Pharmaceuticals

16 pages, 2460 KB

Open AccessEditor’s ChoiceArticle

Enhanced Tumor-to-Background Contrast with [⁵²Mn]Mn-BPPA-Bevacizumab VEGF-Targeted Immuno-PET in Cervical Cancer

by Csaba Csikos, Minh Toàn Ngô, Adrienn Vágner, Gábor Nagy, Gábor Ország, Tamás Nagy, Balázs Váradi, Gergő Zoltán Sajtos, István Kapus, Zoltán Szoboszlai, Dezső Szikra, Gyula Tircsó, Zoárd Tibor Krasznai, Szabolcs Molnár, Ildikó Garai and György Trencsényi

Pharmaceuticals 2026, 19(3), 517; https://doi.org/10.3390/ph19030517 - 22 Mar 2026

Cited by 1 | Viewed by 1465

Abstract

Background/Objectives: Radiolabeled bevacizumab-based immuno-PET tracers enable a non-invasive quantification of VEGF-A expression in gynecologic malignancies. While the previously reported [⁵²Mn]Mn-DOTAGA-bevacizumab demonstrated selective VEGF-A-targeted uptake in a KB-3-1 cervix carcinoma mouse model, further improvements in chelator stability and tumor-to-background contrast remain [...] Read more.

Background/Objectives: Radiolabeled bevacizumab-based immuno-PET tracers enable a non-invasive quantification of VEGF-A expression in gynecologic malignancies. While the previously reported [⁵²Mn]Mn-DOTAGA-bevacizumab demonstrated selective VEGF-A-targeted uptake in a KB-3-1 cervix carcinoma mouse model, further improvements in chelator stability and tumor-to-background contrast remain desirable. The recently developed BPPA chelator exhibits exceptionally high Mn(II) complex stability and favorable radiolabeling characteristics. This study aimed to characterize the in vivo biodistribution of [⁵²Mn]Mn-BPPA-bevacizumab, and to compare the tumor-to-background ratios of [⁵²Mn]Mn-BPPA-bevacizumab with the previously published values of [⁵²Mn]Mn-DOTAGA-bevacizumab in VEGF-A-expressing cervix carcinoma. Methods: Female KB-3-1 tumor-bearing CB17 SCID mice underwent PET/MRI imaging following intravenous administration of [⁵²Mn]Mn-BPPA-bevacizumab. SUV_mean values were measured in various organs and in the subcutaneously injected tumor, and tumor-to-organ ratios were calculated at various time points up to 10 days post-injection. Results: [⁵²Mn]Mn-BPPA-bevacizumab demonstrated sustained tumor uptake, with tumor SUVmean values increasing from approximately 1.0 at 4 h to peak values of approximately 2.4–2.5 at 72 h post-injection. Tumor-to-background ratios increased progressively over time and were significantly higher for [⁵²Mn]Mn-BPPA-bevacizumab compared with previously reported [52Mn]Mn-DOTAGA-bevacizumab, particularly for tumor-to-blood, tumor-to-liver and tumor-to-lung ratios at later imaging time points (p < 0.0001). Conclusions: The novel [⁵²Mn]Mn-BPPA-bevacizumab tracer exhibits satisfactory in vitro and in vivo stability for PET imaging, high VEGF-A-specific tumor uptake, and markedly improved tumor-to-background ratios compared to the previously published DOTAGA-based probe. These results position [⁵²Mn]Mn-BPPA-bevacizumab as a highly promising next-generation immuno-PET agent for imaging VEGF-A-expressing gynecologic malignancies and for guiding anti-angiogenic therapies. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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13 pages, 3228 KB

Open AccessEditor’s ChoiceArticle

Employment of a Resazurin Viability-Based Assay for Minimum Inhibitory and Bactericidal Concentration Determination

by Lorena G. Calvo, Stephanya Corral-Orbe, Rosa-Antía Villarino, Sandra Sánchez and Trinidad de Miguel

Pharmaceuticals 2026, 19(3), 505; https://doi.org/10.3390/ph19030505 - 19 Mar 2026

Cited by 2 | Viewed by 2376

Abstract

Background/Objectives: The increasing prevalence of antimicrobial-resistant bacteria highlights the need for improved methodologies to evaluate antimicrobial activity beyond conventional minimum inhibitory concentration testing. While resazurin-based assays are widely used for minimum inhibitory concentration determination due to their simplicity and sensitivity, minimum bactericidal [...] Read more.

Background/Objectives: The increasing prevalence of antimicrobial-resistant bacteria highlights the need for improved methodologies to evaluate antimicrobial activity beyond conventional minimum inhibitory concentration testing. While resazurin-based assays are widely used for minimum inhibitory concentration determination due to their simplicity and sensitivity, minimum bactericidal concentration assessment still relies on labor-intensive colony-forming unit counting. The objective of this study was to develop and validate a resazurin-based microwell assay capable of determining both the minimum inhibitory concentration and the minimum bactericidal concentration without routine plate counting, thereby simplifying bactericidal evaluation. Methods: A two-step resazurin-based fluorescence assay was designed and performed in microplates. After determining the minimum inhibitory concentration using resazurin as a metabolic indicator, well-showing inhibited bacterial growths were subjected to a regrowth phase by transferring aliquots into fresh antimicrobial-free medium containing resazurin. This additional step allowed discrimination between reversible metabolic inhibition and irreversible bacterial death. The method was evaluated using ciprofloxacin and chloramphenicol against four bacterial species: Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa. Minimum bactericidal concentration values obtained using this assay were compared with those obtained through conventional colony counting on agar plates. Results: Minimum bactericidal concentration values obtained using the two-step fluorescence assay were fully concordant with the conventional colony-forming unit counting method for all tested antibiotics and bacterial species. Conclusions: The proposed two-step resazurin-based microwell assay represents a rapid, reliable, and less labor-intensive alternative for the determination of both the minimum inhibitory concentration and the minimum bactericidal concentration, with potential applications in clinical and industrial microbiology laboratories. Full article

(This article belongs to the Section Natural Products)

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19 pages, 2580 KB

Open AccessEditor’s ChoiceArticle

Quantitative Analysis of the Vitamin D₃ Content in Dietary Supplements Marketed in Hungary Using High-Performance Liquid Chromatography

by András Nagy, Róbert György Vida, Eszter Fliszár-Nyúl, Gábor Lovász, Katalin Fábián and Gábor Pozsgai

Pharmaceuticals 2026, 19(3), 493; https://doi.org/10.3390/ph19030493 - 17 Mar 2026

Viewed by 2025

Abstract

Background/Objectives: The use of over-the-counter vitamin D₃ supplements has increased substantially in recent years. Compared with pharmaceuticals, dietary supplements are subject to less stringent regulatory oversight, raising concerns regarding labeling accuracy, consumer knowledge, and patient safety. This study aimed to assess public [...] Read more.

Background/Objectives: The use of over-the-counter vitamin D₃ supplements has increased substantially in recent years. Compared with pharmaceuticals, dietary supplements are subject to less stringent regulatory oversight, raising concerns regarding labeling accuracy, consumer knowledge, and patient safety. This study aimed to assess public knowledge and preferences related to vitamin D₃ supplementation and to evaluate the content accuracy and short-term stability of commonly used products. Methods: A cross-sectional online survey containing 39 questions was conducted in Hungary between 1 May and 30 June 2024. Based on survey responses, the most frequently used vitamin D₃ supplements (five soft gel capsules and four tablets) were selected for laboratory analysis. Vitamin D₃ content was quantified using a validated high-performance liquid chromatography (HPLC) method with UV detection. Soft gel capsules were additionally exposed to natural daylight for one month to assess short-term photostability. Results: In total, 367 participants (mean age 31.0 ± 12.5 years) completed the survey, and only 3.5% answered correctly all knowledge-based questions. Six commonly reported supplement brands accounted for approximately 90% of responses. Measured vitamin D₃ content remained within the tolerance limit (−20% to +50%). Following sunlight exposure, three of four capsule products showed no substantial vitamin D₃ loss, while one exhibited a 14.7% decrease. Conclusions: Most analyzed vitamin D₃ supplements complied with labeled content claims, but substantial knowledge gaps were identified that may affect patient safety. The validated HPLC method supports pharmacovigilance-oriented quality monitoring of vitamin D₃ supplements and underscores the need for improved professional counseling. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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52 pages, 4585 KB

Open AccessEditor’s ChoiceReview

Expanding the Antimicrobial Toolbox with Therapeutic Viruses: Mechanisms, Pharmaceutical Formulation, and Translational Outlook

by Margarita Strimaite, Holly A. Bailey, Diba Keyhanfar, Roxy Lee and Gareth R. Williams

Pharmaceuticals 2026, 19(3), 478; https://doi.org/10.3390/ph19030478 - 14 Mar 2026

Viewed by 1884

Abstract

Infectious diseases continue to represent one of the most persistent challenges in human health and agricultural productivity. These diseases are caused by a wide range of pathogenic microorganisms, including bacteria, fungi, viruses, and parasites. Antimicrobial resistance, or AMR, is the gradual evolution of [...] Read more.

Infectious diseases continue to represent one of the most persistent challenges in human health and agricultural productivity. These diseases are caused by a wide range of pathogenic microorganisms, including bacteria, fungi, viruses, and parasites. Antimicrobial resistance, or AMR, is the gradual evolution of pathogenic microbes to evade the action of commonly used antimicrobial agents (antibiotics, antifungals, antivirals, and antiparasitics) and is a problem that continues to be exacerbated by the inappropriate use of antimicrobials across multiple global industries. AMR poses a major threat to our society, and without mitigation, will lead to devastating consequences with broad implications beyond human health. The search for alternative or complementary therapies to conventional antimicrobials is, therefore, of the utmost priority. In this review, we first outline the prevalence of AMR and the circumstances driving the proliferation of AMR, which is widely recognised as a One Health issue—through interconnected factors within human and veterinary medicine, agricultural practice, and the environment. We next summarise the various classes of pathogens, common antimicrobial agents, and the mechanisms which pathogens have evolved to evade antimicrobial action. Within this context, we discuss the therapeutic potential of bacteriophages, virophages, and mycoviruses against antimicrobial-resistant infections, and consider the future perspectives of virus-based formulations. Full article

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

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13 pages, 234 KB

Open AccessEditor’s ChoiceProtocol

Fecal Microbiota Transplantation (FMT) as a Prophylaxis of Necrotizing Enterocolitis (NEC)—Protocol for a Safety Study

by Ewa A. Bieganska, Marek Wolski, Magdalena Zarlenga, Jaroslaw Bilinski and Przemyslaw Kosinski

Pharmaceuticals 2026, 19(3), 437; https://doi.org/10.3390/ph19030437 - 9 Mar 2026

Cited by 2 | Viewed by 968

Abstract

Background/Objectives: Necrotizing enterocolitis (NEC) is an inflammatory disease with an incidence of about one in 1000 live births, much higher in premature and low birth weight newborns. Intestinal dysbiosis is an important element in the pathogenesis of NEC, and for this reason, [...] Read more.

Background/Objectives: Necrotizing enterocolitis (NEC) is an inflammatory disease with an incidence of about one in 1000 live births, much higher in premature and low birth weight newborns. Intestinal dysbiosis is an important element in the pathogenesis of NEC, and for this reason, experimental models have been used to administer fecal microbiota transplants (FMTs) for prophylaxis and treatment of NEC with very satisfactory results. The primary endpoint of the study is safety, defined as the incidence of adverse events (AEs) and serious adverse events (SAEs) occurring from the time of intervention until hospital discharge, classified according to severity and assessed for relatedness to the intervention. Methods: This prospective, single-arm, open-label clinical study will include 20 infants born between 24 0/7 and 36 6/7 weeks of gestation. FMTs will be administered twice as a deep rectal infusion via a Foley catheter. The donors of the material from which the FMT will be prepared will be women in the third trimester of pregnancy. The safety of the therapy will be assessed by comparison with a control group, i.e., 20 patients who will meet the same inclusion criteria and will not meet any of the exclusion criteria, subject to the same hospital observation but without undergoing any medical/therapeutic intervention other than the collection of biological material. Discussion: The study will provide data on the safety and initial efficacy of FMT in this group of patients, which will allow for further research into the use of this method in the prevention of infections and NEC. Ethics: The study protocol was approved by the Bioethics Committee of the Medical University of Warsaw, Warsaw, Poland (KB/52/2025). All procedures will follow the principles of the Declaration of Helsinki. The results of the study will be submitted for knowledge translation in peer-reviewed journals and presented at national and international pediatric society conferences. Clinical Trial Registration: The study is registered at ClinicalTrials.gov: ID: NCT06333405. Full article

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

25 pages, 413 KB

Open AccessEditor’s ChoiceReview

Efficacy and Safety of Herbal Supplements with Anxiolytic, Antidepressant, and Sedative Action: A Review of Clinical Data and Toxicological Risks

by Maria-Nina Căuș, Mariana Lupoae and Carmen Lidia Chițescu

Pharmaceuticals 2026, 19(3), 399; https://doi.org/10.3390/ph19030399 - 28 Feb 2026

Cited by 2 | Viewed by 6372

Abstract

Background/Objectives: Plant-based supplements are widely used for the management of anxiety, depression, and insomnia. Despite their over-the-counter availability and perceived safety, these products may pose relevant pharmacological and toxicological risks. This narrative review critically evaluates clinical evidence on commonly used herbal preparations, with [...] Read more.

Background/Objectives: Plant-based supplements are widely used for the management of anxiety, depression, and insomnia. Despite their over-the-counter availability and perceived safety, these products may pose relevant pharmacological and toxicological risks. This narrative review critically evaluates clinical evidence on commonly used herbal preparations, with particular emphasis on herb–drug interactions, adverse effects, and issues related to product adulteration. Methods: Major scientific databases (PubMed, Scopus, and Web of Science) were searched to identify clinical studies evaluating plant-based supplements for mental health and sleep disorders. Data on study design, dosage, efficacy, and adverse events were analyzed, together with regulatory information and reports of product adulteration and quality concerns. Results: Herbal supplements such as Hypericum perforatum, Passiflora incarnata, Valeriana officinalis, Piper methysticum, Withania somnifera, Crocus sativus, and Curcuma longa demonstrated anxiolytic, antidepressant, and sedative effects in clinical studies, with improvements in mood, stress levels, and sleep quality. Proposed mechanisms include modulation of monoaminergic and GABAergic pathways, serotonergic activity, regulation of the hypothalamic–pituitary–adrenal axis, and anti-inflammatory effects. However, clinically relevant risks were identified, including cytochrome P450–mediated drug interactions, excessive sedation, serotonin syndrome, and toxic effects associated with adulterated products, such as hepatotoxicity, cardiovascular events, and neurological disturbances. Conclusions: While plant-based supplements may provide clinically meaningful benefits for anxiety, depression, and insomnia, their use requires careful clinical monitoring due to potential pharmacokinetic and pharmacodynamic interactions and safety concerns. Increased awareness of herb–drug interactions and stricter quality control are essential to optimize therapeutic outcomes and minimize harm. Full article

(This article belongs to the Section Natural Products)

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41 pages, 5770 KB

Open AccessEditor’s ChoiceReview

Azole–Flavonoid Hybrids as Emerging Anticancer Agents: A Bioactivity-Focused Review

by Mihaela Lipovanu, Anca Miron, Nina Filip, Cristina Elena Horhogea and Ana Clara Aprotosoaie

Pharmaceuticals 2026, 19(2), 338; https://doi.org/10.3390/ph19020338 - 20 Feb 2026

Viewed by 2130

Abstract

Despite notable progress in drug discovery, cancer treatment remains hindered by limited therapeutic efficacy, poor target specificity, adverse effects, and the development of drug resistance. Molecular hybridization, which integrates two or more bioactive entities into a single molecule, has shown considerable potential to [...] Read more.

Despite notable progress in drug discovery, cancer treatment remains hindered by limited therapeutic efficacy, poor target specificity, adverse effects, and the development of drug resistance. Molecular hybridization, which integrates two or more bioactive entities into a single molecule, has shown considerable potential to overcome these limitations. Since both azoles and flavonoids have demonstrated anticancer potential, extensive studies have been undertaken to combine the two entities and enhance the bioactivity of the resulting hybrids. In this context, numerous azole–flavonoid hybrids have been synthesized and investigated for their anticancer potential. This review provides an overview of the azole–flavonoid hybrids that are promising candidates for novel anticancer drug development, highlighting their superior antitumor potency compared to reference drugs, multitarget activity, tumor-selective cytotoxicity, efficacy against drug-resistant tumor cells, and structure–activity relationships. The review covers 250 hybrids, primarily triazole–chalcone hybrids but also triazole–flavone, flavanone, flavonol, and isoflavone hybrids, as well as other azole–flavonoid hybrids (imidazole–, pyrazole–, isoxazole–, and thiazole–flavonoid hybrids). Full article

(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)

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32 pages, 1393 KB

Open AccessEditor’s ChoiceReview

CopperNostics—Here We Are Now, Entertain Us!

by Santiago Andrés Brühlmann, Martin Walther, Klaus Kopka, Martin Kreller and Oliver C. Kiss

Pharmaceuticals 2026, 19(2), 321; https://doi.org/10.3390/ph19020321 - 15 Feb 2026

Cited by 2 | Viewed by 2914

Abstract

Diagnosis and endoradiotherapy using copper radioisotopes—defined as Theranostics or, more specifically, CopperNostics—have the potential to play a prominent role in modern precision medicine, as demonstrated by the FDA approval of [⁶⁴Cu]Cu-DOTA-TATE (Detectnet). In this review we highlight current developments in [...] Read more.

Diagnosis and endoradiotherapy using copper radioisotopes—defined as Theranostics or, more specifically, CopperNostics—have the potential to play a prominent role in modern precision medicine, as demonstrated by the FDA approval of [⁶⁴Cu]Cu-DOTA-TATE (Detectnet). In this review we highlight current developments in the production, radiochemical purification, quality control, availability, logistics, and regulatory hurdles of the most relevant copper radioisotopes, ⁶⁰Cu, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu, and ⁶⁷Cu, for nuclear medicine. Radiopharmaceuticals based on their application in registered clinical trials, either as molecular imaging agents, companion diagnostics or therapeutic agents, are also presented addressing unmet medical needs. Full article

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

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60 pages, 1795 KB

Open AccessEditor’s ChoiceReview

Diet and Gut Microbiota in Inflammatory Bowel Disease: A Clinical and Nutritional Perspective

by Luisa Bertin, Sonia Facchin, Brigida Barberio, Daria Maniero, Greta Lorenzon, Francesco Cesaroni, Miriana Zanconato, Giulia Romanelli, Francesco Francini-Pesenti, Luca Busetto, Mara Cananzi, Paola Gaio, Luca Bosa, Fabiana Zingone, Laura Gianolio, Oriana M. Damas and Edoardo Vincenzo Savarino

Pharmaceuticals 2026, 19(2), 318; https://doi.org/10.3390/ph19020318 - 14 Feb 2026

Cited by 7 | Viewed by 5343

Abstract

Inflammatory bowel diseases, comprising Crohn’s disease and ulcerative colitis, represent chronic inflammatory disorders with rising global incidence, underscoring the pivotal role of modifiable environmental factors in disease pathogenesis. Diet and intestinal microbiota have emerged as critical bidirectional therapeutic targets through complex interactions with [...] Read more.

Inflammatory bowel diseases, comprising Crohn’s disease and ulcerative colitis, represent chronic inflammatory disorders with rising global incidence, underscoring the pivotal role of modifiable environmental factors in disease pathogenesis. Diet and intestinal microbiota have emerged as critical bidirectional therapeutic targets through complex interactions with host immune responses. Epidemiological evidence demonstrates that healthy and high fiber diets reduce disease risk, while ultra-processed foods and inflammatory dietary patterns increase susceptibility. Therapeutic nutritional interventions, including exclusive enteral nutrition, the Crohn’s Disease Exclusion Diet combined with partial enteral nutrition, and the Mediterranean diet can induce and maintain clinical remission while promoting favorable microbiome modifications characterized by the enrichment of butyrate-producing taxa such as Faecalibacterium prausnitzii and Roseburia species, alongside a reduction in pathogenic Proteobacteria. Micronutrient deficiencies affect up to 78% of patients through malabsorption, chronic blood losses, dietary restrictions, and drug–nutrient interactions. Nutritional status significantly impacts surgical outcomes, with preoperative malnutrition and sarcopenia associated with increased postoperative complications, and it reciprocally influences biologic therapy response. Integration of personalized, microbiome-informed dietary strategies as complementary components of comprehensive treatment plans represents a promising therapeutic frontier, requiring multidisciplinary collaboration, rigorous clinical trials with standardized microbiome analyses, and precision nutrition algorithms accounting for disease phenotype, baseline microbial composition, and individual patient characteristics to optimize outcomes and improve quality of life. Full article

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

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19 pages, 549 KB

Open AccessEditor’s ChoiceArticle

Pain Management in Italian Elite Athletes: Trends in the Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Glucocorticoids, and Narcotics in Anti-Doping Reports (2013–2023)

by Mario Ruggiero, Stefania Santamaria, Pietro Montesano, Leopoldo Ferrante, Yuri Russo and Filomena Mazzeo

Pharmaceuticals 2026, 19(2), 298; https://doi.org/10.3390/ph19020298 - 11 Feb 2026

Cited by 2 | Viewed by 1624

Abstract

Background: Analgesics are widely used in competitive sports, but their patterns of use and detection in anti-doping controls vary significantly across drug classes. This study examined a decade of Italian anti-doping reports with three aims: to describe trends involving non-steroidal anti-inflammatory drugs [...] Read more.

Background: Analgesics are widely used in competitive sports, but their patterns of use and detection in anti-doping controls vary significantly across drug classes. This study examined a decade of Italian anti-doping reports with three aims: to describe trends involving non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and narcotics; to characterize the distribution of specific active ingredients; and to analyze the relative contribution of these classes to anti-doping violations, placing the findings within the regulatory framework. Methods: Data from national anti-doping reporting systems were analyzed from 2013 to the first half of 2023. Yearly data included tested athletes, athlete declarations of NSAID use, and laboratory analytical findings for prohibited substances (glucocorticoids and narcotics). NSAID prevalence was calculated relative to tested athletes, while glucocorticoid and narcotic findings were assessed as absolute counts and proportions of total violations. Temporal trends were assessed using the Cochran–Armitage test. Results: NSAIDs consistently ranked as the most frequently reported medication, with nearly half of the tested athletes reporting their use and no significant linear trend in overall prevalence. However, a significant shift was observed within the NSAID class, with a marked decrease in declarations of COX-2 selective agents over time. Glucocorticoids accounted for a significant portion of prohibited substances, with fluctuating proportions (showing no significant linear trend), betamethasone being the most common active ingredient. Narcotics appeared only sporadically, although the use of non-prohibited opioids such as tramadol and codeine—absent from official reports—remains relevant for understanding analgesic practices. Conclusions: Analgesic use in Italian elite sports shows distinct patterns driven by therapeutic needs and anti-doping regulations. NSAIDs remain the primary choice for routine pain management, though the type of NSAID reported has shifted significantly. Glucocorticoids represent a notable share of prohibited findings with a fluctuating, rather than steadily increasing, pattern. Narcotics appear only sporadically in violation data. Ongoing monitoring will be crucial to understanding how evolving clinical practices and recent regulatory changes influence future detection trends and athlete health. Full article

(This article belongs to the Special Issue Pharmacology and Toxicology of Opioids, 2nd Edition)

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25 pages, 1269 KB

Open AccessEditor’s ChoiceReview

Cefepime and New Cefepime/Beta-Lactamase Inhibitor Combination for the Treatment of Gram-Negative Bacteria: Chemical Structure and Mechanism of Action, Microbiological Target, Clinical Use and PK/PD Characteristics

by Davide Carcione, Gioconda Brigante, Antonella Carducci, Jari Intra, Simone Ambretti, Floriana Campanile, Gabriele Arcari, Nicasio Mancini, Dario Cattaneo, Floriana Gona, Mariagrazia Perilli, Alessandra Piccirilli, Nicholas Geremia, Verena Zerbato, Stefano Di Bella, Giovanna Maria Nicolò and Luigi Principe

Pharmaceuticals 2026, 19(2), 283; https://doi.org/10.3390/ph19020283 - 7 Feb 2026

Cited by 5 | Viewed by 2423

Abstract

The global spread of multidrug-resistant (MDR) Gram-negative bacteria, particularly extended-spectrum β-lactamase (ESBL)- and carbapenemase-producing Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii, presents a significant public health challenge by limiting effective antimicrobial treatment options. Cefepime, a fourth-generation cephalosporin with broad-spectrum activity, is [...] Read more.

The global spread of multidrug-resistant (MDR) Gram-negative bacteria, particularly extended-spectrum β-lactamase (ESBL)- and carbapenemase-producing Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii, presents a significant public health challenge by limiting effective antimicrobial treatment options. Cefepime, a fourth-generation cephalosporin with broad-spectrum activity, is increasingly compromised by β-lactamase production, efflux pumps, and porin loss. In response, novel cefepime-based β-lactam/β-lactamase inhibitor (BL/BLI) combinations have been developed to overcome these resistance mechanisms. This review examines preclinical and clinical studies on cefepime-based BL/BLI combinations, specifically cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, and cefepime/nacubactam, as found in the PubMed database. Key findings include the restoration of activity against class A ESBLs with cefepime/enmetazobactam, while cefepime/taniborbactam and cefepime/zidebactam show broader inhibition of serine β-lactamases and selected metallo-β-lactamases. Additionally, zidebactam and nacubactam target penicillin-binding protein 2, enhancing bactericidal potency. Preclinical and early-phase clinical trial data indicate potent in vitro activity and favorable pharmacokinetic/pharmacodynamic (PK/PD) profiles. Specifically, the combination of cefepime with enmetazobactam has demonstrated an optimal Cmax/MIC ratio of 8–10, supporting its efficacy in treating MDR Gram-negative infections. Phase III studies are ongoing to confirm efficacy in complicated infections. Cefepime-based BL/BLI combinations are emerging as promising carbapenem-sparing agents, offering broad-spectrum activity, dual mechanisms of action, and encouraging clinical outcomes. These findings support their inclusion in antimicrobial stewardship strategies aimed at mitigating resistance. Full article

(This article belongs to the Special Issue Novel Antimicrobials and the Antimicrobial Activity: New Advances)

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19 pages, 6245 KB

Open AccessEditor’s ChoiceArticle

Aronia Berry Extract Inhibits Cancer Stemness and Overcomes 5-Fluorouracil Resistance by Targeting TLR3/NF-κB Signaling in Colorectal Cancer

by Hongxia Duan, Takayuki Noma and Ajay Goel

Pharmaceuticals 2026, 19(2), 261; https://doi.org/10.3390/ph19020261 - 3 Feb 2026

Cited by 3 | Viewed by 1638

Abstract

Background: Colorectal cancer (CRC) remains a major clinical challenge, in part due to the limited efficacy of 5-fluorouracil (5-FU)-based chemotherapy, which is often compromised by the emergence of acquired resistance. Aronia berry extract (ABE), a phenolic-rich natural compound, has gained increasing attention [...] Read more.

Background: Colorectal cancer (CRC) remains a major clinical challenge, in part due to the limited efficacy of 5-fluorouracil (5-FU)-based chemotherapy, which is often compromised by the emergence of acquired resistance. Aronia berry extract (ABE), a phenolic-rich natural compound, has gained increasing attention for its anticancer and chemosensitizing properties. This study aimed to investigate whether ABE can overcome 5-FU resistance (5-FU-R) in CRC and to elucidate the molecular mechanisms underlying its therapeutic effects. Methods: We conducted a series of in vitro experiments using 5-FU-R CRC cell lines to evaluate the synergistic effects of combined ABE and 5-FU treatment. Genome-wide transcriptomic profiling was performed to identify key regulatory pathways associated with chemoresistance and to determine potential ABE-responsive targets. Findings were further validated using patient-derived 3D organoids (PDOs). Results: Co-treatment with ABE and 5-FU significantly reduced the effective concentration of 5-FU required to inhibit 5-FU-R CRC cells, yielding a Bliss synergy score greater than 10. The combination markedly suppressed cell viability, clonogenic potential, migration, and invasion. ABE also reduced cancer stemness, as evidenced by reduced CD44, Nanog, and Oct4 expression. Functional inhibition of Toll-like receptor 3 (TLR3) impaired spheroid growth, and PDO experiments corroborated these findings, demonstrating reduced organoid growth, diminished survival, and decreased NF-κB expression following ABE treatment. Conclusions: Our findings reveal that ABE effectively overcomes 5-FU resistance in CRC by targeting the TLR3/NF-κB signaling axis. This study highlights ABE as a safe, accessible, and promising adjunctive strategy to enhance therapeutic responses in 5-FU-resistant CRC. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)

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20 pages, 3811 KB

Open AccessEditor’s ChoiceArticle

Enhancing CYP3A4 Inhibition Prediction Using a Hybrid GNN–ML Model with Data Augmentation

by Somin Woo, Ju-Hyeok Jeon, Sangil Han, Changkyu Lee and Sang-Hyun Min

Pharmaceuticals 2026, 19(2), 258; https://doi.org/10.3390/ph19020258 - 2 Feb 2026

Cited by 1 | Viewed by 1267

Abstract

Background/Objectives: Cytochrome P450 3A4 (CYP3A4) metabolizes approximately 30–50% of clinically used drugs; thus, accurate prediction of CYP3A4 inhibition is essential for early assessment of drug–drug interaction (DDI) risk and toxicity. This study evaluated an integrated artificial intelligence framework for predicting CYP3A4 inhibition [...] Read more.

Background/Objectives: Cytochrome P450 3A4 (CYP3A4) metabolizes approximately 30–50% of clinically used drugs; thus, accurate prediction of CYP3A4 inhibition is essential for early assessment of drug–drug interaction (DDI) risk and toxicity. This study evaluated an integrated artificial intelligence framework for predicting CYP3A4 inhibition (%) using a large, curated chemical dataset. Methods: A dataset of 23,713 compounds was compiled from the Korea Chemical Bank and multiple commercial and public databases. Vector-based machine learning (ML) models (LightGBM, XGBoost, CatBoost, and a weighted ML ensemble) and graph neural network (GNN) models (O-GNN with contrastive learning and manifold mixup (O-GNN + CL + Mixup), D-MPNN, GINE, and GATv2) were evaluated. Manifold mixup was applied during GNN training, and SMILES enumeration-based test-time augmentation was used at inference. The best-performing ML and GNN models were integrated using a weighted ensemble strategy. Model interpretability was examined using SHAP analysis for ML models and occlusion sensitivity analysis for O-GNN + CL + Mixup. Results: The weighted ML ensemble achieved the best performance among ML models (RMSE = 19.1031, Pearson correlation coefficient (PCC) = 0.7566); the O-GNN + CL + Mixup model performed the best among GNN models (RMSE = 20.1002, PCC = 0.7265). The hybrid model achieved improved predictive accuracy (RMSE = 19.0784, PCC = 0.7570). External validation on 100 newly generated experimental data points confirmed generalizability (Custom Metric = 0.8035). Conclusions: This study demonstrated that integrating ML and GNN models with data augmentation strategies improves the robustness and interpretability of CYP3A4 inhibition prediction and established a practical framework for metabolic screening and DDI risk assessment. Full article

(This article belongs to the Section Pharmaceutical Technology)

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18 pages, 1590 KB

Open AccessEditor’s ChoiceArticle

Phytochemical Analysis of Lipid Composition and Biological Activities in the Seeds of Evening Primrose from Bulgaria

by Ana Zheleva, Zhana Petkova, Ginka Antova, Olga Teneva, Maria Angelova-Romova, Kaloyan D. Georgiev, Iliya Slavov, Petya Boycheva, Nadezhda Ivanova, Neli Ermenlieva and Velichka Andonova

Pharmaceuticals 2026, 19(2), 225; https://doi.org/10.3390/ph19020225 - 28 Jan 2026

Cited by 1 | Viewed by 1180

Abstract

Background/Objectives: The present study is aimed at evaluating the chemical profile and biological activity of the widespread species Oenothera biennis L. in Bulgaria, collected from its natural habitat. Methods: The seeds of the species were collected in 2023 and 2024, and the fatty [...] Read more.

Background/Objectives: The present study is aimed at evaluating the chemical profile and biological activity of the widespread species Oenothera biennis L. in Bulgaria, collected from its natural habitat. Methods: The seeds of the species were collected in 2023 and 2024, and the fatty acid and unsaponified (sterols, tocopherols, phospholipids) profile of the glyceride oil was investigated using standard chromatographic methods. The oil’s antimicrobial activity was evaluated using MBC/MFC assays, while its antioxidant capacity was assessed using the ORAC method. The proliferative effects of the oil were investigated using an MTT assay in human cell lines BJ, HaCaT, and MCF-12F. Results: The oil content of the seeds remained stable during the two years studied (16.7–16.9%). Variations were observed in the oil’s unsaponified fraction, including sterols, phospholipids, tocopherols, and several fatty acids. The primary fatty acid (linoleic acid) remained at almost the same value (~70%) during both periods, while γ-linolenic acid varied from 7.1% to 13.7%. β-sitosterol and phosphatidylcholine were the leading sterol and phospholipid components, while γ-tocopherol predominated among the tocopherols. The oil exhibited antimicrobial activity only against S. epidermidis and S. pyogenes and showed strong antioxidant capacity. MTT assays present sustained viability in BJ and MCF-12F cells and significantly increased proliferation in HaCaT cells. Conclusions: The oil demonstrated promising antioxidant potential, selective antimicrobial effects, and keratinocyte-stimulating activity, supporting its potential for diverse applications. However, to further confirm these findings, in vivo studies of the oil are needed. Full article

(This article belongs to the Section Natural Products)

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21 pages, 4760 KB

Open AccessEditor’s ChoiceArticle

Experimentally Informed Numerical Simulations of Spray Deposition and Runoff Doses in a 10-Day-Old Nose Model

by Jack Yongfeng Zhang, Mary Ziping Luo, Ray Lameng Lei, Sung-An Lin, Xiuhua Si and Jinxiang Xi

Pharmaceuticals 2026, 19(2), 217; https://doi.org/10.3390/ph19020217 - 27 Jan 2026

Cited by 1 | Viewed by 1160

Abstract

Background: Intranasal drug delivery is a preferred route for emergency administration of naloxone in opioid overdose due to its rapid onset of action and ease of use. However, limited knowledge exists on the delivery efficiency and safety of nasal sprays in neonates, particularly [...] Read more.

Background: Intranasal drug delivery is a preferred route for emergency administration of naloxone in opioid overdose due to its rapid onset of action and ease of use. However, limited knowledge exists on the delivery efficiency and safety of nasal sprays in neonates, particularly in life-threatening situations such as coma states where breathing is compromised. This study presents a physiology-based simulation of spray deposition and runoff loss in a 10-day-old infant nose model. Methods: Spray characteristics, including droplet size distribution, exiting velocity, and plume angle, were measured and implemented in ANSYS Fluent droplet tracking model. Naloxone film thickness was measured on ex vivo porcine nasal mucosa at varying angles and used in the Eulerian Wall-Film model. Simulations were conducted in a 10-day-old nose geometry across multiple doses (0.25, 0.50, 1.0, and 2.0 mL) in supine and 45° inclined postures to quantify regional deposition, liquid film translocation, and pharyngeal runoff. Results: While a 0.25 mL spray was fully retained in the nasal passages, higher doses exceeded the mucosal holding capacity and caused significant runoff. Runoff into the pharynx was 18.5% and 10.1% for the spray volume of 0.50 mL in the 45° back tilt and supine positions, respectively. The 1.0 mL spray caused 55.1% and 53.5% runoff in the 45° back tilt and supine positions, while the 2.0 mL spray caused 77.5% and 76.8% runoff in the 45° back tilt and supine positions, respectively. Conclusions: These findings highlight the critical influence of spray volume on drug delivery outcomes in neonates and provide quantitative guidance for optimizing intranasal naloxone administration in emergency pediatric care. Full article

(This article belongs to the Section Pharmaceutical Technology)

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19 pages, 2675 KB

Open AccessEditor’s ChoiceArticle

Sulfated Polysaccharide-Rich Fractions from Spirulina Platensis (SPPs) Exert Multi-Target Anticancer Activity in Non-Small Cell Lung Cancer (NSCLC) Cells

by Beatrice Polini, Matteo Banti, Anna Mazzierli, Alessandro Corti, Paola Nieri, Clementina Manera and Grazia Chiellini

Pharmaceuticals 2026, 19(2), 202; https://doi.org/10.3390/ph19020202 - 24 Jan 2026

Cited by 1 | Viewed by 1352

Abstract

Background/Objectives: Sulfated polysaccharides from Spirulina platensis have shown various promising biological activities, but their anticancer effects in lung cancer models remain poorly characterized. In this study, sulfated polysaccharide-rich fractions (SPPs) were tested on A549 non-small cell lung cancer (NSCLC) cells to evaluate [...] Read more.

Background/Objectives: Sulfated polysaccharides from Spirulina platensis have shown various promising biological activities, but their anticancer effects in lung cancer models remain poorly characterized. In this study, sulfated polysaccharide-rich fractions (SPPs) were tested on A549 non-small cell lung cancer (NSCLC) cells to evaluate their cytotoxic, oxidative, and immunomodulatory activity. Methods: The potential of SPPs to interfere with A549 cell viability, to modulate intracellular reactive oxygen species (ROS) levels, to produce pro-inflammatory effects, and to induce apoptosis was evaluated. Co-administration experiments were also performed using Gefitinib, a drug commonly used in NSCLC therapy. Non-cancerous human bronchial epithelial cells (16HBE) were included to assess the ability of SPPs to selectively target tumoral cells. Results: Our findings show that SPPs significantly reduced A549 cell viability in a concentration-dependent manner and increased ROS levels. This effect was associated with apoptotic DNA fragmentation and modulation of apoptosis-related genes, including upregulation of BAX and CASP-9, and downregulation of BCL-2, MTOR, and BIRC5. SPPs also induced a controlled pro-inflammatory response by increasing ACE2, NF-κB1, and CCL2 expression while reducing COX-2 levels. In co-administration experiments with Gefitinib, a cancer drug used to treat NSCLC, enhanced cytotoxic and pro-apoptotic effects were observed. Importantly, at active concentrations (150–250 µg/mL) SPPs were not found to produce cytotoxicity or apoptosis in 16HBE cells. Conclusions: Overall, these findings suggest that SPPs may selectively target NSCLC cells by promoting redox imbalance, apoptosis, and immune response, without affecting healthy cells, supporting their potential as natural adjuvants in lung cancer treatment. Full article

(This article belongs to the Special Issue Therapeutic Potential of Natural Extracts in Cancer Prevention and Treatment)

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15 pages, 1036 KB

Open AccessEditor’s ChoiceArticle

Fourier Transform Infrared Spectroscopic Characterization of Aortic Wall Remodeling by Stable Gastric Pentadecapeptide BPC 157 After Unilateral Adrenalectomy in Rats

by Ivan Maria Smoday, Vlasta Vukovic, Katarina Oroz, Hrvoje Vranes, Luka Kalogjera, Ozren Gamulin, Josipa Vlainic, Marija Milavic, Suncana Sikiric, Nora Nikolac Gabaj, Domagoj Marijancevic, Antun Koprivanac, Lidija Beketic Oreskovic, Ivana Oreskovic, Sanja Strbe, Ivan Barisic, Mario Kordic, Ante Tvrdeic, Sven Seiwerth, Predrag Sikiric, Alenka Boban Blagaic and Anita Skrtic Show full author list Hide full author list

Pharmaceuticals 2026, 19(1), 191; https://doi.org/10.3390/ph19010191 - 22 Jan 2026

Cited by 4 | Viewed by 1920

Abstract

Background: No Fourier transform infrared (FTIR) spectroscopy studies have directly evaluated adrenalectomy vessels, the technique’s established ability to probe collagen/elastin-associated spectral features and lipid peroxidation-related signatures, and protein structural damage. Stable gastric pentadecapeptide BPC 157 therapy was found to maintain the vascular function [...] Read more.

Background: No Fourier transform infrared (FTIR) spectroscopy studies have directly evaluated adrenalectomy vessels, the technique’s established ability to probe collagen/elastin-associated spectral features and lipid peroxidation-related signatures, and protein structural damage. Stable gastric pentadecapeptide BPC 157 therapy was found to maintain the vascular function under severe stress, as FTIR spectroscopy recently demonstrated rapid peptide-induced molecular changes in healthy rat blood vessels, particularly in lipid content and protein secondary structure. Methods: To extend these findings and highlight the BPC 157 vascular background in the special circumstances of the course following unilateral adrenalectomy, abdominal aortas were collected at 15 min, 5 h, and 24 h after unilateral adrenalectomy for the FTIR spectroscopy assessment. Results: FTIR spectra were acquired, preprocessed, and analyzed using principal component analysis (PCA), support vector machine discriminant analysis (SVMDA), and band-specific statistics. BPC 157 (10 ng/kg intragatrically immediately after unilateral adrenalectomy) produced a clear, reproducible separation of aortic spectra from control samples at all time points. The main discriminatory spectral signatures were observed in three regions, including amide I and amide II (protein-related bands, consistent with collagen/elastin contributions) and lipid C–H stretching bands. These spectral signatures are consistent with early extracellular matrix reinforcement and membrane preservation in the vascular wall and align with the recovering effect on the lesions in counteraction of the severe vascular and multiorgan failure, attenuation/elimination of thrombosis and blood pressure disturbances in various occlusion/occlusion-like syndromes. Conclusions: Together, after unilateral adrenalectomy, the FTIR data provide molecular-level spectral signatures consistent with rapid remodeling of the aortic wall toward a more structurally stable and functionally favorable state. Full article

(This article belongs to the Section Biopharmaceuticals)

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32 pages, 4721 KB

Open AccessEditor’s ChoiceReview

Benzimidazole-Quinoline Hybrids: Synthesis and Antimicrobial Properties

by Maria Marinescu

Pharmaceuticals 2026, 19(1), 180; https://doi.org/10.3390/ph19010180 - 20 Jan 2026

Cited by 1 | Viewed by 4434

Abstract

Background: Heterocyclic compounds are particularly important in medicinal chemistry. With a range of therapeutic uses, benzimidazoles and quinolines are both key heterocycles in medicinal chemistry. A number of hybrid heterocyclic compounds have been reported in recent years because they typically have better [...] Read more.

Background: Heterocyclic compounds are particularly important in medicinal chemistry. With a range of therapeutic uses, benzimidazoles and quinolines are both key heterocycles in medicinal chemistry. A number of hybrid heterocyclic compounds have been reported in recent years because they typically have better therapeutic properties than single heterocyclic rings. Methods: A literature search was conducted across relevant scientific literature from peer-reviewed sources, using keywords, including “benzimidazole”, “quinoline”, “benzimidazole-quinoline hybrids”, “antibacterial”, “antifungal”, “antimalarial” and “hybrid complexes”. Results: This review summarizes the synthetic methodologies for benzimidazole–quinoline hybrids, benzimidazole– quinolinones, and benzimidazole–quinoline metal complexes, along with their antimicrobial and antimalarial activities and the reported structure–activity relationship (SAR) studies. The importance of halogen substitution, particularly with chlorine and fluorine atoms, as well as the structure of the linker between the benzimidazole and quinoline rings—specifically chain length, the presence of oxygen, sulfur, or nitrogen atoms, and heterocyclic moieties—is highlighted. A series of benzimidazole–quinoline hybrids exhibit antimalarial and antitrypanosomal activities or show enhanced antimicrobial properties due to the incorporation of a five-membered heterocycle in addition to the two existing heterocyclic rings. Notably, several hybrids from different compound series exhibit very low minimum inhibitory concentrations (MICs) in the range of 1–8 µg/mL, along with low cytotoxicity, supporting their potential for further investigation as antimicrobial agents. Conclusions: This review summarizes the synthetic methods, medicinal properties, and structure–activity relationship (SAR) studies of benzimidazole–quinoline hybrids reported between 2002 and 2026. Full article

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

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18 pages, 994 KB

Open AccessEditor’s ChoiceReview

Aptamer-Based Delivery of Genes and Drugs Across the Blood–Brain Barrier

by Luona Yang, Yuan Yin, Xinli Liu and Bin Guo

Pharmaceuticals 2026, 19(1), 164; https://doi.org/10.3390/ph19010164 - 16 Jan 2026

Cited by 4 | Viewed by 2564

Abstract

The blood–brain barrier (BBB) restricts therapeutic delivery to the central nervous system (CNS), hindering the treatment of neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, brain cancers, and stroke. Aptamers, short single-stranded DNA or RNA oligonucleotides that can fold into unique 3D shapes [...] Read more.

The blood–brain barrier (BBB) restricts therapeutic delivery to the central nervous system (CNS), hindering the treatment of neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, brain cancers, and stroke. Aptamers, short single-stranded DNA or RNA oligonucleotides that can fold into unique 3D shapes and bind to specific target molecules, offer high affinity and specificity, low immunogenicity, and promising BBB penetration via receptor-mediated transcytosis targeting receptors such as the transferrin receptor (TfR) and low-density lipoprotein receptor-related protein 1 (LRP1). This review examines aptamer design through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and its variants, mechanisms of BBB crossing, and applications in CNS disorders. Recent advances, including in silico optimization, in vivo SELEX, BBB chip-based MPS-SELEX, and nanoparticle–aptamer hybrids, have identified brain-penetrating aptamers and enhanced the brain delivery efficiency. This review highlights the potential of aptamers to transform CNS-targeted therapies. Full article

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

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21 pages, 707 KB

Open AccessEditor’s ChoiceArticle

Mathematical Modeling in Drug Metabolism and Pharmacokinetics: Correct In Vitro, Not Always Valid In Vivo

by Leslie Z. Benet and Jasleen K. Sodhi

Pharmaceuticals 2026, 19(1), 160; https://doi.org/10.3390/ph19010160 - 15 Jan 2026

Cited by 1 | Viewed by 1560

Abstract

Background/Objectives: Chemical and metabolic kinetics have historically been derived from mass balance differential equations expressed in terms of amounts, and this framework was later extended to pharmacokinetics by converting amount-based equations to concentration-based clearance relationships. That conversion is valid for fixed-volume in [...] Read more.

Background/Objectives: Chemical and metabolic kinetics have historically been derived from mass balance differential equations expressed in terms of amounts, and this framework was later extended to pharmacokinetics by converting amount-based equations to concentration-based clearance relationships. That conversion is valid for fixed-volume in vitro experiments, but may be unreliable in vivo, where input, distribution, and elimination can occur in different volumes of distribution. The objective of this study is to present an alternate, mechanistically agnostic framework for deriving pharmacokinetic relationships by adapting Kirchhoff’s Laws to treat pharmacokinetic systems as networks of parallel and in-series rate-defining processes, and to identify where differential equation approaches fail in vivo. Methods: Clearance and rate constant equations were derived using the adapted Kirchhoff’s Laws by summing parallel rate-defining processes and summing inverses for in-series processes, explicitly incorporating organ blood flow, net transporter, and delivery site effects. The resulting expressions were compared with differential equation hepatic disposition elimination models (well-stirred, parallel tube, dispersion) and the Extended Clearance Concept (ECC). Mean residence time concepts were used to extend the framework to oral input, and the full approach was applied to a case study of a hypothetical drug (KL25A). Results: The adapted Kirchhoff-based approach reproduced standard pharmacokinetic analyses without mechanistic organ assumptions and yielded model-independent hepatic and renal clearance equations that include blood flow, net transport, and delivery kinetics. Inconsistencies with the traditional differential-based derivations were highlighted, including the interpretation of pharmacokinetics associated with slow absorption site clearance, as illustrated by KL25A. Conclusions: For linear drug metabolism and pharmacokinetics, clearance and rate constant relationships can be derived by summing parallel and in-series rate-defining processes, without differential equations. Differential equation methods may misestimate in vivo clearance and bioavailability when drug input is slow or when volumes of distribution differ across processes. The adapted Kirchhoff framework offers a simpler, model-independent basis for interpreting clinical data. Full article

(This article belongs to the Special Issue Mathematical Modeling in Drug Metabolism and Pharmacokinetics)

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21 pages, 1183 KB

Open AccessEditor’s ChoiceArticle

Resistance, Ineffectiveness, and Off-Label Use Related to Cephalosporins from the Reserve Group—A Pharmacovigilance Signal Detection Study on EudraVigilance Database

by Anca Maria Arseniu, Bogdan Ioan Vintila, Anca Butuca, Laurentiu Stoicescu, Adina Frum, Adriana Aurelia Chis, Rares Arseniu, Felicia Gabriela Gligor, Steliana Ghibu, Claudiu Morgovan and Carmen Maximiliana Dobrea

Pharmaceuticals 2026, 19(1), 155; https://doi.org/10.3390/ph19010155 - 15 Jan 2026

Cited by 1 | Viewed by 1273

Abstract

Background/Objectives: Antimicrobial resistance (AMR) is considered a major threat by the healthcare community. In this context, the AWaRe (Access, Watch, Reserve) classification of antibiotics is a valuable tool that can assist physicians during the clinical decision process and pharmacists in promoting the [...] Read more.

Background/Objectives: Antimicrobial resistance (AMR) is considered a major threat by the healthcare community. In this context, the AWaRe (Access, Watch, Reserve) classification of antibiotics is a valuable tool that can assist physicians during the clinical decision process and pharmacists in promoting the rational use of antibiotics. Pharmacovigilance studies based on real-world evidence offer valuable insight into the AMR phenomenon. The aim of this study was the assessment of the resistance, ineffectiveness, and off-label use signals of all five cephalosporins belonging to the Reserve group (ceftazidime/avibactam, ceftaroline, cetolozane/tazobactam, ceftobiprole, and cefiderocol). Methods: The study was conducted using descriptive approaches on EudraVigilance data and disproportionality analyses comparing each of the fourteen cephalosporins in the Watch group. Results: Ceftazidime/avibactam (n = 904, 38.6%) topped the reports, followed by ceftaroline (n = 559, 23.9%) and ceftolazane/tazobactam (n = 560, 23.9%). The lowest number of reports was submitted for cefiderocol (n = 176, 7.5%) and ceftobiprole (n = 146, 6.2%). The resistance to ceftazidime/avibactam, cefiderocol, and ceftolozane/tazobactam was reported with a higher probability than all others, the strongest signal being observed for cefiderocol against cefixime (ROR: 171.25, 95% CI 79.64–368.27). All cephalosporins from the Reserve group (except ceftobiprole) have higher probability for reporting ineffectiveness than cephalosporins from the Watch group; the strongest signal was observed for cefiderocol–cefditoren (ROR: 14.70, 95% CI 6.73–32.11). All cephalosporines from the Reserve group had a higher probability of reporting off-label use by comparison with the ones from the Watch group, except for two cases of no disproportionate signal between cefiderocol–cefoperazone and cefiderocol–ceftizoxime; the strongest signal was observed for ceftolozane/tazobactam–cefotaxim (ROR: 43.61, 95% CI 30.14–63.09). Conclusions: This analysis supplements information from clinical trials and current clinical practice, underscoring the critical need for rigorous antibiotic stewardship programs. Notably, even restricted use of cephalosporins demonstrated therapeutic failure and inappropriate utilization. Full article

(This article belongs to the Special Issue Antibiotic Resistance and Misuse)

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26 pages, 3232 KB

Open AccessEditor’s ChoiceArticle

Tracheocutaneous Fistula Resolved by Pentadecapeptide BPC 157 Therapy Through the NO-System—Triple NO-Agent Approach in Rats

by Goran Madzarac, Tomislav Becejac, Toni Penovic, Dominik Drazenovic, Lucija Kralj, Marta Popović Dolic, Suncana Sikiric, Lidija Beketic Oreskovic, Ivana Oreskovic, Sanja Strbe, Ana Maria Tubikanec, Mihovil Penavic, Hrvoje Vranes, Ivan Krezic, Mario Kordic, Antun Koprivanac, Tinka Vidovic, Josipa Vlainic, Dinko Stancic Rokotov, Alenka Boban Blagaic, Sven Seiwerth, Anita Skrtic and Predrag Sikiric Show full author list Hide full author list

Pharmaceuticals 2026, 19(1), 145; https://doi.org/10.3390/ph19010145 - 14 Jan 2026

Cited by 2 | Viewed by 2352

Abstract

Background/Objectives: This 7-day rat tracheocutaneous fistula study considered the not-studied issues of tracheocutaneous fistula course, wound healing, and fistula in the NO-system relations. Therefore, we focused on fistulas’ severe course, tracheocutaneous fistula → air leak → compensatory diaphragmatic/abdominal “heaving”, NO-system failed relations, and [...] Read more.

Background/Objectives: This 7-day rat tracheocutaneous fistula study considered the not-studied issues of tracheocutaneous fistula course, wound healing, and fistula in the NO-system relations. Therefore, we focused on fistulas’ severe course, tracheocutaneous fistula → air leak → compensatory diaphragmatic/abdominal “heaving”, NO-system failed relations, and therapy resolution. Stable gastric pentadecapeptide BPC 157 was proposed. Methods: Tracheocutaneous fistula rats received daily medication (/kg), alone or combined, BPC 157 therapy (10 µg, 10 ng, in drinking water or intraperitoneally) along with a triple NO-agent approach (L-NAME 5 mg, L-arginine 100 mg, and L-NAME+L-arginine, intraperitoneally). Results: Tracheocutaneous fistulas occurred as specific and NO-system-related as follows: NO system: blockade (L-NAME-aggravation) over-activity (L-arginine-amelioration) or immobilization (L-NAME+L-arginine oppose each other’s effects). Controls presented severe clinical signs of respiratory distress, failed healing, skin and tracheal defects, a not-healed and open, macro/microscopically, and fistulous tract that was well-formed and wide, tracheal shrinking below the fistula, and clinically, open-mouth breathing, “heaving abdomen”, cyanosis (bluish snout, ears, extremities), abundant secretion through the fistula, and weight loss. Fistula tissue NO level decreased, and the malondialdehyde (MDA) level increased. The BPC 157 therapy (both application routes) resulted in rapid recovery. Healing of defects (skin and trachea) and fistula closure, macro/microscopically, corresponded with clinical findings, avoiding observable clinical signs of dyspnea, reducing weight loss, and avoiding any sign of “heaving abdomen”. BPC 157-treated rats displayed regular breathing movements without observable signs of respiratory distress. Finally, when combined, BPC 157 therapy upgrades L-arginine amelioration, abolishes L-NAME-induced worsening, and restores full healing after NO immobilization (L-NAME+L-arginine). BPC 157 counteracted increase in NO level and counteracted increase in MDA level. Conclusions: Thus, first, acting systemically, BPC 157 reverses tracheocutaneous fistula course in rats. It acts through the NO system. Full article

(This article belongs to the Section Biopharmaceuticals)

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23 pages, 1835 KB

Open AccessEditor’s ChoiceArticle

Divergent System Organ Class Safety Profiles of Isotretinoin Versus Topical Retinoids: An EudraVigilance Disproportionality Analysis

by Denisa Viola Szilagyi, Delia Mirela Tit, Ruxandra Cristina Marin, Gabriela S. Bungau, Mirela Marioara Toma, Manuela Bianca Pasca, Daniela Gitea and Laura Maria Endres

Pharmaceuticals 2026, 19(1), 127; https://doi.org/10.3390/ph19010127 - 11 Jan 2026

Cited by 1 | Viewed by 1535

Abstract

Background/Objectives: Isotretinoin remains an essential therapy for severe acne, yet its safety profile continues to raise concerns. This study analyzed adverse event reporting patterns for isotretinoin versus topical retinoids using EudraVigilance data. Methods: Aggregated ADR data for isotretinoin and four topical retinoids (tretinoin, [...] Read more.

Background/Objectives: Isotretinoin remains an essential therapy for severe acne, yet its safety profile continues to raise concerns. This study analyzed adverse event reporting patterns for isotretinoin versus topical retinoids using EudraVigilance data. Methods: Aggregated ADR data for isotretinoin and four topical retinoids (tretinoin, adapalene, tazarotene, trifarotene) were retrieved from the EMA ADRreports portal (April 2025). Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals at the MedDRA system organ class (SOC) level. Significant demographic differences (age and sex; both p < 0.001) justified stratified ROR analyses for SOCs showing positive signals. Results: Among 35,030 isotretinoin and 3795 topical retinoid reports, isotretinoin showed strong over-reporting in six SOCs: psychiatric disorders (ROR 11.96; 95% CI 10.11–14.14), gastrointestinal disorders (3.88; 3.50–4.31), musculoskeletal and connective tissue disorders (2.89; 2.50–3.35), surgical and medical procedures, social circumstances, and ear and labyrinth disorders. Fourteen SOCs demonstrated significant under-reporting, including neoplasms, immune system disorders, cardiac disorders, and blood/lymphatic disorders. Stratified analyses confirmed the robustness of the positive signals. Psychiatric disorders exhibited the highest disproportionality in males (22.10; 16.11–30.31) and adolescents aged 12–17 (25.85; 13.32–50.19). Gastrointestinal and musculoskeletal signals remained significant across all age and sex strata. Conclusions: Isotretinoin presents a distinct safety profile characterized by consistently elevated reporting of psychiatric, gastrointestinal, and musculoskeletal adverse events, independent of age and sex. These results refine the comparative safety landscape of systemic versus topical retinoids and support focused pharmacovigilance monitoring. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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23 pages, 609 KB

Open AccessEditor’s ChoiceReview

Microbiota-Driven Strategies for Managing IBD-Associated Risks: From Infections to Mental Health

by Patrycja Krynicka, Pablo Cortegoso Valdivia, Maciej Morawski, Wojciech Marlicz, Karolina Skonieczna-Żydecka and Anastasios Koulaouzidis

Pharmaceuticals 2026, 19(1), 118; https://doi.org/10.3390/ph19010118 - 9 Jan 2026

Cited by 3 | Viewed by 1808

Abstract

Inflammatory bowel diseases (IBD) are increasingly acknowledged not merely as confined gastrointestinal disorders but as systemic immunometabolic syndromes. Central to this paradigm is the gut microbiota including non-bacterial components such as the virome, whose functional disruption marked by reduced short-chain fatty acids (SCFAs), [...] Read more.

Inflammatory bowel diseases (IBD) are increasingly acknowledged not merely as confined gastrointestinal disorders but as systemic immunometabolic syndromes. Central to this paradigm is the gut microbiota including non-bacterial components such as the virome, whose functional disruption marked by reduced short-chain fatty acids (SCFAs), increasingly implicated in pathogenic processes extending beyond intestinal mucosa. This review outlines how these alternations compromise the epithelial barrier and immune regulation, increasing the risk of recurrent Clostridioides difficile infections to anemia, neuropsychiatric comorbidities, and extraintestinal manifestations. We critically evaluate emerging microbiota-targeted strategies, including fecal microbiota transplantation (FMT), live biotherapeutic products (LBPs), and precision postbiotics, positioning them as potential adjuncts to conventional immunosuppression. Finally, we discuss the current barriers to clinical translation, such as safety and heterogeneity, and propose a future framework for personalized, functionally integrated IBD care aimed at restoring long-term microbiota homeostasis. Full article

(This article belongs to the Section Biopharmaceuticals)

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22 pages, 2746 KB

Open AccessEditor’s ChoiceArticle

Characterization of Novel Sigma Receptor Ligands Derived from Multicomponent Reactions as Efficacious Treatments for Neuropathic Pain

by Ryosuke Shinouchi, Bengisu Turgutalp, Rohini S. Ople, Shainnel O. Eans, Ashai K. Williams, Haylee R. Hammond, Andras Varadi, Rebecca Notis Dardashti, Susruta Majumdar and Jay P. McLaughlin

Pharmaceuticals 2026, 19(1), 117; https://doi.org/10.3390/ph19010117 - 8 Jan 2026

Cited by 1 | Viewed by 1659

Abstract

Background/Objectives: Neuropathic pain remains a significant clinical challenge, with current treatments often providing inadequate relief and adverse effects. Sigma receptors (SRs) modulate nociception and have emerged as potential therapeutic targets for neuropathic pain. Although putative sigma-1 receptor (S1R) ligands have demonstrated analgesic [...] Read more.

Background/Objectives: Neuropathic pain remains a significant clinical challenge, with current treatments often providing inadequate relief and adverse effects. Sigma receptors (SRs) modulate nociception and have emerged as potential therapeutic targets for neuropathic pain. Although putative sigma-1 receptor (S1R) ligands have demonstrated analgesic efficacy in preclinical models, their in vivo efficacy and safety profiles require further clarification. Methods: Analogs of well-known selective S1R ligand UVM147 were synthesized using 3-component Ugi reactions and examined in vitro for receptor affinity in radioligand competition binding assays and in vivo with mouse models of neuropathic and inflammatory pain and adverse effects. Results: Three novel heterocyclic compounds (RO-4-3, RO-5-3, and RO-7-3) displayed in vitro nanomolar affinity with varying selectivity for both SR subtypes (S1R and S2R). When screened in vivo at a dose of 30 mg/kg s.c. in mice first subjected to chronic constriction injury (CCI), RO-5-3 and RO-7-3 possessed anti-allodynic potential, while UVM147 was inactive. Upon full characterization, RO-5-3 significantly attenuated mechanical allodynia in a dose-dependent manner, while RO-7-3 was ineffective at higher doses. Both compounds dose-dependently attenuated nociceptive behaviors in the mouse formalin assay. RO-5-3 induced mild respiratory depression without impairing locomotor activity, whereas RO-7-3 caused transient respiratory depression and locomotor impairment. Additionally, RO-5-3, but not RO-7-3, induced conditioned place aversion consistent with potential S2R involvement. Conclusions: RO-5-3 exerts antinociceptive and anti-allodynic effects with minimal adverse behavioral effects, supporting the role of SRs in pain modulation. These results add to growing evidence supporting the development of SR ligands as efficacious therapeutics for neuropathic pain with fewer clinical liabilities. Full article

(This article belongs to the Special Issue Current Advances in Therapeutic Potential of Sigma Receptor Ligands)

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42 pages, 9322 KB

Open AccessEditor’s ChoiceArticle

Characterization of a New Biocomposite Based on Bioactive Compounds from Ganoderma lucidum and Jellyfish Collagen Destined for In Vitro Evaluation of Antitumor Effects in the Oral Cavity

by Carolina Pascale, Alexandru Burcea, Claudia Florina Bogdan-Andreescu, Emin Cadar, Antoanela Popescu, Ticuta Negreanu-Pirjol, Florica Busuricu, Ana-Maria Pesterau, Adrian Cosmin Rosca and Rodica Sirbu

Pharmaceuticals 2026, 19(1), 108; https://doi.org/10.3390/ph19010108 - 7 Jan 2026

Cited by 1 | Viewed by 1424

Abstract

Background/Objectives: Oral squamous cell carcinoma (OSCC) remains a major therapeutic challenge due to treatment-related toxicity and impaired oral tissue regeneration. This study aimed to develop and characterize a novel biocomposite based on bioactive compounds from Ganoderma lucidum incorporated into marine collagen derived from [...] Read more.

Background/Objectives: Oral squamous cell carcinoma (OSCC) remains a major therapeutic challenge due to treatment-related toxicity and impaired oral tissue regeneration. This study aimed to develop and characterize a novel biocomposite based on bioactive compounds from Ganoderma lucidum incorporated into marine collagen derived from Rhizostoma pulmo and to evaluate its physicochemical properties, antioxidant and antimicrobial activities, and in vitro antitumor potential in the oral cavity. Methods: Hydroalcoholic extracts of G. lucidum and pepsin-soluble collagen peptides from R. pulmo jellyfish were prepared and combined to obtain two hydrogel biocomposites with different component ratios. Chemical and structural characterization was performed using HPLC-DAD, SDS-PAGE, FT-IR, circular dichroism, and spectrophotometric assays. Antioxidant activity was assessed by DPPH radical scavenging and reducing power assays, while antimicrobial activity was evaluated against oral pathogens using diffusion and MIC methods. In vitro biological activity was investigated using MTT viability and scratch migration assays on human OSCC cell lines (SCC-9 and HSC-3). Results: The biocomposites preserved the structural integrity of type I collagen and incorporated polysaccharides and polyphenols from G. lucidum. The combined formulations showed enhanced antioxidant and antimicrobial activities compared with collagen alone. In vitro assays demonstrated dose- and time-dependent reductions in OSCC cell viability and delayed cell migration, with effects comparable to those of G. lucidum extract. Conclusions: The G. lucidum–R. pulmo biocomposite exhibits favorable physicochemical properties and demonstrates antioxidant, antimicrobial, and in vitro antitumor activity. These findings support its potential as a multifunctional biomaterial for further investigation as an adjunct approach in oral cancer-related applications. Full article

(This article belongs to the Special Issue Research Progress and Drug Intervention Strategies for Oral Health-Related Diseases)

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35 pages, 457 KB

Open AccessEditor’s ChoiceReview

Hybrid Cooperative Complexes of Low- and High-Molecular-Weight Hyaluronic Acid in Aesthetic Medicine

by Goran Tintor, Tin Cohadzic, Josipa Bukic, Dario Leskur, Lovre Zekan, Doris Rusic and Mladen Dudukovic

Pharmaceuticals 2026, 19(1), 73; https://doi.org/10.3390/ph19010073 - 30 Dec 2025

Cited by 1 | Viewed by 2991

Abstract

In this review we present a comprehensive overview of the published literature related to the use of Hybrid Cooperative Complexes (HCCs) of low- and high-molecular-weight hyaluronic acid in aesthetic medicine. HCCs have been developed to overcome the shortcomings of traditional hyaluronic based dermal [...] Read more.

In this review we present a comprehensive overview of the published literature related to the use of Hybrid Cooperative Complexes (HCCs) of low- and high-molecular-weight hyaluronic acid in aesthetic medicine. HCCs have been developed to overcome the shortcomings of traditional hyaluronic based dermal fillers. Specifically, HCCs deliver both high- and low-molecular-weight hyaluronic acid (HA), maximizing their complementary effects. They are biocompatible and formulated without the addition of foreign agents. Cooperative hydrogen bonds extend their durability and make them more resistant to hyaluronidase compared to high-molecular-weight HA. The rheological properties of HCC formulations allow for easy exertion through the needle and diffusion in the tissue compared to high-molecular-weight HA alone. In vitro studies have shown that HCCs improve vitality of fibroblasts, keratinocytes and adipocytes, and stimulate production of collagen and elastin. Studies on scratched co-cultures of immortalized human keratinocytes and human dermal fibroblasts demonstrated that HCCs accelerate wound closure. Furthermore, HCCs delayed senescence of mesenchymal stromal cells to a greater extent than high-molecular-weight HA or low-molecular-weight HA alone. Clinical studies show a reduction in wrinkle severity, improvement in skin roughness profile and reduction of skin laxity with pronounced improvement in superficial skin hydration lasting up to 6 months. The formulation intended for restoration of fat compartments demonstrated reduction in cheek volume loss and improvement in skin thickness. Subjects report moderate-to-high satisfaction and are likely to recommend the treatment. Limitations of the published studies are also addressed, as well as reported adverse events and published safety data. 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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24 pages, 1512 KB

Open AccessEditor’s ChoiceReview

Puberty Starts in the Gut: Intestinal Clues to Early Puberty-Rethinking Biomarkers in Pediatric Endocrinology

by Otilia Elena Frăsinariu, Teodora Cristina Vintilă, Ioana Vasiliu, Violeta Ștreangă, Aniela Rugină, Oana Raluca Temneanu, Ionuț Daniel Iancu, Andreea Iațentiuc, Elena Jechel and Alexandru Florescu

Pharmaceuticals 2026, 19(1), 49; https://doi.org/10.3390/ph19010049 - 25 Dec 2025

Cited by 3 | Viewed by 2709

Abstract

Central precocious puberty (CPP) may be influenced by gut microbiota through changes in short-chain fatty acids (SCFAs), β-glucuronidase activity, and enterohepatic estrogen recycling. This narrative review integrates current evidence from human and animal studies exploring microbial contributions to pubertal timing. Across multiple cohorts, [...] Read more.

Central precocious puberty (CPP) may be influenced by gut microbiota through changes in short-chain fatty acids (SCFAs), β-glucuronidase activity, and enterohepatic estrogen recycling. This narrative review integrates current evidence from human and animal studies exploring microbial contributions to pubertal timing. Across multiple cohorts, CPP is associated with loss of SCFA-producing commensals, such as Bacteroides, and increased abundance of taxa like Alistipes, Ruminococcus, and Lachnoclostridium. These microbial shifts are linked to altered SCFA profiles, diminished anti-inflammatory and neuroendocrine modulation, and enhanced reabsorption of estrogens via microbial β-glucuronidase activity. Experimental models support a causal connection: gut dysbiosis accelerates pubertal onset, whereas microbiota-targeted interventions can restore hormonal balance and delay activation of the HPG axis. While some overlap with obesity-associated microbiota exists, the endocrine-specific microbial changes observed in CPP suggest partially distinct mechanisms. Overall, the gut microbiota emerges as both a modulator and potential biomarker of early pubertal onset. Its integration into pediatric endocrine frameworks could improve early risk assessment and guide future interventions, though further validation through standardized, longitudinal, and diverse population studies is still required. Full article

(This article belongs to the Special Issue The Regulatory Roles of the Gut Microbiota in Multisystem Diseases)

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39 pages, 1367 KB

Open AccessEditor’s ChoiceReview

The Therapeutic Pipeline for Eosinophilic Esophagitis: Current Landscape and Future Directions

by Andrea Pasta, Luisa Bertin, Amir Mari, Francesco Calabrese, Amir Farah, Giulia Navazzotti, Matteo Ghisa, Vincenzo Savarino, Edoardo Vincenzo Savarino, Edoardo Giovanni Giannini and Elisa Marabotto

Pharmaceuticals 2025, 18(12), 1882; https://doi.org/10.3390/ph18121882 - 12 Dec 2025

Cited by 4 | Viewed by 4417

Abstract

Eosinophilic esophagitis (EoE) has emerged as a major cause of dysphagia and food impaction worldwide. This narrative review traces the evolving therapeutic pipeline for EoE, highlighting agents spanning from late-stage clinical development to final approval. We summarize mechanistic insights that have driven a [...] Read more.

Eosinophilic esophagitis (EoE) has emerged as a major cause of dysphagia and food impaction worldwide. This narrative review traces the evolving therapeutic pipeline for EoE, highlighting agents spanning from late-stage clinical development to final approval. We summarize mechanistic insights that have driven a shift from broad immunosuppression to precise inhibition of type-2 inflammatory pathways, including blockade of key interleukin pathways. Randomized trials have demonstrated histologic and symptomatic gains, yet regulatory approvals and optimal positioning within treatment algorithms are pending. Parallel innovations in drug delivery aim to maximize mucosal exposure while minimizing systemic burden. Key challenges include heterogeneity in disease phenotype, paucity of long-term safety data, and the need for non-invasive biomarkers to guide precision prescribing. Cost considerations and patient preferences will shape adoption. By integrating advances across immunology, formulation science and clinical trial design, the therapeutic pipeline for EoE holds promise to transform care from empirical suppression to mechanism-based disease modification. Full article

(This article belongs to the Special Issue New and Emerging Treatment Strategies for Gastrointestinal Diseases)

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24 pages, 3190 KB

Open AccessEditor’s ChoiceArticle

Ga-68-Labeled Affibody Molecule-Based Radiopharmaceutical Targeting Platelet Derived Growth Factor Receptor Beta for Detection of Active Fibrosis in Patients with Myocardial Infarction

by Irina Velikyan, Karl-Henrik Grinnemo, Viktor Flodin, Stefan James, Ulrika Thelander, Michael Wagner, Sergey Rodin, Tanja Kero, Olle Korsgren and Olof Eriksson

Pharmaceuticals 2025, 18(12), 1833; https://doi.org/10.3390/ph18121833 - 1 Dec 2025

Cited by 2 | Viewed by 1198

Abstract

Introduction: Platelet-derived growth factor receptor beta (PDGFRβ) is a key regulator of fibrogenesis. Non-invasive imaging of PDGFRβ expression may offer a novel approach to assess fibrotic remodeling, particularly in cardiac patients’ post-intervention, where fibrosis poses clinical risk. This study presents the GMP-compliant [...] Read more.

Introduction: Platelet-derived growth factor receptor beta (PDGFRβ) is a key regulator of fibrogenesis. Non-invasive imaging of PDGFRβ expression may offer a novel approach to assess fibrotic remodeling, particularly in cardiac patients’ post-intervention, where fibrosis poses clinical risk. This study presents the GMP-compliant production of a novel PDGFRβ-targeted PET radiopharmaceutical, [⁶⁸Ga]Ga-DOTA-Z09591 ([⁶⁸Ga]Ga-ATH001), and its preclinical evaluation in mouse and human myocardial tissue, along with initial clinical imaging in patients with ST-elevation myocardial infarction (STEMI). Methods: The precursor was chemically synthesized and radiolabeled with gallium-68 using a fully automated, GMP-compatible system and a pharmaceutical-grade ⁶⁸Ge/⁶⁸Ga generator. Autoradiography, H&E, Sirius Red, Masson’s trichrome, and IHC staining were performed on infarcted mouse hearts and human myocardial biopsies. In vivo PET/MRI with [⁶⁸Ga]Ga-ATH001, ¹⁵O-H₂O, and gadolinium contrast was conducted in STEMI patients one week post-percutaneous coronary intervention. Results: [⁶⁸Ga]Ga-ATH001 was produced with high radiochemical yield and purity. Autoradiography demonstrated specific, receptor-mediated binding of [⁶⁸Ga]Ga-ATH001, co-localizing with PDGFRβ immunoreactivity, collagen deposition, and tissue damage. In STEMI patients, focal tracer uptake was observed in infarcted myocardium correlating with MRI-detected structural abnormalities and perfusion defects on ¹⁵O-H₂O PET. Uptake in unaffected myocardium was low and homogeneous, consistent with minimal physiological PDGFRβ expression. Conclusions: [⁶⁸Ga]Ga-ATH001 was successfully developed and validated for phase 0 clinical study. The tracer demonstrated PDGFRβ-specific binding in human fibrotic myocardium and enabled non-invasive detection of myocardial fibrogenic activity in STEMI patients. These findings support further clinical evaluation of [⁶⁸Ga]Ga-ATH001 as a targeted molecular imaging agent for early assessment of post-infarction fibrosis. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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22 pages, 22951 KB

Open AccessEditor’s ChoiceReview

Advancing PROTAC Discovery Through Artificial Intelligence: Opportunities, Challenges, and Future Directions

by Kwang-Su Park and Minji Jeon

Pharmaceuticals 2025, 18(12), 1793; https://doi.org/10.3390/ph18121793 - 25 Nov 2025

Cited by 8 | Viewed by 4170

Abstract

Proteolysis Targeting Chimeras (PROTACs) represent a transformative modality in drug discovery, enabling the selective degradation of disease-relevant proteins through the ubiquitin proteasome system. Despite their therapeutic promise, the rational design of PROTACs remains a complex and resource-intensive process, involving multiple parameters such as [...] Read more.

Proteolysis Targeting Chimeras (PROTACs) represent a transformative modality in drug discovery, enabling the selective degradation of disease-relevant proteins through the ubiquitin proteasome system. Despite their therapeutic promise, the rational design of PROTACs remains a complex and resource-intensive process, involving multiple parameters such as target and ligase compatibility, ternary complex formation, linker optimization, and degradation efficiency. Recent advances in artificial intelligence (AI) have provided new strategies to address these obstacles, ranging from structure-based modeling of ternary complexes to degradability prediction, generative linker design, and pharmacokinetic property estimation. This review aims to explore how AI can be leveraged directly or indirectly in the PROTAC development pipeline. First, we analyze existing applications of AI, such as ternary complex structure prediction, degradability prediction, linker design, and ADME prediction. We further discuss how other approaches from the related fields may be adapted to address the challenges of PROTAC discovery. Lastly, we discuss challenges that current AI models face, such as limited data, poor interpretability, and low generalizability. Taken together, overcoming these barriers will enable AI-driven strategies to accelerate PROTAC discovery and provide a more rational framework for targeted protein degrader development. Full article

(This article belongs to the Special Issue Computer-Aided Drug Design and Drug Discovery, 2nd Edition)

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21 pages, 2981 KB

Open AccessEditor’s ChoiceArticle

Impact of Ethanol on Electrostatic Behaviour of Fluorocarbon Pharmaceutical Propellants

by Lochana Ranatunge, Manoochehr Rasekh, Hussein Ahmad and Wamadeva Balachandran

Pharmaceuticals 2025, 18(11), 1755; https://doi.org/10.3390/ph18111755 - 18 Nov 2025

Cited by 1 | Viewed by 947

Abstract

Background/Objectives: Triboelectrification in fluid systems, and specifically in hydrofluorocarbon (HFC)-based propellants, used in pressurised metered-dose inhalers (pMDIs) remains understudied despite its impact on aerosol behaviour and does delivery. This study investigates how ethanol concentration affects charge generation and dissipation in HFC-152a (1,1-difluoroethane; R152a) [...] Read more.

Background/Objectives: Triboelectrification in fluid systems, and specifically in hydrofluorocarbon (HFC)-based propellants, used in pressurised metered-dose inhalers (pMDIs) remains understudied despite its impact on aerosol behaviour and does delivery. This study investigates how ethanol concentration affects charge generation and dissipation in HFC-152a (1,1-difluoroethane; R152a) flowing through low-density polyethylene (LDPE) tubing, a common valve-stem material in pMDIs. Methods: Controlled experiments measured electrical current, charge accumulation, and flow stability for HFC-152a with varying ethanol concentrations in LDPE tubing. Statistical analysis (two-way ANOVA, p < 0.05) assessed the effects of the propellant and material. Comparative tests include R134a (1,1,1,2-tetrafluoroethane) and R227ea (1,1,1,2,3,3,3-heptafluoropropane), and the tubing materials are polybutylene terephthalate (PBT), polyvinyl chloride (VINYL), polyoxymethylene (POM), and LDPE. Results: Increasing ethanol concentration produced larger measured currents, reduced net charge accumulation, and improved flow stability; these effects are attributed to ethanol’s higher dielectric constant and conductivity enhancing charge mobility and dissipation. Significant propellant x material interactions were found (p < 0.05): R152a generated the largest responses with PBT and VINYL (~16 nA and ~5.6 nA, respectively), R227ea showed higher responses with POM and LDPE (~8 nA), and R134a delivered the highest flow rates across materials but exhibited limited electrical responsiveness. Conclusions: Ethanol addition mitigates undesirable electrostatic effects in HFC-based propellants by promoting charge dissipation. The results demonstrate the strong material dependence of triboelectric behaviour and underline the importance of optimising propellant–polymer pairings to minimise the electrostatic adhesion of aerosolised particles and improve pMDI drug delivery performance. Full article

(This article belongs to the Special Issue Advances in Drug Analysis and Drug Development, 2nd Edition)

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20 pages, 1717 KB

Open AccessEditor’s ChoiceArticle

Coleus aromaticus Benth.—A Plant with Strong Anticancer and Antioxidant Potential In Vitro

by Justyna Stefanowicz-Hajduk, Anna Hering, Rafał Hałasa, Szymon Masiak, Karolina Turczyn, J. Renata Ochocka and Monika Asztemborska

Pharmaceuticals 2025, 18(11), 1756; https://doi.org/10.3390/ph18111756 - 18 Nov 2025

Cited by 1 | Viewed by 1798

Abstract

Background/Objectives: Gastrointestinal cancers, including gastric and colon cancers, constitute a serious threat to global health due to their high incidence and limited treatment outcomes. Thus, natural products are becoming increasingly popular as potential chemopreventive agents. Coleus aromaticus Benth. is mainly used as [...] Read more.

Background/Objectives: Gastrointestinal cancers, including gastric and colon cancers, constitute a serious threat to global health due to their high incidence and limited treatment outcomes. Thus, natural products are becoming increasingly popular as potential chemopreventive agents. Coleus aromaticus Benth. is mainly used as a tasty addition to dishes and juices due to its aromatic and nutritional properties. The plant has many biological and pharmacological effects that require deeper evaluation. In this study, anticancer, antioxidant, and antimicrobial activities of ethanol, ethanol/water extracts, and juice from C. aromaticus leaves were evaluated. Methods: (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) MTT assay, DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonate)), molybdenum reducing power assay, and broth microdilution technique were used, respectively. Additionally, total phenolic (TPC) and total flavonoid content (TFC) with basic phytochemical composition of volatile compounds by GC-MS and GC-FID were assessed. Results: The results indicate that the strongest anticancer activity was provided by the ethanol extract with IC₅₀ values of 4.94 ± 0.48 and 24.99 ± 1.80 µg/mL on human gastric AGS cells and human colorectal HCT 116 cells, respectively. The antioxidant potential was also the highest for the ethanol extract with IC₅₀ values of 13.34 ± 0.11 (ABTS), 22.90 ± 1.30 (DPPH), and 290.17 ± 4.23 µg/mL (molybdenum reducing power). Antimicrobial experiments revealed that ethanol and ethanol/water extracts were the most potent on Clostridium perfringens (MIC value was <0.02 mg/mL). Phytochemical analysis showed a significant content of phenolic and flavonoid compounds in the ethanol extract (75.87 ± 0.96 mg gallic acid equivalent/g dry extract and 176.01 ± 3.58 mg quercetin equivalent/g dry extract, respectively). Furthermore, all the extracts contained carvacrol (49.09, 28.15, and 25.68% of volatile fraction in ethanol, ethanol/water extracts and juice, respectively). Camphor and oleamide were also detected in large quantity. Conclusions: C. aromaticus can be considered as a potential agent in the prevention and treatment of gastrointestinal cancers, especially the ethanol extract from the plant leaves due to its strong anticancer and antioxidant properties. Full article

(This article belongs to the Special Issue Natural Compounds as Potential Anticancer, Anti-inflammatory and Antioxidant Agents in Medicine)

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14 pages, 1862 KB

Open AccessEditor’s ChoiceArticle

Genistein Inhibits Fine-Dust-Induced Matrix Metalloproteinase-1 in Human Keratinocytes

by Dong Keun Song, Yun Young Jeong, Eunmiri Roh, Hyun Young Shin and Jong-Eun Kim

Pharmaceuticals 2025, 18(11), 1750; https://doi.org/10.3390/ph18111750 - 17 Nov 2025

Cited by 1 | Viewed by 1050

Abstract

Background/Objectives: Particulate matter (PM), which comprises airborne pollutants characterized by small sizes (typically from 5 to 8 μm in Korea), adversely affect skin health and accelerate aging by inducing oxidative stress and upregulating the expression of matrix metalloproteinase-1 (MMP-1), an enzyme responsible for [...] Read more.

Background/Objectives: Particulate matter (PM), which comprises airborne pollutants characterized by small sizes (typically from 5 to 8 μm in Korea), adversely affect skin health and accelerate aging by inducing oxidative stress and upregulating the expression of matrix metalloproteinase-1 (MMP-1), an enzyme responsible for collagen degradation. The skin, which is the largest organ and the primary barrier against harmful external stimuli such as air pollution, is particularly vulnerable to continuous PM exposure, which can cause skin aging and carcinogenesis. Given the effects of PM on skin aging, identifying compounds that can mitigate these adverse effects is crucial. Genistein is a naturally occurring isoflavone that has not been extensively studied in the context of PM-induced skin aging. Methods: In this study, we investigated the protective effects of genistein against PM-induced skin aging in HaCaT human keratinocytes. Results: Our results demonstrated that genistein treatment significantly reduced PM-induced MMP-1 expression, indicating a protective effect against collagen degradation. Additionally, genistein decreased the expression of the transcription factors activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB), both of which are involved in the regulation of MMP-1. Furthermore, genistein markedly reduced the production of reactive oxygen species (ROS), a key marker of oxidative stress induced by PM exposure. Conclusions: These findings suggest that genistein exerts protective effects against PM-induced skin aging by attenuating collagen degradation and oxidative stress, indicating its potential as a therapeutic agent for improving skin aging associated with PM exposure. Full article

(This article belongs to the Special Issue Bioactive Compounds Derived from Plants and Their Medicinal Potential, 2nd Edition)

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19 pages, 1231 KB

Open AccessEditor’s ChoiceReview

Potential Implications of Body Mass Composition Changes in Heart Failure Patients in the Era of SGLT2i, GLP-1 RA, and GIP/GLP-1 RA

by Katarzyna Gryglewska-Wawrzak, Agnieszka Kapłon-Cieślicka, Agnieszka Pawlak, Anna Tomaszuk-Kazberuk, Paweł Rubiś, Jacek Niedziela and Agata Bielecka-Dąbrowa

Pharmaceuticals 2025, 18(11), 1726; https://doi.org/10.3390/ph18111726 - 13 Nov 2025

Viewed by 2080

Abstract

Obesity is a complex, multifactorial disease wherein the excessive accumulation of adipose tissue leads to adverse health outcomes, such as diabetes, cardiovascular disease and musculoskeletal disorders. Obesity also impacts both the risk and the clinical prognosis of heart failure (HF). The accumulation of [...] Read more.

Obesity is a complex, multifactorial disease wherein the excessive accumulation of adipose tissue leads to adverse health outcomes, such as diabetes, cardiovascular disease and musculoskeletal disorders. Obesity also impacts both the risk and the clinical prognosis of heart failure (HF). The accumulation of adipose tissue results in metabolic dysregulation, including increased levels of pro-inflammatory cytokines and adipokines. These alterations are strongly associated with the development and progression of HF. Another significant comorbidity in patients with HF is sarcopenia, characterized by progressive loss of muscle mass and strength, affecting the quality of life. The study aims to critically synthesize the mechanisms by which modern pharmacological treatments—sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dual GIPR/GLP-1R agonists—modulate body mass composition, and to analyze the specific implications of these changes (e.g., visceral fat reduction versus lean mass loss) for heart failure (HF) prognosis and management. Full article

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

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17 pages, 501 KB

Open AccessEditor’s ChoiceArticle

How Regulation 536/2014 Is Changing Academic Research with Therapeutic Radiopharmaceuticals: A Local Experience

by Valentina Di Iorio, Stefano Boschi, Erika Brugugnoli, Maddalena Sansovini, Federica Matteucci, Carla Masini and Manuela Monti

Pharmaceuticals 2025, 18(11), 1709; https://doi.org/10.3390/ph18111709 - 11 Nov 2025

Cited by 2 | Viewed by 1186

Abstract

Background/Objectives: This report examines the future of academic studies involving investigational therapeutic radiopharmaceuticals within the framework of Regulation (EU) No. 536/2014. It discusses the impact of Good Manufacturing Practice (GMP) requirements (EudraLex-Volume 4-Good Manufacturing Practice guidelines) on the development of radiopharmaceuticals, based [...] Read more.

Background/Objectives: This report examines the future of academic studies involving investigational therapeutic radiopharmaceuticals within the framework of Regulation (EU) No. 536/2014. It discusses the impact of Good Manufacturing Practice (GMP) requirements (EudraLex-Volume 4-Good Manufacturing Practice guidelines) on the development of radiopharmaceuticals, based on local experience and analysis. Methods: The report was drafted by analysing multiple factors, including the European regulatory context regarding EMA guidance for investigational medicinal products (IMPs) and GMP requirements for radiopharmaceuticals, as well as position papers from various scientific associations. An analysis of all the relevant changes was conducted by a multidisciplinary team comprising radiopharmacists, nuclear medicine physicians, research experts and technology transfer specialists. They conducted a literature review to examine the clinical implications of the regulatory change and assess the impact of Regulation 536/2014 on academic clinical trials. Results: IRST has around 20 years’ experience in radiopharmaceutical clinical research. From 2008 to 2025, it conducted 16 clinical trials with radiopharmaceuticals under the Directive, and it is currently promoting five studies under the Regulation. During this time, more than 1000 patients were enrolled. The transition was based on staff training in quality documentation, the constitution of a contract research organisation (CRO) to ensure data quality and transfer, careful budget planning, the evaluation of innovative business models and the role of a Contract Development and Manufacturing Organization (CDMO). These integrated approaches enabled IRST to transform regulatory constraints into an opportunity to enhance its organisational model, improve data reliability, and strengthen its position as a centre of excellence for radiopharmaceutical research and production. Conclusions: The implementation of EU Regulation 536/2014 has significantly impacted academic research centres, especially those specialising in radiopharmaceuticals. Adhering to Good Manufacturing Practice (GMP) for therapeutic radiopharmaceuticals requires a considerable investment in infrastructure and personnel. However, the regulation also presents opportunities for research centres to enhance their capabilities. Meeting GMP standards can help institutions improve the quality and reliability of their clinical trials, potentially making them more competitive in the international research arena. Full article

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

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27 pages, 1334 KB

Open AccessEditor’s ChoiceReview

Cardiovascular Therapeutics at the Crossroads: Pharmacological, Genetic, and Digital Frontiers

by Erica Vetrano, Alfredo Caturano, Davide Nilo, Giovanni Di Lorenzo, Giuseppina Tagliaferri, Alessia Piacevole, Mariarosaria Donnarumma, Ilaria Iadicicco, Sabrina Picco, Simona Maria Moretto, Maria Rocco, Raffaele Galiero, Vincenzo Russo, Raffaele Marfella, Luca Rinaldi, Leonilde Bonfrate and Ferdinando Carlo Sasso

Pharmaceuticals 2025, 18(11), 1703; https://doi.org/10.3390/ph18111703 - 10 Nov 2025

Cited by 2 | Viewed by 3247

Abstract

Therapeutic innovation in cardiovascular medicine is rapidly overcoming the limitations of conventional strategies, providing more targeted, durable, and multidimensional solutions. Key advances include next-generation lipid-lowering agents such as PCSK9 inhibitors, inclisiran, and bempedoic acid, as well as metabolic drugs like SGLT2 inhibitors, GLP-1 [...] Read more.

Therapeutic innovation in cardiovascular medicine is rapidly overcoming the limitations of conventional strategies, providing more targeted, durable, and multidimensional solutions. Key advances include next-generation lipid-lowering agents such as PCSK9 inhibitors, inclisiran, and bempedoic acid, as well as metabolic drugs like SGLT2 inhibitors, GLP-1 receptor agonists, and dual GIP/GLP-1 agonists, which offer cardiovascular and renal benefits beyond glucose control. At the same time, gene therapies, RNA-based interventions, genome editing tools, and nanocarriers are paving the way for precision medicine tailored to individual patient profiles. In parallel, digital innovations, including artificial intelligence, remote monitoring, and telehealth platforms, are transforming care delivery by enhancing adherence, enabling earlier intervention, and refining risk stratification. Collectively, these developments signify a paradigm shift toward a more personalized, proactive, and systems-based model of cardiovascular care. Full article

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

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27 pages, 2069 KB

Open AccessEditor’s ChoiceArticle

In Vitro and in Vivo Efficacy of Different Ointment Formulations Containing Centaurium erythraea Rafn. Aerial Extract

by Anett Jolán Karetka, Boglárka Papp, István Lekli, Ana-Maria Vlase, Annamária Pallag, Laura Grațiela Vicaș, Antonia-Maria Lestyán, Liza Józsa, Dóra Kósa, Ágota Pető, Zoltán Ujhelyi, Fruzsina Nacsa, Ildikó Bácskay, Pálma Fehér and Tünde Jurca

Pharmaceuticals 2025, 18(11), 1681; https://doi.org/10.3390/ph18111681 - 6 Nov 2025

Cited by 1 | Viewed by 2857

Abstract

Background: Centaurium erythraea Rafn. (C. erythraea) is a medicinal plant traditionally used in European folk medicine for the treatment of wounds, skin inflammations, and other dermatological conditions, in addition to its well-documented systemic antioxidant and anti-inflammatory effects. However, its [...] Read more.

Background: Centaurium erythraea Rafn. (C. erythraea) is a medicinal plant traditionally used in European folk medicine for the treatment of wounds, skin inflammations, and other dermatological conditions, in addition to its well-documented systemic antioxidant and anti-inflammatory effects. However, its topical applications remain insufficiently investigated, particularly using plant material collected from Romania. The purpose of this study was to prepare different ointment formulations containing C. erythraea Rafn. extract obtained from the aerial parts of the plant, using various excipients, and to evaluate their in vitro and in vivo efficacy. Methods: The phytochemical profile of C. erythraea extract was characterized using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The lyophilized extract was pre-dissolved in different solubilizing agents—Transcutol^® P (diethylene glycol monoethyl ether), Capryol^® 90 (propylene glycol monocaprylate), or a combination of both—and then incorporated into five ointment formulations. Texture analysis and an in vitro membrane diffusion study were performed. The antioxidant capacity of the formulations was assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, ferric reducing antioxidant power (FRAP), and total phenolic content (TPC) assays. Anti-inflammatory activity was evaluated in vitro using tumor necrosis factor-alpha (TNF-α)-induced interleukin-1 beta (IL-1β) production in human keratinocyte (HaCaT) cells, and in vivo using a carrageenan-induced rat paw edema model. Results: LC–MS/MS identified 18 polyphenolic compounds, with hyperoside (3.78 ± 0.05 µg/mL), protocatechuic acid (1.13 ± 0.06 µg/mL), chlorogenic acid (1.07 ± 0.06 µg/mL), and quercetin (0.53 ± 0.03 µg/mL) as the principal constituents. The formulation containing both Transcutol^® P and Capryol^® 90 exhibited the most pronounced antioxidant activity (65% DPPH inhibition; 69.71 ± 0.83 mg gallic acid equivalent/mL) and significantly reduced IL-1β levels by 45.7% compared to the inflamed control. In vivo, this formulation showed comparable anti-edematous effects to a methylprednisolone ointment. Furthermore, it demonstrated the highest skin permeation efficiency, with a quercetin diffusion coefficient of 35.12 × 10⁻⁵ cm²/min. Conclusions: These findings highlight the therapeutic potential of C. erythraea extract from aerial parts in topical formulations and underscore the enhancing role of Transcutol^® P and Capryol^® 90 in improving both the pharmacodynamic and pharmacokinetic properties of bioactive compounds. Full article

(This article belongs to the Special Issue Natural Products for Skin Applications)

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16 pages, 3337 KB

Open AccessEditor’s ChoiceArticle

Comparison of Cholic Acid (MT921) and Deoxycholic Acid (DCA) in Fat Reduction Efficacy and Skin Adverse Reactions in Mini Pigs and Rodent Models

by Sujin Cho, Deu John M. Cruz, Minhee Shin, Jaeyoon Byun, Junho Lee and Seongsung Kwak

Pharmaceuticals 2025, 18(11), 1643; https://doi.org/10.3390/ph18111643 - 30 Oct 2025

Viewed by 3610

Abstract

Background/Objectives: This study compared fat reduction efficacy of cholic acid-based formulation (MT921) and deoxycholic acid (DCA), as well as skin adverse reactions (ADR), in mini pigs, mice, and rats. DCA is the active pharmaceutical ingredient found in several fat-dissolving injectables, such as Kybella [...] Read more.

Background/Objectives: This study compared fat reduction efficacy of cholic acid-based formulation (MT921) and deoxycholic acid (DCA), as well as skin adverse reactions (ADR), in mini pigs, mice, and rats. DCA is the active pharmaceutical ingredient found in several fat-dissolving injectables, such as Kybella^®, V-OLET^®, and Bellacholine^®. Methods: In one study, single subcutaneous (s.c.) injections of 1.5% MT921 and 1% DCA were administered to the back of a mini pig at different sites and time points to ascertain histopathological events. In another study, three mini pigs received six repeated s.c. injections of 1.5% MT921 and 1% DCA at 4-week intervals, and changes in subcutaneous fat volume were monitored by magnetic resonance imaging (MRI), along with visual examination for ADRs. Additional ADRs were assessed in rodents, such as ulcerative dermatitis (UD) following MT921 and DCA s.c. injections in ICR/CD1 mice, and footpad edema after intraplantar injections in SD rats. Results: In mini pigs, 1.5% MT921 and 1% DCA induced comparable localized fat necrosis, accompanied by inflammatory cell influx and fibrosis. Also, repeated injections of 1.5% MT921 and 1% DCA induced comparable fat volume reduction in outer subcutaneous layer, though changes in middle subcutaneous layer was unaffected. Notably, MT921 evoked milder ADR based on lower incidence of hematoma and absence of nodules in mini pigs, less severe UD in mice, and reduced edema in rats. Conclusions: Local injections of 1.5% MT921 demonstrated fat-reduction efficacy comparable to 1% DCA while eliciting fewer and milder ADRs, supporting MT921 as a promising alternative lipolytic agent. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 461 KB

Open AccessEditor’s ChoiceReview

Innovative Strategies to Enhance the Bioavailability of Cannabidiol: Nanotechnology and Advanced Delivery Systems

by Magdalena Paczkowska-Walendowska, Piotr Trzaskoma, Aleksandra Dziopa, Arash Moeini, Michał Soczawa, Zbigniew Krasiński and Judyta Cielecka-Piontek

Pharmaceuticals 2025, 18(11), 1637; https://doi.org/10.3390/ph18111637 - 29 Oct 2025

Cited by 8 | Viewed by 4636

Abstract

Cannabidiol (CBD), a phytocannabinoid with therapeutic potential for neurological and other conditions, faces significant challenges in bioavailability due to its low water solubility, high lipophilicity, and extensive first-pass metabolism. Researchers have developed advanced nanodelivery systems addressing these limitations to enhance CBD’s absorption, stability, [...] Read more.

Cannabidiol (CBD), a phytocannabinoid with therapeutic potential for neurological and other conditions, faces significant challenges in bioavailability due to its low water solubility, high lipophilicity, and extensive first-pass metabolism. Researchers have developed advanced nanodelivery systems addressing these limitations to enhance CBD’s absorption, stability, and efficacy. This review provides not only a comprehensive summary of current nanotechnological delivery strategies for CBD, including nanoemulsions, liposomes, polymeric micelles, nanosuspensions, and cyclodextrin inclusion complexes, but also introduces a distinct comparative and integrative perspective. Unlike previous reviews, our work synthesizes preclinical and clinical evidence while highlighting the novel integration of nanotechnology with bioenhancers and personalized medicine approaches. We further emphasize the emerging concepts of hybrid and smart nanocarriers, which have not yet been systematically discussed, positioning them as next-generation solutions to overcome CBD’s bioavailability challenges and paving the way for precision therapeutics. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of Cannabinoids)

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58 pages, 6052 KB

Open AccessEditor’s ChoiceReview

Cyclodextrin-Based Formulations as a Promising Strategy to Overcome the Blood–Brain Barrier: Historical Overview and Prospects in Glioblastoma Treatment

by Federica De Gaetano, Noemi Totaro and Cinzia Anna Ventura

Pharmaceuticals 2025, 18(11), 1626; https://doi.org/10.3390/ph18111626 - 28 Oct 2025

Cited by 8 | Viewed by 2957

Abstract

Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers affecting the central nervous system (CNS), predominantly in adults. Despite significant advancements in this field, GB treatment still relies primarily on conventional approaches, including surgical resection, radiotherapy, and chemotherapy, which, due to [...] Read more.

Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers affecting the central nervous system (CNS), predominantly in adults. Despite significant advancements in this field, GB treatment still relies primarily on conventional approaches, including surgical resection, radiotherapy, and chemotherapy, which, due to its complex pathological characteristics, resistance mechanisms, and restrictive nature of the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), remain of limited efficacy. In this context, the development of innovative therapeutic strategies able to overcome these barriers, induce cancer cell death, and improve patient prognosis is crucial. Recently, nanoparticle platforms and focused ultrasounds seem to be promising approaches for cancer treatment. Nanoparticles enable targeting and controlled release, whilst focused ultrasounds enhance tissue permeation, increasing drug accumulation in a specific organ. However, nanoparticles can suffer from synthesis complexity, long-term biocompatibility and accumulation in the body with consequent toxicity, whereas focused ultrasounds require specialized equipment and can potentially cause thermal damage, hemorrhage, or cavitation injury. Cyclodextrins (CYDs) possess good properties and represent a versatile and safer alternative able to improve drug stability, solubility, and bioavailability, and depending on the type, dose, and administration route, can reduce local and systemic toxicity. Thus, CYDs emerge as promising novel excipients in GB treatment. Despite these advantages, CYD complexes suffer from receptor specificity, reducing their potential in precision medicine. By combining CYD complexes with polymeric or lipidic platforms, the advantages of CYD safety and drug solubilization together with their specific targeting can be obtained, thus enhancing selectivity and maximizing efficacy while minimizing recurrence and systemic toxicity. This review provides a comprehensive overview of GB pathology, conventional treatments, and emerging CYD-based strategies aimed at enhancing drug delivery and therapeutic efficacy. Full article

(This article belongs to the Section Pharmaceutical Technology)

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15 pages, 4423 KB

Open AccessEditor’s ChoiceArticle

A Multi-Laboratory, Multi-Platform Analysis of the Multi-Attribute Method

by Joshua Shipman, Mercy Oyugi, Tim Andres Marzan, Ilan Geerlof-Vidavsky, Douglas Kirkpatrick, Hongbin Zhu, Milani Rasangika and Sarah Rogstad

Pharmaceuticals 2025, 18(11), 1613; https://doi.org/10.3390/ph18111613 - 25 Oct 2025

Cited by 4 | Viewed by 1872

Abstract

Background/Objectives: The multi-attribute method (MAM) has found diverse use in the analytical characterization of therapeutic protein products during their development and production. As the MAM matures it has the potential to enter quality control (QC) laboratories, consolidating and replacing many less informative [...] Read more.

Background/Objectives: The multi-attribute method (MAM) has found diverse use in the analytical characterization of therapeutic protein products during their development and production. As the MAM matures it has the potential to enter quality control (QC) laboratories, consolidating and replacing many less informative chromatographic techniques; however, this requires an appropriate risk assessment and understanding of method capability. Methods: A validated MAM approach was used to quantify product quality attributes (PQAs) using three different mass spectrometers across two laboratories; the results were compared to conventional hydrophilic interaction chromatography–fluorescence detection (HILIC-FLD) and cation exchange chromatography–ultraviolet (CEX-UV) techniques. Results: Stressed, long-term, and accelerated stability studies were performed, and their effects on glycosylation, deamidation, oxidation and N- and C-termini were quantified. Conclusions: Overall, the inter-instrument inter-laboratory data provided here showed important considerations for transferring methods between laboratories and establishing the correlation between the MAM and conventional data, elements which are necessary to transition the MAM to the QC environment and ultimately achieving the goal of replacing orthogonal QC methods. Full article

(This article belongs to the Special Issue Characterization and Quality Control of Biopharmaceuticals Using the Multi-Attribute Method (MAM): Advantages and Challenges)

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22 pages, 955 KB

Open AccessEditor’s ChoiceReview

Targeting Inflammatory Pathways in Chronic Low Back Pain: Opportunities for Novel Therapeutics

by Panagiota Anyfanti, Paschalis Evangelidis, Konstantinos Tragiannidis, Christina Antza, Dimitrios Poulis, Theodoros Dimitroulas and Vasilios Kotsis

Pharmaceuticals 2025, 18(11), 1612; https://doi.org/10.3390/ph18111612 - 24 Oct 2025

Cited by 2 | Viewed by 3932

Abstract

Low back pain (LBP) is a highly prevalent musculoskeletal problem and a leading cause of disability worldwide. From a pathophysiological perspective, the contribution of inflammation to LBP is being increasingly recognized. In this literature review, we aim to provide an overview of the [...] Read more.

Low back pain (LBP) is a highly prevalent musculoskeletal problem and a leading cause of disability worldwide. From a pathophysiological perspective, the contribution of inflammation to LBP is being increasingly recognized. In this literature review, we aim to provide an overview of the role of inflammation as a mediator of LBP while summarizing clinical studies investigating the potential role of anti-inflammatory treatments in the management of LBP. Although often controversial, the available evidence suggests an important role of inflammation in the pathogenesis of LBP, which can be further translated into novel therapeutic targets. Both anti-tumor necrosis factor (anti-TNF) and anti-nerve growth factor (anti-NGF) agents hold the potential of blocking inflammation and pain pathways in patients with chronic LBP. TNF inhibitors have been tested mostly in small trials with mixed results, and their long-term efficacy remains to be proven. Anti-NGF agents have demonstrated stronger and consistent efficacy in randomized controlled trials, but safety concerns compromise their widespread use. The potential role of other anti-inflammatory molecules is currently under investigation. Presently, the routine use of TNF or NGF inhibitors is not supported in radiculopathy or chronic LBP. However, novel anti-inflammatory therapies introduced in the rheumatology field appear to be promising for specific subsets of patients suffering from chronic, refractory LBP, with a complementary role as therapeutic tools, after the unsuccessful outcome of the conservative approach. Full article

(This article belongs to the Section Pharmacology)

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22 pages, 1723 KB

Open AccessEditor’s ChoiceReview

Clinical Experience with Targeted Alpha-Emitter Peptide Receptor Radionuclide Therapy (α-PRRT) for Somatostatin Receptor-Positive Neuroendocrine Tumors

by Hannes Leupe, Merel Cauwenbergh, Frederik Cleeren, Jeroen Dekervel, Chris Verslype and Christophe M. Deroose

Pharmaceuticals 2025, 18(11), 1608; https://doi.org/10.3390/ph18111608 - 24 Oct 2025

Cited by 7 | Viewed by 4999

Abstract

Background: α-emitting Peptide Receptor Radionuclide Therapy (α-PRRT) is emerging as a promising new generation of PRRT for neuroendocrine tumors (NETs), providing enhanced tumor cell cytotoxicity and reduced irradiation of adjacent healthy tissues due to its high linear energy transfer (LET) and short particle [...] Read more.

Background: α-emitting Peptide Receptor Radionuclide Therapy (α-PRRT) is emerging as a promising new generation of PRRT for neuroendocrine tumors (NETs), providing enhanced tumor cell cytotoxicity and reduced irradiation of adjacent healthy tissues due to its high linear energy transfer (LET) and short particle range. This review summarizes available clinical evidence on α-PRRT using different α-emitting isotopes, including actinium-225, lead-212, and bismuth-213, in somatostatin receptor (SSTR)-positive NETs. Methods: A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov, as well as major oncology congress abstracts (ENETS, ESMO, ASCO). Eligible studies included clinical trials evaluating α-PRRT in patients with advanced SSTR-positive NETs, reporting therapeutic response and adverse events. The primary endpoint was the objective response rate (ORR); secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Seven studies encompassing 150 patients were included. Treatment with [²²⁵Ac]Ac-DOTATATE yielded a pooled ORR of 50% and a DCR of 81.3% across 121 evaluable patients. The best responses were observed in patients who had previously responded to β-PRRT (ORR 70.4%, DCR 96.3%), while one-third of β-PRRT–refractory patients achieved partial or complete responses. [²¹²Pb]Pb-DOTAMTATE demonstrated an ORR of 56.8% and DCR of 100% in preliminary phase II results, though dysphagia was noted in 34% of patients. [²¹³Bi]Bi-DOTATOC and [²¹²Pb]Pb-VMT-α-NET studies also showed promising disease control with minimal grade ≥ 3 hematologic or renal toxicities. Across all studies, α-PRRT was well tolerated, with predominantly low-grade hematologic adverse events and no significant hepatic or renal toxicity. Conclusions: Clinical data to date indicate that α-PRRT offers meaningful therapeutic benefit in patients with metastatic or treatment-refractory NETs, achieving favorable response rates with manageable toxicity. Early results support α-PRRT as a potential first- or second-line therapeutic option. Ongoing phase III trials will be critical to confirm its long-term safety, survival outcomes, and role in routine clinical practice. Full article

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

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32 pages, 1046 KB

Open AccessEditor’s ChoiceReview

Solidification Materials and Technology for Solid Self-Emulsifying Drug Delivery Systems

by Kyungho Baek and Sung Giu Jin

Pharmaceuticals 2025, 18(10), 1550; https://doi.org/10.3390/ph18101550 - 15 Oct 2025

Cited by 8 | Viewed by 3090

Abstract

The low aqueous solubility of many new drug candidates, a key challenge in oral drug development, has been effectively addressed by liquid self-emulsifying drug delivery systems (SEDDS). However, the inherent instability and manufacturing limitations of liquid formulations have prompted significant research into solid [...] Read more.

The low aqueous solubility of many new drug candidates, a key challenge in oral drug development, has been effectively addressed by liquid self-emulsifying drug delivery systems (SEDDS). However, the inherent instability and manufacturing limitations of liquid formulations have prompted significant research into solid SEDDS. This review provides a comprehensive analysis of the recent advancements in solid SEDDS, focusing on the pivotal roles of solid carriers and solidification techniques. We examine a wide range of carrier materials, including mesoporous silica, polymers, mesoporous carbon, porous carbonate salts, and clay-based materials, highlighting how their physicochemical properties can be leveraged to control drug loading, release kinetics, and in vivo performance. We also detail the various solidification methods, such as spray drying, hot melt extrusion, adsorption, and 3D printing, and their impact on the final product’s quality and scalability. Furthermore, this review explores applications of solid SEDDS, including controlled release, mucoadhesive technology, and targeted drug delivery, as well as the key commercial challenges and future perspectives. By synthesizing these diverse aspects, this paper serves as a valuable resource for designing high-performance solid SEDDS with enhanced stability, bioavailability, and functional versatility. Full article

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

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24 pages, 2042 KB

Open AccessEditor’s ChoiceReview

Thermogenic Targets for Obesity Management in the Era of Incretin-Based Therapies

by Sahar Soliman, Rebecca Andrews-Dickert, Petra Rocic and Mihail Mitov

Pharmaceuticals 2025, 18(10), 1519; https://doi.org/10.3390/ph18101519 - 10 Oct 2025

Cited by 1 | Viewed by 5121

Abstract

The global rise in obesity continues to outpace advances in pharmacologic treatment. While incretin-based therapies have demonstrated significant efficacy in promoting weight loss, their widespread use remains limited by gastrointestinal side effects, long-term tolerability concerns, and access issues. Additionally, sustaining weight loss over [...] Read more.

The global rise in obesity continues to outpace advances in pharmacologic treatment. While incretin-based therapies have demonstrated significant efficacy in promoting weight loss, their widespread use remains limited by gastrointestinal side effects, long-term tolerability concerns, and access issues. Additionally, sustaining weight loss over time poses an ongoing clinical challenge. These limitations highlight the need for alternative or complementary pharmacologic strategies. One such approach involves stimulating thermogenesis, particularly through the activation of brown and beige adipose tissue. This narrative review focuses on β3 adrenergic receptors as key mediators of browning and thermogenic energy expenditure. We review preclinical and clinical data, address pharmacokinetic and delivery challenges, and assess the translational potential of targeting thermogenesis in the management of obesity. Future directions are proposed to guide the development of safe and effective therapies that utilize this underexplored pharmacologic pathway. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Obesity, 2nd Edition)

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32 pages, 1390 KB

Open AccessEditor’s ChoiceReview

Discovery of Personalized Treatment for Immuno-Metabolic Depression—Focus on 11beta Hydroxysteroid Dehydrogenase Type 2 (11betaHSD2) and Toll-like Receptor 4 (TLR4) Inhibition with Enoxolone

by Harald Murck

Pharmaceuticals 2025, 18(10), 1517; https://doi.org/10.3390/ph18101517 - 10 Oct 2025

Viewed by 3033

Abstract

Treatment options for major depression are limited: only about one-third of patients achieve remission with first line treatments with no established predictive markers. Parameters associated with treatment refractory depression, including metabolic markers (increased BMI, increased triglyceride levels), inflammation markers (C-reactive protein, CRP), autonomic [...] Read more.

Treatment options for major depression are limited: only about one-third of patients achieve remission with first line treatments with no established predictive markers. Parameters associated with treatment refractory depression, including metabolic markers (increased BMI, increased triglyceride levels), inflammation markers (C-reactive protein, CRP), autonomic disturbances (reduced blood pressure, reduced heart rate variability), and brain morphology changes (increased volume of the choroid plexus and brain ventricle volumes), may serve such purpose. These features can be linked mechanistically to an increase in aldosterone plasma concentration due to a reduced mineralocorticoid receptor (MR) sensitivity. The primary CNS target of aldosterone is the nucleus of the solitary tract (NTS), which is also the entry point of the vagus nerve. This nucleus integrates signals from endocrine, inflammatory, chemoreceptive, and physiological parameters, including blood pressure. In search of a mechanism to overcome this pathology, we identified a molecule which is derived from the licorice plant glycyrrhiza glabra, namely glycyrrhizin and its biologically active metabolite enoxolone. These molecules potentially reverse the above-described pathology. They inhibit the enzyme 11beta hydroxysteroid-dehydrogenase type 2 (11betaHSD2) and the toll-like receptor 4 (TLR4). 11betaHSD2 regulates the activity of the mineralocorticoid receptor (MR) by degrading cortisol/corticosterone, which allows aldosterone to bind to the MR. TLR4 is the ligand for lipopolysaccharide (LPS, endotoxin) and trigger of innate immunity. Consequently, patients with increased inflammation markers, increased aldosterone, or low blood pressure may preferentially benefit from the treatment with glycyrrhizin/enoxolone. Importantly, these patients can be identified BEFORE treatment is initiated. Clinically, patients sharing these biological indicators are primarily young females or patients with a history of childhood trauma. A combination of enoxolone with standard antidepressants may therefore avoid a trial-and-error approach and allow to achieve recovery faster. Full article

(This article belongs to the Special Issue Discovery of Novel Antidepressants and Anxiolytics)

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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

Cited by 5 | Viewed by 100520

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

Cited by 2 | Viewed by 5240

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 2729

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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