Pharmaceuticals

13 pages, 1574 KiB

Open AccessArticle

Pharmacological Evaluation of the Traditional Brazilian Medicinal Plant Monteverdia ilicifolia in Gastroesophageal Reflux Disease: Preliminary Results of a Randomized Double-Blind Controlled Clinical Trial

by Maitê Scherer da Silva, Rebeca Vargas Antunes Schunck, Maicon Pereira Moraes, Giana Blume Corssac, Gabriela Meirelles, Sara Elis Bianchi, Leonardo Vieira Targa, Valquiria Bassani, Marcelo Rodrigues Gonçalves, Caroline Dani and Ionara Rodrigues Siqueira

Pharmaceuticals 2024, 17(11), 1559; https://doi.org/10.3390/ph17111559 - 20 Nov 2024

Viewed by 473

Abstract

Background/Objectives: The present work aimed to compare the effects of the standardized dry extract from the leaves of Monteverdia ilicifolia, popularly known as “espinheira-santa”, with omeprazole in the management of dyspepsia related to gastroesophageal reflux disease (GERD). Methods: A double-blind, randomized, non-inferiority [...] Read more.

Background/Objectives: The present work aimed to compare the effects of the standardized dry extract from the leaves of Monteverdia ilicifolia, popularly known as “espinheira-santa”, with omeprazole in the management of dyspepsia related to gastroesophageal reflux disease (GERD). Methods: A double-blind, randomized, non-inferiority and double-dummy clinical trial was conducted. In total, 86 patients with GERD symptoms were randomized into three groups: Omeprazol (20 mg), M. ilicifolia (400 mg), or M. ilicifolia (860 mg). Capsules were provided by SUSTENTEC^®, Pato Bragato, Brazil. It was requested that the participants take three capsules before breakfast and dinner for 4 weeks. Clinical outcomes were obtained at the beginning and end of the study, with GERD symptoms (QS-GERD), the impact of heartburn symptoms on quality of life (HBQOL), and medical records. Results: Overall, 75.6% of the participants showed adherence without any differences among the experimental groups. All groups had significant reductions in both QS-GERD and HBQOL scores. Omeprazole and 400 and 860 mg of M. ilicifolia decreased the QS-GERD total scores at the endpoint compared to the baseline (Chi-square = 129.808; p < 0.0001), as well as individual item scores, such as heartburn intensity (Chi-square = 93.568, p < 0.0001) and heartburn after meals (Chi-square = 126.426, p < 0.0001). There were no differences among the experimental groups after the intervention. Conclusions: Our results suggest that capsules with a standardized dry extract from the leaves of M. ilicifolia at a dosage of 400 or 860 mg are non-inferior to omeprazole, a proton pump inhibitor. Full article

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26 pages, 11276 KiB

Open AccessArticle

Network Pharmacology and Molecular Docking Reveal Anti-Asthmatic Potential of Zephyranthes rosea Lindl. in an Ovalbumin-Induced Asthma Model

by Amir Ali, Hafiz Majid Rasheed, Siddique Akber Ansari, Shoeb Anwar Ansari and Hamad M. Alkahtani

Pharmaceuticals 2024, 17(11), 1558; https://doi.org/10.3390/ph17111558 - 20 Nov 2024

Viewed by 303

Abstract

Background: This study aimed to evaluate the anti-inflammatory effects of a Zephyranthes rosea in an ovalbumin-induced asthma model. Methods: Allergic asthma was induced in mice via intraperitoneal injection, followed by intranasal ovalbumin challenge. Methanolic extract of Z. rosea bulb was orally administered to [...] Read more.

Background: This study aimed to evaluate the anti-inflammatory effects of a Zephyranthes rosea in an ovalbumin-induced asthma model. Methods: Allergic asthma was induced in mice via intraperitoneal injection, followed by intranasal ovalbumin challenge. Methanolic extract of Z. rosea bulb was orally administered to asthmatic mice for 14 days. Hematological parameters for bronchoalveolar lavage fluid (BALF) and blood were analyzed. The mRNA expression levels of interleukins and transforming growth factor beta (TGF-β1) in lung tissues were determined using reverse transcriptase–polymerase chain reaction (RT–PCR). Network pharmacology analysis was used to find possible Z. rosea targets. After building a protein–protein interaction network to find hub genes, GO and KEGG enrichment analyses were carried out to determine the potential mechanism. In silico analysis was performed by Molecular Operating Environment. Results: GC-MS analysis of Z. rosea extract detected major classes of phytochemicals. Hematological parameters in blood and BALF from Z. rosea extract-treated animals were significantly reduced in a dose-dependent fashion. Histopathology revealed that Z. rosea bulb had an ameliorative effect on lung tissues. Moreover, treatment with Z. rosea bulb extract significantly restored the normal levels of IL-4, IL-6, IL-1β, IL-10, IL-13, and TGF-β1 in allergic asthmatic mice compared to the diseased group. In silico analysis, particularly of the binding affinities of Z. rosea bulb phytoconstituents for IL6, AKT1, and Src, supported in vivo results. Conclusions: These findings indicated that Z. rosea bulb extract significantly ameliorates cellular and molecular biomarkers of bronchial inflammation and could be a potential candidate for treating allergic asthma. Full article

(This article belongs to the Section Natural Products)

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14 pages, 1263 KiB

Open AccessReview

Less Pain with Intra-Articular Hyaluronic Acid Injections for Knee Osteoarthritis Compared to Placebo: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

by Filippo Migliorini, Nicola Maffulli, Luise Schäfer, Joshua Kubach, Marcel Betsch and Mario Pasurka

Pharmaceuticals 2024, 17(11), 1557; https://doi.org/10.3390/ph17111557 - 20 Nov 2024

Viewed by 418

Abstract

The present meta-analysis investigated the efficacy of intra-articular hyaluronic acid (HA) injections for knee osteoarthritis. The outcomes of interest were the visual analogue scale (VAS) and Western Ontario McMaster Osteo-Arthritis Index (WOMAC) scores. This study was conducted according to the 2020 PRISMA statement. [...] Read more.

The present meta-analysis investigated the efficacy of intra-articular hyaluronic acid (HA) injections for knee osteoarthritis. The outcomes of interest were the visual analogue scale (VAS) and Western Ontario McMaster Osteo-Arthritis Index (WOMAC) scores. This study was conducted according to the 2020 PRISMA statement. All the randomised controlled trials (RCTs) comparing the efficacy of intra-articular HA injections versus placebo injections for knee osteoarthritis were accessed in September 2024. Data from 3851 patients were collected. In total, 64% (2467 of 3851 patients) were women, and the mean age of the patients was 63.5 ± 4.9 years. At baseline, good comparability was found for the mean age, BMI, percentage of women, and patient-reported outcome measures (PROMs). Studies which reported data from two to four weeks of follow-up evidenced a lower value of the subscales pain (p < 0.0001) and stiffness (p = 0.01) of the WOMAC score. No difference was observed in VAS at rest (p = 0.4), VAS at exercise (p = 0.1), and subscale function (p = 0.4) of the WOMAC score. Studies which reported data from five to eight weeks of follow-up evidenced lower VAS at rest in favour of the HA group (p = 0.01). No difference in the other PROMs of interest was observed: VAS at exercise (p = 0.1), and the subscales pain (p = 0.3), function (p = 0.4), and stiffness (p = 0.4) of the WOMAC score. The current level I of evidence suggests that intra-articular HA injections in the knee might reduce pain in the short term. Full article

(This article belongs to the Section Pharmacology)

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24 pages, 740 KiB

Open AccessReview

Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine–Glycine–Aspartate) Strategies

by Bojana Bogdanović, Daniel Fagret, Catherine Ghezzi and Christopher Montemagno

Pharmaceuticals 2024, 17(11), 1556; https://doi.org/10.3390/ph17111556 - 20 Nov 2024

Viewed by 343

Abstract

Integrins, an important superfamily of cell adhesion receptors, play an essential role in cancer progression, metastasis, and angiogenesis, establishing them as prime targets for both diagnostic and therapeutic applications. Despite their significant potential, integrin-targeted therapies have faced substantial challenges in clinical trials, including [...] Read more.

Integrins, an important superfamily of cell adhesion receptors, play an essential role in cancer progression, metastasis, and angiogenesis, establishing them as prime targets for both diagnostic and therapeutic applications. Despite their significant potential, integrin-targeted therapies have faced substantial challenges in clinical trials, including variable efficacy and unmet high expectations. Nevertheless, the consistent expression of integrins on tumor and stromal cells underscores their ongoing relevance and potential. Traditional RGD-based imaging and therapeutic agents have faced limitations, such as inconsistent target expression and rapid systemic clearance, which have reduced their effectiveness. To overcome these challenges, recent research has focused on advancing RGD-based strategies and exploring innovative solutions. This review offers a thorough analysis of the latest developments in the RGD–integrin field, with a particular focus on addressing previous limitations. It delves into new dual-targeting approaches and cutting-edge RGD-based agents designed to improve both tumor diagnosis and therapeutic outcomes. By examining these advancements, this review illuminates new pathways for enhancing the specificity and efficacy of integrin-targeted therapies, paving the way for more effective cancer diagnosis and treatment strategies. Full article

(This article belongs to the Special Issue Synthesis and Development of Novel Radiopharmaceuticals for Targeted Radiotherapy and Theranostics)

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30 pages, 4678 KiB

Open AccessReview

Antimicrobial Peptides: The Game-Changer in the Epic Battle Against Multidrug-Resistant Bacteria

by Helal F. Hetta, Nizar Sirag, Shumukh M. Alsharif, Ahmad A. Alharbi, Tala T. Alkindy, Alanoud Alkhamali, Abdullah S. Albalawi, Yasmin N. Ramadan, Zainab I. Rashed and Fawaz E. Alanazi

Pharmaceuticals 2024, 17(11), 1555; https://doi.org/10.3390/ph17111555 - 20 Nov 2024

Viewed by 737

Abstract

The rapid progress of antibiotic resistance among bacteria has prompted serious medical concerns regarding how to manage multidrug-resistant (MDR) bacterial infections. One emerging strategy to combat antibiotic resistance is the use of antimicrobial peptides (AMPs), which are amino acid chains that act as [...] Read more.

The rapid progress of antibiotic resistance among bacteria has prompted serious medical concerns regarding how to manage multidrug-resistant (MDR) bacterial infections. One emerging strategy to combat antibiotic resistance is the use of antimicrobial peptides (AMPs), which are amino acid chains that act as broad-spectrum antimicrobial molecules and are essential parts of the innate immune system in mammals, fungi, and plants. AMPs have unique antibacterial mechanisms that offer benefits over conventional antibiotics in combating drug-resistant bacterial infections. Currently, scientists have conducted multiple studies on AMPs for combating drug-resistant bacterial infections and found that AMPs are a promising alternative to conventional antibiotics. On the other hand, bacteria can develop several tactics to resist and bypass the effect of AMPs. Therefore, it is like a battle between the bacterial community and the AMPs, but who will win? This review provides thorough insights into the development of antibiotic resistance as well as detailed information about AMPs in terms of their history and classification. Furthermore, it addresses the unique antibacterial mechanisms of action of AMPs, how bacteria resist these mechanisms, and how to ensure AMPs win this battle. Finally, it provides updated information about FDA-approved AMPs and those that were still in clinical trials. This review provides vital information for researchers for the development and therapeutic application of novel AMPs for drug-resistant bacterial infections. Full article

(This article belongs to the Special Issue Naturally Occurring Peptides and Proteins and Related Drugs)

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19 pages, 3244 KiB

Open AccessArticle

Cilomilast Modulates Rhinovirus-Induced Airway Epithelial ICAM-1 Expression and IL-6, CXCL8 and CCL5 Production

by Jie Zhu, Michael R. Edwards, Simon D. Message, Luminita A. Stanciu, Sebastian L. Johnston and Peter K. Jeffery

Pharmaceuticals 2024, 17(11), 1554; https://doi.org/10.3390/ph17111554 - 20 Nov 2024

Viewed by 397

Abstract

Background: Cilomilast, a phosphodiesterase-4 (PDE4) selective inhibitor, has anti-inflammatory effects in vitro and in vivo and reduces COPD exacerbations. We tested the hypothesis that cilomilast inhibits virus-induced airway epithelial intercellular adhesion molecule-1 (ICAM-1) expression and inflammatory cytokine/chemoattractants, IL-6, CXCL8, and CCL5 production in [...] Read more.

Background: Cilomilast, a phosphodiesterase-4 (PDE4) selective inhibitor, has anti-inflammatory effects in vitro and in vivo and reduces COPD exacerbations. We tested the hypothesis that cilomilast inhibits virus-induced airway epithelial intercellular adhesion molecule-1 (ICAM-1) expression and inflammatory cytokine/chemoattractants, IL-6, CXCL8, and CCL5 production in vitro. Methods: BEAS-2B bronchial epithelial cells were incubated with 0.5–2 MOI (multiplicity of infection–infectious units/cell) of rhinovirus 16 (RV16). Then, 0.1–10 μM cilomilast or 10 nM dexamethasone, as inhibition control, were added pre- or post-1 h RV16 infection. Supernatant and cells were sampled at 8, 24, 48, and 72 h after infection. Cell surface ICAM-1 expression was detected by immunogold labelling and visualised by high-resolution scanning electron microscopy (HR-SEM), while IL-6, CXCL8, and CCL5 protein release and mRNA expression were measured using an ELISA and RT-PCR. Results: Cilomilast significantly decreased RV16-induced ICAM-1 expression to approximately 45% (p < 0.01). CXCL8 protein/mRNA production was reduced by about 41% (p < 0.05), whereas IL-6 protein/mRNA production was increased to between 41–81% (p < 0.001). There was a trend to reduction by cilomilast of RV16-induced CCL5. Conclusions: Cilomilast has differential effects on RV16-induced ICAM-1 and interleukins, inhibiting virus-induced ICAM-1 expression and CXCL8 while increasing IL-6 production. These in vitro effects may help to explain the beneficial actions of this PDE4 inhibitor in vivo. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 4389 KiB

Open AccessArticle

Evolving Clinical Features of Diabetic Ketoacidosis: The Impact of SGLT2 Inhibitors

by Selin Genc, Bahri Evren, Onur Selcuk Yigit, Ibrahim Sahin, Ramazan Dayanan, Aleksandra Klisic, Ayse Erturk and Filiz Mercantepe

Pharmaceuticals 2024, 17(11), 1553; https://doi.org/10.3390/ph17111553 - 20 Nov 2024

Viewed by 332

Abstract

Background/Objectives: The antidiabetic effect of SGLT2 inhibitors (SGLT2-is) is based on their ability to increase glucose excretion through urine by inhibiting the kidney-resident SGLT2 protein. Euglycemic diabetic ketoacidosis (EuDKA) is an uncommon but potentially life-threatening adverse effect of these medications, which are [...] Read more.

Background/Objectives: The antidiabetic effect of SGLT2 inhibitors (SGLT2-is) is based on their ability to increase glucose excretion through urine by inhibiting the kidney-resident SGLT2 protein. Euglycemic diabetic ketoacidosis (EuDKA) is an uncommon but potentially life-threatening adverse effect of these medications, which are notable for their antidiabetic, cardiovascular, and renal protective properties. This study aimed to clarify the impact of SGLT2-is on demographic, clinical, and biochemical characteristics in patients with DKA. Methods: A total of 51 individuals with a diagnosis of DKA were included in the trial; 19 of these patients were treated with SGLT2-is, while 32 were not. Patients diagnosed with DKA and treated with SGLT2-is were compared to those not treated with the medication in terms of clinical, biochemical, and laboratory characteristics. Results: The age of patients utilizing SGLT2-is was statistically considerably greater than that of non-users (p < 0.001). EuDKA was exclusively noted in the SGLT2-is cohort (p = 0.005). Urinary tract infections, vulvovaginitis, and genitourinary infections were substantially more prevalent among SGLT2-i users compared with non-users among both women and the overall patient group (p = 0.036, p = 0.001, p = 0.005, p = 0.003, respectively). Plasma glucose concentrations were significantly higher in SGLT2-i non-users (p = 0.006). Chloride (Cl⁻) concentrations were elevated among SGLT2-i users (p = 0.036). Conclusions: The study findings indicate that SGLT2 inhibitors may substantially influence age, serum chloride, EuDKA, and the occurrence of genitourinary infections in individuals with DKA. Full article

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

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21 pages, 5812 KiB

Open AccessArticle

GC–MS Characterization and Bioactivity Study of Eucalyptus globulus Labill. (Myrtaceae) Essential Oils and Their Fractions: Antibacterial and Antioxidant Properties and Molecular Docking Modeling

by Abdessamad Ait benlabchir, Kawtar Fikri-Benbrahim, Amina Moutawalli, Mohammed M. Alanazi, Asma Halmoune, Fatima Zahra Benkhouili, Asmaa Oubihi, Atul Kabra, Elbatoul Hanoune, Hamza Assila and Zineb Benziane Ouaritini

Pharmaceuticals 2024, 17(11), 1552; https://doi.org/10.3390/ph17111552 - 19 Nov 2024

Viewed by 499

Abstract

Background/Objectives: Eucalyptus globulus is a medicinal plant extensively used by the Moroccan population for treating a range of illnesses, especially respiratory conditions. Methods: This study aimed to assess the antioxidant and antibacterial properties of E. globulus essential oil and its individual fractions (F1, [...] Read more.

Background/Objectives: Eucalyptus globulus is a medicinal plant extensively used by the Moroccan population for treating a range of illnesses, especially respiratory conditions. Methods: This study aimed to assess the antioxidant and antibacterial properties of E. globulus essential oil and its individual fractions (F1, F2, and F3). Antioxidant activity was evaluated through iron-reducing power, 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays. Antibacterial activity was tested using disk diffusion and dilution methods, supported by molecular docking studies. Furthermore, GC–MS analysis was conducted on the essential oil and its individual fractions. Results: GC–MS analysis identified the major compounds in the essential oil and its fractions as eucalyptol (62.32–42.60%), globulol (5.9–26.24%), o-cymene (6.89–24.35%), cryptone (7.10–15.95%), terpinen-4-ol (2.43–15.24%), and α-pinene (2.46–7.89%). Fraction F3 displayed the highest antioxidant activity in DPPH (IC₅₀ = 3.329 ± 0.054 mg/mL) and ABTS assays (IC₅₀ = 3.721 ± 0.027 mg/mL), while fraction F2 was most effective in the FRAP assay (IC₅₀ = 1.054 ± 0.008 mg/mL). The essential oil and its fractions also showed antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, and Acinetobacter baumannii. Molecular docking further corroborated these findings, supporting both antioxidant and antibacterial activities. Conclusions: The present findings demonstrate the antioxidant and antimicrobial properties of Eucalyptus globulus essential oil and its fractions, underscoring the need for further research to confirm their medicinal potential and explore pharmaceutical applications. Full article

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

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20 pages, 3880 KiB

Open AccessArticle

Zingiber officinale Uncovered: Integrating Experimental and Computational Approaches to Antibacterial and Phytochemical Profiling

by Abdel Moneim Elhadi Sulieman, Safa Mustafa Ibrahim, Mamdouh Alshammari, Fahad Abdulaziz, Hajo Idriss, Naimah Asid H. Alanazi, Emad M. Abdallah, Arif Jamal Siddiqui, Sohair A. M. Shommo, Arshad Jamal and Riadh Badraoui

Pharmaceuticals 2024, 17(11), 1551; https://doi.org/10.3390/ph17111551 - 19 Nov 2024

Viewed by 488

Abstract

Background: Zingiber officinale rhizome is widely cultivated in the central region of Sudan (Gezira) and data on the biological properties of this variety grown in Sudan’s climate are scarce. This study aims to comprehensively analyze the antibacterial, antioxidant, phytochemical, and GC-MS properties of [...] Read more.

Background: Zingiber officinale rhizome is widely cultivated in the central region of Sudan (Gezira) and data on the biological properties of this variety grown in Sudan’s climate are scarce. This study aims to comprehensively analyze the antibacterial, antioxidant, phytochemical, and GC-MS properties of Zingiber officinale (ginger rhizome) to explore its potential applications. Methods and Results: The in vitro antibacterial assessment of the aqueous extract of Sudanese ginger revealed moderate activity against Staphylococcus aureus, Salmonella typhi, Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumonia, as determined by the disc diffusion method. The inhibition zones ranged from 12.87 ± 0.11 mm to 14.5 ± 0.12 mm at 30 µg/disc. The minimum inhibitory concentration ranged from 6.25 to 25 µg/mL, while the MBC ranged from 25 to 50 µg/mL. The MBC/MIC exhibited a bactericidal effect against all tested bacteria. Phytochemical screening revealed the presence of various chemical constituents, such as saponins, flavonoids, glycosides, alkaloids, steroids, terpenoids, and the absence of tannins in Sudanese ginger rhizome. Furthermore, GC-MS analysis of ginger rhizome identified 22 chemical compounds with retention times ranging from 7.564 to 17.023 min. The identification of 22 chemical compounds through GC-MS analysis further underscores the prospect of harnessing ginger rhizome for the development of novel medications. Computational analyses showed that ginger compounds bind the Protein Data Bank (PDB) codes 1JIJ and 2QZW with high binding affinities, reaching −9.5 kcal/mol. Ginger compounds also established promising molecular interactions with some key residues, satisfactorily explaining the in vitro results and supporting the pharmacokinetic and experimental findings. Conclusions: This study lays the groundwork for future research and pharmaceutical exploration aimed at harnessing the beneficial properties of ginger rhizome for medicinal and therapeutic purposes, particularly its antimicrobial potential. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals 2024)

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26 pages, 2932 KiB

Open AccessArticle

Artificial Intelligence and Machine Learning Models for Predicting Drug-Induced Kidney Injury in Small Molecules

by Mohan Rao, Vahid Nassiri, Sanjay Srivastava, Amy Yang, Satjit Brar, Eric McDuffie and Clifford Sachs

Pharmaceuticals 2024, 17(11), 1550; https://doi.org/10.3390/ph17111550 - 19 Nov 2024

Viewed by 573

Abstract

Background/Objectives: Drug-Induced Kidney Injury (DIKI) presents a significant challenge in drug development, often leading to clinical-stage failures. The early prediction of DIKI risk can improve drug safety and development efficiency. Existing models tend to focus on physicochemical properties alone, often overlooking drug–target interactions [...] Read more.

Background/Objectives: Drug-Induced Kidney Injury (DIKI) presents a significant challenge in drug development, often leading to clinical-stage failures. The early prediction of DIKI risk can improve drug safety and development efficiency. Existing models tend to focus on physicochemical properties alone, often overlooking drug–target interactions crucial for DIKI. This study introduces an AI/ML (artificial intelligence/machine learning) model that integrates both physicochemical properties and off-target interactions to enhance DIKI prediction. Methods: We compiled a dataset of 360 FDA-classified compounds (231 non-nephrotoxic and 129 nephrotoxic) and predicted 6064 off-target interactions, 59% of which were validated in vitro. We also calculated 55 physicochemical properties for these compounds. Machine learning (ML) models were developed using four algorithms: Ridge Logistic Regression (RLR), Support Vector Machine (SVM), Random Forest (RF), and Neural Network (NN). These models were then combined into an ensemble model for enhanced performance. Results: The ensemble model achieved an ROC-AUC of 0.86, with a sensitivity and specificity of 0.79 and 0.78, respectively. The key predictive features included 38 off-target interactions and physicochemical properties such as the number of metabolites, polar surface area (PSA), pKa, and fraction of Sp3-hybridized carbons (fsp3). These features effectively distinguished DIKI from non-DIKI compounds. Conclusions: The integrated model, which combines both physicochemical properties and off-target interaction data, significantly improved DIKI prediction accuracy compared to models that rely on either data type alone. This AI/ML model provides a promising early screening tool for identifying compounds with lower DIKI risk, facilitating safer drug development. Full article

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

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16 pages, 561 KiB

Open AccessReview

A Comprehensive Review and Update on Cannabis Hyperemesis Syndrome

by Priyadarshini Loganathan, Mahesh Gajendran and Hemant Goyal

Pharmaceuticals 2024, 17(11), 1549; https://doi.org/10.3390/ph17111549 - 18 Nov 2024

Viewed by 805

Abstract

Cannabis, derived from Cannabis sativa plants, is a prevalent illicit substance in the United States, containing over 400 chemicals, including 100 cannabinoids, each affecting the body’s organs differently upon ingestion. Cannabis hyperemesis syndrome (CHS) is a gut–brain axis disorder characterized by recurring nausea [...] Read more.

Cannabis, derived from Cannabis sativa plants, is a prevalent illicit substance in the United States, containing over 400 chemicals, including 100 cannabinoids, each affecting the body’s organs differently upon ingestion. Cannabis hyperemesis syndrome (CHS) is a gut–brain axis disorder characterized by recurring nausea and vomiting intensified by excessive cannabis consumption. CHS often goes undiagnosed due to inconsistent criteria, subjective symptoms, and similarity to cyclical vomiting syndrome (CVS). Understanding the endocannabinoid system (ECS) and its dual response (pro-emetic at higher doses and anti-emetic at lower doses) is crucial in the pathophysiology of CHS. Recent research noted that type 1 cannabinoid receptors in the intestinal nerve plexus exhibit an inhibitory effect on gastrointestinal motility. At the same time, the thermoregulatory function of endocannabinoids might explain compulsive hot bathing in CHS patients. The prevalence of cannabis CHS is expected to rise as legal restrictions on its recreational use decrease in several states. Education and awareness are vital in diagnosing and treating CHS as its prevalence increases. This comprehensive review explores the ECS’s involvement, CHS management approaches, and knowledge gaps to enhance understanding of this syndrome. Full article

(This article belongs to the Special Issue Medical Cannabis and Its Derivatives)

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24 pages, 1579 KiB

Open AccessReview

The Potential Therapeutic Use of Agarwood for Diabetes: A Scoping Review

by Mohammad Adi Mohammad Fadzil, Norhashimah Abu Seman and Aswir Abd Rashed

Pharmaceuticals 2024, 17(11), 1548; https://doi.org/10.3390/ph17111548 - 18 Nov 2024

Viewed by 531

Abstract

Introduction: In 2019, 9.3% (463 million) of adults worldwide had diabetes, according to the International Diabetes Federation (IDF). By 2030, the number will rise to 10.2% (578 million) and 10.9% (700 million) by 2045 if effective prevention methods are not implemented. Agarwood is [...] Read more.

Introduction: In 2019, 9.3% (463 million) of adults worldwide had diabetes, according to the International Diabetes Federation (IDF). By 2030, the number will rise to 10.2% (578 million) and 10.9% (700 million) by 2045 if effective prevention methods are not implemented. Agarwood is a pathological product and valuable plant due to its numerous medicinal properties, and it is used as an essential ingredient in medicine. Therefore, we conducted this review to determine agarwood’s potential health benefit effect on type 2 diabetes. Results and Discussion: Although no clinical trials were found, the evidence from in vitro and in vivo studies is promising. Agarwood has shown the ability to reduce the activity of α-glucosidase, α-amylase, and lipase, promote adiponectin secretion during adipogenesis, and reduce oxidative stress. Animal studies elucidated hypoglycaemic, antidyslipidemia, anti-obesity, and organ protective effects from agarwood. Materials and Methods: Original articles were searched in three databases (PubMed, Scopus, and Cochrane Library) using the medical subject heading (MeSH) term “diabetes” crossed with the term “agarwood” from 2008 to 2024. Synonyms and relevant search terms were also searched. Conclusions: This effect underscores the need for further research and the potential for groundbreaking discoveries in the field of diabetes treatment. Full article

(This article belongs to the Special Issue Natural Products in Diabetes Mellitus: 2nd Edition)

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9 pages, 3316 KiB

Open AccessArticle

Lung Toxicity Occurring During Enfortumab Vedotin Treatment: From a Priming Case Report to a Retrospective Analysis

by Grégoire Desimpel, François Zammit, Sarah Lejeune, Guillaume Grisay and Emmanuel Seront

Pharmaceuticals 2024, 17(11), 1547; https://doi.org/10.3390/ph17111547 - 18 Nov 2024

Viewed by 434

Abstract

Background/Objectives: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that combines monomethyl auristatin E (MMAE), a potent cytotoxic agent, with a monoclonal antibody targeting Nectin-4. It has emerged as a promising therapy for metastatic urothelial carcinoma (mUC), either as monotherapy or in combination [...] Read more.

Background/Objectives: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that combines monomethyl auristatin E (MMAE), a potent cytotoxic agent, with a monoclonal antibody targeting Nectin-4. It has emerged as a promising therapy for metastatic urothelial carcinoma (mUC), either as monotherapy or in combination with pembrolizumab, improving significantly the overall survival of these patients. EV is associated with common adverse events, including skin reactions, glucose imbalance, and peripheral neuropathy, which are usually mild in severity and easily manageable. Methods: Following an initial case of pleuro-pneumopathy occurring in a patient treated with EV, we conducted a retrospective analysis of EV effects on pulmonary imaging. Results: In a cohort of 20 all-comers mUC patients, we identified three cases of potentially EV-related lung toxicity, resulting in a pleuro-pneumopathy rate of 15%. Two of these cases appeared highly symptomatic and required high steroid doses, with a rapid resolution of symptoms and normalization of radiological findings. In one patient, rechallenge of EV was associated with reoccurrence of pneumopathy. We described the clinical and radiological features of these cases, as well as their evolution after EV discontinuation and rechallenge. Conclusions: This case series underscores the importance of close pulmonary monitoring during EV treatment. Full article

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

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24 pages, 7530 KiB

Open AccessArticle

Immobilization of Silver Nanoparticles with Defensive Gum of Moringa oleifera for Antibacterial Efficacy Against Resistant Bacterial Species from Human Infections

by Liaqat Ali, Nisar Ahmad, Muhammad Nazir Uddin, Mostafa A. Abdel-Maksoud, Hina Fazal, Sabiha Fatima, Mohamed A. El-Tayeb, Bushra Hafeez Kiani, Wajid Khan, Murad Ali Rahat, Mohammad Ali, Yaqub Khan, Kamran Rauf, Salman Khan, Sami Ullah, Tanveer Ahmad, Afshan Salam and Sajjad Ahmad

Pharmaceuticals 2024, 17(11), 1546; https://doi.org/10.3390/ph17111546 - 18 Nov 2024

Viewed by 479

Abstract

Background: The worldwide misuse of antibiotics is one of the main factors in microbial resistance that is a serious threat worldwide. Alternative strategies are needed to overcome this issue. Objectives: In this study, a novel strategy was adopted to suppress the [...] Read more.

Background: The worldwide misuse of antibiotics is one of the main factors in microbial resistance that is a serious threat worldwide. Alternative strategies are needed to overcome this issue. Objectives: In this study, a novel strategy was adopted to suppress the growth of resistant pathogens through immobilization of silver nanoparticles (AgNPs) in gum of Moringa oleifera. Methods: The AgNPs were prepared from the leaves of Moringa oleifera and subsequently characterized through UV-spectrophotometry, FTIR, SEM, and XRD. The differential ratios of characterized AgNPs were immobilized with gum of M. oleifera and investigated for antimicrobial potential against highly resistant pathogens. Results: The immobilized AgNPs displayed promising activities against highly resistant B. subtilis (23.6 mm; 50 µL:200 µL), E. coli (19.3 mm; 75 µL:200 µL), K. pneumoniae (22 mm; 200 µL:200 µL), P. mirabilis (16.3 mm; 100 µL:200 µL), P. aeruginosa (22 mm; 175 µL:200 µL), and S. typhi (19.3; 25 µL:200 µL) than either AgNPs alone or gum. The immobilized AgNPs released positive sliver ions that easily attached to negatively charged bacterial cells. After attachment and permeation to bacterial cells, the immobilized NPs alter the cell membrane permeability, protein/enzymes denaturation, oxidative stress (ROS), damage DNA, and change the gene expression level. It has been mechanistically considered that the immobilized AgNPs can kill bacteria by damaging their cell membranes, dephosphorylating tyrosine residues during their signal transduction pathways, inducing cell apoptosis, rupturing organelles, and inhibiting cell division, which finally leads to cell death. Conclusions: This study proposes a potential alternative drug for curing various infections. Full article

(This article belongs to the Special Issue Therapeutic Potential of Silver Nanoparticles (AgNPs))

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15 pages, 4245 KiB

Open AccessArticle

Structure of a Cyclic Peptide as an Inhibitor of Mycobacterium tuberculosis Transcription: NMR and Molecular Dynamics Simulations

by Filia Stephanie, Usman Sumo Friend Tambunan, Krzysztof Kuczera and Teruna J. Siahaan

Pharmaceuticals 2024, 17(11), 1545; https://doi.org/10.3390/ph17111545 - 18 Nov 2024

Viewed by 437

Abstract

Background and Objectives: A novel antitubercular cyclic peptide, Cyclo(1,6)-Ac-CLYHFC-NH₂, was designed to bind at the rifampicin (RIF) binding site on the RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). This peptide inhibits RNA elongation in the MTB transcription initiation assay in the [...] Read more.

Background and Objectives: A novel antitubercular cyclic peptide, Cyclo(1,6)-Ac-CLYHFC-NH₂, was designed to bind at the rifampicin (RIF) binding site on the RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). This peptide inhibits RNA elongation in the MTB transcription initiation assay in the nanomolar range, which can halt the MTB transcription initiation complex, similar to RIF. Therefore, determining the solution conformation of this peptide is useful in improving the peptide’s binding affinity to the RNAP. Methods: Here, the solution structure of Cyclo(1,6)-Ac-CLYHFC-NH₂ was determined by two-dimensional (2D) NMR experiments and NMR-restrained molecular dynamic (MD) simulations. Results: All protons of Cyclo(1,6)-Ac-CLYHFC-NH₂ were assigned using TOCSY and NOE NMR spectroscopy. The NOE cross-peak intensities were used to calculate interproton distances within the peptide. The J_NH-HCα coupling constants were used to determine the possible Phi angles within the peptide. The interproton distances and calculated Phi angles from NMR were used in NMR-restrained MD simulations. The NOE spectra showed NH-to-NH cross-peaks at Leu2-to-Tyr3 and Tyr3-to-His4, indicating a βI-turn formation at the Cys1-Leu2-Tyr3-His4 sequence. Conclusions: The NMR-restrained MD simulations showed several low-energy conformations that were congruent with the NMR data. Finally, the conformation of this peptide will be used to design derivatives that can better inhibit RNAP activity. Full article

(This article belongs to the Special Issue Novel Insights into Tuberculosis Research and Drug Discovery)

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14 pages, 2420 KiB

Open AccessArticle

Adaptation to Sodium Hypochlorite and Potassium Permanganate May Lead to Their Ineffectiveness Against Candida albicans

by Tomasz M. Karpiński, Marzena Korbecka-Paczkowska, Marcin Ożarowski, Donald Włodkowic, Marzena Liliana Wyganowska, Agnieszka Seremak-Mrozikiewicz and Judyta Cielecka-Piontek

Pharmaceuticals 2024, 17(11), 1544; https://doi.org/10.3390/ph17111544 - 17 Nov 2024

Viewed by 498

Abstract

Background/Objectives: Adaptation can reduce or completely eliminate the effectiveness of antibiotics and antiseptics at clinical concentrations. To our knowledge, no studies have examined fungal adaptation to antiseptics. This study aimed to preliminarily investigate the potential for Candida albicans adaptation to eight antiseptics. Methods: [...] Read more.

Background/Objectives: Adaptation can reduce or completely eliminate the effectiveness of antibiotics and antiseptics at clinical concentrations. To our knowledge, no studies have examined fungal adaptation to antiseptics. This study aimed to preliminarily investigate the potential for Candida albicans adaptation to eight antiseptics. Methods: The minimal inhibitory concentration (MIC), drug susceptibility, adaptation to antiseptics, and Karpinski Adaptation Index (KAI) of C. albicans strains were assessed. Results: The antiseptics with the most effective MICs activity against C. albicans were octenidine dihydrochloride (OCT), chlorhexidine digluconate (CHX), and polyhexamethylene biguanide (polyhexanide, PHMB). Sodium hypochlorite (NaOCl) and ethacridine lactate (ET) demonstrated moderate activity, while boric acid (BA), povidone–iodine (PVI), and potassium permanganate (KMnO₄) showed the weakest activity. The MIC values for NaOCl and KMnO₄ were close to or equal to the clinical concentrations used in commercial products. The studied strains were susceptible to econazole, miconazole, and voriconazole. Resistance to other drugs occurred in 10–30% of the strains. Antifungal resistance remained unchanged after antiseptic adaptation testing. The lowest KAI values, indicating very low resistance risk, were observed for CHX, OCT, and PHMB. PVI and BA presented a low risk, ET a moderate risk. KMnO₄ and NaOCl had the highest KAI values, indicating high and very high resistance risk in Candida yeasts. Conclusions: C. albicans strains can adapt to antiseptics to varying extents. For most antiseptics, adaptation does not significantly affect their clinical efficacy. However, due to adaptation, NaOCl and KMnO₄ may become ineffective against C. albicans strains even at clinical concentrations. Full article

(This article belongs to the Section Pharmacology)

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24 pages, 5913 KiB

Open AccessReview

The Entourage Effect in Cannabis Medicinal Products: A Comprehensive Review

by Rebeca André, Ana Patrícia Gomes, Catarina Pereira-Leite, António Marques-da-Costa, Luis Monteiro Rodrigues, Michael Sassano, Patricia Rijo and Maria do Céu Costa

Pharmaceuticals 2024, 17(11), 1543; https://doi.org/10.3390/ph17111543 - 17 Nov 2024

Viewed by 626

Abstract

This study explores the complementary or synergistic effects of medicinal cannabis constituents, particularly terpenes, concerning their therapeutic potential, known as the entourage effect. A systematic review of the literature on cannabis “entourage effects” was conducted using the PRISMA model. Two research questions directed [...] Read more.

This study explores the complementary or synergistic effects of medicinal cannabis constituents, particularly terpenes, concerning their therapeutic potential, known as the entourage effect. A systematic review of the literature on cannabis “entourage effects” was conducted using the PRISMA model. Two research questions directed the review: (1) What are the physiological effects of terpenes and terpenoids found in cannabis? (2) What are the proven “entourage effects” of terpenes in cannabis? The initial approach involved an exploratory search in electronic databases using predefined keywords and Boolean phrases across PubMed/MEDLINE, Web of Science, and EBSCO databases using Medical Subject Headings (MeSH). Analysis of published studies shows no evidence of neuroprotective or anti-aggregatory effects of α-pinene and β-pinene against β-amyloid-mediated toxicity; however, modest lipid peroxidation inhibition by α-pinene, β pinene, and terpinolene may contribute to the multifaceted neuroprotection properties of these C. sativa L. prevalent monoterpenes and the triterpene friedelin. Myrcene demonstrated anti-inflammatory proprieties topically; however, in combination with CBD, it did not show significant additional differences. Exploratory evidence suggests various therapeutic benefits of terpenes, such as myrcene for relaxation; linalool as a sleep aid and to relieve exhaustion and mental stress; D-limonene as an analgesic; caryophyllene for cold tolerance and analgesia; valencene for cartilage protection; borneol for antinociceptive and anticonvulsant potential; and eucalyptol for muscle pain. While exploratory research suggests terpenes as influencers in the therapeutic benefits of cannabinoids, the potential for synergistic or additive enhancement of cannabinoid efficacy by terpenes remains unproven. Further clinical trials are needed to confirm any terpenes “entourage effects.” Full article

(This article belongs to the Special Issue Innovative Applications and Therapeutic Potential of Cannabinoids)

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23 pages, 3691 KiB

Open AccessArticle

Predicting Structural Consequences of Antibody Light Chain N-Glycosylation in AL Amyloidosis

by Gareth J. Morgan, Zach Yung, Brian H. Spencer, Vaishali Sanchorawala and Tatiana Prokaeva

Pharmaceuticals 2024, 17(11), 1542; https://doi.org/10.3390/ph17111542 - 16 Nov 2024

Viewed by 540

Abstract

Background/Objectives: Antibody light chains form amyloid fibrils that lead to progressive tissue damage in amyloid light chain (AL) amyloidosis. The properties of each patient’s unique light chain appear to determine its propensity to form amyloid. One factor is N-glycosylation, which is more frequent [...] Read more.

Background/Objectives: Antibody light chains form amyloid fibrils that lead to progressive tissue damage in amyloid light chain (AL) amyloidosis. The properties of each patient’s unique light chain appear to determine its propensity to form amyloid. One factor is N-glycosylation, which is more frequent in amyloid-associated light chains than in light chains from the normal immune repertoire. However, the mechanisms underlying this association are unknown. Here, we investigate the frequency and position within the light chain sequence of the N-glycosylation sequence motif, or sequon. Methods: Monoclonal light chains from AL amyloidosis and multiple myeloma were identified from the AL-Base repository. Polyclonal light chains were obtained from the Observed Antibody Space resource. We compared the fraction of light chains from each group harboring an N-glycosylation sequon, and the positions of these sequons within the sequences. Results: Sequons are enriched among AL-associated light chains derived from a subset of precursor germline genes. Sequons are observed at multiple positions, which differ between the two types of light chains, κ and λ, but are similar between light chains from AL amyloidosis and multiple myeloma. Positions of sequons map to residues with surface-exposed sidechains that are compatible with the folded structures of light chains. Within the known structures of λ AL amyloid fibrils, many residues where sequons are observed are buried, inconsistent with N-glycosylation. Conclusions: There is no clear structural rationale for why N-glycosylation of κ light chains is associated with AL amyloidosis. A better understanding of the roles of N-glycosylation in AL amyloidosis is required before it can be used as a marker for disease risk. Full article

(This article belongs to the Special Issue Amyloid Composition and Structure-Based Development of Therapeutic and Diagnostic Agents)

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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 - 16 Nov 2024

Viewed by 380

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 - 16 Nov 2024

Viewed by 622

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 - 16 Nov 2024

Viewed by 465

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 - 16 Nov 2024

Viewed by 469

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 - 16 Nov 2024

Viewed by 599

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, 9834 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 Shahwan, Azna Zuberi and Nojood Altwaijry

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

Viewed by 389

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)

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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

Viewed by 439

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

Viewed by 352

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

Viewed by 234

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

Viewed by 417

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

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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

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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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Pharmaceuticals, Volume 17, Issue 11 (November 2024) – 150 articles

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