-231 breast cancer cells, and 0.37 mM in leukemia HL-60 cells. In addition, compound 22b demonstrated potent activity in the sub-micromolar range against the NCI 60 cancer cell line panel including prostate, melanoma, colon, leukemia, and non-small cell lung cancers. G₂/M phase cell cycle arrest and the induction of apoptosis in MCF-7 cells together with inhibition of tubulin polymerization were demonstrated. Immunofluorescence studies confirmed that compound 22b targeted tubulin in MCF-7 cells, while computational docking studies predicted binding conformations for 22b in the colchicine binding site of tubulin. Compound 22b also selectively inhibited aromatase. Conclusions: Based on the results obtained, these novel compounds are suitable candidates for further investigation as antiproliferative microtubule-targeting agents for breast cancer. Full article

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

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35 pages, 7073 KB

Open AccessEditor’s ChoiceReview

Anti-Biofilm Agents to Overcome Pseudomonas aeruginosa Antibiotic Resistance

by Marie Hanot, Elodie Lohou and Pascal Sonnet

Pharmaceuticals 2025, 18(1), 92; https://doi.org/10.3390/ph18010092 - 13 Jan 2025

Cited by 2 | Viewed by 8495

Abstract

Pseudomonas aeruginosa is one of world’s most threatening bacteria. In addition to the emerging prevalence of multi-drug resistant (MDR) strains, the bacterium also possesses a wide variety of virulence traits that worsen the course of the infections. Particularly, its ability to form biofilms [...] Read more.

Pseudomonas aeruginosa is one of world’s most threatening bacteria. In addition to the emerging prevalence of multi-drug resistant (MDR) strains, the bacterium also possesses a wide variety of virulence traits that worsen the course of the infections. Particularly, its ability to form biofilms that protect colonies from antimicrobial agents is a major cause of chronic and hard-to-treat infections in immune-compromised patients. This protective barrier also ensures cell growth on abiotic surfaces and thus enables bacterial survival on medical devices. Hence, as the WHO alerted to the need to develop new treatments, the use of anti-biofilm agents (ABAs) appeared as a promising approach. Given the selection pressure imposed by conventional antibiotics, a new therapeutic strategy has emerged that aims at reducing bacterial virulence without inhibiting cell growth. So-called anti-virulence agents (AVAs) would then restore the efficacy of conventional antibiotics (ATBs) or potentiate the effectiveness of the immune system. The last decade has seen the development of ABAs as AVAs against P. aeruginosa. This review aims to highlight the design strategy and critical features of these molecules to pave the way for further discoveries of highly potent compounds. Full article

(This article belongs to the Special Issue New Approaches to Fighting Infectious Diseases: Overcoming the Antimicrobial Resistance in Current Treatments)

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