Pharmaceuticals

18 pages, 3747 KiB

Open AccessReview

Bibliometric Review on New Possibilities of Antimycobacterial Agents: Exploring Siderophore Desferrioxamine’s Applications as an Antimicrobial Agent

by Patrícia Vieira de Oliveira, Roseane Lustosa de Santana Lira, Rafael de Abreu Lima, Yasmim Costa Mendes, Antenor Bezerra Martins, Bruna de Oliveira de Melo, Millena Ferreira Goiano, Rivaldo Lira Filho, Flávia Baluz Bezerra de Farias Nunes, Amanda Silva dos Santos Aliança, Wellyson da Cunha Araújo Firmo, Rafael Cardoso Carvalho, Adrielle Zagmignan and Eduardo Martins de Sousa

Pharmaceuticals 2023, 16(9), 1335; https://doi.org/10.3390/ph16091335 - 21 Sep 2023

Cited by 2 | Viewed by 1601

Abstract

Mycobacteria cause tuberculosis and other serious diseases. Understanding their mechanisms of resistance to our immune system and exploring novel drugs are critical strategies to combat infections. A bibliometric analysis was performed to identify publication trends and critical research areas in the field of [...] Read more.

Mycobacteria cause tuberculosis and other serious diseases. Understanding their mechanisms of resistance to our immune system and exploring novel drugs are critical strategies to combat infections. A bibliometric analysis was performed to identify publication trends and critical research areas in the field of the antimicrobial activity of desferrioxamine. A total of twenty-four publications on the topic, from 2012 to 2023, were retrieved from databases including Web of Science, Scopus, PubMed, and Embase, using specific keywords. The quality of the publications was assessed using impact and productivity metrics, with an average annual publication rate of 2.1 articles. The United States emerged as the most productive country, with medicine (23.4%, 11 publications) and biochemistry, genetics, and molecular biology (21.3%, 10 publications) as the top research fields. The five most cited publications accounted for 672 citations, with a relatively low h-index (11:11). In conclusion, there has been a lack of publications on this topic in the last decade. The United States dominates production and publication in this area, and there appears to be limited exchange of knowledge, ideas, and technology within the field. Therefore, fostering international cooperation through funding is essential to facilitate further research and development of desferrioxamine-related studies. Full article

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

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11 pages, 624 KiB

Open AccessReview

Mesenchymal Stem Cell Therapies Approved by Regulatory Agencies around the World

by Luis E. Fernández-Garza, Silvia A. Barrera-Barrera and Hugo A. Barrera-Saldaña

Pharmaceuticals 2023, 16(9), 1334; https://doi.org/10.3390/ph16091334 - 21 Sep 2023

Cited by 9 | Viewed by 5862

Abstract

Cellular therapy has used mesenchymal stem cells (MSCs), which in cell culture are multipotent progenitors capable of producing a variety of cells limited to the mesoderm layer. There are two types of MSC sources: (1) adult MSCs, which are obtained from bone marrow, [...] Read more.

Cellular therapy has used mesenchymal stem cells (MSCs), which in cell culture are multipotent progenitors capable of producing a variety of cells limited to the mesoderm layer. There are two types of MSC sources: (1) adult MSCs, which are obtained from bone marrow, adipose tissue, peripheral blood, and dental pulp; and (2) neonatal-tissue-derived MSCs, obtained from extra-embryonic tissues such as the placenta, amnion, and umbilical cord. Until April 2023, 1120 registered clinical trials had been using MSC therapies worldwide, but there are only 12 MSC therapies that have been approved by regulatory agencies for commercialization. Nine of the twelve MSC-approved products are from Asia, with Republic of Korea being the country with the most approved therapies. In the future, MSCs will play an important role in the treatment of many diseases. However, there are many issues to deal with before their application and usage in the medical field. Some strategies have been proposed to face these problems with the hope of reaching the objective of applying these MSC therapies at optimal therapeutic levels. Full article

(This article belongs to the Special Issue New Advances in Mesenchymal Stromal Cells as Therapeutic Tools)

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21 pages, 6195 KiB

Open AccessArticle

Evaluation of Ayush-64 (a Polyherbal Formulation) and Its Ingredients in the Syrian Hamster Model for SARS-CoV-2 Infection Reveals the Preventative Potential of Alstonia scholaris

by Zaigham Abbas Rizvi, Upasna Madan, Manas Ranjan Tripathy, Sandeep Goswami, Shailendra Mani, Amit Awasthi and Madhu Dikshit

Pharmaceuticals 2023, 16(9), 1333; https://doi.org/10.3390/ph16091333 - 21 Sep 2023

Cited by 3 | Viewed by 2030

Abstract

In the current study, we evaluated the efficacy of Ayush-64 (A64), a polyherbal formulation containing Alstonia scholaris (L.) R. Br. (A. scholaris), Caesalpinia crista L. (C. crista), Picrorhiza kurroa Royle ex Benth (P. kurroa), and Swertia chirata [...] Read more.

In the current study, we evaluated the efficacy of Ayush-64 (A64), a polyherbal formulation containing Alstonia scholaris (L.) R. Br. (A. scholaris), Caesalpinia crista L. (C. crista), Picrorhiza kurroa Royle ex Benth (P. kurroa), and Swertia chirata (Roxb.) H. Karst. (S. chirata) against COVID-19 in a Syrian hamster infection model. Preventative use of A64 resulted in the late-phase recovery of body weight loss in severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected hamsters, suppression of pro-inflammatory cytokines, and blunted pulmonary pathology. In addition, we also investigated the efficacy of individual ingredients of A64, viz., A. scholaris, C. crista, P. kurroa, and S. chirata, in the hamster model. The hamster challenge data showed robust anti-viral and immunomodulatory potential in A. scholaris, followed by P. kurroa. However, C. crista and S. chirata of A64 showed prominent immunomodulatory potential without limiting the lung viral load. In order to better understand the immunomodulatory potential of these herbal extracts, we used an in vitro assay of helper T cell differentiation and found that A. scholaris mediated a more profound suppression of Th1, Th2, and Th17 cell differentiation as compared to A64 and other ingredients. Taken together, our animal study data identifies the ameliorative potential of A64 in mitigating coronavirus disease-19 (COVID-19) pulmonary pathology. A. scholaris, a constituent extract of A64, showed relatively higher anti-viral and immunomodulatory potential against COVID-19. The present study warrants further investigations to identify the active pharmaceutical ingredients of A. scholaris for further studies. Full article

(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants 2023)

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17 pages, 6268 KiB

Open AccessArticle

Repurposing Terfenadine as a Novel Antigiardial Compound

by Daniel Osmar Suárez-Rico, Francisco Javier Munguía-Huizar, Rafael Cortés-Zárate, José Manuel Hernández-Hernández, Sirenia González-Pozos, Armando Perez-Rangel and Araceli Castillo-Romero

Pharmaceuticals 2023, 16(9), 1332; https://doi.org/10.3390/ph16091332 - 21 Sep 2023

Viewed by 1527

Abstract

Giardia lamblia is a highly infectious protozoan that causes giardiasis, a gastrointestinal disease with short-term and long-lasting symptoms. The currently available drugs for giardiasis treatment have limitations such as side effects and drug resistance, requiring the search for new antigiardial compounds. Drug repurposing [...] Read more.

Giardia lamblia is a highly infectious protozoan that causes giardiasis, a gastrointestinal disease with short-term and long-lasting symptoms. The currently available drugs for giardiasis treatment have limitations such as side effects and drug resistance, requiring the search for new antigiardial compounds. Drug repurposing has emerged as a promising strategy to expedite the drug development process. In this study, we evaluated the cytotoxic effect of terfenadine on Giardia lamblia trophozoites. Our results showed that terfenadine inhibited the growth and cell viability of Giardia trophozoites in a time–dose-dependent manner. In addition, using scanning electron microscopy, we identified morphological damage; interestingly, an increased number of protrusions on membranes and tubulin dysregulation with concomitant dysregulation of Giardia GiK were observed. Importantly, terfenadine showed low toxicity for Caco-2 cells, a human intestinal cell line. These findings highlight the potential of terfenadine as a repurposed drug for the treatment of giardiasis and warrant further investigation to elucidate its precise mechanism of action and evaluate its efficacy in future research. Full article

(This article belongs to the Special Issue Drug Discovery of Antiprotozoal Agents)

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28 pages, 7360 KiB

Open AccessArticle

Curcuminoid Chalcones: Synthesis, Stability, and New Neuroprotective and Sonosensitising Activities

by Dorota Olender, Małgorzata Józkowiak, Hanna Piotrowska-Kempisty, Katarzyna Sowa-Kasprzak, Lucjusz Zaprutko, Izabela Muszalska-Kolos, Ewa Baranowska-Wójcik and Dominik Szwajgier

Pharmaceuticals 2023, 16(9), 1331; https://doi.org/10.3390/ph16091331 - 21 Sep 2023

Cited by 5 | Viewed by 1494

Abstract

The primary purpose of this work was to design and obtain a series of curcuminoid chalcone–NSAID hybrid derivatives. The ester-type hybrid compounds with ibuprofen (i), ketoprofen (ii), and naproxen (iii) were obtained in two ways, using the [...] Read more.

The primary purpose of this work was to design and obtain a series of curcuminoid chalcone–NSAID hybrid derivatives. The ester-type hybrid compounds with ibuprofen (i), ketoprofen (ii), and naproxen (iii) were obtained in two ways, using the Claisen–Schmidt reaction and the Steglich esterification reaction. The designed molecules were successfully synthesised, and FT-IR, MS, and NMR spectroscopy confirmed their structures. Moreover, the cytotoxic effect of the sonodynamic therapy and the anti-inflammatory, antioxidant, and anticholinergic properties of some curcuminoid chalcones and curcuminoid chalcones hybrids were evaluated. The curcuminoid chalcone derivatives showed promising neuroprotective activity as sonosensitisers for sonodynamic therapy in the studied cell lines. Additionally, the stability of the ester-type hybrid compounds with promising activity was determined. The RP-HPLC method was used to observe the degradation of the tested compounds. Studies have shown that structural isomers of ester-type hybrid compounds (3ai, 3bi) are characterised by a similar susceptibility to degradation factors, i.e., they are extremely unstable in alkaline environments, very unstable in acidic environments, unstable in neutral environments, practically stable in oxidising environments, and photolabile in solutions and in the solid phase. These compounds maintain adequate stability in environment at pH 1.2 and 6.8, which may make them good candidates for developing formulations for oral administration. Full article

(This article belongs to the Special Issue Recent Developments of Chalcones and Their Derivatives in Medicinal Chemistry)

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18 pages, 5742 KiB

Open AccessArticle

Cellular Efficacy of Fattigated Nanoparticles and Real-Time ROS Occurrence Using Microfluidic Hepatocarcinoma Chip System: Effect of Anticancer Drug Solubility and Shear Stress

by Hoyoung Kim, Eun-Ji Kim, Hai V. Ngo, Hy D. Nguyen, Chulhun Park, Kyung Hyun Choi, Jun-Bom Park and Beom-Jin Lee

Pharmaceuticals 2023, 16(9), 1330; https://doi.org/10.3390/ph16091330 - 20 Sep 2023

Cited by 2 | Viewed by 1511

Abstract

The objective of this study was to evaluate the effectiveness of organ-on-chip system investigating simultaneous cellular efficacy and real-time reactive oxygen species (ROS) occurrence of anticancer drug-loaded nanoparticles (NPs) using hepatocarcinoma cells (HepG2) chip system under static and hepatomimicking shear stress conditions (5 [...] Read more.

The objective of this study was to evaluate the effectiveness of organ-on-chip system investigating simultaneous cellular efficacy and real-time reactive oxygen species (ROS) occurrence of anticancer drug-loaded nanoparticles (NPs) using hepatocarcinoma cells (HepG2) chip system under static and hepatomimicking shear stress conditions (5 dyne/cm²). Then, the role of hepatomimetic shear stress exposed to HepG2 and drug solubility were compared. The highly soluble doxorubicin (DOX) and poorly soluble paclitaxel (PTX) were chosen. Fattigated NPs (AONs) were formed via self-assembly of amphiphilic albumin (HSA)-oleic acid conjugate (AOC). Then, drug-loaded AONs (DOX-AON or PTX-AON) were exposed to a serum-free HepG2 medium at 37 °C and 5% carbon dioxide for 24 h using a real-time ROS sensor chip-based microfluidic system. The cellular efficacy and simultaneous ROS occurrence of free drugs and drug-loaded AONs were compared. The cellular efficacy of drug-loaded AONs varied in a dose-dependent manner and were consistently correlated with real-time of ROS occurrence. Drug-loaded AONs increased the intracellular fluorescence intensity and decreased the cellular efficacy compared to free drugs under dynamic conditions. The half-maximal inhibitory concentration (IC₅₀) values of free DOX (13.4 μg/mL) and PTX (54.44 μg/mL) under static conditions decreased to 11.79 and 38.43 μg/mL, respectively, under dynamic conditions. Furthermore, DOX- and PTX-AONs showed highly decreased IC₅₀ values of 5.613 and 21.86 μg/mL, respectively, as compared to free drugs under dynamic conditions. It was evident that cellular efficacy and real-time ROS occurrence were well-correlated and highly dependent on the drug-loaded nanostructure, drug solubility and physiological shear stress. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs)

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15 pages, 7276 KiB

Open AccessArticle

Putting a “C₆₀ Ball” and Chain to Chlorin e6 Improves Its Cellular Uptake and Photodynamic Performances

by Manuele Di Sante, Alena Kaltenbrunner, Marco Lombardo, Alberto Danielli, Paolo Emidio Costantini, Matteo Di Giosia and Matteo Calvaresi

Pharmaceuticals 2023, 16(9), 1329; https://doi.org/10.3390/ph16091329 - 20 Sep 2023

Cited by 2 | Viewed by 1473

Abstract

Chlorin e6 (Ce6) and fullerene (C₆₀) are among the most used photosensitizers (PSs) for photodynamic therapy (PDT). Through the combination of the chemical and photophysical properties of Ce6 and C₆₀, in principle, we can obtain an “ideal” photosensitizer that [...] Read more.

Chlorin e6 (Ce6) and fullerene (C₆₀) are among the most used photosensitizers (PSs) for photodynamic therapy (PDT). Through the combination of the chemical and photophysical properties of Ce6 and C₆₀, in principle, we can obtain an “ideal” photosensitizer that is able to bypass the limitations of the two molecules alone, i.e., the low cellular uptake of Ce6 and the scarce solubility and absorption in the red region of the C₆₀. Here, we synthesized and characterized a Ce6–C₆₀ dyad. The UV-Vis spectrum of the dyad showed the typical absorption bands of both fullerene and Ce6, while a quenching of Ce6 fluorescence was observed. This behavior is typical in the formation of a fullerene–antenna system and is due to the intramolecular energy, or electron transfer from the antenna (Ce6) to the fullerene. Consequently, the Ce6–C₆₀ dyad showed an enhancement in the generation of reactive oxygen species (ROS). Flow cytometry measurements demonstrated how the uptake of the Ce6 was strongly improved by the conjugation with C₆₀. The Ce6–C₆₀ dyad exhibited in A431 cancer cells low dark toxicity and a higher PDT efficacy than Ce6 alone, due to the enhancement of the uptake and the improvement of ROS generation. Full article

(This article belongs to the Special Issue Fluorescence Approaches in Drug Delivery)

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15 pages, 2533 KiB

Open AccessSystematic Review

Effects of Preoperative Chronic Steroid Use on Postoperative Outcomes in Orthopedic Surgery: A Systematic Review and Meta-Analysis

by Yu-Ting Hung, Wei-Kai Hung and Ching-Chi Chi

Pharmaceuticals 2023, 16(9), 1328; https://doi.org/10.3390/ph16091328 - 20 Sep 2023

Cited by 3 | Viewed by 3423

Abstract

Higher rates of postoperative complications have been found in preoperative chronic steroid users. However, the effects of preoperative chronic steroid use on outcomes in orthopedic surgery were unclear. We performed a systematic review of cohort studies examining the effects of chronic steroid use [...] Read more.

Higher rates of postoperative complications have been found in preoperative chronic steroid users. However, the effects of preoperative chronic steroid use on outcomes in orthopedic surgery were unclear. We performed a systematic review of cohort studies examining the effects of chronic steroid use on postoperative outcomes following orthopedic surgery and searched PubMed, Embase, and CENTRAL through 29 April 2023. We included 17 studies with 1,546,562 patients. No increase in 30-day mortality (adjusted odds ratio (aOR) 1.40, 95% confidence interval (CI) 0.64–3.09) and composite thromboembolic events (aOR 1.61, 95% CI 0.99–2.63) but increases in 30-day overall complications (aOR 1.42, 95% CI 1.16–1.75), wound dehiscence (aOR 2.91, 95% CI 1.49–5.66), infectious complications (any infection (aOR 1.61, 95% CI 1.44–1.80), sepsis (aOR 2.07, 95% CI 1.34–3.21), superficial surgical site infection (SSI) (aOR 1.73, 95% CI 1.03–2.89) and deep SSI (aOR 1.96, 95% CI 1.26–3.05)), re-admission (aOR 1.62, 95% CI 1.48–1.77), both 30-day (aOR 1.28, 95% CI 1.03–1.59) and 1-year re-operation (aOR 1.78, 95% CI 1.09–2.92), pulmonary embolism (aOR 5.94, 95% CI 1.52–23.29), and deep vein thrombosis (aOR 2.07, 95% CI 1.24–3.46) were detected in preoperative steroid users. An increased risk of adverse outcomes following orthopedic surgery in chronic steroid users was found. Full article

(This article belongs to the Special Issue Drug Safety and Relevant Issues in the Real-World)

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13 pages, 1997 KiB

Open AccessArticle

Expanding the Analytical Toolbox: Developing New Lys-C Peptide Mapping Methods with Minimized Assay-Induced Artifacts to Fully Characterize Antibodies

by Y. Diana Liu, Michelle Irwin Beardsley and Feng Yang

Pharmaceuticals 2023, 16(9), 1327; https://doi.org/10.3390/ph16091327 - 20 Sep 2023

Cited by 2 | Viewed by 2134

Abstract

Peptide mapping is an important tool used to confirm that the correct sequence has been expressed for a protein and to evaluate protein post-translational modifications (PTMs) that may arise during the production, processing, or storage of protein drugs. Our new orally administered drug [...] Read more.

Peptide mapping is an important tool used to confirm that the correct sequence has been expressed for a protein and to evaluate protein post-translational modifications (PTMs) that may arise during the production, processing, or storage of protein drugs. Our new orally administered drug (Ab-1), a single-domain antibody, is highly stable and resistant to proteolysis. Analysis via the commonly used tryptic mapping method did not generate sufficient sequence coverage. Alternative methods were needed to study the Ab-1 drug substance (75 mg/mL) and drug product (3 mg/mL). To meet these analytical needs, we developed two new peptide mapping methods using lysyl endopeptidase (Lys-C) digestion. These newly developed protein digestion protocols do not require desalting/buffer-exchange steps, thereby reducing sample preparation time and improving method robustness. Additionally, the protein digestion is performed under neutral pH with methionine acting as a scavenger to minimize artifacts, such as deamidation and oxidation, which are induced during sample preparation. Further, the method for low-concentration samples performs comparably to the method for high-concentration samples. Both methods provide 100% sequence coverage for Ab-1, and, therefore, enable comprehensive characterization for its product quality attribute (PQA) assessment. Both methods can be used to study other antibody formats. Full article

(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences 2023)

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15 pages, 1248 KiB

Open AccessArticle

Evaluation of Anti-Inflammatory and Anti-Tubercular Activity of 4-Methyl-7-Substituted Coumarin Hybrids and Their Structure Activity Relationships

by Muthipeedika Nibin Joy, Mallikarjuna R. Guda and Grigory V. Zyryanov

Pharmaceuticals 2023, 16(9), 1326; https://doi.org/10.3390/ph16091326 - 19 Sep 2023

Cited by 6 | Viewed by 1588

Abstract

Four sets of previously synthesized 4-methyl-7-substituted coumarin derivatives were screened for their in vitro anti-inflammatory and anti-tubercular activities. The anti-inflammatory potential of 3a–t, 5a–o, 6a–n, and 7a–f synthesized compounds was evaluated by [...] Read more.

Four sets of previously synthesized 4-methyl-7-substituted coumarin derivatives were screened for their in vitro anti-inflammatory and anti-tubercular activities. The anti-inflammatory potential of 3a–t, 5a–o, 6a–n, and 7a–f synthesized compounds was evaluated by an anti-denaturation assay using diclofenac sodium as the reference standard. Evaluation of the anti-tuberculous activity of the mentioned compounds was performed by the Resazurin test method against four different TB strains using rifampicin and isoniazid as reference drugs. Based on the anti-inflammatory results, compounds 3o, 5f, 6c, and 7d proved to be the most active compounds in their respective series. Additionally, compounds 3k–n, 5b–d, 6d–f, 6k, 7a, and 7f were found to be the most potent anti-tuberculous agents. In fact, most of the screened compounds exhibited promising activity profiles compared to the respective standard drugs. The structure–activity connections revealed a few intriguing aspects, indicating that the presence of electron-donating and nitrogen-rich fragments boost the anti-inflammatory effects of the examined compounds. However, the presence of electron-withdrawing substituents was required to boost the anti-tubercular activity of the evaluated compounds. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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15 pages, 25042 KiB

Open AccessArticle

Piper nigrum Extract Inhibits the Growth of Human Colorectal Cancer HT-29 Cells by Inducing p53-Mediated Apoptosis

by Rui Wu, Jiajia Zhao, Panhong Wei, Minghai Tang, Ziyan Ma, Yunyan Zhao, Leilei Du and Li Wan

Pharmaceuticals 2023, 16(9), 1325; https://doi.org/10.3390/ph16091325 - 19 Sep 2023

Cited by 4 | Viewed by 2004

Abstract

Colorectal cancer (CRC) is a prevalent malignancy of the digestive tract with the second highest mortality rate globally. Piper nigrum is a widely used traditional medicinal plant, exhibiting antitumor activity against various tumor cells. At present, research on the effect of Piper nigrum [...] Read more.

Colorectal cancer (CRC) is a prevalent malignancy of the digestive tract with the second highest mortality rate globally. Piper nigrum is a widely used traditional medicinal plant, exhibiting antitumor activity against various tumor cells. At present, research on the effect of Piper nigrum on CRC is limited to in vitro cytotoxicity, lacking comprehensive mechanism investigations. This study aimed to explore the inhibitory effect and mechanism of Piper nigrum extract (PNE) on HT-29 cells. Firstly, we identified the chemical components of PNE. Then, MTT assay, colony formation assay, JC-1 staining, and flow cytometry were used to analyze the effect of PNE on HT-29 cells in vitro. A xenograft model, histopathological examination, immunohistochemistry, and western blot were used to evaluate the tumor growth inhibitory activity and mechanism of PNE in vivo. The results indicated that PNE could inhibit cell proliferation and colony formation, reduce mitochondrial membrane potential, induce cell apoptosis in vitro, and inhibit tumor growth in vivo. Furthermore, PNE could regulate p53 and its downstream proteins, and subsequently activate the caspase-3 pathway. In summary, PNE probably induced apoptosis of HT-29 cells through the mitochondrial pathway mediated by p53. All these results suggested that PNE might be a potential natural-origin anti-CRC drug candidate. Full article

(This article belongs to the Section Natural Products)

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22 pages, 6388 KiB

Open AccessArticle

Discovery of New Pyrrolo[2,3-d]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers

by AbdulAziz A. Alotaibi, Mohammed M. Alanazi and A. F. M. Motiur Rahman

Pharmaceuticals 2023, 16(9), 1324; https://doi.org/10.3390/ph16091324 - 19 Sep 2023

Cited by 5 | Viewed by 1732

Abstract

In the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(E)-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N’-benzylidenebenzohydrazides’, were successfully synthesized in three steps with high yields. Among these novel compounds, namely [...] Read more.

In the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(E)-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N’-benzylidenebenzohydrazides’, were successfully synthesized in three steps with high yields. Among these novel compounds, namely 5e, 5h, 5k, and 5l, promising cytotoxic effects were observed against four different cancer cell lines, with IC₅₀ values ranging from 29 to 59 µM. Notably, compound 5k emerged as the most potent inhibitor, exhibiting significant activity against EGFR, Her2, VEGFR2, and CDK2 enzymes, with IC₅₀ values ranging from 40 to 204 nM, comparable to the well-known TKI sunitinib (IC₅₀ = 261 nM). Mechanistic investigations of compound 5k revealed its ability to induce cell cycle arrest and apoptosis in HepG2 cells, accompanied by a notable increase in proapoptotic proteins caspase-3 and Bax, as well as the downregulation of Bcl-2 activity. Furthermore, molecular docking studies indicated similar binding interactions between compound 5k and the four enzymes, as observed with sunitinib. These findings highlight the potential of compound 5k as a promising candidate for further development as a multi-targeted kinase inhibitor with enhanced potency. Full article

(This article belongs to the Section Medicinal Chemistry)

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13 pages, 2752 KiB

Open AccessArticle

Captopril Polyvinyl Alcohol/Sodium Alginate/Gelatin-Based Oral Dispersible Films (ODFs) with Modified Release and Advanced Oral Bioavailability for the Treatment of Pediatric Hypertension

by Hamdy Abdelkader, Jelan A. Abdel-Aleem, Heba Salah Mousa, Marwa O. Elgendy, Adel Al Fatease and Heba A. Abou-Taleb

Pharmaceuticals 2023, 16(9), 1323; https://doi.org/10.3390/ph16091323 - 19 Sep 2023

Cited by 2 | Viewed by 1689

Abstract

Hypertension can begin in childhood; elevated blood pressure in children is known as pediatric hypertension. Contrary to adult hypertension, there is a scarcity of commercial medications suitable for the treatment of pediatric hypertension. The aim of this study was to develop orally dispersible [...] Read more.

Hypertension can begin in childhood; elevated blood pressure in children is known as pediatric hypertension. Contrary to adult hypertension, there is a scarcity of commercial medications suitable for the treatment of pediatric hypertension. The aim of this study was to develop orally dispersible films (ODFs) loaded with captopril for the treatment of hypertension in children. Captopril-loaded ODFs were composed of different blends of synthetic polymers, such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone, and natural polymers, such as sodium alginate (SA) and gelatin. The ODFs were characterized based on their mechanical and thermal properties, drug content, surface morphology, in vitro disintegration, in vitro release, and bioavailability. A novel HPLC method with precolumn derivatization was developed to precisely and selectively determine captopril levels in plasma. A low concentration of PVA and a high concentration of SA generated ODFs with faster hydration and disintegration rates. SA-based films exhibited fast disintegration properties (1–2 min). The optimized modified-release film (F2) showed significant (p < 0.05) enhancement in bioavailability (AUC = 1000 ng min/mL), with a value 1.43 times that of Capoten^® tablets (701 ng min/mL). While the plasma concentration peaking was in favor of the immediate-release tablet, T_max was significantly prolonged by 5.4 times for the optimized ODF (3.59 h) compared with that of the tablets (0.66 h). These findings indicate uniform and sustained plasma concentrations, as opposed to the pulsatile and rapid plasma peaking of captopril from the immediate-release tablets. These findings suggest that the modified release of oral films could offer more favorable plasma profiles and better control of hypertension than the conventional release tablets. Full article

(This article belongs to the Section Pharmaceutical Technology)

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13 pages, 1378 KiB

Open AccessArticle

Follicle-Targeted Delivery of Betamethasone and Minoxidil Co-Entrapped in Polymeric and Lipid Nanoparticles for Topical Alopecia Areata Treatment

by Breno N. Matos, Ana Luiza Lima, Camila O. Cardoso, Marcilio Cunha-Filho, Tais Gratieri and Guilherme M. Gelfuso

Pharmaceuticals 2023, 16(9), 1322; https://doi.org/10.3390/ph16091322 - 19 Sep 2023

Cited by 3 | Viewed by 2593

Abstract

Alopecia areata is managed with oral corticosteroids, which has known side effects for patients. Given that a topical application of formulations containing a corticoid and a substance controlling hair loss progression could reduce or eliminate such adverse effects and increase the patient’s adherence [...] Read more.

Alopecia areata is managed with oral corticosteroids, which has known side effects for patients. Given that a topical application of formulations containing a corticoid and a substance controlling hair loss progression could reduce or eliminate such adverse effects and increase the patient’s adherence to the treatment, this study prepares polymeric and lipidic nanoparticles (PNPs and NLCs) to co-entrap minoxidil and betamethasone and compares the follicular drug delivery provided by topical application of these nanoparticles. The prepared PNPs loaded 99.1 ± 13.0% minoxidil and 70.2 ± 12.8% betamethasone, while the NLCs entrapped 99.4 ± 0.1 minoxidil and 80.7 ± 0.1% betamethasone. PNPs and NLCs presented diameters in the same range, varying from 414 ± 10 nm to 567 ± 30 nm. The thermal analysis revealed that the production conditions favor the solubilization of the drugs in the nanoparticles, preserving their stability. In in vitro permeation studies with porcine skin, PNPs provided a 2.6-fold increase in minoxidil penetration into the follicular casts compared to the control and no remarkable difference in terms of betamethasone; in contrast, NLCs provided a significant (specifically, a tenfold) increase in minoxidil penetration into the hair follicles compared to the control, and they delivered higher concentrations of betamethasone in hair follicles than both PNPs and the control. Neither PNPs nor NLCs promoted transdermal permeation of the drugs to the receptor solution, which should favor a topical therapy. Furthermore, both nanoparticles targeted approximately 50% of minoxidil delivery to the follicular casts and NLCs targeted 74% of betamethasone delivery to the hair follicles. In conclusion, PNPs and NLCs are promising drug delivery systems for enhancing follicular targeting of drugs, but NLCs showed superior performance for lipophilic drugs. Full article

(This article belongs to the Special Issue Recent Advances in Skin Drug Delivery)

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17 pages, 2438 KiB

Open AccessArticle

Development of a Bilayer Tablet by Fused Deposition Modeling as a Sustained-Release Drug Delivery System

by Andrea Gabriela Crișan, Alina Porfire, Sonia Iurian, Lucia Maria Rus, Raluca Lucăcel Ciceo, Alexandru Turza and Ioan Tomuță

Pharmaceuticals 2023, 16(9), 1321; https://doi.org/10.3390/ph16091321 - 19 Sep 2023

Cited by 7 | Viewed by 2296

Abstract

Three-dimensional printing by fused deposition modeling (FDM) coupled with hot-melt extrusion (HME) is a point of convergence of research efforts directed toward the development of personalized dosage forms. In addition to the customization in terms of shapes, sizes, or delivered drug doses, the [...] Read more.

Three-dimensional printing by fused deposition modeling (FDM) coupled with hot-melt extrusion (HME) is a point of convergence of research efforts directed toward the development of personalized dosage forms. In addition to the customization in terms of shapes, sizes, or delivered drug doses, the modulation of drug release profiles is crucial to ensure the superior efficacy and safety of modern 3D-printed medications compared to those of conventional ones. Our work aims to solidify the groundwork for the preparation of 3D-printed tablets that ensure the sustained release of diclofenac sodium. Specifically, we achieved the fast release of a diclofenac sodium dose to allow for the prompt onset of its pharmacological effect, further sustaining by the slow release of another dose to maintain the effect over a prolonged timeframe. In this regard, proper formulation and design strategies (a honeycomb structure for the immediate-release layer and a completely filled structure for the sustained-release layer) were applied. Secondarily, the potential of polyvinyl alcohol to function as a multifaceted polymeric matrix for both the immediate and slow-release layers was explored, with the objective of promoting the real-life applicability of the technique by downsizing the number of materials required to obtain versatile pharmaceutical products. The present study is a step forward in the translation of HME-FDM-3DP into a pharmaceutical manufacturing methodology. Full article

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17 pages, 3273 KiB

Open AccessSystematic Review

Effect of Growth Hormone and Estrogen Replacement Therapy on Bone Mineral Density in Women with Turner Syndrome: A Meta-Analysis and Systematic Review

by Weronika Szybiak, Barbara Kujawa, Miłosz Miedziaszczyk and Katarzyna Lacka

Pharmaceuticals 2023, 16(9), 1320; https://doi.org/10.3390/ph16091320 - 19 Sep 2023

Cited by 4 | Viewed by 1840

Abstract

Osteoporosis is a serious implication of Turner syndrome (TS). Common methods for the treatment of TS are growth hormone (GHT) and estrogen replacement therapy (ERT). We examined the relationship between the treatment of TS and bone mineral density (BMD) of the lumbar spine. [...] Read more.

Osteoporosis is a serious implication of Turner syndrome (TS). Common methods for the treatment of TS are growth hormone (GHT) and estrogen replacement therapy (ERT). We examined the relationship between the treatment of TS and bone mineral density (BMD) of the lumbar spine. The purpose of our study was to show the currency of BMD states among patients with TS for treatment with GHT and ERT. We searched databases for studies published from inception to April 2023. The articles were related to TS, osteoporosis, ERT, GHT, BMD and treatment patients with TS. We applied the selection criteria: lumbar spine values at L1–L4; dual-energy X-ray absorptiometry (DXA); treatment which was applied: one group of articles: ERT and two group of articles: GHT; results performed as means ± SD. In total, 79 articles were analyzed, of which 20 studies were included and 5 were considered for meta-analysis. The total number of women in the articles selected was 71. Based on the results of the meta-analysis, the effect of ERT on BMD demonstrated a significant increase in BMD (the standardized mean difference in the random model was 0.593 g/cm², 95% CI: 0.0705 to 1.116; p = 0.026), which showed that treatment with estrogen particularly increases bone mass during treatment, which contributes to reducing the risk of fractures. The effect of GHT on BMD demonstrated a non-significant decrease in BMD in patients with TS. The results for growth hormone show that this therapy does not improve bone density. However, our review emphasizes the beneficial effect of supplementing growth hormone (GH) on the clinical presentation of TS. Full article

(This article belongs to the Special Issue Pharmacotherapy of Bone Diseases)

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16 pages, 4248 KiB

Open AccessArticle

Evaluating Known Zika Virus NS2B-NS3 Protease Inhibitor Scaffolds via In Silico Screening and Biochemical Assays

by Lucianna H. Santos, Rafael E. O. Rocha, Diego L. Dias, Beatriz M. R. M. Ribeiro, Mateus Sá M. Serafim, Jônatas S. Abrahão and Rafaela S. Ferreira

Pharmaceuticals 2023, 16(9), 1319; https://doi.org/10.3390/ph16091319 - 19 Sep 2023

Cited by 2 | Viewed by 1742

Abstract

The NS2B-NS3 protease (NS2B-NS3pro) is regarded as an interesting molecular target for drug design, discovery, and development because of its essential role in the Zika virus (ZIKV) cycle. Although no NS2B-NS3pro inhibitors have reached clinical trials, the employment of drug-like scaffolds can facilitate [...] Read more.

The NS2B-NS3 protease (NS2B-NS3pro) is regarded as an interesting molecular target for drug design, discovery, and development because of its essential role in the Zika virus (ZIKV) cycle. Although no NS2B-NS3pro inhibitors have reached clinical trials, the employment of drug-like scaffolds can facilitate the screening process for new compounds. In this study, we performed a combination of ligand-based and structure-based in silico methods targeting two known non-peptide small-molecule scaffolds with micromolar inhibitory activity against ZIKV NS2B-NS3pro by a virtual screening (VS) of promising compounds. Based on these two scaffolds, we selected 13 compounds from an initial library of 509 compounds from ZINC15’s similarity search. These compounds exhibited structural modifications that are distinct from previously known compounds yet keep pertinent features for binding. Despite promising outcomes from molecular docking and initial enzymatic assays against NS2B-NS3pro, confirmatory assays with a counter-screening enzyme revealed an artifactual inhibition of the assessed compounds. However, we report two compounds, 9 and 11, that exhibited antiviral properties at a concentration of 50 μM in cellular-based assays. Overall, this study provides valuable insights into the ongoing research on anti-ZIKV compounds to facilitate and improve the development of new inhibitors. Full article

(This article belongs to the Special Issue New Perspectives on Chemoinformatics and Drug Design)

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25 pages, 873 KiB

Open AccessReview

Metformin in Gestational Diabetes Mellitus: To Use or Not to Use, That Is the Question

by Vera Tocci, Maria Mirabelli, Alessandro Salatino, Luciana Sicilia, Stefania Giuliano, Francesco S. Brunetti, Eusebio Chiefari, Giovambattista De Sarro, Daniela P. Foti and Antonio Brunetti

Pharmaceuticals 2023, 16(9), 1318; https://doi.org/10.3390/ph16091318 - 18 Sep 2023

Cited by 7 | Viewed by 8399

Abstract

In recent years, there has been a dramatic increase in the number of pregnancies complicated by gestational diabetes mellitus (GDM). GDM occurs when maternal insulin resistance develops and/or progresses during gestation, and it is not compensated by a rise in maternal insulin secretion. [...] Read more.

In recent years, there has been a dramatic increase in the number of pregnancies complicated by gestational diabetes mellitus (GDM). GDM occurs when maternal insulin resistance develops and/or progresses during gestation, and it is not compensated by a rise in maternal insulin secretion. If not properly managed, this condition can cause serious short-term and long-term problems for both mother and child. Lifestyle changes are the first line of treatment for GDM, but if ineffective, insulin injections are the recommended pharmacological treatment choice. Some guidance authorities and scientific societies have proposed the use of metformin as an alternative pharmacological option for treating GDM, but there is not yet a unanimous consensus on this. Although the use of metformin appears to be safe for the mother, concerns remain about its long-term metabolic effects on the child that is exposed in utero to the drug, given that metformin, contrary to insulin, crosses the placenta. This review article describes the existing lines of evidence about the use of metformin in pregnancies complicated by GDM, in order to clarify its potential benefits and limits, and to help clinicians make decisions about who could benefit most from this drug treatment. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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19 pages, 6089 KiB

Open AccessArticle

Nature-Inspired Compounds: Synthesis and Antibacterial Susceptibility Testing of Eugenol Derivatives against H. pylori Strains

by Simone Carradori, Alessandra Ammazzalorso, Sofia Niccolai, Damiano Tanini, Ilaria D’Agostino, Francesco Melfi, Antonella Capperucci, Rossella Grande and Francesca Sisto

Pharmaceuticals 2023, 16(9), 1317; https://doi.org/10.3390/ph16091317 - 18 Sep 2023

Cited by 4 | Viewed by 1870

Abstract

The antimicrobial properties of one of the most important secondary metabolites, Eugenol (EU), inspired us to design and synthesize three different series of derivatives enhancing its parent compound’s anti-Helicobacter pylori activity. Thus, we prepared semisynthetic derivatives through (A) diazo aryl [...] Read more.

The antimicrobial properties of one of the most important secondary metabolites, Eugenol (EU), inspired us to design and synthesize three different series of derivatives enhancing its parent compound’s anti-Helicobacter pylori activity. Thus, we prepared semisynthetic derivatives through (A) diazo aryl functionalization, (B) derivatization of the hydroxy group of EU, and (C) elongation of the allyl radical by incorporating a chalcogen atom. The antibacterial evaluation was performed on the reference NCTC 11637 strain and on three drug-resistant clinical isolates and the minimal inhibitory and bactericidal concentrations (MICs and MBCs) highlight the role of chalcogens in enhancing the antimicrobial activity (less than 4 µg/mL for some compounds) of the EU scaffold (32–64 µg/mL). Full article

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

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21 pages, 4577 KiB

Open AccessArticle

Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays

by Elena Abbotto, Beatrice Casini, Francesco Piacente, Naomi Scarano, Elena Cerri, Michele Tonelli, Cecilia Astigiano, Enrico Millo, Laura Sturla, Santina Bruzzone and Elena Cichero

Pharmaceuticals 2023, 16(9), 1316; https://doi.org/10.3390/ph16091316 - 18 Sep 2023

Cited by 7 | Viewed by 1685

Abstract

Recently, the development of sirtuin small molecule inhibitors (SIRTIs) has been gaining attention for the treatment of different cancer types, but also to contrast neurodegenerative disease, diabetes, and autoimmune syndromes. In the search for SIRT2 modulators, the availability of several X-crystallographic data regarding [...] Read more.

Recently, the development of sirtuin small molecule inhibitors (SIRTIs) has been gaining attention for the treatment of different cancer types, but also to contrast neurodegenerative disease, diabetes, and autoimmune syndromes. In the search for SIRT2 modulators, the availability of several X-crystallographic data regarding SIRT2−ligand complexes has allowed for setting up a structure-based study, which is herein presented. A set of 116 SIRT2 inhibitors featuring different chemical structures has been collected from the literature and used for molecular docking studies involving 4RMG and 5MAT PDB codes. The information found highlights key contacts with the SIRT2 binding pocket such as Van der Waals and π–π stacking with Tyr104, Phe119, Phe234, and Phe235 in order to achieve high inhibitory ability values. Following the preliminary virtual screening studies, a small in-house library of compounds (1a–7a), previously investigated as putative HSP70 inhibitors, was described to guide the search for dual-acting HSP70/SIRT2 inhibitors. Biological and enzymatic assays validated the whole procedure. Compounds 2a and 7a were found to be the most promising derivatives herein proposed. Full article

(This article belongs to the Section Biopharmaceuticals)

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20 pages, 1527 KiB

Open AccessReview

Clinical Efficacy, Pharmacokinetics, and Safety of the Available Medical Options in the Treatment of Endometriosis-Related Pelvic Pain: A Scoping Review

by Mislav Mikuš, Marina Šprem Goldštajn, Antonio Simone Laganà, Franka Vukorepa and Mario Ćorić

Pharmaceuticals 2023, 16(9), 1315; https://doi.org/10.3390/ph16091315 - 18 Sep 2023

Cited by 2 | Viewed by 2715

Abstract

Background: In this scoping review, we sought to identify published studies evaluating the drugs currently used in the treatment of endometriosis-related pelvic pain, with reflection on their chemical properties, pharmacokinetics, safety profile, and clinical efficacy. Methods: A literature search was conducted with the [...] Read more.

Background: In this scoping review, we sought to identify published studies evaluating the drugs currently used in the treatment of endometriosis-related pelvic pain, with reflection on their chemical properties, pharmacokinetics, safety profile, and clinical efficacy. Methods: A literature search was conducted with the use of the PubMed and EMBASE electronic databases, focusing on identifying articles published in English between January 1990 and 2023. Results: Based on the included studies, current therapy options for the treatment of endometriosis-related pain identified and reviewed in this article were: (1) non-steroidal anti-inflammatory drugs; (2) combined oral contraceptive (COCs); (3) progestins; (4) gonadotropin-releasing hormone agonists and antagonists; (5) aromatase inhibitors (AIs); (6) selective estrogen and progesterone receptor modulators; and (7) levonorgestrel-intrauterine device. Conclusions: Based on the published evidence, clinicians should consider NSAIDs, COCs, and progestins as the first-line medical therapies. Compared with second-line options, such as GnRH agonists/antagonists or AIs, the abovementioned first-line options are well tolerated, efficacious, and exhibit lower overall price. Future research priorities should be to identify novel target therapies and to evaluate the effects of available drugs through different routes of administration. Full article

(This article belongs to the Special Issue Current Therapies for Endometriosis, Adenomyosis and Endometrial Cancer)

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13 pages, 7188 KiB

Open AccessArticle

Protective Effect of Peptide Calcium Channel Blocker Omega-Hexatoxin-Hv1a on Epithelial Cell during Ischemia–Reperfusion Injury

by Elena Iurova, Eugenia Rastorgueva, Evgenii Beloborodov, Evgeniya Pogodina, Aleksandr Fomin, Dmitrii Sugak, Denis Viktorov, Ivan Tumozov and Yury Saenko

Pharmaceuticals 2023, 16(9), 1314; https://doi.org/10.3390/ph16091314 - 18 Sep 2023

Cited by 2 | Viewed by 1232

Abstract

Ischemia–reperfusion injury (IRI) is a common phenomenon that develops both from natural causes and during major operations. Many intracellular processes mediated by calcium ions are involved in the development of IRI. Currently, chemical calcium channel blockers are used but they have a number [...] Read more.

Ischemia–reperfusion injury (IRI) is a common phenomenon that develops both from natural causes and during major operations. Many intracellular processes mediated by calcium ions are involved in the development of IRI. Currently, chemical calcium channel blockers are used but they have a number of limitations. In this article, we study the effect of the omega-hexatoxin-Hv1a peptide toxin, an alternative to chemical calcium channel blockers, on the mechanisms of IRI development in epithelial cell culture. The toxin was produced using solid phase peptide synthesis. IRI was caused by deprivation of glucose, serum and oxygen. The data obtained demonstrate that the omega-hexatoxin-Hv1a toxin in nanomolar concentrations is able to prevent the development of apoptosis and necrosis in epithelial cells by reducing the concentration of calcium, sodium and potassium ions, as well as by delaying rapid normalization of the pH level, affecting the mitochondrial potential and oxidative stress. This toxin can be used as an alternative to chemical calcium channel blockers for preventing tissue and organ IRI due to its low-dose requirement and high bioavailability. Full article

(This article belongs to the Special Issue Pharmaceutical Functions of Natural Compounds Derived from Molluscs and Arthropods)

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17 pages, 2172 KiB

Open AccessSystematic Review

The Benefits of Probiotics on Oral Health: Systematic Review of the Literature

by Francesco Inchingolo, Angelo Michele Inchingolo, Giuseppina Malcangi, Nicole De Leonardis, Roberta Sardano, Carmela Pezzolla, Elisabetta de Ruvo, Daniela Di Venere, Andrea Palermo, Alessio Danilo Inchingolo, Alberto Corriero and Gianna Dipalma

Pharmaceuticals 2023, 16(9), 1313; https://doi.org/10.3390/ph16091313 - 16 Sep 2023

Cited by 16 | Viewed by 5876

Abstract

Aim: Probiotic microorganisms, commonly used to bolster gut health, might also have benefits for dental health, according to certain studies. Probiotics (PBs) are associated with reducing cariogenic pathogens and protecting against periodontal diseases, although the exact way they function in the mouth [...] Read more.

Aim: Probiotic microorganisms, commonly used to bolster gut health, might also have benefits for dental health, according to certain studies. Probiotics (PBs) are associated with reducing cariogenic pathogens and protecting against periodontal diseases, although the exact way they function in the mouth is not fully clear. Our study aimed to explore the use of PBs to improve oral health, focusing on issues such as cavities, gum disease, bad breath, mucositis, and periimplantitis. Materials and Methods: We utilized the Boolean keywords “Probiotics” AND “Oral health” to search the databases of PubMed, Scopus, and Web of Science. The search was restricted to English-language papers published from 1 January 2019 to 13 April 2023. Results: A total of 3460 articles were found through our computerized search. After removing duplicates, reviewing the papers, and determining their relevance, 12 were selected for inclusion. Conclusions: Assessing how bacteria in food or dietary supplements might alter the stable oral microbiota is a complex task. Although probiotic microorganisms have been found to have proven therapeutic benefits, their application in dental health is not yet solidly backed by evidence. Further research is necessary to thoroughly understand the long-term effects of probiotic bacteria on the oral environment, including their ability to colonize and form biofilms. Full article

(This article belongs to the Special Issue Pharmacological Therapeutic Strategies and Drug Delivery for Craniofacial District)

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12 pages, 2666 KiB

Open AccessArticle

The Impact of Metformin on the Development of Hypothyroidism and Cardiotoxicity Induced by Cyclophosphamide, Methotrexate, and Fluorouracil in Rats

by Ahmad H. Alhowail and Maha A. Aldubayan

Pharmaceuticals 2023, 16(9), 1312; https://doi.org/10.3390/ph16091312 - 16 Sep 2023

Cited by 1 | Viewed by 1452

Abstract

Cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) are extensively utilized in the therapeutic management of various malignancies. It is noteworthy, however, that potential chemotherapy-related complications include the occurrence of hypothyroidism and cardiotoxicity. Metformin (MET) is a pharmacological agent for managing type 2 diabetes. [...] Read more.

Cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) are extensively utilized in the therapeutic management of various malignancies. It is noteworthy, however, that potential chemotherapy-related complications include the occurrence of hypothyroidism and cardiotoxicity. Metformin (MET) is a pharmacological agent for managing type 2 diabetes. It has been reported to mitigate certain toxic manifestations associated with chemotherapy. This study’s primary objective is to investigate MET’s protective effects against hypothyroidism and cardiotoxicity induced by CMF treatment. A total of forty male rats were allocated into four distinct groups, each consisting of ten rats per group. These groups were categorized as follows: saline, MET, CMF, and CMF + MET. The experimental group of rats were administered CMF via intraperitoneal injection, receiving two doses of CMF, and fed MET in their daily drinking water, with a 2.5 mg/mL concentration. Blood samples were collected into EDTA tubes for assessment of TSH, free and total (T4 and T3), troponin I, CK, and CK-MB levels utilizing Electrochemiluminescence Immunoassays (ECI). The saline and MET groups did not exhibit significant alterations in thyroid hormones or cardiotoxic biomarkers. In contrast, in the CMF group, there was a notable reduction in T4, FT4, T3, and FT3 levels but no significant changes in TSH levels; however, troponin I, CK, and CK-MB levels were notably elevated. MET co-treatment with CMF did not ameliorate these effects caused by CMF. In conclusion, CMF treatment induced hypothyroidism and cardiotoxicity in rats, but MET co-treatment did not rescue the reduction of thyroid hormones or the elevation of cardiotoxic biomarkers. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)

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16 pages, 3014 KiB

Open AccessArticle

Process Optimization for the Bioinspired Synthesis of Gold Nanoparticles Using Cordyceps militaris, Its Characterization, and Assessment of Enhanced Therapeutic Efficacy

by Girish Gawas, Muniappan Ayyanar, Nilambari Gurav, Dinesh Hase, Vaishali Murade, Sameer Nadaf, Mohd Shahnawaz Khan, Rupesh Chikhale, Mohan Kalaskar and Shailendra Gurav

Pharmaceuticals 2023, 16(9), 1311; https://doi.org/10.3390/ph16091311 - 16 Sep 2023

Cited by 10 | Viewed by 1772

Abstract

The promising therapeutic implications of nanoparticles have spurred their development for biomedical applications. An eco-friendly methodology synthesizes gold nanoparticles using Cordyceps militaris, an edible mushroom (Cord-Au-NPs), using a quality-by-design approach (central composite design). UV-visible spectroscopy analysis revealed an absorption peak [...] Read more.

The promising therapeutic implications of nanoparticles have spurred their development for biomedical applications. An eco-friendly methodology synthesizes gold nanoparticles using Cordyceps militaris, an edible mushroom (Cord-Au-NPs), using a quality-by-design approach (central composite design). UV-visible spectroscopy analysis revealed an absorption peak at 540–550 nm, thus confirming the synthesis of gold nanoparticles. Cord-Au-NPs have a crystalline structure, as evidenced by the diffraction peaks. The zeta potential value of −19.42 mV signifies the stability of Cord-Au-NPs. XRD study shows gold facets and EDX analysis revealed a strong peak of spherical nanoparticles in the gold region with a mean particle size of 7.18 nm and a polydispersity index of 0.096. The obtained peaks are closely associated with phenolic groups, lipids, and proteins, as examined by FTIR, suggesting that they function as the reducing agent. Cord-Au-NPs exhibited dose-dependent antioxidant, antidiabetic, and antibacterial activity. The method is eco-friendly, nontoxic, less time-consuming, and does not use synthetic materials, leading to higher capabilities in biomedical applications. Full article

(This article belongs to the Special Issue Metal Nanoparticles’ Biological Activity and Pharmaceutical Applications)

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31 pages, 10604 KiB

Open AccessReview

A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023

by Reshma Susan Ipe, Sunil Kumar, Feba Benny, Jayalakshmi Jayan, Amritha Manoharan, Sachitra Thazhathuveedu Sudevan, Ginson George, Prashant Gahtori, Hoon Kim and Bijo Mathew

Pharmaceuticals 2023, 16(9), 1310; https://doi.org/10.3390/ph16091310 - 15 Sep 2023

Cited by 6 | Viewed by 1735

Abstract

Monoamine oxidases (MAOs) are a family of flavin adenine dinucleotide-dependent enzymes that catalyze the oxidative deamination of a wide range of endogenous and exogenous amines. Multiple neurological conditions, including Parkinson’s disease (PD) and Alzheimer’s disease (AD), are closely correlated with altered biogenic amine [...] Read more.

Monoamine oxidases (MAOs) are a family of flavin adenine dinucleotide-dependent enzymes that catalyze the oxidative deamination of a wide range of endogenous and exogenous amines. Multiple neurological conditions, including Parkinson’s disease (PD) and Alzheimer’s disease (AD), are closely correlated with altered biogenic amine concentrations in the brain caused by MAO. Toxic byproducts of this oxidative breakdown, including hydrogen peroxide, reactive oxygen species, and ammonia, can cause oxidative damage and mitochondrial dysfunction in brain cells. Certain MAO-B blockers have been recognized as effective treatment options for managing neurological conditions, including AD and PD. There is still a pressing need to find potent therapeutic molecules to fight these disorders. However, the focus of neurodegeneration studies has recently increased, and certain compounds are now in clinical trials. Chromones are promising structures for developing therapeutic compounds, especially in neuronal degeneration. This review focuses on the MAO-B inhibitory potential of several synthesized chromones and their structural activity relationships. Concerning the discovery of a novel class of effective chromone-based selective MAO-B-inhibiting agents, this review offers readers a better understanding of the most recent additions to the literature. Full article

(This article belongs to the Section Biopharmaceuticals)

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25 pages, 7170 KiB

Open AccessArticle

Bedaquiline-Loaded Solid Lipid Nanoparticles Drug Delivery in the Management of Non-Small-Cell Lung Cancer (NSCLC)

by Shehla Nasar Mir Najib Ullah, Obaid Afzal, Abdulmalik Saleh Alfawaz Altamimi, Manal A. Alossaimi, Waleed H Almalki, Abdulaziz Alzahrani, Md. Abul Barkat, Tahani M. Almeleebia, Hanan Alshareef, Eman M. Shorog, Gyas Khan, Tanuja Singh and J. K. Singh

Pharmaceuticals 2023, 16(9), 1309; https://doi.org/10.3390/ph16091309 - 15 Sep 2023

Cited by 3 | Viewed by 1903

Abstract

Non-small-cell lung cancer (NSCLC) mortality and new case rates are both on the rise. Most patients have fewer treatment options accessible due to side effects from drugs and the emergence of drug resistance. Bedaquiline (BQ), a drug licensed by the FDA to treat [...] Read more.

Non-small-cell lung cancer (NSCLC) mortality and new case rates are both on the rise. Most patients have fewer treatment options accessible due to side effects from drugs and the emergence of drug resistance. Bedaquiline (BQ), a drug licensed by the FDA to treat tuberculosis (TB), has demonstrated highly effective anti-cancer properties in the past. However, it is difficult to transport the biological barriers because of their limited solubility in water. Our study developed a UPLC method whose calibration curves showed linearity in the range of 5 ng/mL to 500 ng/mL. The UPLC method was developed with a retention time of 1.42 and high accuracy and precision. Its LOQ and LOD were observed to be 10 ng/mL and 5 ng/mL, respectively, whereas in the formulation, capmul MCM C10, Poloxamer 188, and PL90G were selected as solid lipids, surfactants, and co-surfactants, respectively, in the development of SLN. To combat NSCLC, we developed solid lipid nanoparticles (SLNs) loaded with BQ, whereas BQ suspension is prepared by the trituration method using acacia powder, hydroxypropyl methylcellulose, polyvinyl acrylic acid, and BQ. The developed and optimized BQ-SLN3 has a particle size of 144 nm and a zeta potential of (−) 16.3 mV. whereas BQ-loaded SLN3 has observed entrapment efficiency (EE) and loading capacity (LC) of 92.05% and 13.33%, respectively. Further, BQ-loaded suspension revealed a particle size of 1180 nm, a PDI of 0.25, and a zeta potential of −0.0668. whereas the EE and LC of BQ-loaded suspension were revealed to be 88.89% and 11.43%, respectively. The BQ-SLN3 exhibited insignificant variation in particle size, homogeneous dispersion, zeta potential, EE, and LC and remained stable over 90 days of storage at 25 °C/60% RH, whereas at 40 °C/75% RH, BQ-SLN3 observed significant variation in the above-mentioned parameters and remained unstable over 90 days of storage. Meanwhile, the BQ suspension at both 25 °C (60% RH) and 40 °C (75% RH) was found to be stable up to 90 days. The optimized BQ-SLN3 and BQ-suspension were in vitro gastrointestinally stable at pH 1.2 and 6.8, respectively. The in vitro drug release of BQ-SLN3 showed 98.19% up to 12 h at pH 7.2 whereas BQ suspensions observed only 40% drug release up to 4 h at pH 7.2 and maximum drug release of >99% within 4 h at pH 4.0. The mathematical modeling of BQ-SLN3 followed first-order release kinetics followed by a non-Fickian diffusion mechanism. After 24 to 72 h, the IC50 value of BQ-SLN3 was 3.46-fold lower than that of the BQ suspension, whereas the blank SLN observed cell viability of 98.01% and an IC50 of 120 g/mL at the end of 72 h. The bioavailability and higher biodistribution of BQ-SLN3 in the lung tumor were also shown to be greater than those of the BQ suspension. The effects of BQ-SLN3 on antioxidant enzymes, including MDA, SOD, CAT, GSH, and GR, in the treated group were significantly improved and reached the level nearest to that of the control group of rats over the cancer group of rats and the BQ suspension-treated group of rats. Moreover, the pharmacodynamic activity resulted in greater tumor volume and tumor weight reduction by BQ-SLN3 over the BQ suspension-treated group. As far as we are aware, this is the first research to look at the potential of SLN as a repurposed oral drug delivery, and the results suggest that BQ-loaded SLN3 is a better approach for NSCLC due to its better action potential. Full article

(This article belongs to the Special Issue Self-Assembled Nanoparticles: An Emerging Delivery Platform for Drugs)

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16 pages, 1626 KiB

Open AccessReview

Treatment of Chronic Gastritis with Traditional Chinese Medicine: Pharmacological Activities and Mechanisms

by Lisheng Chen, Shizhang Wei, Yong He, Xin Wang, Tingting He, Aozhe Zhang, Manyi Jing, Haotian Li, Ruilin Wang and Yanling Zhao

Pharmaceuticals 2023, 16(9), 1308; https://doi.org/10.3390/ph16091308 - 15 Sep 2023

Cited by 6 | Viewed by 7841

Abstract

Chronic gastritis (CG) is a common clinical digestive system disease, which is not easyily cured and is prone to recurrence. Traditional Chinese medicine (TCM) plays a significant role in the treatment of CG and has attracted increasing attention for clinical applications. In recent [...] Read more.

Chronic gastritis (CG) is a common clinical digestive system disease, which is not easyily cured and is prone to recurrence. Traditional Chinese medicine (TCM) plays a significant role in the treatment of CG and has attracted increasing attention for clinical applications. In recent years, a large number of reports have shown that TCM has good therapeutic effect on CG. The aim of this paper is to investigate the pharmacological activities and mechanism of action of TCM in the treatment of CAG. Therefore, by searching the databases of Pubmed, China National Knowledge Infrastructure, Wanfang, and Baidu academic databases, this paper has summarized the molecular mechanisms of TCM in improving CG. The results show that the improvement of GC by TCM is closely related to a variety of molecular mechanisms, including the inhibition of Helicobacter pylori (Hp) infection, alleviation of oxidative stress, improvement of gastric function, repair of gastric mucosa, inhibition of inflammatory response, and apoptosis. More importantly, IRF8-IFN-γ, IL-4-STAT6, Hedgehog, pERK1/2, MAPK, PI3K-Akt, NF-κB, TNFR-c-Src-ERK1/2-c-Fos, Nrf2/HO-1, and HIF-1α/VEGF signaling pathways are considered as important molecular targets for TCM in the treatment of GC. These important findings will provide a direction and a basis for further exploring the pathogenesis of GC and tapping the potential of TCM in clinical treatment. This review also puts forward a bright prospect for future research of TCM in the treatment of CG. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 3967 KiB

Open AccessArticle

A Window to the Brain: The Retina to Monitor the Progression and Efficacy of Saffron Repron^® Pre-Treatment in an LPS Model of Neuroinflammation and Memory Impairment

by Mattia Di Paolo, Francesca Corsi, Chiara Cerri, Silvia Bisti, Ilaria Piano and Claudia Gargini

Pharmaceuticals 2023, 16(9), 1307; https://doi.org/10.3390/ph16091307 - 15 Sep 2023

Cited by 3 | Viewed by 1889

Abstract

A mechanism shared by most neurodegenerative diseases, like Alzheimer’s disease (AD) and Parkinson’s disease (PD), is neuroinflammation. It has been shown to have a link between cognitive impairment and retinal function under neuroinflammatory conditions, confirming the essential role of the retina as a [...] Read more.

A mechanism shared by most neurodegenerative diseases, like Alzheimer’s disease (AD) and Parkinson’s disease (PD), is neuroinflammation. It has been shown to have a link between cognitive impairment and retinal function under neuroinflammatory conditions, confirming the essential role of the retina as a window to the brain. Here, we characterize a mouse model of LPS-induced neuroinflammation describing the parallel deterioration of both memory and visual function. Then, we demonstrate, using the Novel Object Recognition test (NOR) and electroretinogram (ERG) recordings, that preventive, chronic treatment with saffron Repron^® is able to reduce the neuroinflammation process and prevent the impairment of both cognitive and visual function. The improvement in behavioral and visual function is confirmed by the pattern of expression of neuroinflammation-related genes and related proteins where pre-treatment with Repron^® saffron presents a positive modulation compared with that obtained in animals treated with LPS alone. These results hold for retinal tissue and partially in the brain, where it appears that the onset of damage was delayed. This trend underlines the critical role of the retina as a most sensitive portion of the central nervous system to LPS-induced damage and could be used as a “sensor” for the early detection of neurodegenerative diseases such as Alzheimer’s. Full article

(This article belongs to the Special Issue Inflammation and Brain Diseases)

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Open AccessArticle

Neuroprotective Effect of Nosustrophine in a 3xTg Mouse Model of Alzheimer’s Disease

by Iván Carrera, Lola Corzo, Olaia Martínez-Iglesias, Vinogran Naidoo and Ramón Cacabelos

Pharmaceuticals 2023, 16(9), 1306; https://doi.org/10.3390/ph16091306 - 15 Sep 2023

Cited by 1 | Viewed by 1209

Abstract

Neurodegeneration, characterized by the progressive deterioration of neurons and glial cells, is a feature of Alzheimer’s disease (AD). The present study aims to demonstrate that the onset and early progression of neurodegenerative processes in transgenic mice models of AD can be delayed by [...] Read more.

Neurodegeneration, characterized by the progressive deterioration of neurons and glial cells, is a feature of Alzheimer’s disease (AD). The present study aims to demonstrate that the onset and early progression of neurodegenerative processes in transgenic mice models of AD can be delayed by a cocktail of neurotrophic factors and derived peptides named Nosustrophine, a nootropic supplement made by a peptide complex extracted from the young porcine brain, ensuring neuroprotection and improving neuro-functional recovery. Experimental 3xTg-APP/Bin1/COPS5 transgenic mice models of AD were treated with Nosustrophine at two different early ages, and their neuropathological hallmark and behavior response were analyzed. Results showed that Nosustrophine increased the activity of the immune system and reduced pathological changes in the hippocampus and cortex by halting the development of amyloid plaques, mainly seen in mice of 3–4 months of age, indicating that its effect is more preventive than therapeutic. Taken together, the results indicate the potent neuroprotective activity of Nosustrophine and its stimulating effects on neuronal plasticity. This study shows for the first time an effective therapy using nootropic supplements against degenerative diseases, although further investigation is needed to understand their molecular pathways. Full article

(This article belongs to the Section Biopharmaceuticals)

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Pharmaceuticals, Volume 16, Issue 9 (September 2023) – 149 articles

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