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Pharmaceuticals, Volume 18, Issue 2 (February 2025) – 96 articles

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9 pages, 892 KiB  
Article
Sacubitril Does Not Exert Proarrhythmic Effects in Combination with Different Antiarrhythmic Drugs
by Christian Ellermann, Carlo Mengel, Julian Wolfes, Felix K. Wegner, Benjamin Rath, Julia Köbe, Lars Eckardt and Gerrit Frommeyer
Pharmaceuticals 2025, 18(2), 230; https://doi.org/10.3390/ph18020230 (registering DOI) - 8 Feb 2025
Abstract
Background: Previous studies suggest a direct effect of sacubitril on cardiac electrophysiology and indicate potential arrhythmic interactions between sacubitril and antiarrhythmic drugs. Therefore, the aim of this study was to explore the electrophysiologic effects of combining sacubitril with the antiarrhythmic drugs d,l-sotalol and [...] Read more.
Background: Previous studies suggest a direct effect of sacubitril on cardiac electrophysiology and indicate potential arrhythmic interactions between sacubitril and antiarrhythmic drugs. Therefore, the aim of this study was to explore the electrophysiologic effects of combining sacubitril with the antiarrhythmic drugs d,l-sotalol and mexiletine in isolated hearts. Methods and results: A total of 25 rabbit hearts were perfused using a Langendorff setup. Following baseline data collection, hearts were treated with mexiletine (25 µM, 13 hearts) or d,l-sotalol (100 µM, 12 hearts). Monophasic action potential demonstrated an abbreviation of action potential duration (APD90) after administration of mexiletine. Spatial dispersion of repolarization remained unchanged after mexiletine treatment, whereas effective refractory periods (ERP) were significantly prolonged. D,l-sotalol prolonged cardiac repolarization and amplified spatial dispersion. Further infusion of sacubitril (5 µM) led to a significant reduction in APD90 and ERP in the mexiletine group. In the d,l-sotalol group, additional administration of sacubitril shortened cardiac repolarization duration without affecting spatial dispersion. No proarrhythmic effect was observed after mexiletine treatment as assessed by a predefined pacing protocol. Additional sacubitril treatment did not increase ventricular vulnerability. When potassium concentration was reduced, 30 episodes of torsade de pointes tachycardia occurred after d,l-sotalol treatment. Additional sacubitril treatment significantly suppressed torsade de pointes tachycardia (eight episodes) in the d,l-sotalol-group. Conclusions: In class IB- and class III-pretreated hearts, sacubitril shortened refractory periods and cardiac repolarization duration. The combination of sacubitril with the antiarrhythmic drugs d,l-sotalol and mexiletine demonstrates a safe electrophysiologic profile and sacubitril reduces the occurrence of class III-related proarrhythmia, i.e., torsade de pointes tachycardia. Full article
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16 pages, 417 KiB  
Review
The Use of [11C]C-Methionine in Diagnostics of Endocrine Disorders with Focus on Pituitary and Parathyroid Glands
by Adam Daniel Durma, Marek Saracyn, Maciej Kołodziej, Katarzyna Jóźwik-Plebanek and Grzegorz Kamiński
Pharmaceuticals 2025, 18(2), 229; https://doi.org/10.3390/ph18020229 - 7 Feb 2025
Abstract
The rapid development of nuclear medicine offers vast opportunities for diagnosing neoplasms, particularly in endocrinology. The use of the [11C]C-methionine radiotracer is currently limited due to its physical properties and the complex production process. However, studies conducted so far have demonstrated [...] Read more.
The rapid development of nuclear medicine offers vast opportunities for diagnosing neoplasms, particularly in endocrinology. The use of the [11C]C-methionine radiotracer is currently limited due to its physical properties and the complex production process. However, studies conducted so far have demonstrated its utility in PET imaging, helping to detect lesions that often remain elusive with other modalities. This systematic review focuses on [11C]C-methionine in diagnosing hyperparathyroidism and pituitary tumors, highlighting its high effectiveness, which can be crucial in diagnosis. Despite some disadvantages, it should be considered when available, especially when other modalities or radiotracers fail. Full article
(This article belongs to the Section Medicinal Chemistry)
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13 pages, 571 KiB  
Article
Fast Analgesic Effect in Response Test with Topical Phenytoin Cream Correlates with Prolonged Pain Relief After Extended Use in Painful Diabetic Neuropathy
by David J. Kopsky, Alexander F. J. E. Vrancken, Ruben P. A. van Eijk, Ricardo Alvarez-Jimenez, Karolina M. Szadek, Remko Liebregts and Monique A. H. Steegers
Pharmaceuticals 2025, 18(2), 228; https://doi.org/10.3390/ph18020228 - 7 Feb 2025
Abstract
Background: Treatment of painful diabetic neuropathy (PDN) poses several challenges due to the limited effectiveness, high incidence of side effects, and potential drug interactions of oral neuropathic pain medication. Lacking systemic side effects, topical phenytoin cream offers a promising innovative approach to addressing [...] Read more.
Background: Treatment of painful diabetic neuropathy (PDN) poses several challenges due to the limited effectiveness, high incidence of side effects, and potential drug interactions of oral neuropathic pain medication. Lacking systemic side effects, topical phenytoin cream offers a promising innovative approach to addressing unmet needs in neuropathic pain treatment. In this retrospective study in patients with PDN, we evaluated the analgesic effect of topical phenytoin cream in response tests and after extended use. Methods: We collected data from PDN patients who, prior to prolonged use of phenytoin 10% or 20% cream, either had an open response test (ORET), a single-blind (SIBRET), or a double-blind (DOBRET) placebo-controlled response test with phenytoin cream between November 2016 and February 2023. A positive ORET was defined as pain reduction of at least two points on the 11-point numerical scale (NRS) within 30 min after phenytoin cream application. A positive SIBRET or DOBRET required an additional pain reduction of 1 NRS point in the phenytoin treated area compared to the placebo. In patients with a positive response test, we evaluated the sustained pain reduction and the proportion of patients experiencing minimum pain relief of at least 30% (MPR30: moderate pain relief) and 50% (MPR50: considerable pain relief) after the extended use of phenytoin cream. We also assessed the correlation between the response test analgesic effect and the sustained pain relief. Results: We identified 65 patients with PDN of whom 31 (47.7%) had a positive response test. The median pain reduction in response tests was 3.0 NRS points (IQR 2.0–4.0). Extended use (median 3.3 months, IQR 1.5–12.1]) resulted in a median pain reduction of 4.0 NRS points (IQR 3.0–5.0); 26/31 (83.9%) of patients achieved MPR30, and 21/31 (67.7%) MPR50 achieved pain relief. The response test analgesic effect correlated significantly with sustained pain relief after extended use (τ = 0.72, p < 0.0001). Conclusions: In PDN patients who had a positive phenytoin cream response test, extended use of phenytoin cream provided a significant sustained pain relief. Full article
(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)
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24 pages, 25092 KiB  
Article
An Integration of RNA Sequencing and Network Pharmacology Approaches Predicts the Molecular Mechanisms of the Huo-Xue-Shen Formula in the Treatment of Liver Fibrosis
by Keying Jiang, Jianfeng Bao, Zhonghan Lou, Fei Liu, Keyang Xu and Hiu Yee Kwan
Pharmaceuticals 2025, 18(2), 227; https://doi.org/10.3390/ph18020227 - 7 Feb 2025
Abstract
Background: Liver fibrosis is a prevalent, chronic inflammatory condition characterized by the excessive accumulation of extracellular matrix components and, primarily, collagen in the liver. Huo-xue-shen (HXS) has proven effective for the treatment of liver fibrosis. However, the mechanism is yet to be [...] Read more.
Background: Liver fibrosis is a prevalent, chronic inflammatory condition characterized by the excessive accumulation of extracellular matrix components and, primarily, collagen in the liver. Huo-xue-shen (HXS) has proven effective for the treatment of liver fibrosis. However, the mechanism is yet to be deciphered. Methods: Network pharmacology, machine learning algorithms and RNA-seq were used to predict the immune-treated targets and mechanisms associated with HXS in liver fibrosis. Molecular docking was employed to screen for effective agents based on the drug–compound–hub gene network in HXS, aiming to identify the most critical bioactive compound in HXS for the treatment of liver fibrosis. Results: A total of 100 immune-treated targets (ITTs) of HXS were found to significantly regulate the PI3K-Akt signaling pathway and the MAPK signaling pathway. Among these, CDKN1A, NR1I3, and TUBB1, which can concurrently interact with quercetin, were associated with the prognosis of liver fibrosis, indicating that HXS may inhibit or reverse HSC activation primarily by suppressing neutrophil extracellular trap formation, stimulating oxidative phosphorylation and promoting thyroid hormone synthesis in the regulation of the liver microenvironment. Conclusions: Our study suggests that HXS may delay the progression of liver fibrosis by targeting multiple pathways, as shown by the network pharmacology and transcriptome profiling used to examine the liver immune environment. Quercetin, its key ingredient, likely plays an important role by mediating the CDKN1A, NR1I3, and TUBB1 signaling pathways. Overall, our findings provide a new perspective on the potential biological mechanisms of this traditional Chinese medicine formula. Full article
(This article belongs to the Section Pharmacology)
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1 pages, 133 KiB  
Retraction
RETRACTED: Ezz Eldin et al. Design and Synthesis of Novel 5-((3-(Trifluoromethyl)piperidin-1-yl)sulfonyl)indoline-2,3-dione Derivatives as Promising Antiviral Agents: In Vitro, In Silico, and Structure–Activity Relationship Studies. Pharmaceuticals 2023, 16, 1247
by Rogy R. Ezz Eldin, Marwa A. Saleh, Sefat A. Alwarsh, Areej Rushdi, Azza Ali Althoqapy, Hoda S. El Saeed and Ayman Abo Elmaaty
Pharmaceuticals 2025, 18(2), 226; https://doi.org/10.3390/ph18020226 - 7 Feb 2025
Abstract
The Pharmaceuticals Editorial Office retracts the article “Design and Synthesis of Novel 5-((3-(Trifluoromethyl)piperidin-1-yl)sulfonyl)indoline-2,3-dione Derivatives as Promising Antiviral Agents: In Vitro, In Silico, and Structure–Activity Relationship Studies” [...] Full article
(This article belongs to the Section Medicinal Chemistry)
22 pages, 6295 KiB  
Article
Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness Against M. abscessus Infections
by Elizaveta Dzalamidze, Mylene Gorzynski, Rebecca Vande Voorde, Dylan Nelson and Lia Danelishvili
Pharmaceuticals 2025, 18(2), 225; https://doi.org/10.3390/ph18020225 - 7 Feb 2025
Viewed by 133
Abstract
Background/Objectives: Mycobacterium abscessus (MAB) is a highly resilient pathogen that causes difficult-to-treat pulmonary infections, particularly in individuals with cystic fibrosis (CF) and other underlying conditions. Its ability to form robust biofilms within the CF lung environment is a major factor contributing to [...] Read more.
Background/Objectives: Mycobacterium abscessus (MAB) is a highly resilient pathogen that causes difficult-to-treat pulmonary infections, particularly in individuals with cystic fibrosis (CF) and other underlying conditions. Its ability to form robust biofilms within the CF lung environment is a major factor contributing to its resistance to antibiotics and evasion of the host immune response, making conventional treatments largely ineffective. These biofilms, encased in an extracellular matrix, enhance drug tolerance and facilitate metabolic adaptations in hypoxic conditions, driving the bacteria into a persistent, non-replicative state that further exacerbates antimicrobial resistance. Treatment options remain limited, with multidrug regimens showing low success rates, highlighting the urgent need for more effective therapeutic strategies. Methods: In this study, we employed artificial sputum media to simulate the CF lung environment and conducted high-throughput screening of 24,000 compounds from diverse chemical libraries to identify inhibitors of MAB biofilm formation, using the Crystal Violet (CV) assay. Results: The screen established 17 hits with ≥30% biofilm inhibitory activity in mycobacteria. Six of these compounds inhibited MAB biofilm formation by over 60%, disrupted established biofilms by ≥40%, and significantly impaired bacterial viability within the biofilms, as confirmed by reduced CFU counts. In conformational assays, select compounds showed potent inhibitory activity in biofilms formed by clinical isolates of both MAB and Mycobacterium avium subsp. hominissuis (MAH). Key compounds, including ethacridine, phenothiazine, and fluorene derivatives, demonstrated potent activity against pre- and post-biofilm conditions, enhanced antibiotic efficacy, and reduced intracellular bacterial loads in macrophages. Conclusions: This study results underscore the potential of these compounds to target biofilm-associated resistance mechanisms, making them valuable candidates for use as adjuncts to existing therapies. These findings also emphasize the need for further investigations, including the initiation of a medicinal chemistry campaign to leverage structure–activity relationship studies and optimize the biological activity of these underexplored class of compounds against nontuberculous mycobacterial (NTM) strains. Full article
(This article belongs to the Topic Challenges and Future Prospects of Antibacterial Therapy)
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18 pages, 3686 KiB  
Article
Drug Repurposing of Voglibose, a Diabetes Medication for Skin Health
by Hyeon-Mi Kim and Chang-Gu Hyun
Pharmaceuticals 2025, 18(2), 224; https://doi.org/10.3390/ph18020224 - 7 Feb 2025
Viewed by 205
Abstract
Background/Objectives: Voglibose, an α-glucosidase inhibitor commonly prescribed to manage postprandial hyperglycemia in diabetes mellitus, demonstrates potential for repurposing as an anti-melanogenic agent. This study aims to explore the inhibitory effects of voglibose on melanogenesis and elucidate its molecular mechanisms, highlighting its possible applications [...] Read more.
Background/Objectives: Voglibose, an α-glucosidase inhibitor commonly prescribed to manage postprandial hyperglycemia in diabetes mellitus, demonstrates potential for repurposing as an anti-melanogenic agent. This study aims to explore the inhibitory effects of voglibose on melanogenesis and elucidate its molecular mechanisms, highlighting its possible applications in treating hyperpigmentation disorders. Methods: The anti-melanogenic effects of voglibose were investigated using B16F10 melanoma cells. Cell viability, melanin content, and tyrosinase activity were assessed following voglibose treatment. Western blot analysis was performed to examine changes in melanogenic proteins and transcription factors. The role of signaling pathways, including PKA/CREB, MAPK, PI3K/AKT, and GSK3β/β-Catenin, was analyzed. Primary human skin irritation tests were conducted to evaluate the topical safety of voglibose. Results: Voglibose significantly reduced melanin synthesis and tyrosinase activity in B16F10 cells in a dose-dependent manner. Western blot analysis revealed decreased expression of MITF, TRP-1, and TRP-2, indicating the inhibition of melanogenesis. Voglibose modulated key signaling pathways, including the suppression of PKA/CREB, MAPK, and AKT activation, while restoring GSK3β activity to inhibit β-catenin stabilization. Human skin irritation tests confirmed voglibose’s safety for topical application, showing no adverse reactions at 50 and 100 μM concentrations. Conclusions: Voglibose demonstrates anti-melanogenic properties through the modulation of multiple signaling pathways and the inhibition of melanin biosynthesis. Its safety profile and efficacy suggest its potential as a repurposed drug for managing hyperpigmentation and advancing cosmeceutical applications. Full article
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19 pages, 785 KiB  
Review
Exploring Calcium Channels as Potential Therapeutic Targets in Blast Traumatic Brain Injury
by Noemi Wachtler, Rory O’Brien, Barbara E. Ehrlich and Declan McGuone
Pharmaceuticals 2025, 18(2), 223; https://doi.org/10.3390/ph18020223 - 6 Feb 2025
Viewed by 345
Abstract
Background/Objectives: Repeat low-level blast exposure has emerged as a significant concern for military populations exposed to explosive events. Blast-Related Traumatic Brain Injury (bTBI) is a unique form of brain trauma with poorly understood molecular mechanisms. Loss of calcium homeostasis has emerged as [...] Read more.
Background/Objectives: Repeat low-level blast exposure has emerged as a significant concern for military populations exposed to explosive events. Blast-Related Traumatic Brain Injury (bTBI) is a unique form of brain trauma with poorly understood molecular mechanisms. Loss of calcium homeostasis has emerged as a mediator of early neuronal dysfunction after blast injury. This review aims to examine the role of calcium signaling in bTBI, focusing on the dual function of calcium channels as mediators and modulators of injury, and to explore therapeutic strategies targeting calcium homeostasis. Methods: We conducted a review of peer-reviewed articles published between 2000 and 2024, using the databases PubMed, Scopus, and EBSCO. Search terms included “blast traumatic brain injury”, “calcium channels”, and “calcium”. Studies investigating intracellular calcium dynamics after bTBI were included. Exclusion criteria included studies lacking evaluation of calcium signaling, biomarker studies, and studies on extracellular calcium. Results: We identified 13 relevant studies, primarily using preclinical models. Dysregulated calcium signaling was consistently linked to cellular dysfunction, including plasma membrane abnormalities, cytoskeletal destabilization, mitochondrial dysfunction, and proteolytic enzyme activation. Studies highlighted spatially compartmentalized vulnerabilities across neurons and astrocytes, suggesting that targeting specific cellular regions, such as the neuronal soma or axons, could enhance the therapeutic outcome. Therapeutic strategies included pharmacological inhibitors, plasma membrane stabilizers, and modulators of secondary injury. Conclusions: Calcium signaling is implicated in the pathophysiology of bTBI. Standardized experimental approaches would reduce variability in findings and improve the understanding of the relationship between calcium channel dynamics and bTBI and help guide the development of neuroprotective interventions that mitigate injury and promote recovery. Full article
(This article belongs to the Special Issue Calcium Channels as Therapeutic Targets)
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19 pages, 2136 KiB  
Review
Exploring the Therapeutic Potential of Mitragynine and Corynoxeine: Kratom-Derived Indole and Oxindole Alkaloids for Pain Management
by Ahmed S. Alford, Hope L. Moreno, Menny M. Benjamin, Cody F. Dickinson and Mark T. Hamann
Pharmaceuticals 2025, 18(2), 222; https://doi.org/10.3390/ph18020222 - 6 Feb 2025
Viewed by 329
Abstract
The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an [...] Read more.
The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an estimated economic burden of USD 1.5 trillion annually—exceeding the gross domestic product (GDP) of most US industrial sectors. A remarkable breakthrough lies in the discovery that indole and oxindole alkaloids, produced by several genera within the plant Tribe Naucleeae, act on opioid receptors without activating the beta-arrestin-2 pathway, the primary driver of respiratory depression and overdose deaths. This systematic review explores the pharmacological properties, mechanisms of action, dosing considerations, interactions, and long-term effects of mitragynine and corynoxeine, alkaloids from the Southeast Asian plant Mitragyna speciosa (kratom) and others in the Tribe Naucleeae. Mitragynine, a partial opioid receptor agonist, and corynoxeine, known for its anti-inflammatory and neuroprotective effects, demonstrate significant therapeutic potential for managing diverse pain types—including neuropathic, inflammatory, nociceptive, visceral, and central pain syndromes—with a focus on cancer pain. Unlike traditional opioids, these compounds do not recruit beta-arrestin-2, avoiding key adverse effects such as respiratory depression, severe constipation, and rapid tolerance development. Their distinct pharmacological profiles make them innovative candidates for safer, non-lethal pain relief. However, challenges persist, including the unregulated nature of kratom products, inconsistencies in potency due to crude extract variability, potential for misuse, and adverse drug interactions. Addressing these issues requires establishing standardized quality control protocols, such as Good Manufacturing Practices (GMP), to ensure consistent potency and purity. Clear labeling requirements with dosage guidelines and warnings should be mandated to ensure safe use and prevent misuse. Furthermore, the implementation of regulatory oversight to monitor product quality and enforce compliance is essential. This review emphasizes the urgency of focused research to optimize dosing regimens, characterize the pharmacodynamic profiles of these alkaloids, and evaluate long-term safety. By addressing these gaps, the mitragynine- and corynoxeine-related drug classes can transition from promising plant-derived molecules to validated pharmacotherapeutic agents, potentially revolutionizing the field of pain management. Full article
(This article belongs to the Section Natural Products)
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31 pages, 2053 KiB  
Article
Repeated-Dose Toxicity of Lauric Acid and Its Preventive Effect Against Tracheal Hyper-Responsiveness in Wistar Rats with Possible In Silico Molecular Targets
by Indyra Alencar Duarte Figueiredo, Alissa Maria de Oliveira Martins, Alexya Mikelle Teixeira Cavalcanti, Jayne Muniz Fernandes, Ludmila Emilly da Silva Gomes, Mateus Mendes Vieira, Gabriel Nunes Machado de Oliveira, Isabela Motta Felício, Lucas Nóbrega de Oliveira, Igor Gabriel da Silva Ramalho, Natália Ferreira de Sousa, Luciana Scotti, Marcus Tullius Scotti, José Luiz de Brito Alves, Margareth de Fátima Formiga Melo Diniz, Daniele Idalino Janebro Ximenes, Luiz Henrique César Vasconcelos and Fabiana de Andrade Cavalcante
Pharmaceuticals 2025, 18(2), 221; https://doi.org/10.3390/ph18020221 - 6 Feb 2025
Viewed by 293
Abstract
Background/Objectives: Lauric acid (LA), a medium-chain fatty acid, is a promising drug for asthma treatment. This study evaluated the toxicity of repeated doses and the effect of LA on pulmonary ventilation and tracheal reactivity in asthmatic Wistar rats and identified possible molecular targets [...] Read more.
Background/Objectives: Lauric acid (LA), a medium-chain fatty acid, is a promising drug for asthma treatment. This study evaluated the toxicity of repeated doses and the effect of LA on pulmonary ventilation and tracheal reactivity in asthmatic Wistar rats and identified possible molecular targets of LA action in silico. Methods: The rats were divided into control (CG) and LA-treated groups at 100 mg/kg (AL100G) for toxicity analysis. Pulmonary ventilation and tracheal reactivity were assessed in the control (CG), asthmatic (AG), asthmatic treated with LA at 25, 50, or 100 mg/kg (AAL25G, AAL50G, and AAL100G), and dexamethasone-treated groups (ADEXAG). Results: The results showed that LA at a dose of 100 mg/kg did not cause death or toxicity. A pulmonary ventilation analysis indicated that AG had reduced minute volume, which was prevented in AAL25G. LA at all doses prevented carbachol-induced tracheal hyper-responsiveness and reduced the relaxing effect of aminophylline, as observed in AG. An in silico analysis revealed that LA had a good affinity for nine proteins (β2-adrenergic receptor, CaV, BKCa, KATP, adenylyl cyclase, PKG, eNOS, iNOS, and COX-2). Conclusions: LA at 100 mg/kg has low toxicity, prevents hyper-responsiveness in an asthma model in rats, and acts as a multitarget compound with a good affinity for proteins related to airway hyper-responsiveness. Full article
(This article belongs to the Section Pharmacology)
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14 pages, 1082 KiB  
Article
Association of OPRM1 and OPRD1 Polymorphisms with Pain and Opioid Adverse Reactions in Colorectal Cancer
by Carolina Gutiérrez-Cáceres, Nikolas Ávila, Leslie C. Cerpa, Matías F. Martínez, Carlos E. Irarrazabal, Benjamín Torres, Olga Barajas, Nelson M. Varela and Luis A. Quiñones
Pharmaceuticals 2025, 18(2), 220; https://doi.org/10.3390/ph18020220 - 6 Feb 2025
Viewed by 355
Abstract
Background/Objectives: Pain management in colorectal cancer is influenced by genetic variability in opioid receptor genes (OPRM1 and OPRD1), potentially affecting opioid efficacy and adverse drug reactions (ADRs). This study evaluated the association of OPRM1 (rs1799971 and rs510769) and OPRD1 (rs2236861) [...] Read more.
Background/Objectives: Pain management in colorectal cancer is influenced by genetic variability in opioid receptor genes (OPRM1 and OPRD1), potentially affecting opioid efficacy and adverse drug reactions (ADRs). This study evaluated the association of OPRM1 (rs1799971 and rs510769) and OPRD1 (rs2236861) polymorphisms with pain severity, opioid efficacy, and ADRs in Chilean colorectal cancer patients. Methods: The genotypes of OPRM1 and OPRD1 polymorphisms and clinical data from 69 colorectal cancer patients were analyzed. Associations between genotypes, ADRs, and pain severity (maximum Visual Analog Scale, VAS) were evaluated under inheritance models. Results: The OPRM1 rs1799971 G allele was significantly associated with pain presence (p = 0.008), while OPRD1 rs2236861 was linked to ADR risk (p = 0.042). Allelic distribution analysis revealed higher frequencies of the OPRD1 G allele and OPRM1 rs510769 T allele in patients with ADRs and pain, respectively. For OPRM1 rs510769, the dominant model showed a significant association with pain severity (p = 0.033), while the overdominant model revealed a trend toward significance (p = 0.0504). Logistic regression model tests showed no significant predictive associations for the maximum VAS or ADRs under inheritance models. Conclusions: Genetic variations in OPRM1 and OPRD1 may play a role in pain perception and ADRs in colorectal cancer patients. These findings contribute to the understanding of pharmacogenomic factors in opioid therapy, emphasizing the need for further research to validate the clinical utility of these genetic markers. Full article
(This article belongs to the Section Pharmacology)
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14 pages, 3108 KiB  
Article
Acetoacetate Ameliorates Hepatic Fibrosis by Targeting Peroxisome Proliferator-Activated Receptor Gamma to Restore Lipid Droplets in Activated Hepatic Stellate Cells
by Ya Zhou, Feixia Wang, Mengru Hu, Siwei Xia, Yang Li, Shizhong Zheng and Feng Zhang
Pharmaceuticals 2025, 18(2), 219; https://doi.org/10.3390/ph18020219 - 6 Feb 2025
Viewed by 298
Abstract
Background: Hepatic fibrosis (HF) is a progressive liver disease characterized by the activation of hepatic stellate cells (HSCs) and changes in lipid metabolism. Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in patients with HF, but the [...] Read more.
Background: Hepatic fibrosis (HF) is a progressive liver disease characterized by the activation of hepatic stellate cells (HSCs) and changes in lipid metabolism. Abnormal ketone body (KD) levels, including acetoacetate (AcAc) and beta-hydroxybutyrate (BHB), have been observed in patients with HF, but the mechanisms linking ketone metabolism to fibrosis progression remain unclear. Objectives: This study aimed to investigate the role of AcAc in modulating HSCs activation and its potential mechanisms in HF. Methods: We examined the effects of AcAc on HSCs activation by Western blot analysis and RT-PCR both in vivo and in vitro. The impact of AcAc on lipid droplet accumulation in HSCs was assessed using total cholesterol (TC), triglyceride (TG), and Retinol (RET) kits, along with Nile Red and Oil Red O staining. RT-PCR screening was performed to analyze the expression of genes involved in lipid droplet formation and lipid metabolism. Results: Our findings show that AcAc inhibited HSCs activation by restoring LD levels. Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) was identified as a key regulator through gene screening. AcAc primarily regulated PPARγ expression, and knocking down PPARγ significantly aggravated HF progression. Conclusions: The ability of AcAc to restore LD levels and regulate PPARγ suggests that it may represent a promising therapeutic strategy for HF by inhibiting HSCs activation. Full article
(This article belongs to the Section Pharmacology)
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11 pages, 453 KiB  
Article
Enhanced Anti-Babesia Efficacy of Buparvaquone and Imidocarb When Combined with ELQ-316 In Vitro Culture of Babesia bigemina
by Natalia M. Cardillo, Nicolas F. Villarino, Paul A. Lacy, Joseph S. Doggett, Michael K. Riscoe, Carlos E. Suarez, Massaro W. Ueti and Chungwon J. Chung
Pharmaceuticals 2025, 18(2), 218; https://doi.org/10.3390/ph18020218 - 6 Feb 2025
Viewed by 312
Abstract
Background/Objectives: B. bigemina is a highly pathogenic and widely distributed tick-borne disease parasite responsible for bovine babesiosis. The development of effective and safe therapies is urgently needed for global disease control. The aim of this study is to compare the effects of [...] Read more.
Background/Objectives: B. bigemina is a highly pathogenic and widely distributed tick-borne disease parasite responsible for bovine babesiosis. The development of effective and safe therapies is urgently needed for global disease control. The aim of this study is to compare the effects of endochin-like quinolone (ELQ-316), buparvaquone (BPQ), imidocarb (ID), and the combinations of ID + ELQ-316 and BPQ + ELQ-316, on in vitro survival of B. bigemina. Methods: Parasites at a starting parasitemia level of 2%, were incubated with each single drug and a combination of drugs, ranging from 25 to 1200 nM of concentration over four consecutive days. The inhibitory concentrations, 50% (IC50%) and 99% (IC99%), were estimated. Parasitemia levels were evaluated daily using microscopic examination. Data were statistically compared using the non-parametrical Kruskall–Wallis test. Results: All drugs tested significantly inhibited (p < 0.05) the growth of B. bigemina at 2% parasitemia. The combination of ID + ELQ-316 exhibited a lower mean (IC50%: 9.2; confidence interval 95%: 8.7–9.9) than ID (IC50%: 61.5; confidence interval 95%: 59.54–63.46), ELQ-316 (IC50%: 48.10; confidence interval 95%: 42.76–58.83), BPQ (IC50%: 44.66; confidence interval 95%: 43.56–45.81), and BPQ + ELQ-316 (IC50%: 27.59; confidence interval: N/A). Parasites were no longer viable in cultures treated with the BPQ + ELQ-316 combination, as well as with BPQ alone at a concentration of 1200 nM, on days 2 and 3 of treatment, respectively. Conclusions: BPQ and ID increase the babesiacidal effect of ELQ-316. The efficacy of these combinations deserves to be evaluated in vivo, which could lead to a promising and safer treatment option for B. bigemina. Full article
(This article belongs to the Special Issue Drug Discovery and Development for Parasitic Diseases)
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25 pages, 2999 KiB  
Review
Computational Modeling of Pharmaceuticals with an Emphasis on Crossing the Blood–Brain Barrier
by Patrícia Alencar Alves, Luana Cristina Camargo, Gabriel Mendonça de Souza, Márcia Renata Mortari and Mauricio Homem-de-Mello
Pharmaceuticals 2025, 18(2), 217; https://doi.org/10.3390/ph18020217 - 6 Feb 2025
Viewed by 361
Abstract
The discovery and development of new pharmaceutical drugs is a costly, time-consuming, and highly manual process, with significant challenges in ensuring drug bioavailability at target sites. Computational techniques are highly employed in drug design, particularly to predict the pharmacokinetic properties of molecules. One [...] Read more.
The discovery and development of new pharmaceutical drugs is a costly, time-consuming, and highly manual process, with significant challenges in ensuring drug bioavailability at target sites. Computational techniques are highly employed in drug design, particularly to predict the pharmacokinetic properties of molecules. One major kinetic challenge in central nervous system drug development is the permeation through the blood–brain barrier (BBB). Several different computational techniques are used to evaluate both BBB permeability and target delivery. Methods such as quantitative structure–activity relationships, machine learning models, molecular dynamics simulations, end-point free energy calculations, or transporter models have pros and cons for drug development, all contributing to a better understanding of a specific characteristic. Additionally, the design (assisted or not by computers) of prodrug and nanoparticle-based drug delivery systems can enhance BBB permeability by leveraging enzymatic activation and transporter-mediated uptake. Neuroactive peptide computational development is also a relevant field in drug design, since biopharmaceuticals are on the edge of drug discovery. By integrating these computational and formulation-based strategies, researchers can enhance the rational design of BBB-permeable drugs while minimizing off-target effects. This review is valuable for understanding BBB selectivity principles and the latest in silico and nanotechnological approaches for improving CNS drug delivery. Full article
(This article belongs to the Special Issue Classical and Quantum Molecular Simulations in Drug Design)
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14 pages, 2984 KiB  
Article
Association of Tramadol-Induced Ovarian Damage and Reproductive Dysfunction with Adenosine Triphosphate and the Protective Role of Exogenous ATP Treatment
by Neset Gumusburun, Ilhan Bahri Delibasi, Seval Bulut, Halis Suleyman, Betul Kalkan Yilmaz, Taha Abdulkadir Coban, Ali Sefa Mendil and Zeynep Suleyman
Pharmaceuticals 2025, 18(2), 216; https://doi.org/10.3390/ph18020216 - 6 Feb 2025
Viewed by 227
Abstract
Background: Tramadol, a weak opioid analgesic agent, is known to induce ovarian damage. Previous studies have held oxidative stress responsible for the adverse effects of tramadol on female reproduction. This study examined the protective effects of ATP against tramadol-induced ovarian damage and reproductive [...] Read more.
Background: Tramadol, a weak opioid analgesic agent, is known to induce ovarian damage. Previous studies have held oxidative stress responsible for the adverse effects of tramadol on female reproduction. This study examined the protective effects of ATP against tramadol-induced ovarian damage and reproductive dysfunction in rats. Methods: Rats were divided into four groups (n = 12); healthy (HG), only ATP (ATPG), only tramadol (TMDG), and ATP + tramadol (ATMG). ATP was injected intraperitoneally at 25 mg/kg. Tramadol at 50 mg/kg was initiated one hour after ATP. The treatment was administered once a day for 14 days. Six rats from each group were euthanized. For two months, the remaining rats were paired with male rats. Rats that failed to give birth during this period were considered infertile. A maternity period was calculated for the rats that were delivered. Results: Tramadol caused an increase in malondialdehyde and interleukin-6, and decreased total glutathione, superoxide dismutase, and catalase levels in the ovarian tissue. Furthermore, tramadol disrupted the histological structure of the ovaries, and immunohistochemical staining revealed severe immunopositivity. Tramadol again caused infertility and delayed pregnancy in fertile women. By suppressing biochemical changes, ATP significantly reduced tramadol-induced ovarian damage. Both histopathologically and immunohistochemically, ATP treatment regressed ovarian damage. Additionally, ATP significantly reduced tramadol-induced infertility and maternal delay. Conclusions: The results indicate that tramadol-induced oxidative and inflammatory ovarian injury, infertility, and caspase 3 were suppressed by ATP, as demonstrated by our experimental findings. Full article
(This article belongs to the Section Pharmacology)
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15 pages, 2411 KiB  
Article
Enhancement of In Vivo Bone Regeneration by the Carbohydrate Derivative DP2
by Nissrine Ballout, Sylvestre Toumieux, Walaa Darwiche, Cathy Gomila, Eric Trécherel, Franck Accadbled, Sara Laurencin-Dalicieux, Isabelle Gennero, José Kovensky, Agnès Boullier and Jérôme Ausseil
Pharmaceuticals 2025, 18(2), 215; https://doi.org/10.3390/ph18020215 - 5 Feb 2025
Viewed by 389
Abstract
Background/Objectives: Delays in bone healing and complications of remodeling constitute a major medical problem—particularly in older adults and patients with comorbidities. Current therapeutic approaches are based on strategies that promote bone regeneration. We recently identified a disaccharide compound (DP2) that enhances in [...] Read more.
Background/Objectives: Delays in bone healing and complications of remodeling constitute a major medical problem—particularly in older adults and patients with comorbidities. Current therapeutic approaches are based on strategies that promote bone regeneration. We recently identified a disaccharide compound (DP2) that enhances in vitro mineralization in human osteoblast cells via the early activation of Runx2 and the induction of osteoblast differentiation. Methods: First, a calcium quantification assay was performed to assess mineralization in MC3T3-E1 cells. Next, microcomputed tomography and histological analyses were used to examine in vivo bone repair in a rat 5 mm cranial defect model following the implantation of DP2 coupled to a micro/macroporous biphasic CaP ceramic (MBCP+) or collagen scaffold. Results: Here, we demonstrated that DP2 induced osteogenic differentiation and significantly elevated calcium matrix deposition in the murine preosteoblast cell line MC3T3-E1. We found that treatment with DP2 coupled to MBCP+ repaired the calvarial defect on post-implantation day 91. It significantly increased bone mineral density starting on day 29 post-treatment. In addition, DP2 did not induce ectopic bone formation. Conclusion: Taken as a whole, these results show that DP2 is a promising candidate treatment for delayed bone healing. Full article
(This article belongs to the Section Pharmacology)
15 pages, 447 KiB  
Article
Diabetic Ketoacidosis and the Use of New Hypoglycemic Groups: Real-World Evidence Utilizing the Food and Drug Administration Adverse Event Reporting System
by Hilal A. Thaibah, Otilia J. F. Banji, David Banji and Thamir M. Alshammari
Pharmaceuticals 2025, 18(2), 214; https://doi.org/10.3390/ph18020214 - 5 Feb 2025
Viewed by 215
Abstract
Background: Diabetic ketoacidosis (DKA), a life-threatening complication, can occur in individuals with type 2 diabetes during illness, stress, or medication use. This study examines DKA signals in type 2 diabetes, focusing on sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and [...] Read more.
Background: Diabetic ketoacidosis (DKA), a life-threatening complication, can occur in individuals with type 2 diabetes during illness, stress, or medication use. This study examines DKA signals in type 2 diabetes, focusing on sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors. Methods: DKA reports from Q1 2019 to Q3 2024 were retrieved from the FDA Adverse Event Reporting System (FAERS). Associations between primary exposure and outcomes were ascertained using four key metrics: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Component (IC). Results: SGLT2 inhibitors exhibited the higher DKA risk in 2019–2021 (ROR: 314.86 [95% CI 301.76–328.53], PRR of 245.69 [95% CI 235.47- 256.36], IC of 6.90, and EBGM of 120), declining in 2022–2024. GLP-1 receptor agonists showed an ROR increase from 2.88 [95% CI 2.56–3.25] in 2019–2021 to 4.64 [95% CI 4.06–5.29] in 2022–2023, slightly declining to 3.95 [95% CI 3.27–4.74] in 2024. DPP-4 inhibitors exhibited a steady ROR rise from 6.81 [95% CI 5.52–8.40] in 2019–2021 to 8.57 [95% CI 6.24–11.76] in 2022–2023 and further to 11.02 [95% CI 6.71–18.10] in 2024. PRR, EBGM, and IC values followed similar trends. The age groups 41–60 and 61–91 years were the most affected, with hospitalization at its highest rate for DPP4-inhibitors in Q1-Q3 of 2024. Hospitalizations were also observed with GLP-1 receptor agonists and SGLT2 inhibitors. Life-threatening events and fatalities were also reported, with physicians contributing to most reports. Conclusions: DKA signals were observed for all three drug classes, particularly among elderly patients, highlighting the need for careful monitoring, especially during periods of illness or stress. However, the risk was higher in the SGLT2 inhibitor group than in the other groups. Full article
(This article belongs to the Section Pharmacology)
22 pages, 1059 KiB  
Article
Phaseolus acutifolius Recombinant Lectin Exerts Differential Proapoptotic Activity on EGFR+ and EGFR Colon Cancer Cells and Provokes T Cell-Assisted Antitumor Responses in Mice
by Francisco Luján-Méndez, Patricia García-López, Laura C. Berumen, Guadalupe García-Alcocer, Roberto Ferriz-Martínez, Anette Ramírez-Carrera, Jaqueline González-Barrón and Teresa García-Gasca
Pharmaceuticals 2025, 18(2), 213; https://doi.org/10.3390/ph18020213 - 5 Feb 2025
Viewed by 253
Abstract
Background: rTBL-1, a recombinant lectin from Phaseolus acutifolius, exhibit proapoptotic activity on colon cancer cells and inhibitory properties on colon tumorigenesis in vivo. Apoptosis has been associated with a phospho-EGFR/phospho-p38/phospho-p53 mechanistic axis. Immunogenicity data have been observed in treated animals, but [...] Read more.
Background: rTBL-1, a recombinant lectin from Phaseolus acutifolius, exhibit proapoptotic activity on colon cancer cells and inhibitory properties on colon tumorigenesis in vivo. Apoptosis has been associated with a phospho-EGFR/phospho-p38/phospho-p53 mechanistic axis. Immunogenicity data have been observed in treated animals, but its possible involvement in the antitumor response remained unexplored. Objective: We investigated whether the cytotoxic activity of rTBL-1 depends on EGFR and its capacity to produce antitumor responses on syngeneic colon cancer in mice, with and without T cells, in order to explore its possible involvement in the process. Results: rTBL-1 exhibited cytotoxic effects in a concentration-dependent manner in both EGFR+ (MC-38) and EGFR (CT-26) colon cancer cells with LC50 values of 23.50 and 30.01 µg/mL, respectively (p = 0.063). Apoptotic effects were slower and longer-lasting in MC-38 than in CT-26 cells. Significant increases in caspase-3 proteolytic activation and PARP1 cleavage were detected in both cell types, despite PARP1 rheostasis in CT-26 cells. Intralesional treatment with rTBL-1 inhibited the growth of established tumors in immunocompetent BALB/c mice in 27.81% (p = 0.0008) with a benefit in survival (p = 0.022), but not in immunodeficient BALB/c nude mice. Conclusions: rTBL-1 induces apoptosis in colon cancer cells by EGFR independent mechanisms, although its presence could be related to deeper responses. Unresponsiveness in nude mice indicated that rTBL-1 antitumor effect is the synergistic result of apoptosis induction and T cell-mediated cytotoxicity in the tumor. Future studies will focus on the immunogenic effects triggered by the antitumor activity of rTBL-1 in colon cancer. Full article
16 pages, 2361 KiB  
Article
Potential of Newly Synthesized Sea Buckthorn Phytocarriers as Anti-Inflammatory Active Agents
by Ionela Daniela Popescu, Elena Codrici, Sevinci Pop, Tudor Emanuel Fertig, Maria Dudău, Iliuta Laurentiu Anghelache, Nicoleta Constantin, Radu Marian Marinescu, Vlad Mihai Voiculescu, Georgiana Ileana Badea, Mirela Diaconu, Monica Elisabeta Maxim, Mihaela Scurtu, Kliment Zanov, Ana-Maria Enciu, Simona Carmen Litescu and Cristiana Tanase
Pharmaceuticals 2025, 18(2), 212; https://doi.org/10.3390/ph18020212 - 5 Feb 2025
Viewed by 278
Abstract
Background: Phytocarriers are advanced drug delivery systems that use biocompatible and biodegradable materials to enhance the efficacy, stability, and bioavailability of natural products. The sea buckthorn (Hippophae rhamnoides L.) berry extract is rich in essential fatty acids and antioxidants, including vitamin C, [...] Read more.
Background: Phytocarriers are advanced drug delivery systems that use biocompatible and biodegradable materials to enhance the efficacy, stability, and bioavailability of natural products. The sea buckthorn (Hippophae rhamnoides L.) berry extract is rich in essential fatty acids and antioxidants, including vitamin C, vitamin E, and anthocyanins, which contribute to its wide-ranging health benefits. In this study, we assessed the morphology, intracellular delivery, and anti-inflammatory effect of sodium cholate (NaC) and sodium deoxycholate (NaDC)-based phytocarriers loaded with ethanolic extract from sea buckthorn berries (sea buckthorn carrier nanostructures, further defined as phytocarriers). Methods: Negative and electron cryo-microscopy were used to analyze hollow and loaded nanocarriers. The cyto-compatibility of nanocarriers was assessed by endpoint (LDH and MTS) and real-time cell assays, on both human fibroblasts (HS27) and human normal monocytes (SC). The anti-inflammatory effect of hollow and loaded nanocarriers was tested by multiplexing. Results: The negative and electron cryo-microscopy analyses showed that NaC-based phytocarriers were spherical, whilst NaDC-based phytocarriers were predominantly polymorphic. Moreover, the NaDC-based phytocarriers frequently formed large lipid networks or “plaques”. Although 24 h cytotoxicity testing showed both types of nanocarriers are biocompatible with human fibroblasts and monocytes, based on a long-term real-time assay, NaDC delayed fibroblast proliferation. NaC sea buckthorn phytocarriers did not impair fibroblast proliferation in the long term and they were uptaken by cells, as shown by hyperspectral microscopy. NaC nanocarriers and NaC sea buckthorn phytocarriers induced an anti-inflammatory effect, lowering IL-8 cytokine production in normal human monocytes as soon as 4 h of treatment lapsed. Conclusions: NaC-derived phytocarriers loaded with sea buckthorn alcoholic extract are a cell-compatible delivery system with anti-inflammatory properties. Full article
(This article belongs to the Special Issue Bioactive Compounds Derived from Plants and Their Medicinal Potential)
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23 pages, 4671 KiB  
Article
Thermodynamic and Structural Characterization of a Mechanochemically Synthesized Pyrazinamide–Acetylsalicylic–Acid Eutectic Mixture
by Luís H. S. Queiroz, Mateus R. Lage, Clenilton C. dos Santos, Mafalda C. Sarraguça and Paulo R. S. Ribeiro
Pharmaceuticals 2025, 18(2), 211; https://doi.org/10.3390/ph18020211 - 5 Feb 2025
Viewed by 315
Abstract
Background/Objectives: This study aims to develop a sustainable and environmentally friendly drug delivery system by synthesizing a novel drug–drug eutectic mixture (DDEM) of acetylsalicylic acid (ASA) and pyrazinamide (PZA) using a green and efficient mechanochemical approach. Methods: The DDEM was characterized using various [...] Read more.
Background/Objectives: This study aims to develop a sustainable and environmentally friendly drug delivery system by synthesizing a novel drug–drug eutectic mixture (DDEM) of acetylsalicylic acid (ASA) and pyrazinamide (PZA) using a green and efficient mechanochemical approach. Methods: The DDEM was characterized using various techniques, including differential scanning calorimetry (DSC), thermogravimetry and differential thermal analysis (TG-DTA), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), and Raman spectroscopy. Binary phase diagrams and Tammann’s triangle analysis determined the eutectic point. Density functional theory (DFT) calculations were performed on the starting compounds. The new system was evaluated for aqueous solubility, dissolution, and hygroscopicity. Results: A V-shaped binary phase diagram indicated the formation of a DDEM with a 2:1 molar ratio of ASA to PZA. A positive mixing enthalpy suggested a quasi-eutectic structure. The solubility of ASA and PZA increased by 61.5% and 85.8%, respectively, in the DDEM compared to the pure drugs. Conclusions: These findings highlight the potential of DDEMs to enhance drug properties and delivery. The synergistic interaction between ASA and PZA in the eutectic mixture may further improve therapeutic efficacy, warranting further investigation. Full article
(This article belongs to the Section Medicinal Chemistry)
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39 pages, 2172 KiB  
Review
Current Trends in Clinical Trials of Prodrugs
by Diogo Boreski, Valentine Fabienne Schmid, Priscila Longhin Bosquesi, Jean Leandro dos Santos, Cauê Benito Scarim, Viktor Reshetnikov and Chung Man Chin
Pharmaceuticals 2025, 18(2), 210; https://doi.org/10.3390/ph18020210 - 4 Feb 2025
Viewed by 367
Abstract
The development of new drugs is a lengthy and complex process regarding its conception and ideation, passing through in silico studies, synthesis, in vivo studies, clinical trials, approval, and commercialization, with an exceptionally low success rate. The lack of efficacy, safety, and suboptimal [...] Read more.
The development of new drugs is a lengthy and complex process regarding its conception and ideation, passing through in silico studies, synthesis, in vivo studies, clinical trials, approval, and commercialization, with an exceptionally low success rate. The lack of efficacy, safety, and suboptimal pharmacokinetic parameters are commonly identified as significant challenges in the discovery of new drugs. To help address these challenges, various approaches have been explored in medicinal chemistry, including the use of prodrug strategies. As a well-established approach, prodrug design remains the best option for improving physicochemical properties, reducing toxicity, and increasing selectivity, all while minimizing costs and saving on biological studies. This review article aims to analyze the current advances using the prodrug approach that has allowed the advance of drug candidates to clinical trials in the last 10 years. The approaches presented here aim to inspire further molecular optimization processes and highlight the potential of this strategy to facilitate the advancement of new compounds to clinical study phases. Full article
(This article belongs to the Special Issue Prodrugs: Design and Development)
27 pages, 792 KiB  
Review
Nanoparticle-Encapsulated Plant Polyphenols and Flavonoids as an Enhanced Delivery System for Anti-Acne Therapy
by Ririn Puspadewi, Tiana Milanda, Muhaimin Muhaimin and Anis Yohana Chaerunisaa
Pharmaceuticals 2025, 18(2), 209; https://doi.org/10.3390/ph18020209 - 4 Feb 2025
Viewed by 394
Abstract
This study conducted a literature review by searching for articles related to the treatment of skin infections/wrinkles using nano-delivery systems containing natural compounds. The search was conducted in various databases for articles published in the last 10 years, with strict inclusion and exclusion [...] Read more.
This study conducted a literature review by searching for articles related to the treatment of skin infections/wrinkles using nano-delivery systems containing natural compounds. The search was conducted in various databases for articles published in the last 10 years, with strict inclusion and exclusion criteria. Of the 490 articles found, 40 were considered relevant. Acne vulgaris is a common dermatological disorder characterised by inflammation of the sebaceous glands, often resulting in the development of pimples, cysts, and scarring. Conventional treatments, including antibiotics and topical retinoids, frequently demonstrate limitations such as side effects, resistance, and insufficient skin absorption. Recent advancements in nanotechnology have enabled the creation of innovative drug-delivery systems that enhance the effectiveness and reduce the adverse effects of anti-acne medications. Polyphenols and flavonoids, natural bioactive compounds with notable anti-inflammatory, antioxidant, and antibacterial properties, are recognised for their therapeutic effectiveness in acne treatment. However, their practical application is hindered by insufficient solubility, stability, and bioavailability. The incorporation of these compounds into nanoparticle-based delivery systems has shown promise in resolving these challenges. Various nanoparticle platforms, including lipid-based nanoparticles, polymeric nanoparticles, and solid lipid nanoparticles, are evaluated for their ability to improve the stability, controlled release, and targeted delivery of polyphenols and flavonoids to the skin. The advent of polyphenol and flavonoid-loaded nanoparticles marks a new acne therapy era. Full article
(This article belongs to the Section Pharmaceutical Technology)
16 pages, 2274 KiB  
Article
A New Trick of Old Dogs: Can Kappa Opioid Receptor Antagonist Properties of Antidepressants Assist in Treating Treatment-Resistant Depression (TRD)?
by Shaul Schreiber, Lee Keidan and Chaim G. Pick
Pharmaceuticals 2025, 18(2), 208; https://doi.org/10.3390/ph18020208 - 3 Feb 2025
Viewed by 472
Abstract
Background/Objectives: Approximately one in five individuals will experience major depressive disorder (MDD), and 30% exhibit resistance to standard antidepressant treatments, resulting in a diagnosis of treatment-resistant depression (TRD). Historically, opium was used effectively to treat depression; however, when other medications were introduced, its [...] Read more.
Background/Objectives: Approximately one in five individuals will experience major depressive disorder (MDD), and 30% exhibit resistance to standard antidepressant treatments, resulting in a diagnosis of treatment-resistant depression (TRD). Historically, opium was used effectively to treat depression; however, when other medications were introduced, its use was discontinued due to addiction and other hazards. Recently, kappa opioid receptor (KOR) antagonism has been proposed as a potential mechanism for treating TRD. The main research question is whether commonly used psychotropic medications possess KOR antagonist properties and whether this characteristic could contribute to their efficacy in TRD. Methods: We investigated the antinociceptive effects of many psychotropic medications and their interactions with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of these agents. Results: The antidepressants mianserin and mirtazapine (separately) induced dose-dependent antinociception, each yielding a biphasic dose–response curve. Similarly, the antidepressant venlafaxine produced a potent effect and reboxetine produced a weak effect. The antipsychotics risperidone and amisulpride exhibited a dose-dependent antinociceptive effect. The sedative–hypnotic zolpidem induced a weak bi-phasic dose-dependent antinociceptive effect. All seven psychotropic medications elicited antinociception, which was reversed by the non-selective opiate antagonist naloxone and, separately, by the kappa-selective antagonist Nor-BNI. Conclusions: Clinical studies are mandatory to establish the potential efficacy of augmentation of the treatment with antidepressants with these drugs in persons with treatment-resistant depression and the optimal dosage of medications prescribed. We suggest a possible beneficial effect of antidepressants with kappa antagonistic properties. Full article
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26 pages, 1546 KiB  
Review
Cellular Epigenetic Targets and Epidrugs in Breast Cancer Therapy: Mechanisms, Challenges, and Future Perspectives
by Ibrahim S. Alalhareth, Saleh M. Alyami, Ali H. Alshareef, Ahmed O. Ajeibi, Manea F. Al Munjem, Ahmad A. Elfifi, Meshal M. Alsharif, Seham A. Alzahrani, Mohammed A. Alqaad, Marwa B. Bakir and Basel A. Abdel-Wahab
Pharmaceuticals 2025, 18(2), 207; https://doi.org/10.3390/ph18020207 - 3 Feb 2025
Viewed by 614
Abstract
Breast cancer is the most common malignancy affecting women, manifesting as a heterogeneous disease with diverse molecular characteristics and clinical presentations. Recent studies have elucidated the role of epigenetic modifications in the pathogenesis of breast cancer, including drug resistance and efflux characteristics, offering [...] Read more.
Breast cancer is the most common malignancy affecting women, manifesting as a heterogeneous disease with diverse molecular characteristics and clinical presentations. Recent studies have elucidated the role of epigenetic modifications in the pathogenesis of breast cancer, including drug resistance and efflux characteristics, offering potential new diagnostic and prognostic markers, treatment efficacy predictors, and therapeutic agents. Key modifications include DNA cytosine methylation and the covalent modification of histone proteins. Unlike genetic mutations, reprogramming the epigenetic landscape of the cancer epigenome is a promising targeted therapy for the treatment and reversal of drug resistance. Epidrugs, which target DNA methylation and histone modifications, can provide novel options for the treatment of breast cancer by reversing the acquired resistance to treatment. Currently, the most promising approach involves combination therapies consisting of epidrugs with immune checkpoint inhibitors. This review examines the aberrant epigenetic regulation of breast cancer initiation and progression, focusing on modifications related to estrogen signaling, drug resistance, cancer progression, and the epithelial–mesenchymal transition (EMT). It examines existing epigenetic drugs for treating breast cancer, including agents that modify DNA, inhibitors of histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone demethyltransferases. It also delves into ongoing studies on combining epidrugs with other therapies and addresses the upcoming obstacles in this field. Full article
(This article belongs to the Section Pharmacology)
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18 pages, 505 KiB  
Review
Breakthrough Advances in Beta-Lactamase Inhibitors: New Synthesized Compounds and Mechanisms of Action Against Drug-Resistant Bacteria
by Ya-Si Huang and Hong Zhou
Pharmaceuticals 2025, 18(2), 206; https://doi.org/10.3390/ph18020206 - 3 Feb 2025
Viewed by 533
Abstract
Beta-lactam drugs hold a central place in the antibacterial arsenal, and the production of beta-lactamases by drug-resistant bacteria has severely compromised the effectiveness of nearly all available beta-lactams. Therefore, in the face of the increasing threat of drug resistance, the combined use of [...] Read more.
Beta-lactam drugs hold a central place in the antibacterial arsenal, and the production of beta-lactamases by drug-resistant bacteria has severely compromised the effectiveness of nearly all available beta-lactams. Therefore, in the face of the increasing threat of drug resistance, the combined use of beta-lactamase inhibitors (BLIs) with beta-lactam antibiotics is crucial for treating infections caused by drug-resistant bacteria. Hence, the development of BLIs has always been a hot topic in the field of medicinal chemistry. In recent years, significant progress has been made in screening active drugs by enhancing the affinity of inhibitors for enzymes and the stability of their complexes, based on the design concept of competitive inhibitors. Here, we review the effects and mechanisms of newly synthesized beta-lactamase inhibitors on various BLIs in recent years, to provide ideas for the development of subsequent beta-lactamase inhibitors. Full article
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27 pages, 4842 KiB  
Article
Discovery of a Novel Multitarget Analgesic Through an In Vivo-Guided Approach
by Guo Zhen, Nayeon Do, Nguyen Van Manh, Hee-Jin Ha, Hee Kim, Hyunsoo Kim, Kwanghyun Choi, Jihyae Ann and Jeewoo Lee
Pharmaceuticals 2025, 18(2), 205; https://doi.org/10.3390/ph18020205 - 3 Feb 2025
Viewed by 482
Abstract
Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget [...] Read more.
Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget analgesic with improved pharmacological properties. Methods: An in vivo-guided screening approach was used to discover a new analgesic compound. Compound 29, derived from a novel scaffold inspired by opiranserin and vilazodone pharmacophores, was identified through analog screening in the formalin test. Its efficacy was further evaluated in the spinal nerve ligation (SNL) model of neuropathic pain. Mechanistic studies explored its interaction with neurotransmitter transporters and receptors, while pharmacokinetic and safety assessments were conducted to determine its stability, brain penetration, and potential toxicity. Results: Compound 29 demonstrated high potency in the formalin test, with an ED50 of 0.78 mg/kg in the second phase and a concentration-dependent effect in the first phase. In the SNL model, it produced dose-dependent analgesic effects, increasing withdrawal thresholds by 24% and 45% maximum possible effect (MPE) at 50 and 100 mg/kg, respectively. Mechanistic studies revealed strong triple uptake inhibition, particularly at dopamine (DAT) and serotonin (SERT) transporters, alongside high-affinity 5-HT2A receptor antagonism. Pharmacokinetic analysis indicated enhanced stability and blood–brain barrier permeability. In vitro studies confirmed its nontoxicity to HT-22 cells but revealed potential hERG inhibition and strong CYP3A4 inhibition. Conclusions: Compound 29 is a promising multitarget analgesic with potent efficacy and favorable pharmacokinetics. Ongoing optimization efforts aim to mitigate side effects and enhance its therapeutic profile for clinical application. Full article
(This article belongs to the Special Issue Discovery and Development of Novel Analgesics)
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18 pages, 933 KiB  
Article
Formulation, Quality Control and Stability Study of Pediatric Oral Dextrose Gel
by Edouard Lamy, Caroline Orneto, Oumil Her Abdou Ali, Lyna Kireche, Fanny Mathias, Cyrielle Bouguergour, Florence Peyron, Nicolas Primas, Christophe Sauzet, Philippe Piccerelle, Anne-Marie Maillotte, Veronique Brevaut-Malaty, Pascal Rathelot, Patrice Vanelle and Christophe Curti
Pharmaceuticals 2025, 18(2), 204; https://doi.org/10.3390/ph18020204 - 3 Feb 2025
Viewed by 511
Abstract
Background/Objective: Little information is available on the stability and quality controls of compounded 40% dextrose gel required to ensure its safe use in the treatment and prevention of neonatal hypoglycemia. Whether its efficacy relies on buccal absorption also remains uncertain. This study investigates [...] Read more.
Background/Objective: Little information is available on the stability and quality controls of compounded 40% dextrose gel required to ensure its safe use in the treatment and prevention of neonatal hypoglycemia. Whether its efficacy relies on buccal absorption also remains uncertain. This study investigates the stability, microbiological safety, rheological properties and dextrose diffusion of a compounded 40% oral dextrose gel, ensuring it can be widely compounded and stored for clinical use. Methods: A 40% dextrose gel compounded with anhydrous dextrose, carboxymethylcellulose, citric acid, sorbic acid and sterile water was subjected to quality control measures including a dextrose content assay, degradation product analysis, microbiological testing and preservative efficacy. Stability studies were conducted at refrigerated (4–8 °C) and ambient temperatures for 7 days and 3 months, respectively. Rheological properties were assessed, and dextrose permeation was measured through an artificial membrane model that mimics a biological membrane. Results: The compounded gel demonstrated stability for up to 7 days at ambient temperature and 90 days when refrigerated. The dextrose content remained within the acceptable range (90–110%) and microbiological tests confirmed compliance with safety standards. The gel exhibited the consistent rheological properties and shear-thinning behavior appropriate for oral mucosal administration. In vitro permeation studies showed no evidence of dextrose diffusion with a long lag time followed by a low steady-state permeation flux. Conclusions: This study validates the compounding process of a stable 40% oral dextrose gel formulation for neonatal hypoglycemia management, which meets quality control criteria and can be safely administered in clinical practice, offering a cost-effective and safe alternative for neonatal care. Full article
(This article belongs to the Special Issue Pharmaceutical Formulation Characterization Design)
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7 pages, 847 KiB  
Case Report
Assessment of Treatment Effects of Aminaphtone by Capillaroscopy in a Patient with Raynaud’s Phenomenon
by Gianluca Screm, Lucrezia Mondini, Francesco Salton, Paola Confalonieri, Chiara Bozzi, Chiara Torregiani, Caterina Antonaglia, Pietro Geri, Mario D’Oria, Giulia Bandini, Michael Hughes, Marco Confalonieri and Barbara Ruaro
Pharmaceuticals 2025, 18(2), 203; https://doi.org/10.3390/ph18020203 - 2 Feb 2025
Viewed by 504
Abstract
Background: Aminaphtone is a well-established pharmaceutical agent that has been utilized for over 40 years, primarily due to its effectiveness in treating microvascular disorders. Recent studies have explored its impact on various conditions, including chronic venous insufficiency, diabetic microangiopathy, leg ulcers, systemic sclerosis, [...] Read more.
Background: Aminaphtone is a well-established pharmaceutical agent that has been utilized for over 40 years, primarily due to its effectiveness in treating microvascular disorders. Recent studies have explored its impact on various conditions, including chronic venous insufficiency, diabetic microangiopathy, leg ulcers, systemic sclerosis, and Raynaud’s phenomenon. These investigations have consistently demonstrated that aminaphtone enhances skin blood perfusion and mitigates endothelial damage, all while maintaining a robust safety profile over time. Case Summary: This report highlights the potential of aminaphtone in improving microcirculation in a young patient who experienced spontaneous capillary rupture in her second finger. A 38-year-old woman with undifferentiated connective tissue disease presented to the clinic for periungual videocapillaroscopy (NVC). Given the microangiopathic changes observed during the NVC, she was prescribed aminaphtone. After seven months of treatment, a follow-up NVC revealed significant improvement in the capillaroscopic findings. A comprehensive literature review on aminaphtone was conducted using electronic databases (PUBMED, Google Scholar, ResearchGate, UpToDate), along with manual searches, focusing on articles published until November 2024. Conclusion: Treatment with aminaphtone led to notable improvements in microangiopathic health. Following the introduction of this medication, the nailfold microvascular bed, which previously exhibited severe alterations, showed a remarkable transition to only mild abnormalities. Full article
(This article belongs to the Section Pharmacology)
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19 pages, 7523 KiB  
Article
Discovering the Potential of Cannabidiol for Cosmeceutical Development at the Cellular Level
by Natjira Tassaneesuwan, Mattaka Khongkow, Siriyakorn Jansrinual and Pasarat Khongkow
Pharmaceuticals 2025, 18(2), 202; https://doi.org/10.3390/ph18020202 - 2 Feb 2025
Viewed by 646
Abstract
Backgrounds: Cannabidiol (CBD) has been used for the development of extensive cosmeceutical commercial products. However, the safety and unclear bioactivity of CBD are still concerns and need to be examined to assess the impact of CBD on skin cells through cosmeceutical applications, particularly [...] Read more.
Backgrounds: Cannabidiol (CBD) has been used for the development of extensive cosmeceutical commercial products. However, the safety and unclear bioactivity of CBD are still concerns and need to be examined to assess the impact of CBD on skin cells through cosmeceutical applications, particularly its impact on anti-aging and wound healing activities. Methods: In our study, the cytotoxicity of CBD was investigated on keratinocytes and fibroblasts in short-term and long-term treatments using a sulforhodamine B (SRB) assay and a clonogenic assay, respectively. Next, the antioxidant, anti-aging, and wound healing bioactivities of CBD were assessed. Then, we investigated the expression of the related genes. Results: Our results show that CBD at low concentrations (0.625–2.5 µg/mL) was not toxic to cells in the short-term treatment and significantly enhanced the growth of keratinocytes and fibroblasts under long-term exposure. Furthermore, CBD exhibited promising cellular bioactivities, including antioxidant and anti-aging activities in keratinocytes and fibroblasts, and it enhanced wound healing in skin cells. Moreover, CBD has affected the expression of skin regenerative genes in fibroblasts via TGF-β, VEGF, and NF-κB expression. In addition, CBD promoted CO1A2 expression, which is related to collagen production. Conclusions: Altogether, our findings confirm the promising potential of CBD, showing that it can be applied in various topical cosmeceutical products. However, further studies, including in vivo studies and clinical trials, should be conducted to confirm the safety and long-term effectiveness of CBD on the skin. Full article
(This article belongs to the Section Biopharmaceuticals)
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26 pages, 10611 KiB  
Article
BuZhong YiQi Formula Alleviates Postprandial Hyperglycemia in T2DM Rats by Inhibiting α-Amylase and α-Glucosidase In Vitro and In Vivo
by Xin-Xin Zeng, Liang Wang, Ming-Yu Wang, Zhen-Ran Hu, Xiang-Ke Li, Guo-Jun Fei, Ling Ling, Yu-Ting Fan and Ze-Min Yang
Pharmaceuticals 2025, 18(2), 201; https://doi.org/10.3390/ph18020201 - 2 Feb 2025
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Abstract
Background/Objectives: BuZhong YiQi Formula (BZYQF) can alleviate type 2 diabetes mellitus (T2DM). However, its efficacy in managing postprandial hyperglycemia in T2DM needs to be further confirmed, and its underlying mechanism and pharmacodynamic material basis have not been sufficiently investigated. Methods: A T2DM rat [...] Read more.
Background/Objectives: BuZhong YiQi Formula (BZYQF) can alleviate type 2 diabetes mellitus (T2DM). However, its efficacy in managing postprandial hyperglycemia in T2DM needs to be further confirmed, and its underlying mechanism and pharmacodynamic material basis have not been sufficiently investigated. Methods: A T2DM rat model was induced to measure postprandial glycemic responses following glucose and starch ingestion. In vitro assays of enzymatic inhibition and the kinetic mode were performed to evaluate the inhibitory effect of BZYQF on α-amylase and α-glucosidase activities. The main constituent contents of BZYQF in a simulated digestion assay were measured to screen the active constituents in BZYQF against α-amylase and α-glucosidase activities via Pearson correlation and multiple linear regression analyses. Finally, the total flavonoids were purified from BZYQF to perform in vitro activity validation, and the flavonoid constituent activity was verified through molecular docking. Results: In vivo assays showed that BZYQF significantly reduced the blood glucose values of CON rats but not T2DM rats after glucose ingestion, while BZYQF significantly reduced the blood glucose levels by 15 min after starch ingestion in CON and T2DM rats, with more significant decreases in blood glucose levels in T2DM rats. In vitro enzymatic assays showed that BZYQF could inhibit the activities of α-amylase and α-glucosidase in competitive and non-competitive modes and in an uncompetitive mode, respectively. Furthermore, BZYQF showed a stronger inhibitory effect on α-glucosidase activity than on α-amylase activity. Simulated digestion showed that simulated gastric fluid and intestinal fluid changed the main constituent contents of BZYQF and their inhibition rates against α-amylase and α-glucosidase activities, and similar results were rarely found in simulated salivary fluid. Pearson correlation and multiple linear regression analyses revealed that the total flavonoids were the active constituents in BZYQF inhibiting α-amylase and α-glycosidase activities. This result was verified by examining the total flavonoids purified from BZYQF. A total of 1909 compounds were identified in BZYQF using UPLC-MS/MS, among which flavones were the most abundant and consisted of 467 flavonoids. Molecular docking showed that flavonoids in BZYQF were bound to the active site of α-amylase, while they were bound to the inactive site of α-glucosidase. This result supported the results of the enzyme kinetic assay. Conclusions: BZYQF significantly alleviated postprandial hyperglycemia in T2DM rats by inhibiting α-amylase and α-glycosidase activities, in which flavonoids in BZYQF were the active constituents. Full article
(This article belongs to the Special Issue Natural Products in Diabetes Mellitus: 2nd Edition)
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