Pharmaceuticals

13 pages, 347 KiB

Open AccessArticle

Complexity of the Therapeutic Regimen in Older Adults with Cancer: Associated Factors

by Rita F. Oliveira, Ana I. Oliveira, Agostinho Cruz, Oscar Ribeiro, Vera Afreixo and Francisco Pimentel

Pharmaceuticals 2024, 17(11), 1541; https://doi.org/10.3390/ph17111541 (registering DOI) - 16 Nov 2024

Abstract

Background/Objectives: Population aging is a worldwide phenomenon and is often associated with multimorbidity and polypharmacy. Complex medication regimens are common among older adults and contribute to the occurrence of harmful health outcomes. Age is one of the main risk factors for cancer. This [...] Read more.

Background/Objectives: Population aging is a worldwide phenomenon and is often associated with multimorbidity and polypharmacy. Complex medication regimens are common among older adults and contribute to the occurrence of harmful health outcomes. Age is one of the main risk factors for cancer. This study aimed to determine and characterize the therapeutic complexity in older patients with cancer, and analyze the factors associated with high complexity and the impact of the oncological context. Methods: A cross-sectional study with patients aged ≥65 years with cancer was conducted in three hospitals in northern Portugal. Data collection was obtained using self-reports. The medication regimen complexity was assessed using the Medication Regimen Complexity Index (MRCI). Descriptive and association statistical analysis were performed. Logistic, linear, simple and multiple regression analysis were conducted, with and without automatic variable selection. Results: A total of 552 patients were included (median age, 71; IQR, 68–76). The mean MRCI before the oncological context was 18.67 (SD 12.60) and 27.39 (SD 16.67) after the oncological context, presenting a statistically significant difference in the values obtained (p < 0.001). An elevated complexity was significantly associated with polypharmacy, chronic diseases and with the administration of high-risk medications (p < 0.05). High MRCI values showed a relationship with the occurrence of potential drug interactions (p < 0.001). There was no relationship with the existence of cardiac risk comorbidity. Conclusions: This study demonstrated the existence of high therapeutic complexity in older patients with cancer, suggesting the need for intervention to prevent medication-related problems in this vulnerable population. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 11771 KiB

Open AccessArticle

In Silico Study of the Potential Inhibitory Effects on Escherichia coli DNA Gyrase of Some Hypothetical Fluoroquinolone–Tetracycline Hybrids

by Ioana-Andreea Lungu, Octavia-Laura Oancea and Aura Rusu

Pharmaceuticals 2024, 17(11), 1540; https://doi.org/10.3390/ph17111540 (registering DOI) - 16 Nov 2024

Abstract

Background/Objectives: Despite the discovery of antibiotics, bacterial infections persist globally, exacerbated by rising antimicrobial resistance that results in millions of cases, increased healthcare costs, and more extended hospital stays. The urgent need for new antibacterial drugs continues as resistance evolves. Fluoroquinolones and tetracyclines [...] Read more.

Background/Objectives: Despite the discovery of antibiotics, bacterial infections persist globally, exacerbated by rising antimicrobial resistance that results in millions of cases, increased healthcare costs, and more extended hospital stays. The urgent need for new antibacterial drugs continues as resistance evolves. Fluoroquinolones and tetracyclines are versatile antibiotics that are effective against various bacterial infections. A hybrid antibiotic combines two or more molecules to enhance antimicrobial effectiveness and combat resistance better than monotherapy. Fluoroquinolones are ideal candidates for hybridization due to their potent bactericidal effects, ease of synthesis, and ability to form combinations with other molecules. Methods: This study explored the mechanisms of action for 40 hypothetical fluoroquinolone–tetracycline hybrids, all of which could be obtained using a simple, eco-friendly synthesis method. Their interaction with Escherichia coli DNA Gyrase and similarity to albicidin were evaluated using the FORECASTER platform. Results: Hybrids such as Do-Ba, Mi-Fi, and Te-Ba closely resembled albicidin in physicochemical properties and FITTED Scores, while Te-De surpassed it with a better score. Similar to fluoroquinolones, these hybrids likely inhibit DNA synthesis by binding to enzyme–DNA complexes. Conclusions: These hybrids could offer broad-spectrum activity and help mitigate bacterial resistance, though further in vitro and in vivo studies are needed to validate their potential. Full article

(This article belongs to the Special Issue Development of Antibacterial Drugs to Combat Drug-Resistant Bacteria)

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22 pages, 4209 KiB

Open AccessArticle

Exploring the Antiviral Potential of Artemisia annua Through JAK-STAT Pathway Targeting: A Network Pharmacology Approach

by Mebarka Ouassaf, Lotfi Bourougaa, Farial Bahaz and Bader Y. Alhatlani

Pharmaceuticals 2024, 17(11), 1539; https://doi.org/10.3390/ph17111539 (registering DOI) - 16 Nov 2024

Abstract

Background: Artemisia annua, a plant with antiviral potential, has shown promise against various viral infections, yet its mechanisms of action are not fully understood. This study explores A. annua’s antiviral effects using network pharmacology and molecular docking, focusing on key active [...] Read more.

Background: Artemisia annua, a plant with antiviral potential, has shown promise against various viral infections, yet its mechanisms of action are not fully understood. This study explores A. annua’s antiviral effects using network pharmacology and molecular docking, focusing on key active compounds and their interactions with viral protein targets, particularly within the JAK-STAT signaling pathway—a critical mediator of immune responses to viral infections. Methods: From the TCMSP database, we identified eight active compounds and 335 drug targets for A. annua, with 19 intersecting targets between A. annua compounds and viral proteins. A protein–protein interaction (PPI) network highlighted 10 key hub genes, analyzed further through Gene Ontology (GO) and KEGG pathways to understand their immune and antiviral roles. ADMET properties of the active compound Patuletin (MOL004112) were assessed, followed by 200 ns molecular dynamics simulations to examine its stability in complex with JAK2. Results: PPI analysis identified JAK2, MAPK3, MAPK1, JAK1, PTPN1, HSPA8, TYK2, RAF1, MAPT, and HMOX1 as key hub genes, with JAK2 emerging as a critical regulator of immune and antiviral pathways. ADMET analysis confirmed Patuletin’s favorable pharmacokinetic properties, and molecular dynamics simulations showed a stable Patuletin-JAK2 complex, with FEL analysis indicating minimal disruption to JAK2’s intrinsic flexibility. Conclusions: These findings highlight JAK2 as a promising target in the antiviral activity of A. annua compounds, particularly Patuletin, supporting its potential as an antiviral agent and providing a foundation for further research on A. annua’s therapeutic applications. Full article

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

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12 pages, 4272 KiB

Open AccessArticle

Effects of Short-Term Treatment with α-Lipoic Acid on Neuropathic Pain and Biomarkers of DNA Damage in Patients with Diabetes Mellitus

by Juozas R. Lazutka, Kristina Daniūnaitė, Veronika Dedonytė, Aistė Popandopula, Karolina Žukaitė, Žydrūnė Visockienė and Laura Šiaulienė

Pharmaceuticals 2024, 17(11), 1538; https://doi.org/10.3390/ph17111538 (registering DOI) - 16 Nov 2024

Abstract

Background/Objectives: Diabetes mellitus (DM) is a complex and heterogenous disease classified as a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It leads to various complications, some of which are macrovascular or microvascular [...] Read more.

Background/Objectives: Diabetes mellitus (DM) is a complex and heterogenous disease classified as a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It leads to various complications, some of which are macrovascular or microvascular complications, like diabetic polyneuropathy (DPN), having a profound impact on patients’ quality of life. Oxidative stress (OS) is one of the significant mechanisms in the development and progression of DPN. Thus, targeting OS pathways by antioxidants, such as α-lipoic acid (ALA), could represent a promising therapeutic strategy for alleviating neuropathic symptoms. The aim of our study was to evaluate whether short-term (from 4 to 9 days) intravenous administration of ALA could cause any measurable improvement in subjects with DM. Methods: Sixteen subjects with DM (six type 1 and ten type 2) and sixteen nondiabetic subjects matched by sex and age were recruited to this study. Only subjects with DM received treatment with ALA (600 mg daily). Pain intensity and biomarkers of DNA damage including plasma concentration of 8-hydroxy-2′-deoxyguanosine (8-OHdG), frequency of micronucleated lymphocytes (MN), and frequency of sister-chromatid exchanges (SCEs), were measured before and after the treatment with ALA. Results: Pain intensity and 8-OHdG levels were significantly lower in DM subjects after the ALA treatment than before the treatment. However, no changes in the frequency of SCEs and MN were observed. Conclusions: Our results show some evidence that even a short-term intravenous treatment with ALA could be beneficial for diabetic subjects, reducing pain intensity and concentration of 8-OHdG in blood plasma. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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16 pages, 1043 KiB

Open AccessReview

Antibacterial Mechanisms and Clinical Impact of Sitafloxacin

by Elian M. A. Kuhn, Levy A. Sominsky, Marco Chittò, Edward M. Schwarz and T. Fintan Moriarty

Pharmaceuticals 2024, 17(11), 1537; https://doi.org/10.3390/ph17111537 (registering DOI) - 16 Nov 2024

Abstract

Sitafloxacin is a 4th generation fluoroquinolone antibiotic with broad activity against a wide range of Gram-negative and Gram-positive bacteria. It is approved in Japan and used to treat pneumonia and urinary tract infections (UTIs) as well as other upper and lower respiratory infections, [...] Read more.

Sitafloxacin is a 4th generation fluoroquinolone antibiotic with broad activity against a wide range of Gram-negative and Gram-positive bacteria. It is approved in Japan and used to treat pneumonia and urinary tract infections (UTIs) as well as other upper and lower respiratory infections, genitourinary infections, oral infections and otitis media. Compared to other fluoroquinolones, sitafloxacin displays a low minimal inhibitory concentration (MIC) for many bacterial species but also activity against anaerobes, intracellular bacteria, and persisters. Furthermore, it has also shown strong activity against biofilms of P. aeruginosa and S. aureus in vitro, which was recently validated in vivo with murine models of S. aureus implant-associated bone infection. Although limited in scale at present, the published literature supports the further evaluation of sitafloxacin in implant-related infections and other biofilm-related infections. The aim of this review is to summarize the chemical-positioning-based mechanisms, activity, resistance profile, and future clinical potential of sitafloxacin. Full article

(This article belongs to the Special Issue Fluoroquinolones)

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19 pages, 1055 KiB

Open AccessArticle

Identification of Potential Inhibitors of Histone Deacetylase 6 Through Virtual Screening and Molecular Dynamics Simulation Approach: Implications in Neurodegenerative Diseases

by Anas Shamsi, Moyad J.S.A. Shahwan, Azna Zuberi and Nojood Altwaijry

Pharmaceuticals 2024, 17(11), 1536; https://doi.org/10.3390/ph17111536 (registering DOI) - 15 Nov 2024

Abstract

Background: Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, [...] Read more.

Background: Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved. Methods: This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide. Results: The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein–ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6–ligand complexes, confirming the stability of their interactions. Conclusions: The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems. Full article

(This article belongs to the Special Issue Structural and Computationally Driven Molecule Design in Drug Discovery: 2nd Edition)

21 pages, 3481 KiB

Open AccessArticle

Corema album Berry Juice as a Protective Agent Against Neurodegeneration

by Antonio Canoyra, Carmen Martín-Cordero, Dolores Muñoz-Mingarro, Antonio J. León-González, Richard B. Parsons and Nuria Acero

Pharmaceuticals 2024, 17(11), 1535; https://doi.org/10.3390/ph17111535 - 15 Nov 2024

Abstract

Background/Objectives: Corema album berries are edible fruits from the Iberian Atlantic coast, characterized by a rich polyphenolic composition, which endows their juice with potential protective effects against neurodegeneration. This study aimed to evaluate the potential of the relatively lesser-known C. album berries [...] Read more.

Background/Objectives: Corema album berries are edible fruits from the Iberian Atlantic coast, characterized by a rich polyphenolic composition, which endows their juice with potential protective effects against neurodegeneration. This study aimed to evaluate the potential of the relatively lesser-known C. album berries as a novel neuroprotective agent against neurodegenerative diseases. Methods: The phenolic compounds of the juice were characterized using UHPLC-HRMS (Orbitrap). The SH-SY5Y neuroblastoma line was used to determine the preventive effect of the juice against H₂O₂-induced oxidative stress. Furthermore, neuronal cells were differentiated into dopaminergic and cholinergic lines and exposed to 6-hydroxydopamine and okadaic acid, respectively, to simulate in vitro models of Parkinson’s disease and Alzheimer’s disease. The ability of the juice to enhance neuronal viability under toxic conditions was examined. Additionally, its inhibitory effects on neuroprotective-related enzymes, including MAO-A and MAO-B, were assessed in vitro. Results: Phytochemical characterization reveals that 5-O-caffeoylquinic acid constitutes 80% of the total phenolic compounds. Higher concentrations of the juice effectively protected both differentiated and undifferentiated SH-SY5Y cells from H₂O₂-induced oxidative damage, reducing oxidative stress by approximately 20% and suggesting a dose-dependent mechanism. Moreover, the presence of the juice significantly enhanced the viability of dopaminergic and cholinergic cells exposed to neurotoxic agents. In vitro, the juice inhibited the activity of MAO-A (IC₅₀ = 87.21 µg/mL) and MAO-B (IC₅₀ = 56.50 µg/mL). Conclusions: While these findings highlight C. album berries as a promising neuroprotective agent, further research is required to elucidate its neuroprotective mechanisms in cell and animal models and, ultimately, in human trials. Full article

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

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18 pages, 4131 KiB

Open AccessArticle

Phytochemicals from Passiflora coriacea Juss. Have Anti-Inflammatory and Neuroprotective Effects in Mouse Models

by Samir Castolo-Sanchez, Alejandro Zamilpa, Maribel Herrera-Ruiz, José Luis Trejo-Espino, Blanca Eda Domínguez-Mendoza, Manasés González-Cortazar and Gabriela Trejo-Tapia

Pharmaceuticals 2024, 17(11), 1534; https://doi.org/10.3390/ph17111534 - 15 Nov 2024

Abstract

Background: Neuroinflammatory diseases trigger an inflammatory response and a state of oxidative stress. Passiflora coriacea Juss. has been used to treat conditions related to inflammatory processes in the central nervous system; however, to date, there has been no study on the anti-inflammatory and [...] Read more.

Background: Neuroinflammatory diseases trigger an inflammatory response and a state of oxidative stress. Passiflora coriacea Juss. has been used to treat conditions related to inflammatory processes in the central nervous system; however, to date, there has been no study on the anti-inflammatory and neuroprotective effects of this species. Methods: The anti-inflammatory effect of P. coriacea was evaluated in a TPA-induced auricular edema model, and the percentage of edema inhibition (Ei) was recorded. The Morris water maze was used to assess the neuroprotective effect, measuring the latency time (LT), and lipopolysaccharide was administered to induce neuroinflammation. The concentrations of cytokines (IL-6, IL-10, and TNF-α) and activities of antioxidant system components (CAT, SOD, GR, NO, and MDA) were measured in the mouse brains. The chemical composition was determined using chromatographic and nuclear magnetic resonance techniques. Results: T1.1, T2.1, and T3.1 showed anti-inflammatory (Ei = 92.5, 88.3, and 64.8%, respectively) and neuroprotective (LT = 27.2, 22.9, and 27.7 s, respectively) effects. T1.1 was identified as scopolin with immunomodulatory (IL-6 = 3307 pg/g) and antioxidant (CAT = 1198 mmol, SOD = 23%, GR = 5.34 units/mL, NO = 11.5 µM, MDA = 1526 nmol/mL) effects; T2.1 was a mixture of terpenes (fitone, 7-dehydrodiosgenin, tremulone) with immunomodulatory (TNF-α = 857 pg/g) and antioxidant (CAT = 1245 mmol, NO = 8.75 µM) effects; and T3.1 was a mixture of isoquercetin and astragalin with immunomodulatory (IL-6 = 3135 pg/g, IL-10 = 1300 pg/g, TNF-α = 751 pg/g) and antioxidant (SOD = 1204 nmol/mL, CAT = 1131 nmol/mL, NO = 6.37 µM, MDA = 1204 nmol/mL) effects. Conclusions: The administration of P. coriacea treatments generated anti-inflammatory, neuroprotective, immunomodulatory, and antioxidant effects. These effects are attributable to its chemical composition, comprising scopolin, terpenes, and a mixture of isoquercetin and astragalin, which have not previously been described in this species. Full article

(This article belongs to the Section Natural Products)

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3 pages, 2124 KiB

Open AccessCorrection

Correction: Taha et al. Activation of SIRT-1 Pathway by Nanoceria Sheds Light on Its Ameliorative Effect on Doxorubicin-Induced Cognitive Impairment (Chemobrain): Restraining Its Neuroinflammation, Synaptic Dysplasticity and Apoptosis. Pharmaceuticals 2022, 15, 918

by Medhat Taha, Sara T. Elazab, Alaa. M. Badawy, Abdullah A. Saati, Naeem F. Qusty, Abdullah G. Al-Kushi, Anas Sarhan, Amira Osman and Amira E. Farage

Pharmaceuticals 2024, 17(11), 1533; https://doi.org/10.3390/ph17111533 - 15 Nov 2024

Abstract

In the original publication [...] Full article

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25 pages, 5269 KiB

Open AccessArticle

Discovery of New 3-(Benzo[b]Thiophen-2-yl)Pyrrolidine-2,5-Dione Derivatives as Potent Antiseizure and Antinociceptive Agents—In Vitro and In Vivo Evaluation

by Anna Rapacz, Marcin Jakubiec, Michał Abram, Jakub Jasiński, Karolina Chrzan, Małgorzata Góra, Anna Dziubina, Katarzyna Wójcik-Pszczoła, Paulina Koczurkiewicz-Adamczyk, Katarzyna Ciepiela, Elżbieta Pękala, Jolanta Obniska and Krzysztof Kamiński

Pharmaceuticals 2024, 17(11), 1532; https://doi.org/10.3390/ph17111532 - 15 Nov 2024

Abstract

Background/Objectives: To address the unmet clinical needs in the treatment of epilepsy and pain, the continued development of more effective and safer anticonvulsants and analgesics is still necessary. Therefore, herein we report synthesis and antiseizure/antinociceptive evaluation of a focused series of 3-(benzo[b]thiophen-2-yl)pyrrolidine-2,5-dione [...] Read more.

Background/Objectives: To address the unmet clinical needs in the treatment of epilepsy and pain, the continued development of more effective and safer anticonvulsants and analgesics is still necessary. Therefore, herein we report synthesis and antiseizure/antinociceptive evaluation of a focused series of 3-(benzo[b]thiophen-2-yl)pyrrolidine-2,5-dione derivatives. Methods: The anticonvulsant properties were investigated in acute models of seizures, namely the maximal electroshock (MES), the 6 Hz (32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas analgesic activity was tested in the model of a tonic pain/formalin test and oxaliplatin-induced neuropathic pain (in CD-1-mice, i.p.). In addition, a number of in vitro assays were performed, aiming at the evaluation of the drug-like properties of the compounds disclosed herein. Results: We identified 33 as a lead compound with the most promising antiseizure properties, i.e., ED₅₀ (MES) = 27.4 mg/kg and ED₅₀ (6 Hz, 32 mA) = 30.8 mg/kg. Furthermore, 33 at a dose of 100 mg/kg significantly prolonged the latency time to the first seizure episode in the scPTZ model and at high doses did not impaire coordination of mice in the rotarod test (TD₅₀ > 200 mg/kg). Apart from broad antiseizure protection, 33 demonstrated a significant analgesic effect in the formalin test (45 mg/kg, i.p.), and effectively alleviated allodynia in the oxaliplatin-induced neuropathic pain model (30 and 45 mg/kg). The binding assays suggest that the most plausible mechanism of action relies on interaction with the neuronal voltage-sensitive sodium channel (site 2). Furthermore, the drug-like potential of 33 supports favorable in vitro results, i.e., no hepatocytotoxicity and neurocytotoxicity at a high concentration of 100 μM, as well as a lack of mutagenicity at a concentration as high as 500 μM. Conclusions: Compound 33 identified in the current studies is proposed to be an interesting candidate for further preclinical development as therapy for epilepsy and neuropathic pain. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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12 pages, 708 KiB

Open AccessArticle

The Use of Osteogenon as an Adjunctive Treatment in Lower Leg Fractures

by Piotr Morasiewicz, Monika Zaborska, Michał Sobczak, Łukasz Tomczyk, Paweł Leyko, Andrzej Bobiński, Joanna Kochańska-Bieri, Daniele Pili and Krystian Kazubski

Pharmaceuticals 2024, 17(11), 1531; https://doi.org/10.3390/ph17111531 - 14 Nov 2024

Abstract

Background: The goal of the orthopedic treatment of fractures is to achieve bone union as rapidly as possible in the largest possible number of patients and to minimize the number of complications. The purpose of this study was to assess if the use [...] Read more.

Background: The goal of the orthopedic treatment of fractures is to achieve bone union as rapidly as possible in the largest possible number of patients and to minimize the number of complications. The purpose of this study was to assess if the use of Osteogenon would have a positive effect on radiological and clinical parameters in patients with lower leg bone fractures treated with the Ilizarov method. Methods: We evaluated 26 patients who had their lower leg bone fractures treated with the Ilizarov method and received Osteogenon at our clinic in the years 2021–2023. The control group comprised 25 patients with lower leg bone fractures treated with the Ilizarov method who did not receive Osteogenon. We assessed the following parameters: time to achieving bone union, bone union rate, time to resuming normal physical activity, time to achieving pain relief, the number of patients reporting pain relief, and the rate of complications. Results: The median time to achieve bone union after lower leg bone fracture treated with the Ilizarov method was shorter in the Osteogenon group (108.5 days) compared to the control group (134 days), p < 0.001. Bone union was achieved in all the patients in the Osteogenon group and in 96% of the patients in the control group; the difference was not statistically significant. The median time to resuming normal physical activity was shorter in the Osteogenon group (22.5 weeks) compared to the control group (27 weeks), p < 0.001. The median time to achieving pain relief was shorter in the Osteogenon group (21 weeks) compared to the control group (30 weeks), p < 0.001. The proportion of patients who reported pain relief was 88.46% in the group receiving Osteogenon and 76% in the control group; this difference was not statistically significant. The number of complications was lower in the Osteogenon group (8 patients; 30.77%) compared to the control group (15 patients; 60%), p = 0.035. Conclusions: The use of Osteogenon has a beneficial impact on the treatment of lower leg bone fractures with the Ilizarov method. Osteogenon shortens the time to achieve bone union. Moreover, the use of the ossein–hydroxyapatite complex helps reduce the number of complications and shortens the time to achieve pain relief and to resume normal activities. Full article

(This article belongs to the Special Issue The Pharmacological Management of Bone and Muscle Disorders)

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19 pages, 4321 KiB

Open AccessArticle

Sustainable Intervention: Grape Pomace Flour Ameliorates Fasting Glucose and Mitigates Streptozotocin-Induced Pancreatic Damage in a Type 2 Diabetes Animal Model

by Raphaela Cassol Piccoli, William Sanabria Simões, Solange Vega Custódio, Kelen Cristiane Machado Goularte, Karina Pereira Luduvico, Julia Eisenhardt de Mello, Anita Avila de Souza, Ana Carolina Teixeira, Diego Araujo da Costa, Alethéa Gatto Barschak, Bruna Ferrary Deniz, Wellington de Almeida, Paula Pereira, Marisa Nicolai, Roselia Maria Spanevello, Francieli Moro Stefanello, Rejane Giacomelli Tavares and Maria Lídia Palma

Pharmaceuticals 2024, 17(11), 1530; https://doi.org/10.3390/ph17111530 - 14 Nov 2024

Abstract

Background/Objectives: Type 2 Diabetes Mellitus (T2DM) is characterized by hyperglycemia, increased risk of cardiovascular diseases, and oxidative imbalances. This study aimed to investigate the impact of dietary supplementations with ‘Arinto’ grape pomace flour (GPF) (WGPF) and ‘Touriga Nacional’ GPF (RGPF) in an [...] Read more.

Background/Objectives: Type 2 Diabetes Mellitus (T2DM) is characterized by hyperglycemia, increased risk of cardiovascular diseases, and oxidative imbalances. This study aimed to investigate the impact of dietary supplementations with ‘Arinto’ grape pomace flour (GPF) (WGPF) and ‘Touriga Nacional’ GPF (RGPF) in an animal model of T2DM. Methods: T2DM was induced by a high-fat diet (HFD) for 28 days and a single dose of streptozotocin (STZ) (35 mg/kg) on the 21st day. Forty adult male Wistar rats were divided into five groups: Control (CT), T2DM, T2DM + Metformin (250 mg/kg), T2DM + 10% ‘Arinto’ GPF (WGPF), and T2DM + 10% ‘Touriga Nacional’ GPF (RGPF). On the 21st day of the experimental protocol, animals were submitted to an oral glucose tolerance test. An oral glucose tolerance test, oxidative stress parameters, biochemical analysis, and pancreas histological analyses were performed. Results: T2DM impaired glucose tolerance, elevated serum triglycerides and cholesterol, increased oxidative damage in the liver, and induced pancreatic histological abnormalities. However, supplementation with WGPF and RGPF demonstrated positive effects, mitigating glycemic and lipid disruptions, ameliorating oxidative stress, and protecting pancreatic Islets β-cells. Conclusions: Our findings highlight the protective effects of WGPF and RGPF in the adverse impacts of T2DM. Additionally, our study emphasizes the innovative use of grape pomace, a winemaking by-product, promoting sustainability by transforming waste into functional foods with significant health benefits. Full article

(This article belongs to the Special Issue Bioactive Substances, Oxidative Stress, and Inflammation)

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18 pages, 3056 KiB

Open AccessArticle

Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors

by Manuela Giansanti, Tiziana Ottone, Serena Travaglini, Maria Teresa Voso, Grazia Graziani and Isabella Faraoni

Pharmaceuticals 2024, 17(11), 1529; https://doi.org/10.3390/ph17111529 - 14 Nov 2024

Abstract

Background: Arsenic trioxide (ATO) is an anticancer agent for treating acute promyelocytic leukemia (APL). However, 5–10% of patients fail to respond, developing relapsed/refractory disease. The aim of this study was to identify potential new therapeutic approaches for ATO-unresponsive APL by targeting the anti-apoptotic [...] Read more.

Background: Arsenic trioxide (ATO) is an anticancer agent for treating acute promyelocytic leukemia (APL). However, 5–10% of patients fail to respond, developing relapsed/refractory disease. The aim of this study was to identify potential new therapeutic approaches for ATO-unresponsive APL by targeting the anti-apoptotic genes that contribute to drug resistance. Methods: RNA expression of dysregulated genes involved in the apoptotic pathway was analyzed by comparing ATO-resistant APL cell clones generated in our lab with the corresponding sensitive clones, at basal levels and after 48 h of treatment with ATO. Results: ATO-resistant APL cells showed upregulation of APAF1, BCL2, BIRC3, and NOL3 genes, while CD70 and IL10 genes were downregulated, compared to ATO-sensitive cells. Treatment with ATO strongly increased the expression of the anti-apoptotic genes BIRC3, NOL3, and BCL2A1 and significantly downregulated BCL2 in ATO-sensitive clones. Although all these genes can be relevant to ATO-resistance, we selected BCL2 and BIRC3 as druggable targets. A direct correlation between BCL2 expression and the sensitivity to the BCL2 inhibitor venetoclax was observed, indicating BCL2 as predictive biomarker of the response. Moreover, the combination of venetoclax with ATO exerted synergistic cytotoxic effects, thus reverting the resistance to ATO. APL treatment with SMAC mimetics such as LCL161 and xevinapant (inhibitors of BIRC3) was not as effective as the BCL2 inhibitor as a monotherapy but exerted synergistic effects in combination with ATO in cells with low BIRC expression. Conclusions: This study demonstrates the therapeutic potential of venetoclax in combination with ATO in vitro and strongly encourages further investigation of relapsed/refractory APL with high BCL2 expression. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 7777 KiB

Open AccessArticle

Exploring Moroccan Medicinal Plants for Anticancer Therapy Development Through In Silico Studies

by Amal Bouribab, El Mehdi Karim, Meriem Khedraoui, Oussama Abchir, Abdelkbir Errougui, Yasir S. Raouf, Abdelouahid Samadi and Samir Chtita

Pharmaceuticals 2024, 17(11), 1528; https://doi.org/10.3390/ph17111528 - 13 Nov 2024

Abstract

Background: Angiogenesis is a crucial process in the growth and proliferation of cancer, enabling tumor growth through the formation of new vasculature and the supply of nutrients and oxygen to growing malignant cells. This disease-promoting process can be targeted through the inhibition of [...] Read more.

Background: Angiogenesis is a crucial process in the growth and proliferation of cancer, enabling tumor growth through the formation of new vasculature and the supply of nutrients and oxygen to growing malignant cells. This disease-promoting process can be targeted through the inhibition of tyrosine kinase enzymes. Objectives: The objective of this study is to evaluate the anticancer potential of various Moroccan plants from different regions. While these plants have a rich history of traditional medicinal use, they have not been extensively investigated as anticancer therapies. Methods: This study employed a multifaceted approach to evaluate the anticancer potential of various Moroccan plants. Receptor–ligand docking and virtual screening were used to assess the binding affinity of phytocompounds to the EGFR and VEGFR2 receptors. Additionally, predictive pharmacokinetic analyses were conducted to evaluate the ADMET properties of the selected compounds, followed by molecular dynamics simulations to analyze the stability of the receptor–ligand complexes. Results: In our research, we identified three notable active compounds—catechin, 4-O-glucoside ferulic acid, and 3-glucoside resveratrol—in the Moroccan plant Ajuga iva L. These findings suggest that Ajuga iva L. may possess significant potential for cancer inhibition. Conclusions: This research highlights the potential of the Moroccan plant Ajuga iva L. as a source of active compounds with significant anticancer properties. Further investigation is essential to validate these findings and explore new therapeutic avenues based on these traditional resources. Full article

(This article belongs to the Section Natural Products)

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20 pages, 2323 KiB

Open AccessReview

Mapping of c-Fos Expression in Rat Brain Sub/Regions Following Chronic Social Isolation: Effective Treatments of Olanzapine, Clozapine or Fluoxetine

by Andrijana Stanisavljević Ilić and Dragana Filipović

Pharmaceuticals 2024, 17(11), 1527; https://doi.org/10.3390/ph17111527 - 13 Nov 2024

Abstract

The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie [...] Read more.

The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie depressive- and anxiety-like behaviors of adult male rats following three and six weeks of chronic social isolation (CSIS), relative to controls, as well as the antipsychotic-like effects of olanzapine (Olz), and clozapine (Clz), and the antidepressant-like effect of fluoxetine (Flx) in CSIS relative to CSIS alone. Additionally, drug-treated controls relative to control rats were also characterized. The overlapping rat brain sub/regions with increased expression of c-Fos immunoreactivity following three or six weeks of CSIS were the retrosplenial granular cortex, c subregion, retrosplenial dysgranular cortex, dorsal dentate gyrus, paraventricular nucleus of the thalamus (posterior part, PVP), lateral/basolateral (LA/BL) complex of the amygdala, caudate putamen, and nucleus accumbens shell. Increased activity of the nucleus accumbens core following exposure of CSIS rats either to Olz, Clz, and Flx treatments was found, whereas these treatments in controls activated the LA/BL complex of the amygdala and PVP. We also outline sub/regions that might represent potential neuroanatomical targets for the aforementioned antipsychotics or antidepressant treatments. Full article

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18 pages, 7026 KiB

Open AccessArticle

IL-13Rα2 Is Involved in Resistance to Doxorubicin and Survival of Osteosarcoma Patients

by Maryam Karamikheirabad, Junyue Zhang, Ae-Ri Ahn, Ho Sung Park, See-Hyoung Park, Young Jae Moon, Kyoung Min Kim and Kyu Yun Jang

Pharmaceuticals 2024, 17(11), 1526; https://doi.org/10.3390/ph17111526 - 13 Nov 2024

Abstract

Background/Objectives: Interleukin 13 receptor alpha 2 (IL-13Rα2) is a receptor with a high affinity for IL-13 and is involved in the progression of human cancers. However, studies on the role of IL-13Rα2 in osteosarcoma are limited. Therefore, this study aimed to investigate the [...] Read more.

Background/Objectives: Interleukin 13 receptor alpha 2 (IL-13Rα2) is a receptor with a high affinity for IL-13 and is involved in the progression of human cancers. However, studies on the role of IL-13Rα2 in osteosarcoma are limited. Therefore, this study aimed to investigate the expression and roles of IL-13Rα2 in the progression of osteosarcoma. Methods: This study evaluated the roles of IL-13Rα2 in osteosarcomas by evaluating tumor tissues from 37 human osteosarcomas and osteosarcoma cells. Results: Immunohistochemical positivity of IL-13Rα2 was an independent indicator of shorter overall survival and relapse-free survival of 37 osteosarcoma patients and 26 subpopulations of patients who received adjuvant chemotherapy with multivariate analysis. In U2OS and KHOS/NP osteosarcoma cells, overexpression of IL-13Rα2 significantly increased proliferation, migration, and invasion of cells, all of which decreased with knockdown of IL-13Rα2. Overexpression of IL-13Rα2 increased expression of TGF-β, snail, cyclin D1, and BCL2 but decreased BAX, and knockdown of IL-13Rα2 caused a decrease in expression of these molecules. In addition, both in vitro and in vivo, proliferation of osteosarcoma cells increased, and apoptosis decreased with overexpression of IL-13Rα2 under treatment with doxorubicin. Knockdown of IL-13Rα2 sensitized osteosarcoma cells to the cytotoxic effect of doxorubicin. Conclusions: The results of this study suggest that the expression of IL13Rα2 might be used as a potential prognostic indicator in osteosarcoma patients. Furthermore, it is observed that IL13Rα2 influences the resistance to the chemotherapeutic agent doxorubicin. Therefore, a therapeutic trial targeting IL13Rα2 might be a new therapeutic strategy for osteosarcoma, especially those highly expressing IL13Rα2. Full article

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

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Graphical abstract

12 pages, 1529 KiB

Open AccessArticle

Pharmaceutical Equivalence of Film-Coated and Chewable Tablets: A Comparative Dissolution Study Using Pulverized Chewable Tablets

by Suck-Yong Park and Sung-Up Choi

Pharmaceuticals 2024, 17(11), 1525; https://doi.org/10.3390/ph17111525 - 12 Nov 2024

Abstract

Famotidine is a histamine H2 receptor antagonist used in the treatment of gastrointestinal disorders. It is available in multiple formulations, including film-coated tablets, chewable tablets, oral suspension, and injections. The purpose of this study was to develop and evaluate the film-coated tablet (FT) [...] Read more.

Famotidine is a histamine H2 receptor antagonist used in the treatment of gastrointestinal disorders. It is available in multiple formulations, including film-coated tablets, chewable tablets, oral suspension, and injections. The purpose of this study was to develop and evaluate the film-coated tablet (FT) containing famotidine, magnesium hydroxide, and precipitated calcium carbonate, designed to be pharmaceutically equivalent to the marketed chewable tablet (CT). To achieve the pharmaceutical equivalence of two tablets, the dissolution profiles of FT should be similar to those of CT. However, since CT is intended to be chewed before swallowing, testing it in its intact form would not provide accurate results. Therefore, pulverized chewable tablets (PCT) were used as the reference product. The dissolution, performed by the paddle method at 50 rpm, was analyzed by the validated UV method. Similarity factor (f₂) and difference factor (f₁) were calculated to assess the equivalence of the dissolution profiles. The results demonstrated that the dissolution profiles of the FT and CT were similar. Additionally, the acid-neutralizing capacity test confirmed the equivalence of the two antacids. This study is one of the first to propose that dissolution tests for pharmaceutical equivalence should be conducted on pulverized CTs when developing generic equivalents to CTs. Full article

(This article belongs to the Section Medicinal Chemistry)

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37 pages, 2629 KiB

Open AccessReview

The Genus Commiphora: An Overview of Its Traditional Uses, Phytochemistry, Pharmacology, and Quality Control

by Yujia Yang, Xiuting Sun, Chuhang Peng, Jianhe Wei and Xinquan Yang

Pharmaceuticals 2024, 17(11), 1524; https://doi.org/10.3390/ph17111524 - 12 Nov 2024

Abstract

Myrrh is the resinous substance secreted by plants of the genus Commiphora. In traditional Chinese medicine, Ayurvedic medicine, and traditional Arabic medicine, myrrh is regarded as an important medicinal material, widely used in the treatment of trauma, arthritis, hyperlipidemia, and other diseases. [...] Read more.

Myrrh is the resinous substance secreted by plants of the genus Commiphora. In traditional Chinese medicine, Ayurvedic medicine, and traditional Arabic medicine, myrrh is regarded as an important medicinal material, widely used in the treatment of trauma, arthritis, hyperlipidemia, and other diseases. This review explores the evolving scientific understanding of the genus Commiphora, covering facets of ethnopharmacology, phytochemistry, pharmacology, artificial cultivation, and quality control. In particular, the chemical constituents and pharmacological research are reviewed. More than 300 types of secondary metabolites have been identified through phytochemical studies of this genus. Guggulsterone is a bioactive steroid isolated mainly from Commiphora mukul. The two isomers, Z- and E-guggulsterone, have shown a wide range of in vitro and in vivo pharmacological effects, including anti-proliferation, antioxidant, anti-inflammatory, and antibacterial. However, the current scientific research on quality control of medicinal materials and identification of original plants is insufficient, which limits the reproducibility and accuracy of biological activity evaluation experiments. Therefore, the establishment of analytical protocols and standardization of extracts is an important step before biological evaluation. At the same time, in order to find more bioactive substances, it is necessary to strengthen the research on the stems, barks, and leaves of this genus. The sources used in this study include PubMed, CNKI, Web of Science, Google Scholar, and other databases, as well as multinational pharmacopoeias, ancient books of traditional medicine, herbal classics, and modern monographs. Full article

(This article belongs to the Section Natural Products)

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19 pages, 4182 KiB

Open AccessArticle

Rutin-Activated Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Attenuates Corneal and Heart Damage in Mice

by Promise M. Emeka, Lorina I. Badger-Emeka, Krishnaraj Thirugnanasambantham and Abdulaziz S. Alatawi

Pharmaceuticals 2024, 17(11), 1523; https://doi.org/10.3390/ph17111523 - 12 Nov 2024

Abstract

Background: Corneal degeneration is a form of progressive cell death caused by multiple factors, such as diabetic retinopathy. It is the most well-known neural degenerative disease caused by macular degeneration in the aged and those with retinitis pigmentosa. Myocardial infarction is becoming a [...] Read more.

Background: Corneal degeneration is a form of progressive cell death caused by multiple factors, such as diabetic retinopathy. It is the most well-known neural degenerative disease caused by macular degeneration in the aged and those with retinitis pigmentosa. Myocardial infarction is becoming a more common burden, causing cardiomyocyte degeneration, ischemia, and heart tissue death. This study examined the preventive effects of rutin on isoproterenol (ISO)-induced oxidative damage (that is, inflammation) on rabbit corneal epithelial cells and mouse heart injuries. Methods: These investigations involved a cytotoxicity test, biochemical analysis, qRT-PCR, Western blotting, and mouse cardiac histopathology. Results: The results showed that rutin enhanced ADH7 and ALDH1A1, retinoic acid signaling components in SIRC1 rabbit corneal cell lines. The production of NO by ocular epithelial cells was significantly reduced. It reduced cTnT and cTnI, CK-MB, and LDH contents in mouse cardiac tissue. The nuclear expressions of Nrf2, Sirt, and HO-1 were all increased by rutin. Docking studies revealed a good interaction between rutin and the Keap protein, enhancing Nrf2 nuclear activity. Conclusions: This showed that rutin can potentially enhance ADH7 and ALDH1A1 corneal signaling components, preventing corneal degeneration and mitigating ISO-induced myocardial infarction (MI) via Keap/Nrf2 expressions. Full article

(This article belongs to the Special Issue Bioactive Compounds From Plants and Their Therapeutic Applications in Lifestyle-Related Diseases)

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