Pharmaceuticals

15 pages, 3888 KiB

Open AccessArticle

Development of a Biodegradable PLGA Carrier to Provide Wnt Agonists and Antibiotics to Meet the Requirements for Patients with Bone Infections

by Song-Shu Lin, Shih-Jung Liu, Err-Cheng Chan, Kowit-Yu Chong, Yi-Sheng Chan, Tsung-Ting Tsai, Chi-Chien Niu, Li-Jen Yuan, Chuen-Yung Yang, Hui-Yi Hsiao, Yi-Jen Hsueh, Chung-An Chen and Steve W. N. Ueng

Pharmaceuticals 2024, 17(8), 1038; https://doi.org/10.3390/ph17081038 - 6 Aug 2024

Viewed by 163

Abstract

Antibiotic beads can be used to treat surgical infections. In this study, polylactide–polyglycolide (PLGA) was mixed with vancomycin, the osteogenic enhancer lithium chloride (LiCl), and hot compression to form PLGA-vancomycin-LiCl delivery beads to treat bone infection. An elution method was used to characterize [...] Read more.

Antibiotic beads can be used to treat surgical infections. In this study, polylactide–polyglycolide (PLGA) was mixed with vancomycin, the osteogenic enhancer lithium chloride (LiCl), and hot compression to form PLGA-vancomycin-LiCl delivery beads to treat bone infection. An elution method was used to characterize in vitro release characteristics of vancomycin and Li over a 42-day period. The release profiles lasted for more than 42 days for vancomycin and 28 days for Li. The concentration of vancomycin in each sample was well above the breakpoint sensitivity. Lithium cotreatment enhanced the bactericidal effect of vancomycin. Released Li and vancomycin increased the mRNA or protein expressions of osteogenic markers of mesenchymal stem cells (MSCs). In vivo, the PLGA delivery systems were implanted into the distal femoral cavities of rabbits, and the cavity fluid content was aspirated and analyzed at each time point. The released Li and vancomycin lasted more than 6 weeks, and the vancomycin concentrations were much greater than the breakpoint sensitivity. Four rabbits in each group were sacrificed at 8 weeks for histological observation. More mature bone tissue was observed in the Li treatment group. This study provides a PLGA drug delivery system to meet the requirements of patients with bone infections. Full article

(This article belongs to the Section Pharmaceutical Technology)

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22 pages, 3434 KiB

Open AccessArticle

Antinociceptive and Anti-Inflammatory Activities of Acetonic Extract from Bougainvillea x buttiana (var. Rose)

by Gabriela Castañeda-Corral, Mayra Cedillo-Cortezano, Magdalena Aviles-Flores, Misael López-Castillo, Juan José Acevedo-Fernández and Vera L. Petricevich

Pharmaceuticals 2024, 17(8), 1037; https://doi.org/10.3390/ph17081037 - 6 Aug 2024

Viewed by 190

Abstract

Background:Bougainvillea x buttiana is an ornamental plant with antioxidant, anti-inflammatory, and cytotoxic activities, which has been traditionally used to treat respiratory diseases. This study aimed to investigate whether the acetonic extract of Bougainvillea x buttiana Var. Rose (BxbRAE-100%) has analgesic and anti-inflammatory [...] Read more.

Background:Bougainvillea x buttiana is an ornamental plant with antioxidant, anti-inflammatory, and cytotoxic activities, which has been traditionally used to treat respiratory diseases. This study aimed to investigate whether the acetonic extract of Bougainvillea x buttiana Var. Rose (BxbRAE-100%) has analgesic and anti-inflammatory properties and its potential action mechanisms. Methods: Analgesic and anti-inflammatory activities were evaluated using three murine pain models and two acute inflammation models. In vitro, the ability of the extract to inhibit proteolytic activity and the activities of the enzymes phospholipase A2 (PLA2) and cyclooxygenase (COX) were evaluated. In silico analysis was performed to predict the physicochemical and Absorption, distribution, metabolism, and excretion (ADME) profiles of the compounds previously identified in BxbRAE-100%. Results: In vivo BxbRAE-100% decreased the nociceptive behaviors in the writhing model, the tail immersion, and the formalin test, suggesting that the extract has the potential to relieve pain at peripheral and central levels. Additionally, topical or oral BxbRAE-100% treatment reduced dose-dependent 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammation and carrageenan-induced paw edema, respectively. In vitro, BxbRAE-100% significantly inhibited proteolytic activity and PLA2, COX-1 and COX-2 activities. In silico, the compounds previously identified in BxbRAE-100% met Lipinski’s rule of five and showed adequate ADME properties. Conclusions: These results support the use of B. x buttiana in Traditional Mexican Medicine and highlight its potential for the development of new treatments for pain and inflammation. Full article

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

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18 pages, 2630 KiB

Open AccessArticle

Agave-Laurate-Bioconjugated Fructans Decrease Hyperinsulinemia and Insulin Resistance, Whilst Increasing IL-10 in Rats with Metabolic Syndrome Induced by a High-Fat Diet

by Angélica Sofía González-Garibay, Georgina Sandoval, Omar Ricardo Torres-González, Blanca Estela Bastidas-Ramírez, Iván Moisés Sánchez-Hernández and Eduardo Padilla-Camberos

Pharmaceuticals 2024, 17(8), 1036; https://doi.org/10.3390/ph17081036 - 6 Aug 2024

Viewed by 277

Abstract

Metabolic syndrome (MetS) comprises a cluster of metabolic risk factors, which include obesity, hypertriglyceridemia, high blood pressure, and insulin resistance. The purpose of this study was to evaluate the effects of laurate-bioconjugated fructans on pro- and anti-inflammatory cytokines in Wistar rats with MetS [...] Read more.

Metabolic syndrome (MetS) comprises a cluster of metabolic risk factors, which include obesity, hypertriglyceridemia, high blood pressure, and insulin resistance. The purpose of this study was to evaluate the effects of laurate-bioconjugated fructans on pro- and anti-inflammatory cytokines in Wistar rats with MetS induced by a high-fat diet. Laurate-bioconjugated fructans were synthesized with agave fructans, immobilized lipase B, and vinyl laureate as the acylant. Groups were fed a standard diet (NORMAL), a high-fat diet (HFD), or a high-fat diet plus laurate-bioconjugated fructans (FL PREV) for 9 weeks. A fourth group received a high-fat diet for 6 weeks, followed by simultaneous exposure to a high-fat diet and laurate-bioconjugated fructans for 3 additional weeks (FL REV). The dose of laurate-bioconjugated fructans was 130 mg/kg. Laurate-bioconjugated fructans reduced food and energy intake, body weight, body mass index, abdominal circumference, adipose tissue, adipocyte area, serum triglycerides, insulin, insulin resistance, and C-reactive protein but they increased IL-10 protein serum levels and mRNA expression. The impact of laurate-bioconjugated fructans on zoometric and metabolic parameters supports their potential as therapeutic agents to improve obesity, obesity comorbidities, insulin resistance, type 2 diabetes mellitus, and MetS. Full article

(This article belongs to the Special Issue Bioactive Compounds through Structural Modification of Natural Products)

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16 pages, 2660 KiB

Open AccessReview

Drug-Drug Interactions between COVID-19 and Tuberculosis Medications: A Comprehensive Review of CYP450 and Transporter-Mediated Effects

by M. Rasheduzzaman Jony and Sangzin Ahn

Pharmaceuticals 2024, 17(8), 1035; https://doi.org/10.3390/ph17081035 - 6 Aug 2024

Viewed by 230

Abstract

Most medications undergo metabolism and elimination via CYP450 enzymes, while uptake and efflux transporters play vital roles in drug elimination from various organs. Interactions often occur when multiple drugs share CYP450-transporter-mediated metabolic pathways, necessitating a unique clinical care strategy to address the diverse [...] Read more.

Most medications undergo metabolism and elimination via CYP450 enzymes, while uptake and efflux transporters play vital roles in drug elimination from various organs. Interactions often occur when multiple drugs share CYP450-transporter-mediated metabolic pathways, necessitating a unique clinical care strategy to address the diverse types of CYP450 and transporter-mediated drug-drug interactions (DDI). The primary focus of this review is to record relevant mechanisms regarding DDI between COVID-19 and tuberculosis (TB) treatments, specifically through the influence of CYP450 enzymes and transporters on drug absorption, distribution, metabolism, elimination, and pharmacokinetics. This understanding empowers clinicians to prevent subtherapeutic and supratherapeutic drug levels of COVID medications when co-administered with TB drugs, thereby mitigating potential challenges and ensuring optimal treatment outcomes. A comprehensive analysis is presented, encompassing various illustrative instances of TB drugs that may impact COVID-19 clinical behavior, and vice versa. This review aims to provide valuable insights to healthcare providers, facilitating informed decision-making and enhancing patient safety while managing co-infections. Ultimately, this study contributes to the body of knowledge necessary to optimize therapeutic approaches and improve patient outcomes in the face of the growing challenges posed by infectious diseases. Full article

(This article belongs to the Section Pharmacology)

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67 pages, 15389 KiB

Open AccessArticle

Synthesis and Biochemical Evaluation of Ethanoanthracenes and Related Compounds: Antiproliferative and Pro-Apoptotic Effects in Chronic Lymphocytic Leukemia (CLL)

by James P. McKeown, Andrew J. Byrne, Sandra A. Bright, Clara E. Charleton, Shubhangi Kandwal, Ivan Čmelo, Brendan Twamley, Anthony M. McElligott, Darren Fayne, Niamh M. O’Boyle, D. Clive Williams and Mary J. Meegan

Pharmaceuticals 2024, 17(8), 1034; https://doi.org/10.3390/ph17081034 - 5 Aug 2024

Viewed by 302

Abstract

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow [...] Read more.

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow and spleen. We report the synthesis and antiproliferative effects of a series of novel ethanoanthracene compounds in CLL cell lines. Structural modifications were achieved via the Diels–Alder reaction of 9-(2-nitrovinyl)anthracene and 3-(anthracen-9-yl)-1-arylprop-2-en-1-ones (anthracene chalcones) with dienophiles, including maleic anhydride and N-substituted maleimides, to afford a series of 9-(E)-(2-nitrovinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones, 9-(E)-3-oxo-3-phenylprop-1-en-1-yl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones and related compounds. Single-crystal X-ray analysis confirmed the structures of the novel ethanoanthracenes 23f, 23h, 24a, 24g, 25f and 27. The products were evaluated in HG-3 and PGA-1 CLL cell lines (representative of poor and good patient prognosis, respectively). The most potent compounds were identified as 20a, 20f, 23a and 25n with IC₅₀ values in the ranges of 0.17–2.69 µM (HG-3) and 0.35–1.97 µM (PGA-1). The pro-apoptotic effects of the potent compounds 20a, 20f, 23a and 25n were demonstrated in CLL cell lines HG-3 (82–95%) and PGA-1 (87–97%) at 10 µM, with low toxicity (12–16%) observed in healthy-donor peripheral blood mononuclear cells (PBMCs) at concentrations representative of the compounds IC₅₀ values for both the HG-3 and PGA-1 CLL cell lines. The antiproliferative effect of the selected compounds, 20a, 20f, 23a and 25n, was mediated through ROS flux with a marked increase in cell viability upon pretreatment with the antioxidant NAC. 25n also demonstrated sub-micromolar activity in the NCI 60 cancer cell line panel, with a mean GI₅₀ value of 0.245 µM. This ethanoanthracene series of compounds offers potential for the further development of lead structures as novel chemotherapeutics to target CLL. Full article

(This article belongs to the Special Issue Advances in Pharmaceutical Sciences: In Honor of Dr. Jean Jacques Vanden Eynde (JJ))

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13 pages, 3434 KiB

Open AccessArticle

Energy Transfer between AGuIX Nanoparticles and Photofrin under Light or X-ray Excitation for PDT Applications

by Batoul Dhaini, Philippe Arnoux, Joël Daouk, François Lux, Olivier Tillement, Agnès Hagège, Tayssir Hamieh, Gal Shafirstein and Céline Frochot

Pharmaceuticals 2024, 17(8), 1033; https://doi.org/10.3390/ph17081033 - 5 Aug 2024

Viewed by 244

Abstract

Photodynamic therapy is an accepted therapy cancer treatment. Its advantages encourage researchers to delve deeper. The use of nanoparticles in PDT has several advantages including the passive targeting of cancer cells. The aim of this article is to evaluate the effectiveness of AGuIX [...] Read more.

Photodynamic therapy is an accepted therapy cancer treatment. Its advantages encourage researchers to delve deeper. The use of nanoparticles in PDT has several advantages including the passive targeting of cancer cells. The aim of this article is to evaluate the effectiveness of AGuIX nanoparticles (activation and guiding of irradiation by X-ray) in the presence or absence of a photosensitizer, Photofrin, under illumination of 630 nm or under X-ray irradiation. The goal is to improve local tumor control by combining PDT with low-dose-X-ray-activated NPs in the treatment of locally advanced metastatic lung cancer. The study of the energy transfer, which occurs after excitation of Gd/Tb chelated in AGuIX in the presence of Photofrin, was carried out. We could observe the formation of singlet oxygen after the light or X-ray excitation of Gd and Tb that was not observed for AGuIX or Photofrin alone, proving that it is possible to realize energy transfer between both compounds. Full article

(This article belongs to the Special Issue Photosensitizers and Drug Delivery Systems for Photodynamic Therapy)

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12 pages, 5159 KiB

Open AccessArticle

Ixeris polycephala Extract Alleviates Progression of Benign Prostatic Hyperplasia via Modification of Proliferation, Apoptosis, and Inflammation

by Eun-Bok Baek, Youn-Hwan Hwang, Eun-Ju Hong, Young-Suk Won and Hyo-Jung Kwun

Pharmaceuticals 2024, 17(8), 1032; https://doi.org/10.3390/ph17081032 - 5 Aug 2024

Viewed by 230

Abstract

Benign prostatic hyperplasia (BPH) is a urogenital disorder that is common in aging men. Ixeris polycephala (IP) is used in traditional medicine and contains pharmacologically active compounds. However, the effect for BPH progression has not been elucidated. We herein examined the protective potential [...] Read more.

Benign prostatic hyperplasia (BPH) is a urogenital disorder that is common in aging men. Ixeris polycephala (IP) is used in traditional medicine and contains pharmacologically active compounds. However, the effect for BPH progression has not been elucidated. We herein examined the protective potential of IP extract on a testosterone-induced model of BPH in rats. To generate the BPH model, daily subcutaneous administration of testosterone was applied for 4 weeks. During this period, the rats were also administered a daily oral gavage of IP (150 mg/kg), finasteride (positive control), or vehicle. Testosterone treatment was associated with a significantly higher prostate-to-body weight ratio, serum dihydrotestosterone (DHT) level, and prostatic gene expression of 5α-reductase compared to untreated controls. Notably, IP plus testosterone co-treatment was associated with decreased epithelial thickness, down-regulation of proliferating cell nuclear antigen (PCNA) and cyclin D1, and upregulation of pro-apoptotic signaling molecules. IP co-treatment also down-regulated pro-inflammatory cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and decreased inflammatory cell infiltration compared to the levels seen in the testosterone-induced BPH. IP appears to protect rats against the progression of testosterone-induced BPH by alleviating prostate cell growth and inflammatory responses, and thus may have potential for clinical use against BPH progression. Full article

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

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48 pages, 5287 KiB

Open AccessReview

Future Treatment Strategies for Cancer Patients Combining Targeted Alpha Therapy with Pillars of Cancer Treatment: External Beam Radiation Therapy, Checkpoint Inhibition Immunotherapy, Cytostatic Chemotherapy, and Brachytherapy

by Ruth Christine Winter, Mariam Amghar, Anja S. Wacker, Gábor Bakos, Harun Taş, Mareike Roscher, James M. Kelly and Martina Benešová-Schäfer

Pharmaceuticals 2024, 17(8), 1031; https://doi.org/10.3390/ph17081031 - 5 Aug 2024

Viewed by 360

Abstract

Cancer is one of the most complex and challenging human diseases, with rising incidences and cancer-related deaths despite improved diagnosis and personalized treatment options. Targeted alpha therapy (TαT) offers an exciting strategy emerging for cancer treatment which has proven effective even in patients [...] Read more.

Cancer is one of the most complex and challenging human diseases, with rising incidences and cancer-related deaths despite improved diagnosis and personalized treatment options. Targeted alpha therapy (TαT) offers an exciting strategy emerging for cancer treatment which has proven effective even in patients with advanced metastatic disease that has become resistant to other treatments. Yet, in many cases, more sophisticated strategies are needed to stall disease progression and overcome resistance to TαT. The combination of two or more therapies which have historically been used as stand-alone treatments is an approach that has been pursued in recent years. This review aims to provide an overview on TαT and the four main pillars of therapeutic strategies in cancer management, namely external beam radiation therapy (EBRT), immunotherapy with checkpoint inhibitors (ICI), cytostatic chemotherapy (CCT), and brachytherapy (BT), and to discuss their potential use in combination with TαT. A brief description of each therapy is followed by a review of known biological aspects and state-of-the-art treatment practices. The emphasis, however, is given to the motivation for combination with TαT as well as the pre-clinical and clinical studies conducted to date. Full article

(This article belongs to the Special Issue Advances in Pharmaceutical Sciences: In Honor of Dr. Jean Jacques Vanden Eynde (JJ))

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15 pages, 1041 KiB

Open AccessReview

The Pathogenic Mechanisms of and Novel Therapies for Lamin A/C-Related Dilated Cardiomyopathy Based on Patient-Specific Pluripotent Stem Cell Platforms and Animal Models

by Xin-Yi Wu, Yee-Ki Lee, Yee-Man Lau, Ka-Wing Au, Yiu-Lam Tse, Kwong-Man Ng, Chun-Ka Wong and Hung-Fat Tse

Pharmaceuticals 2024, 17(8), 1030; https://doi.org/10.3390/ph17081030 - 5 Aug 2024

Viewed by 277

Abstract

Variants (pathogenic) of the LMNA gene are a common cause of familial dilated cardiomyopathy (DCM), which is characterised by early-onset atrioventricular (AV) block, atrial fibrillation and ventricular tachyarrhythmias (VTs), and progressive heart failure. The unstable internal nuclear lamina observed in LMNA-related DCM [...] Read more.

Variants (pathogenic) of the LMNA gene are a common cause of familial dilated cardiomyopathy (DCM), which is characterised by early-onset atrioventricular (AV) block, atrial fibrillation and ventricular tachyarrhythmias (VTs), and progressive heart failure. The unstable internal nuclear lamina observed in LMNA-related DCM is a consequence of the disassembly of lamins A and C. This suggests that LMNA variants produce truncated or alternative forms of protein that alter the nuclear structure and the signalling pathway related to cardiac muscle diseases. To date, the pathogenic mechanisms and phenotypes of LMNA-related DCM have been studied using different platforms, such as patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) and transgenic mice. In this review, point variants in the LMNA gene that cause autosomal dominantly inherited forms of LMNA-related DCM are summarised. In addition, potential therapeutic targets based on preclinical studies of LMNA variants using transgenic mice and human iPSC-CMs are discussed. They include mitochondria deficiency, variants in nuclear deformation, chromatin remodelling, altered platelet-derived growth factor and ERK1/2-related pathways, and abnormal calcium handling. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Where Do We Stand with Human-Derived Stem Cells?)

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12 pages, 259 KiB

Open AccessReview

The Role of Monoclonal Antibodies in the Treatment of Myeloma Kidney Disease

by Daniele Derudas and Sabrina Chiriu

Pharmaceuticals 2024, 17(8), 1029; https://doi.org/10.3390/ph17081029 - 5 Aug 2024

Viewed by 263

Abstract

Renal failure is one of the most important manifestations of multiple myeloma. It is caused by renal lesions such as cast nephropathy, immunoglobulin deposition disease, AL amyloidosis or other glomerular and/or tubular diseases, mostly due to the toxic effect of free light chains [...] Read more.

Renal failure is one of the most important manifestations of multiple myeloma. It is caused by renal lesions such as cast nephropathy, immunoglobulin deposition disease, AL amyloidosis or other glomerular and/or tubular diseases, mostly due to the toxic effect of free light chains in serum. Renal failure can represent a clinical emergency and is associated with poor outcome in newly diagnosed and relapsed/refractory multiple myeloma patients. Although progression-free survival and overall survival have improved with the introduction of novel agents, renal failure remains a challenge for the treatment of patients with multiple myeloma. Monoclonal antibodies are a component of therapy for newly diagnosed and relapsed/refractory patients and, based on clinical trials and real-world experience, are also safe and effective for subjects with renal failure, even if they are on dialysis. Most of the data are on anti-CD38 and anti-SLAM7 antibodies, but new antibody–drug conjugates such as belantamab mafodotin and bispecific antibodies also appear to be effective in myeloma kidney disease. In the future, we will have to face some challenges, such as defining new criteria for renal response to treatment, defining specific trials for these difficult-to-treat patients and integrating different therapeutic options. Full article

(This article belongs to the Special Issue Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024)

19 pages, 1345 KiB

Open AccessArticle

Adverse Event Profiles of Adalimumab in Children: A Disproportionality Analysis

by Wenting Zhang, Ziqi Xu, Yamin Shu, Sainan Shu and Qilin Zhang

Pharmaceuticals 2024, 17(8), 1028; https://doi.org/10.3390/ph17081028 - 5 Aug 2024

Viewed by 217

Abstract

Background: Adalimumab has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult rheumatoid arthritis (RA), and subsequently approved for pediatric treatment of various autoimmune diseases in children of different ages. Due to genetic differences between children and [...] Read more.

Background: Adalimumab has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult rheumatoid arthritis (RA), and subsequently approved for pediatric treatment of various autoimmune diseases in children of different ages. Due to genetic differences between children and adults in terms of physiology and immunity, there is a need to explore the safety of adalimumab in children in the real world. The aim of this study is to identify potential adverse event (AE) signals associated with the use of adalimumab in pediatric patients (<18 years old) using data from the FDA Adverse Event Reporting System (FAERS). Methods: AEs associated with adalimumab in pediatric patients reported in the FAERS database from the first quarter (Q1) of 2017 to the third quarter (Q3) of 2022 were systematically gathered. Reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the empirical Bayes geometric mean (EBGM) were used to assess the relationship between adalimumab and AEs in children. Results: Out of 8,363,304 reports collected from the FAERS database during the study period, 3819 reports on children on adalimumab were identified. Adalimumab-related AEs reports were concentrated on 10 toxicity areas and a total of 202 positive signals were detected, of which injection site papule (ROR = 261.97) and intestinal fistula (ROR = 122.09) had the strongest signals. Unexpected significant AEs, including intestinal obstruction, immunodeficiency, abdominal abscess, and Takayasu’s arteritis might also occur. In comparison with patients of all ages in the same time window, the median onset time of children was shorter (99 vs. 149 days). Most of the AE cases occurred in children within the first 1 (1.71%), 2 (8.12%), and 3 months (8.39%) and had early failure types after adalimumab initiation. Methotrexate, folic acid, prednisone, azathioprine, and mesalamine were the top five drugs used concomitantly for adalimumab-associated AEs. Conclusions: When adalimumab is used in children, especially in the first 3 months of treatment, in addition to the AEs recorded in the drug package insert, close attention should be paid to the new potential AEs off-label to ensure the safety of adalimumab in children. Full article

(This article belongs to the Special Issue Pharmacovigilance in Drug Therapy: Drug–Drug Interactions and Safety Evaluation)

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19 pages, 7047 KiB

Open AccessArticle

Azobenzenesulfonamide Carbonic Anhydrase Inhibitors as New Weapons to Fight Helicobacter pylori: Synthesis, Bioactivity Evaluation, In Vivo Toxicity, and Computational Studies

by Letizia Giampietro, Beatrice Marinacci, Alice Della Valle, Ilaria D’Agostino, Aldo Lauro, Mattia Mori, Simone Carradori, Alessandra Ammazzalorso, Barbara De Filippis, Cristina Maccallini, Andrea Angeli, Clemente Capasso, Santolo Francati, Adriano Mollica, Rossella Grande and Claudiu T. Supuran

Pharmaceuticals 2024, 17(8), 1027; https://doi.org/10.3390/ph17081027 - 5 Aug 2024

Viewed by 352

Abstract

Research into novel anti-Helicobacter pylori agents represents an important approach for the identification of new treatments for chronic gastritis and peptic ulcers, which are associated with a high risk of developing gastric carcinoma. In this respect, two series of azobenzenesulfonamides were designed, [...] Read more.

Research into novel anti-Helicobacter pylori agents represents an important approach for the identification of new treatments for chronic gastritis and peptic ulcers, which are associated with a high risk of developing gastric carcinoma. In this respect, two series of azobenzenesulfonamides were designed, synthesized, and tested against a large panel of human and bacterial CAs to evaluate their inhibitory activity. In addition, computational studies of the novel primary benzenesulfonamides (4a–j) were performed to predict the putative binding mode to both HpCAs. Then, the antimicrobial activity versus H. pylori of the two series was also studied. The best-in-class compounds were found to be 4c and 4e among the primary azobenzenesulfonamides and 5c and 5f belonging to the secondary azobenzenesulfonamides series, showing themselves to exert a promising anti-H. pylori activity, with MIC values of 4–8 μg/mL and MBCs between 4 and 16 μg/mL. Moreover, the evaluation of their toxicity on a G. mellonella larva in vivo model indicated a safe profile for 4c,e and 5c,f. The collected results warrant considering these azobenzenesulfonamides as an interesting starting point for the development of a new class of anti-H. pylori agents. Full article

(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)

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9 pages, 228 KiB

Open AccessArticle

Potentially Inappropriate Medications Involved in Drug–Drug Interactions in a Polish Population over 80 Years Old: An Observational, Cross-Sectional Study

by Emilia Błeszyńska-Marunowska, Kacper Jagiełło, Łukasz Wierucki, Marcin Renke, Tomasz Grodzicki, Zbigniew Kalarus and Tomasz Zdrojewski

Pharmaceuticals 2024, 17(8), 1026; https://doi.org/10.3390/ph17081026 - 5 Aug 2024

Viewed by 211

Abstract

The clinical context of drug interactions detected by automated analysis systems is particularly important in older patients with multimorbidities. We aimed to provide unique, up-to-date data on the prevalence of potentially inappropriate medications (PIMs) and drug–drug interactions (DDIs) in the Polish geriatric population [...] Read more.

The clinical context of drug interactions detected by automated analysis systems is particularly important in older patients with multimorbidities. We aimed to provide unique, up-to-date data on the prevalence of potentially inappropriate medications (PIMs) and drug–drug interactions (DDIs) in the Polish geriatric population over 80 years old and determine the frequency and the most common PIMs involved in DDIs. We analyzed all non-prescription and prescription drugs in a representative national group of 178 home-dwelling adults over 80 years old with excessive polypharmacy (≥10 drugs). The FORTA List was used to assess PIMs, and the Lexicomp^® Drug Interactions database was used for DDIs. DDIs were detected in 66.9% of the study group, whereas PIMs were detected in 94.4%. Verification of clinical indications for the use of substances involved in DDIs resulted in a reduction in the total number of DDIs by more than 1.5 times, as well as in a nearly 3-fold decrease in the number of interactions requiring therapy modification and drug combinations that should be strictly avoided. The most common PIMs involved in DDIs were painkillers, and drugs used in psychiatry and neurology. Special attention should be paid to DDIs with PIMs since they could increase their inappropriate character. The use of automated interaction analysis systems, while maintaining appropriate clinical criticism, can increase both chances for a good therapeutic effect and the safety of the elderly during treatment processes. Full article

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

18 pages, 2242 KiB

Open AccessArticle

Comparing the Differences in Adverse Events among Chimeric Antigen Receptor T-Cell Therapies: A Real-World Pharmacovigilance Study

by Zihan Guo, Yunlan Ding, Mengmeng Wang, Qing Zhai, Jiyong Liu and Qiong Du

Pharmaceuticals 2024, 17(8), 1025; https://doi.org/10.3390/ph17081025 - 5 Aug 2024

Viewed by 330

Abstract

In this study, we compared the similarities and differences in adverse events (AEs) among CAR T-cell products through signal mining via the FDA Adverse Event Reporting System (FAERS) and identified unknown AEs to provide a reference for safe clinical medication. Data from the [...] Read more.

In this study, we compared the similarities and differences in adverse events (AEs) among CAR T-cell products through signal mining via the FDA Adverse Event Reporting System (FAERS) and identified unknown AEs to provide a reference for safe clinical medication. Data from the FAERS database spanning from the fourth quarter of 2017 to the first quarter of 2024 were extracted. Signals were identified using the reporting odds ratio (ROR) method and the Medicines and Healthcare Products Regulatory Agency (MHRA) method. A total of 11,386 AE reports related to six CAR T-cell products were selected. The top three categories of AEs reported were nervous system disorders, immune system disorders, and general disorders and administration site conditions. However, there were variations in the AE spectra among the different CAR T-cell products. The BCMA-targeting drugs idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel) were found to be associated with parkinsonism, which were not observed in CD19-targeting drugs. Tisagenlecleucel (Tisa-cel) and axicabtagene ciloleucel (Axi-cel) exhibited cerebrovascular accident-related AEs, graft versus host disease, and abnormal coagulation indices. Cilta-cel was associated with cerebral hemorrhage, intracranial hemorrhage, cranial nerve disorder, and facial nerve disorder. Cardiopulmonary toxicity, including hypoxia, tachypnoea, cardiorenal syndrome, and hypotension, exhibited strong signal intensities and considerable overlap with CRS. The number of positive signals for cardiopulmonary toxicity associated with drugs targeting CD-19 is greater. Clinicians should assess patients prior to medication and closely monitor their vital signs, mental status, and laboratory parameters during treatment. Full article

(This article belongs to the Section Pharmacology)

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14 pages, 2195 KiB

Open AccessArticle

Bioequivalence Analysis of Terazosin Hydrochloride Tablets Based on Parallel Artificial Membrane Permeability Analysis

by Jianzhao Niu, Hanhan Huang, Ming Ji, Wenjing Zhang, Yin Huang, Lingyun Ma, Baolian Wang and Qian Liu

Pharmaceuticals 2024, 17(8), 1024; https://doi.org/10.3390/ph17081024 - 5 Aug 2024

Viewed by 234

Abstract

Parallel artificial membrane permeability analysis (PAMPA) is used to determine the permeability of compounds through concentrated negatively charged phospholipid bilayer barriers. We employed MacroFlux (a scaled-up version of PAMPA) to test the permeation rate of terazosin hydrochloride (TH) tablets and predict in vivo [...] Read more.

Parallel artificial membrane permeability analysis (PAMPA) is used to determine the permeability of compounds through concentrated negatively charged phospholipid bilayer barriers. We employed MacroFlux (a scaled-up version of PAMPA) to test the permeation rate of terazosin hydrochloride (TH) tablets and predict in vivo bioequivalence. The dissolution profiles and permeability of one reference formulation, and seven generic TH tablets, were compared. The dissolution profiles of these generic tablets were equivalent to that of the reference drug in four different media. However, the flux and the total permeated amount of some generic TH tablets were below the lower limit of the confidence interval of the original acceptance range in MacroFlux, which implied risk in the bioequivalence test in vivo. We further evaluated potential factors responsible for this discrepancy by µFlux, including active pharmaceutical ingredient (API) permeability and excipient prescriptions. The analysis showed that different properties of API were a main factor leading to biological inequivalence in the MacroFlux assay, while excipient prescriptions did not have an impact on bioequivalence risk. These data indicated that the flux assay may be a helpful as an auxiliary method for predicting bioequivalence of generic drugs and analyze the factors responsible for bioequivalence risk. Full article

(This article belongs to the Section Pharmaceutical Technology)

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18 pages, 4283 KiB

Open AccessArticle

Siraitia grosvenorii Extract Protects Lipopolysaccharide-Induced Intestinal Inflammation in Mice via Promoting M2 Macrophage Polarization

by Huining Wu, Mengru Guo, Linlu Zhao, Jin Zhang, Jieyi He, Anning Xu, Zhichao Yu, Xingbin Ma, Yanhong Yong, Youquan Li, Xianghong Ju and Xiaoxi Liu

Pharmaceuticals 2024, 17(8), 1023; https://doi.org/10.3390/ph17081023 - 4 Aug 2024

Viewed by 285

Abstract

Siraitia grosvenorii has anti-inflammatory, antioxidant, and immune-regulating effects, while macrophages play an important role in reducing inflammation. However, it is still unclear whether Siraitia grosvenorii extract (SGE) is effective in reducing inflammation by regulating macrophages. This study investigated the regulatory effect of SGE [...] Read more.

Siraitia grosvenorii has anti-inflammatory, antioxidant, and immune-regulating effects, while macrophages play an important role in reducing inflammation. However, it is still unclear whether Siraitia grosvenorii extract (SGE) is effective in reducing inflammation by regulating macrophages. This study investigated the regulatory effect of SGE on macrophage polarization in a lipopolysaccharide (LPS)-induced intestinal inflammation model after establishing the model in vitro and in vivo. The results from the in vivo model showed that, compared with the LPS group, SGE significantly improved ileal morphology, restored the ileal mucosal barrier, and reduced intestinal and systemic inflammation by increasing CD206 and reducing iNOS proteins. In the in vitro model, compared with the LPS group, SGE significantly reduced the expression of iNOS protein and cytokines (TNF-α, IL-1β, and IFN-γ) while significantly increasing the protein expression of CD206 in RAW264.7 cells. In conclusion, SGE can alleviate intestinal inflammation, protect the mucus barrier, and block the systemic immunosuppressive response by increasing M2 macrophages. Full article

(This article belongs to the Special Issue Discovery, Metabolism and Potential Bio-Activities of Natural Products in Traditional Medicine 2024)

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9 pages, 1137 KiB

Open AccessArticle

Development of a Lateral Flow Assay for the Detection of the Hepatitis C Virus Core Antigen

by Erick Joan Vidal-Alcántara, Sonia Hernández Antón, Paloma Rueda, María Belén Yélamos, Julián Gómez, Salvador Resino, Alba Fresco-Taboada and Isidoro Martínez

Pharmaceuticals 2024, 17(8), 1022; https://doi.org/10.3390/ph17081022 - 4 Aug 2024

Viewed by 356

Abstract

Background: Hepatitis C virus (HCV) infection remains a global health challenge, with millions of people affected annually. Current diagnostic methods, reliant on antibody screening and viral RNA detection, are complex, costly, and often inaccessible, particularly in resource-limited settings. Aim: Development of a lateral [...] Read more.

Background: Hepatitis C virus (HCV) infection remains a global health challenge, with millions of people affected annually. Current diagnostic methods, reliant on antibody screening and viral RNA detection, are complex, costly, and often inaccessible, particularly in resource-limited settings. Aim: Development of a lateral flow immunochromatography-based assay for detecting the highly conserved hepatitis C core antigen (HCVcAg). Methods: The assay relies on the interaction of four highly specific and cross-reactive monoclonal antibodies with recombinant HCVcAg from five different genotypes in a double antibody sandwich format. Latex and colloidal gold were evaluated as detector nanoparticles. Results: Extensive evaluation of 32 antibody combinations led to identifying the most sensitive antibody pairs. The chosen assay, named LN17, demonstrated a target sensitivity of 10 ng/strip, with potential clinical implications for detecting HCV. Furthermore, the study examined matrix effects in serum samples, providing valuable insights for future clinical application. Conclusions: The developed assay holds promise as a rapid, cost-effective, and user-friendly tool to enhance accessibility to hepatitis C screening, especially in high-risk populations and resource-limited environments. Full article

(This article belongs to the Special Issue HIV and Viral Hepatitis: Prevention, Treatment and Coinfection)

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12 pages, 1826 KiB

Open AccessArticle

Lactoferrin Binds through Its N-Terminus to the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein

by Patrik Babulic, Ondrej Cehlar, Gabriela Ondrovičová, Tetiana Moskalets, Rostislav Skrabana and Vladimir Leksa

Pharmaceuticals 2024, 17(8), 1021; https://doi.org/10.3390/ph17081021 - 4 Aug 2024

Viewed by 704

Abstract

Since Coronavirus disease 2019 (COVID-19) still presents a considerable threat, it is beneficial to provide therapeutic supplements against it. In this respect, glycoprotein lactoferrin (LF) and lactoferricin (LFC), a natural bioactive peptide yielded upon digestion from the N-terminus of LF, are of utmost [...] Read more.

Since Coronavirus disease 2019 (COVID-19) still presents a considerable threat, it is beneficial to provide therapeutic supplements against it. In this respect, glycoprotein lactoferrin (LF) and lactoferricin (LFC), a natural bioactive peptide yielded upon digestion from the N-terminus of LF, are of utmost interest, since both have been shown to reduce infections of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19, in particular via blockade of the virus priming and binding. Here, we, by means of biochemical and biophysical methods, reveal that LF directly binds to the S-protein of SARS-CoV-2. We determined thermodynamic and kinetic characteristics of the complex formation and mapped the mutual binding sites involved in this interaction, namely the N-terminal region of LF and the receptor-binding domain of the S-protein (RBD). These results may not only explain many of the observed protective effects of LF and LFC in SARS-CoV-2 infection but may also be instrumental in proposing potent and cost-effective supplemental tools in the management of COVID-19. Full article

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

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16 pages, 2245 KiB

Open AccessOpinion

Is There an Interplay between Environmental Factors, Microbiota Imbalance, and Cancer Chemotherapy-Associated Intestinal Mucositis?

by Camila Fernandes, Mahara Coelho Crisostomo Miranda, Cássia Rodrigues Roque, Ana Lizeth Padilla Paguada, Carlos Adrian Rodrigues Mota, Katharine Gurgel Dias Florêncio, Anamaria Falcão Pereira, Deysi Viviana Tenazoa Wong, Reinaldo Barreto Oriá and Roberto César Pereira Lima-Júnior

Pharmaceuticals 2024, 17(8), 1020; https://doi.org/10.3390/ph17081020 - 3 Aug 2024

Viewed by 366

Abstract

Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes. While pharmacogenetics and pharmacogenomics have long been considered the primary causes of such heterogeneous responses, pharmacomicrobiomics has recently gained attention. The microbiome, [...] Read more.

Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes. While pharmacogenetics and pharmacogenomics have long been considered the primary causes of such heterogeneous responses, pharmacomicrobiomics has recently gained attention. The microbiome, a community of microorganisms living in or on the human body, is a critical determinant of drug response and toxicity. Factors such as diet, lifestyle, exposure to xenobiotics, antibiotics use, illness, and genetics can influence the composition of the microbiota. Changes in the intestinal microbiota are particularly influential in drug responsiveness, especially in cancer chemotherapy. The microbiota can modulate an individual’s response to a drug, affecting its bioavailability, clinical effect, and toxicity, affecting treatment outcomes and patient quality of life. For instance, the microbiota can convert drugs into active or toxic metabolites, influencing their efficacy and side effects. Alternatively, chemotherapy can also alter the microbiota, creating a bidirectional interplay. Probiotics have shown promise in modulating the microbiome and ameliorating chemotherapy side effects, highlighting the potential for microbiota-targeted interventions in improving cancer treatment outcomes. This opinion paper addresses how environmental factors and chemotherapy-induced dysbiosis impact cancer chemotherapy gastrointestinal toxicity. Full article

(This article belongs to the Special Issue Cancer Treatment Toxicities: Molecular Insights and Novel Therapeutic Approaches)

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29 pages, 7238 KiB

Open AccessArticle

Unveiling the Bioactive Efficacy of Cupressus sempervirens ‘Stricta’ Essential Oil: Composition, In Vitro Activities, and In Silico Analyses

by Eman Fikry, Raha Orfali, Nora Tawfeek, Shagufta Perveen, Safina Ghafar, Maher M. El-Domiaty and Azza M. El-Shafae

Pharmaceuticals 2024, 17(8), 1019; https://doi.org/10.3390/ph17081019 - 2 Aug 2024

Viewed by 371

Abstract

Prior studies have extensively investigated the essential oil derived from the Mediterranean cypress, Cupressus sempervirens. However, the ‘Stricta’ variety, known for its ornamental value, has received less attention in terms of its oil composition and potential health benefits. The objective of this [...] Read more.

Prior studies have extensively investigated the essential oil derived from the Mediterranean cypress, Cupressus sempervirens. However, the ‘Stricta’ variety, known for its ornamental value, has received less attention in terms of its oil composition and potential health benefits. The objective of this research was to comprehensively analyze the chemical components and medicinal properties of the essential oil extracted from C. sempervirens ‘Stricta’ (CSSLEO) grown in Egypt. Utilizing gas chromatography–mass spectrometry (GC–MS), the investigation identified 22 compounds within CSSLEO, with α-pinene and δ-3-carene being predominant, accounting for 96.01% of the oil. In vitro assays evaluated CSSLEO’s cytotoxic effects on cancer cell lines, revealing notable anticancer potential. Additionally, the oil displayed antidiabetic properties by impeding crucial enzymes involved in glucose metabolism. Complementary in silico network pharmacology and molecular docking studies provided insights into the possible interactions between CSSLEO’s key compounds and essential proteins and pathways in cancer treatment. The results underscored CSSLEO’s intricate composition and its promising applications in cancer prevention and diabetes management. The conclusions drawn from this research underscore the need for further investigation to validate CSSLEO’s clinical effectiveness and to gain a deeper understanding of its therapeutic mechanisms, with a view to harnessing its potential in oncology and endocrinology. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products)

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28 pages, 11202 KiB

Open AccessArticle

Anti-Inflammatory Activities of Yataprasen Thai Traditional Formulary and Its Active Compounds, Beta-Amyrin and Stigmasterol, in RAW264.7 and THP-1 Cells

by Jaenjira Angsusing, Sudarshan Singh, Weerasak Samee, Sarin Tadtong, Leanne Stokes, Maria O’Connell, Hanna Bielecka, Nopparut Toolmal, Supachoke Mangmool and Chuda Chittasupho

Pharmaceuticals 2024, 17(8), 1018; https://doi.org/10.3390/ph17081018 - 1 Aug 2024

Viewed by 463

Abstract

Yataprasen (YTPS) remedy formulary, a national Thai traditional medicine formulary, comprises 13 herbal plants. It has been extensively prescribed to relieve osteoarthritis and musculoskeletal pain in the Thai traditional medicine healthcare system. The aim of this study was to investigate the antioxidant and [...] Read more.

Yataprasen (YTPS) remedy formulary, a national Thai traditional medicine formulary, comprises 13 herbal plants. It has been extensively prescribed to relieve osteoarthritis and musculoskeletal pain in the Thai traditional medicine healthcare system. The aim of this study was to investigate the antioxidant and anti-inflammatory properties of the bioactive compounds (β-amyrin and stigmasterol) of YTPS remedy formulary ethanolic extract, along with its composition. The YTPS formulary extract contains 70.30 nM of β-amyrin and 605.76 nM of stigmasterol. The YTPS formulary extract exhibited ABTS and DPPH free radical scavenging activity, with IC₅₀ values of 144.50 ± 2.82 and 31.85 ± 0.18 µg/mL, respectively. The ethanolic extract of YTPS at a concentration of 1000 µg/mL showed a significant (p < 0.01) anti-inflammatory effect, mainly by reducing IL-6 and TNF-α release in response to LPS. NO production was prominently lowered by 50% at 24.76 ± 1.48 µg/mL, 55.52 ± 24.40 µM, and more than 570 µM of YTPS formulary extract, β-amyrin, and stigmasterol, respectively. Major components of YTPS, β-amyrin, and stigmasterol exerted significant anti-inflammatory effects by inhibiting LPS-induced IL-1β, IL-6, TNF-α secretion in THP-1 cells. Our findings suggest that the ethanolic extract from YTPS holds promise as an alternative topical treatment for osteoarthritis and inflammatory disorders, potentially with fewer side effects than non-steroidal anti-inflammatory medications (NSAIDs). Full article

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14 pages, 5041 KiB

Open AccessArticle

3D-Printed Melatonin Tablets with Braille Motifs for the Visually Impaired

by Chrystalla Protopapa, Angeliki Siamidi, Aikaterini Sakellaropoulou, Siva Kolipaka, Laura Andrade Junqueira, Atabak Ghanizadeh Tabriz, Dennis Douroumis and Marilena Vlachou

Pharmaceuticals 2024, 17(8), 1017; https://doi.org/10.3390/ph17081017 - 1 Aug 2024

Viewed by 503

Abstract

An innovative approach for creating customized dosage forms and supporting patient populations with specific requirements who need additional support to improve drug adherence is 3D printing. This work introduces liquid crystal display (LCD) 3D printing as a means of developing melatonin (MLT) tablets. [...] Read more.

An innovative approach for creating customized dosage forms and supporting patient populations with specific requirements who need additional support to improve drug adherence is 3D printing. This work introduces liquid crystal display (LCD) 3D printing as a means of developing melatonin (MLT) tablets. For patients who are blind or visually challenged, Braille patterns were displayed on the tablet surface in addition to the optimization of printing hydrogel inks. Owing to the great printing accuracy, blind patients could validate the Braille patterns that provided the required information. Upon further examination MLT was found to be present in the photopolymerized resins in an amorphous state. The choice of poly(ethylene glycol)-diacrylate (PEGDA) with varying molecular weights and the inclusion of surfactants or solubilizers interfered with the photopolymerization of the resin, hence controlling the rates of MLT dissolution towards the sought sustained release. Nuclear magnetic resonance (NMR) analysis showed that photopolymerization of the PEGDA resins in the printed dosage forms has taken place. A small batch scale-up investigation showed that LCDs could print a significant number of tablets quickly—about twenty-four minutes. Full article

(This article belongs to the Section Pharmaceutical Technology)

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16 pages, 2278 KiB

Open AccessArticle

Electrospun Poly-ε-Caprolactone Nanofibers Incorporating Keratin Hydrolysates as Innovative Antioxidant Scaffolds

by Naiara Jacinta Clerici, Aline Aniele Vencato, Rafael Helm Júnior, Daniel Joner Daroit and Adriano Brandelli

Pharmaceuticals 2024, 17(8), 1016; https://doi.org/10.3390/ph17081016 - 1 Aug 2024

Viewed by 307

Abstract

This manuscript describes the development and characterization of electrospun nanofibers incorporating bioactive hydrolysates obtained from the microbial bioconversion of feathers, a highly available agro-industrial byproduct. The electrospun nanofibers were characterized using different instrumental methods, and their antioxidant properties and toxicological potential were evaluated. [...] Read more.

This manuscript describes the development and characterization of electrospun nanofibers incorporating bioactive hydrolysates obtained from the microbial bioconversion of feathers, a highly available agro-industrial byproduct. The electrospun nanofibers were characterized using different instrumental methods, and their antioxidant properties and toxicological potential were evaluated. Keratin hydrolysates (KHs) produced by Bacillus velezensis P45 were incorporated at 1, 2.5, and 5% (w/w) into poly-ε-caprolactone (PCL; 10 and 15%, w/v solutions) before electrospinning. The obtained nanofibers were between 296 and 363 nm in diameter, showing a string-like morphology and adequate structural continuity. Thermogravimetric analysis showed three weight loss events, with 5% of the mass lost up to 330 °C and 90% from 350 to 450 °C. Infrared spectroscopy showed typical peaks of PCL and amide bands corresponding to keratin peptides. The biological activity was preserved after electrospinning and the hemolytic activity was below 1% as expected for biocompatible materials. In addition, the antioxidant capacity released from the nanofibers was confirmed by DPPH and ABTS radical scavenging activities. The DPPH scavenging activity observed for the nanofibers was greater than 30% after 24 h of incubation, ranging from 845 to 1080 µM TEAC (Trolox equivalent antioxidant capacity). The antioxidant activity for the ABTS radical assay was 44.19, 49.61, and 56.21% (corresponding to 972.0, 1153.3, and 1228.7 µM TEAC) for nanofibers made using 15% PCL with 1, 2.5, and 5% KH, respectively. These nanostructures may represent interesting antioxidant biocompatible materials for various pharmaceutical applications, including wound dressings, topical drug delivery, cosmetics, and packaging. Full article

(This article belongs to the Special Issue Recent Advances in Natural Product Based Nanostructured Systems)

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20 pages, 7499 KiB

Open AccessArticle

Bacteroides uniformis Ameliorates Carbohydrate and Lipid Metabolism Disorders in Diabetic Mice by Regulating Bile Acid Metabolism via the Gut–Liver Axis

by Xue-Xue Zhu, Chen-Yang Zhao, Xin-Yu Meng, Xiao-Yi Yu, Lin-Chun Ma, Tian-Xiao Chen, Chang Chang, Xin-Yu Chen, Yuan Zhang, Bao Hou, Wei-Wei Cai, Bin Du, Zhi-Jun Han, Li-Ying Qiu and Hai-Jian Sun

Pharmaceuticals 2024, 17(8), 1015; https://doi.org/10.3390/ph17081015 - 1 Aug 2024

Viewed by 309

Abstract

Background: Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterized by chronic inflammation, insulin resistance, and islet cell damage. The prevention of T2DM and its associated complications is an urgent public health issue that affects hundreds of millions of people globally. Numerous [...] Read more.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterized by chronic inflammation, insulin resistance, and islet cell damage. The prevention of T2DM and its associated complications is an urgent public health issue that affects hundreds of millions of people globally. Numerous studies suggest that disturbances in gut metabolites are important driving forces for the pathogenesis of diabetes. However, the functions and mechanisms of action of most commensal bacteria in T2DM remain largely unknown. Methods: The quantification of bile acids (BAs) in fecal samples was performed using ultra-performance liquid chromatography–tandem mass spectrometer (UPLC-MS/MS). The anti-diabetic effects of Bacteroides uniformis (B. uniformis) and its metabolites cholic acid (CA) and chenodeoxycholic acid (CDCA) were assessed in T2DM mice induced by streptozocin (STZ) plus high-fat diet (HFD). Results: We found that the abundance of B. uniformis in the feces and the contents of CA and CDCA were significantly downregulated in T2DM mice. B. uniformis was diminished in diabetic individuals and this bacterium was sufficient to promote the production of BAs. Colonization of B. uniformis and intragastric gavage of CA and CDCA effectively improved the disorder of glucose and lipid metabolism in T2DM mice by inhibiting gluconeogenesis and lipolysis in the liver. CA and CDCA improved hepatic glucose and lipid metabolism by acting on the Takeda G protein-coupled receptor 5 (TGR5)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway since knockdown of TGR5 minimized the benefit of CA and CDCA. Furthermore, we screened a natural product—vaccarin (VAC)—that exhibited anti-diabetic effects by promoting the growth of B. uniformis in vitro and in vivo. Gut microbiota pre-depletion abolished the favorable effects of VAC in diabetic mice. Conclusions: These data suggest that supplementation of B. uniformis may be a promising avenue to ameliorate T2DM by linking the gut and liver. Full article

(This article belongs to the Section Natural Products)

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8 pages, 648 KiB

Open AccessBrief Report

In Vitro Evaluation of the Combinatorial Effect of Naringenin and Miltefosine against Leishmania amazonensis

by Vinícius Lopes Lessa, Gustavo Gonçalves, Beatriz Santos, Victoria Cruz Cavalari, Rafael Felipe da Costa Vieira and Fabiano Borges Figueiredo

Pharmaceuticals 2024, 17(8), 1014; https://doi.org/10.3390/ph17081014 - 1 Aug 2024

Viewed by 296

Abstract

Leishmania amazonensis causes a clinical form called diffuse cutaneous leishmaniasis (DCL) with challenges to treatment, like low efficiency and drug toxicity. Therefore, it is necessary to investigate new therapies using less toxic leishmanicidal compounds, such as flavonoids like naringenin, and their combination with [...] Read more.

Leishmania amazonensis causes a clinical form called diffuse cutaneous leishmaniasis (DCL) with challenges to treatment, like low efficiency and drug toxicity. Therefore, it is necessary to investigate new therapies using less toxic leishmanicidal compounds, such as flavonoids like naringenin, and their combination with conventional drugs, such as miltefosine. Antileishmanial dose/response activity, isobologram, calculation of dose reduction index (DRI), and fractional inhibitory concentration index (FICI) tests were performed on in vitro assays using reference promastigote forms of L. amazonensis (IFLA/BR/67/PH8) to assess the combinatorial effect between naringenin and miltefosine. The in vitro results of isobologram, DRI, and FICI calculations showed that the combination of the compounds had an additive effect and was able to reduce the half maximal inhibitory concentration (IC₅₀) of miltefosine in the promastigote forms of the parasite compared to the treatment of the drug alone. This study demonstrated in vitro the viability of a combination action of the flavonoid with the treatment with miltefosine, opening space for further investigations on the association of natural compounds with the drugs used for the treatment of L. amazonensis. Full article

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

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13 pages, 1149 KiB

Open AccessArticle

Chemical Content and Cytotoxic Activity on Various Cancer Cell Lines of Chaga (Inonotus obliquus) Growing on Betula pendula and Betula pubescens

by Ain Raal, Hedi Kaldmäe, Karin Kütt, Katrin Jürimaa, Maidu Silm, Uko Bleive, Alar Aluvee, Kalev Adamson, Marili Vester, Mart Erik, Oleh Koshovyi, Khan Viet Nguyen, Hoai Thi Nguyen and Rein Drenkhan

Pharmaceuticals 2024, 17(8), 1013; https://doi.org/10.3390/ph17081013 - 1 Aug 2024

Viewed by 446

Abstract

Chaga mushroom (Inonotus obliquus) is a pathogenic fungus that grows mostly on birch species (Betula pendula Roth and B. pubescens Ehrh.) and has traditionally been used as an anticancer medicine. This study aimed to compare the chemical composition and cytotoxic [...] Read more.

Chaga mushroom (Inonotus obliquus) is a pathogenic fungus that grows mostly on birch species (Betula pendula Roth and B. pubescens Ehrh.) and has traditionally been used as an anticancer medicine. This study aimed to compare the chemical composition and cytotoxic activity of chagas growing on both Betula spp. on various cancer cell lines. The freeze-dried extracts contained triterpenes inotodiol, lanosterol betulin, and betulinic acid typical to conks growing on Betula species. The cytotoxic activity of chaga growing on Betula pendula and B. pubescens 80% ethanolic extracts against 31 human cancer cell lines was evaluated by a sulforhodamine B assay. Chaga extract showed moderate activity against all cancer cell lines examined; it did not result in high cytotoxicity (IC₅₀ ≤ 20 µg/mL). The strongest inhibitions were observed with chaga (growing on B. pendula) extract on the HepG2 and CAL-62 cell line and with chaga (from B. pubescens) extract on the HepG2 cell line, with IC₅₀ values of 37.71, 43.30, and 49.99 μg/mL, respectively. The chaga extracts from B. pendula exert somewhat stronger effects on most cancer cell lines studied than B. pubescens extracts, which can be attributed to a higher content of inotodiol in B. pendula extracts. This study highlights the potential of chaga as a source of bioactive compounds with selective anticancer properties. To the best of our knowledge, this study is the first investigation of the chemical composition of I. obliquus parasitizing on B. pubescens. Full article

(This article belongs to the Section Natural Products)

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7 pages, 1732 KiB

Open AccessArticle

Cytotoxicity of Benzofuran-Containing Simplified Viniferin Analogues

by Salvatore Princiotto, Cecilia Pinna, Luce Micaela Mattio, Francesca Annunziata, Giovanni Luca Beretta, Andrea Pinto and Sabrina Dallavalle

Pharmaceuticals 2024, 17(8), 1012; https://doi.org/10.3390/ph17081012 - 1 Aug 2024

Viewed by 251

Abstract

Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids show wide structural diversity and mediate a great number of biological responses relevant for human health, including cancer prevention and cytotoxicity. Resveratrol is known to modulate several pathways directly linked to cancer progression, [...] Read more.

Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids show wide structural diversity and mediate a great number of biological responses relevant for human health, including cancer prevention and cytotoxicity. Resveratrol is known to modulate several pathways directly linked to cancer progression, as well as its analogue pterostilbene, characterized by an increased metabolic stability and significant pharmacological activities. To study the potential anticancer activity of other stilbenoids, a home-made collection of resveratrol dimers and simplified analogues was tested on melanoma A375, non-small cell lung cancer H460 and PC3 prostate cancer cell lines. The structural determinants responsible for the antiproliferative activity have been highlighted. Moreover, to investigate the DNA damage ability of the selected molecules, the expression of the γ-H2AX after compound exposure was evaluated. Full article

(This article belongs to the Section Natural Products)

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64 pages, 1707 KiB

Open AccessSystematic Review

A Systematic Review of Laser Photobiomodulation Dosimetry and Treatment Protocols in the Management of Medications-Related Osteonecrosis of the Jaws: A Rationalised Consensus for Future Randomised Controlled Clinical Trials

by Reem Hanna, Ioana Cristina Miron, Snehal Dalvi, Praveen Arany, René Jean Bensadoun and Stefano Benedicenti

Pharmaceuticals 2024, 17(8), 1011; https://doi.org/10.3390/ph17081011 - 31 Jul 2024

Viewed by 481

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating adverse effect of bisphosphates, antiresorptive therapy or antiangiogenic agents that can potentially increase oxidative stress, leading to progressive osteonecrosis of the jaws. Despite the large number of published systematic reviews, there is a lack [...] Read more.

Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating adverse effect of bisphosphates, antiresorptive therapy or antiangiogenic agents that can potentially increase oxidative stress, leading to progressive osteonecrosis of the jaws. Despite the large number of published systematic reviews, there is a lack of potential MRONJ treatment protocols utilising photobiomodulation (PBM) as a single or adjunct therapy for preventive or therapeutic oncology or non-oncology cohort. Hence, this systematic review aimed to evaluate PBM laser efficacy and its dosimetry as a monotherapy or combined with the standard treatments for preventive or therapeutic approach in MRONJ management. The objectives of the review were as follows: (1) to establish PBM dosimetry and treatment protocols for preventive, therapeutic or combined approaches in MRONJ management; (2) to highlight and bridge the literature gaps in MRONJ diagnostics and management; and (3) to suggest rationalised consensus recommendations for future randomised controlled trials (RCTs) through the available evidence-based literature. This review was conducted according to the PRISMA guidelines, and the protocol was registered at PROSPERO under the ID CRD42021238175. A multi-database search was performed to identify articles of clinical studies published from their earliest records until 15 December 2023. The data were extracted from the relevant papers and analysed according to the outcomes selected in this review. In total, 12 out of 126 studies met the eligibility criteria. The striking inconsistent conclusions made by the various authors of the included studies were due to the heterogeneity in the methodology, diagnostic criteria and assessment tools, as well as in the reported outcomes, made it impossible to conduct a meta-analysis. PBM as a single or adjunct treatment modality is effective for MRONJ preventive or therapeutic management, but it was inconclusive to establish a standardised and replicable protocol due to the high risk of bias in a majority of the studies, but it was possible to extrapolate the PBM dosimetry of two studies that were close to the WALT recommended parameters. In conclusion, the authors established suggested rationalised consensus recommendations for future well-designed robust RCTs, utilising PBM as a monotherapy or an adjunct in preventive or therapeutic approach of MRONJ in an oncology and non-oncology cohort. This would pave the path for standardised PBM dosimetry and treatment protocols in MRONJ management. Full article

(This article belongs to the Section Pharmacology)

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34 pages, 16779 KiB

Open AccessReview

Navigating Preclinical Models and Medications for Peripheral Neuropathy: A Review

by Abdulmajeed M. Jali, David Banji, Otilia J. F. Banji, Khalid Y. Hurubi, Faisal Y. Tawhari, Atheer A. Alameer, Atyaf S. Dohal and Raha A. Zanqoti

Pharmaceuticals 2024, 17(8), 1010; https://doi.org/10.3390/ph17081010 - 31 Jul 2024

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Abstract

Peripheral neuropathy (PN) is a multifaceted disorder characterised by peripheral nerve damage, manifesting in symptoms like pain, weakness, and autonomic dysfunction. This review assesses preclinical models in PN research, evaluating their relevance to human disease and their role in therapeutic development. The Streptozotocin [...] Read more.

Peripheral neuropathy (PN) is a multifaceted disorder characterised by peripheral nerve damage, manifesting in symptoms like pain, weakness, and autonomic dysfunction. This review assesses preclinical models in PN research, evaluating their relevance to human disease and their role in therapeutic development. The Streptozotocin (STZ)-induced diabetic rat model is widely used to simulate diabetic neuropathy but has limitations in faithfully replicating disease onset and progression. Cisplatin-induced PN models are suitable for studying chemotherapy-induced peripheral neuropathy (CIPN) and closely resemble human pathology. However, they may not fully replicate the spectrum of sensory and motor deficits. Paclitaxel-induced models also contribute to understanding CIPN mechanisms and testing neuroprotective agents. Surgical or trauma-induced models offer insights into nerve regeneration and repair strategies. Medications such as gabapentin, pregabalin, duloxetine, and fluoxetine have demonstrated promise in these models, enhancing our understanding of their therapeutic efficacy. Despite progress, developing models that accurately mirror human PN remains imperative due to its complex nature. Continuous refinement and innovative approaches are critical for effective drug discovery. This review underscores the strengths and limitations of current models and advocates for an integrated approach to address the complexities of PN better and optimise treatment outcomes. Full article

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

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26 pages, 1345 KiB

Open AccessReview

Misuse, Abuse and Medication Errors’ Adverse Events Associated with Opioids—A Systematic Review

by Moa Gustafsson, Vítor Silva, Carolina Valeiro, João Joaquim, Florence van Hunsel and Cristiano Matos

Pharmaceuticals 2024, 17(8), 1009; https://doi.org/10.3390/ph17081009 - 31 Jul 2024

Viewed by 351

Abstract

Opioids are the strongest analgesics available and are crucial in the treatment of acute and chronic pain. The line between these critical medications and how they are used beyond standard therapeutics in cases such as abuse, misuse, and medication errors needs to be [...] Read more.

Opioids are the strongest analgesics available and are crucial in the treatment of acute and chronic pain. The line between these critical medications and how they are used beyond standard therapeutics in cases such as abuse, misuse, and medication errors needs to be understood, as it affects their safety, efficacy, and manner of use. The aim of this systematic review was to identify what is known about the adverse events resulting from the abuse, misuse, and medication errors associated with opioid use. A systematic search was conducted in the PubMed^®, Scopus^® and, EBSCO^® databases to retrieve studies from the inception to December 2023 reporting abuse, misuse, and medication errors associated with medicinal opioid use. Two authors independently screened titles and abstracts and full text according to eligibility using Covidence^® software. Full articles were examined by two independent reviewers, and disagreements were resolved by a third reviewer. The risk of bias was assessed by the JBI’s critical appraisal tools. A total of 934 articles were screened by their title and abstract. Then, 151 articles were selected for full text screening. Of these, 34 studies were eligible for inclusion in this review. The included studies varied significantly in their population sizes, ranging from 9 individuals to 298,433 patients, and encompassed a diverse demographic, including all ages and both sexes. The studies consistently reported a range of adverse events associated with opioid use. Fentanyl, morphine, oxycodone, tramadol, and hydrocodone were frequently implicated. The data heterogeneity in this field resulted in challenges in drawing conclusions. The review highlights that some opioids, particularly fentanyl, morphine, and oxycodone, are frequently associated with preventable adverse drug reactions, abuse, and medication errors, underscoring the need for robust preventative measures and ongoing research to mitigate opioid-related harm. Full article

(This article belongs to the Special Issue Drug Safety and Relevant Issues in the Real-World 2024)

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Pharmaceuticals, Volume 17, Issue 8 (August 2024) – 66 articles

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