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Pharmaceuticals, Volume 17, Issue 6 (June 2024) – 153 articles

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19 pages, 1110 KiB  
Article
The Antimicrobial Effect of Cornus mas L. and Sorbus aucuparia L. Fruit Extracts against Resistant Uropathogens in Correlation with the Prevalence of Urinary Tract Infections in Companion Animals
by Mara Aurori, Cristiana Ștefania Novac, George Cosmin Nadăș, Smaranda Crăciun, Nicodim Fiţ and Sanda Andrei
Pharmaceuticals 2024, 17(6), 814; https://doi.org/10.3390/ph17060814 - 20 Jun 2024
Viewed by 384
Abstract
Urinary tract infections (UTIs) are a widespread condition in pets, with many antibiotics being prescribed, contributing to the rise in antimicrobial resistance, which is a worldwide threat. This study’s main objective was to analyze the in vitro antimicrobial activity of Cornus mas and [...] Read more.
Urinary tract infections (UTIs) are a widespread condition in pets, with many antibiotics being prescribed, contributing to the rise in antimicrobial resistance, which is a worldwide threat. This study’s main objective was to analyze the in vitro antimicrobial activity of Cornus mas and Sorbus aucuparia fruit hydro-ethanolic extracts towards bacteria identified in the urine of companion animals experiencing UTIs. Urine samples were collected from dogs and cats (n = 83; 47 negative, 36 positive); several bacterial strains were identified (n = 49) belonging to the Escherichia, Enterococcus, Staphylococcus, Proteus, Klebsiella, Enterobacter, Pseudomonas, Acinetobacter, Leclercia, and Kocuria genera. Bacterial susceptibility was tested using the disk diffusion method, with the majority being resistant to several beta-lactams, quinolones, trimethoprim/sulfamethoxazole, and nitrofurantoin. Subsequently, 13 resistant isolates were selected to evaluate the fruits extracts’ antimicrobial potential using the agar well diffusion and broth microdilution methods. Cornus mas exhibited the greatest activity against Gram-negatives (primarily Pseudomonas luteola), while Sorbus aucuparia showed maximum effects towards Gram-positives (particularly Enterococcus faecalis). The MIC was 0.01 μg/μL for both extracts; the MBC was 0.08 μg/μL for Cornus mas and 0.05 μg/μL for Sorbus aucuparia. However, Cornus mas showed a stronger bactericidal effect. This is the first study to investigate these fruit extracts in UTI isolates of companion animals, and these extracts might be used as substitutes or adjuvants for antibiotics, thus contributing to a reduction in antimicrobial resistance. Full article
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31 pages, 618 KiB  
Review
Cannabinoids: Potential for Modulation and Enhancement When Combined with Vitamin B12 in Case of Neurodegenerative Disorders
by Anna Aleksandra Kaszyńska
Pharmaceuticals 2024, 17(6), 813; https://doi.org/10.3390/ph17060813 - 20 Jun 2024
Viewed by 213
Abstract
The enduring relationship between humanity and the cannabis plant has witnessed significant transformations, particularly with the widespread legalization of medical cannabis. This has led to the recognition of diverse pharmacological formulations of medical cannabis, containing 545 identified natural compounds, including 144 phytocannabinoids like [...] Read more.
The enduring relationship between humanity and the cannabis plant has witnessed significant transformations, particularly with the widespread legalization of medical cannabis. This has led to the recognition of diverse pharmacological formulations of medical cannabis, containing 545 identified natural compounds, including 144 phytocannabinoids like Δ9-THC and CBD. Cannabinoids exert distinct regulatory effects on physiological processes, prompting their investigation in neurodegenerative diseases. Recent research highlights their potential in modulating protein aggregation and mitochondrial dysfunction, crucial factors in conditions such as Alzheimer’s Disease, multiple sclerosis, or Parkinson’s disease. The discussion emphasizes the importance of maintaining homeodynamics in neurodegenerative disorders and explores innovative therapeutic approaches such as nanoparticles and RNA aptamers. Moreover, cannabinoids, particularly CBD, demonstrate anti-inflammatory effects through the modulation of microglial activity, offering multifaceted neuroprotection including mitigating aggregation. Additionally, the potential integration of cannabinoids with vitamin B12 presents a holistic framework for addressing neurodegeneration, considering their roles in homeodynamics and nervous system functioning including the hippocampal neurogenesis. The potential synergistic therapeutic benefits of combining CBD with vitamin B12 underscore a promising avenue for advancing treatment strategies in neurodegenerative diseases. However, further research is imperative to fully elucidate their effects and potential applications, emphasizing the dynamic nature of this field and its potential to reshape neurodegenerative disease treatment paradigms. Full article
(This article belongs to the Special Issue Therapeutic Potential for Cannabinoid and Its Receptor)
18 pages, 1168 KiB  
Article
Iron−Based Metal–Organic Frameworks as Multiple Cascade Synergistic Therapeutic Effect Nano−Drug Delivery Systems for Effective Tumor Elimination
by Heming Zheng, Guanghui An, Xiaohui Yang, Lei Huang, Nannan Wang and Yanqiu Zhu
Pharmaceuticals 2024, 17(6), 812; https://doi.org/10.3390/ph17060812 - 20 Jun 2024
Viewed by 206
Abstract
Efforts have been made to improve the therapeutic efficiency of tumor treatments, and metal–organic frameworks (MOFs) have shown excellent potential in tumor therapy. Monotherapy for the treatment of tumors has limited effects due to the limitation of response conditions and inevitable multidrug resistance, [...] Read more.
Efforts have been made to improve the therapeutic efficiency of tumor treatments, and metal–organic frameworks (MOFs) have shown excellent potential in tumor therapy. Monotherapy for the treatment of tumors has limited effects due to the limitation of response conditions and inevitable multidrug resistance, which seriously affect the clinical therapeutic effect. In this study, we chose to construct a multiple cascade synergistic tumor drug delivery system MIL−101(Fe)−DOX−TCPP−MnO2@PDA−Ag (MDTM@P−Ag) using MOFs as drug carriers. Under near−infrared (NIR) laser irradiation, 5,10,15,20−tetrakis(4−carboxyphenyl)porphyrin (TCPP) and Ag NPs loaded on MDTM@P−Ag can be activated to generate cytotoxic reactive oxygen species (ROS) and achieve photothermal conversion, thus effectively inducing the apoptosis of tumor cells and achieving a combined photodynamic/photothermal therapy. Once released at the tumor site, manganese dioxide (MnO2) can catalyze the decomposition of hydrogen peroxide (H2O2) in the acidic microenvironment of the tumor to generate oxygen (O2) and alleviate the hypoxic environment of the tumor. Fe3+/Mn2+ will mediate a Fenton/Fenton−like reaction to generate cytotoxic hydroxyl radicals (·OH), while depleting the high concentration of glutathione (GSH) in the tumor, thus enhancing the chemodynamic therapeutic effect. The successful preparation of the tumor drug delivery system and its good synergistic chemodynamic/photodynamic/photothermal therapeutic effect in tumor treatment can be demonstrated by the experimental results of material characterization, performance testing and in vitro experiments. Full article
(This article belongs to the Section Pharmaceutical Technology)
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14 pages, 7973 KiB  
Systematic Review
Efficacy and Safety of Pharmacological Treatment in Patients with Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis
by He Zhu, Bei Wen, Jijun Xu, Yuelun Zhang, Li Xu and Yuguang Huang
Pharmaceuticals 2024, 17(6), 811; https://doi.org/10.3390/ph17060811 - 20 Jun 2024
Viewed by 163
Abstract
Complex regional pain syndrome (CRPS) is a disabling condition that usually affects the extremities after trauma or surgery. At present, there is no FDA-approved pharmacological treatment for patients with CRPS. We performed this systematic review and meta-analysis to evaluate the efficacy and safety [...] Read more.
Complex regional pain syndrome (CRPS) is a disabling condition that usually affects the extremities after trauma or surgery. At present, there is no FDA-approved pharmacological treatment for patients with CRPS. We performed this systematic review and meta-analysis to evaluate the efficacy and safety of pharmacological therapies and determine the best strategy for CRPS. We searched the databases, including PubMed, Embase, Cochrane, Web of Science, Scopus, and ClinicalTrials.gov, for published eligible randomized controlled trials (RCTs) comparing pharmacological treatment with placebo in CRPS patients. Target patients were diagnosed with CRPS according to Budapest Criteria in 2012 or the 1994 consensus-based IASP CRPS criteria. Finally, 23 RCTs comprising 1029 patients were included. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty (confidence in evidence and quality of evidence). Direct meta-analysis showed that using bisphosphonates (BPs) (mean difference [MD] −2.21, 95% CI −4.36–−0.06, p = 0.04, moderate certainty) or ketamine (mean difference [MD] −0.78, 95% CI −1.51–−0.05, p = 0.04, low certainty) could provide long-term (beyond one month) pain relief. However, there was no statistically significant difference in the efficacy of short-term pain relief. Ketamine (rank p = 0.55) and BPs (rank p = 0.61) appeared to be the best strategies for CRPS pain relief. Additionally, BPs (risk ratio [RR] = 1.86, 95% CI 1.34–2.57, p < 0.01, moderate certainty) and ketamine (risk ratio [RR] = 3.45, 95% CI 1.79–6.65, p < 0.01, moderate certainty) caused more adverse events, which were mild, and no special intervention was required. In summary, among pharmacological interventions, ketamine and bisphosphonate injection seemed to be the best treatment for CRPS without severe adverse events. Full article
(This article belongs to the Section Pharmacology)
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24 pages, 7124 KiB  
Article
Pharmacological Activation of SIRT3 Modulates the Response of Cancer Cells to Acidic pH
by Michele Aventaggiato, Tania Arcangeli, Enza Vernucci, Federica Barreca, Luigi Sansone, Laura Pellegrini, Elena Pontemezzo, Sergio Valente, Rossella Fioravanti, Matteo Antonio Russo, Antonello Mai and Marco Tafani
Pharmaceuticals 2024, 17(6), 810; https://doi.org/10.3390/ph17060810 - 20 Jun 2024
Viewed by 234
Abstract
Cancer cells modulate their metabolism, creating an acidic microenvironment that, in turn, can favor tumor progression and chemotherapy resistance. Tumor cells adopt strategies to survive a drop in extracellular pH (pHe). In the present manuscript, we investigated the contribution of mitochondrial sirtuin 3 [...] Read more.
Cancer cells modulate their metabolism, creating an acidic microenvironment that, in turn, can favor tumor progression and chemotherapy resistance. Tumor cells adopt strategies to survive a drop in extracellular pH (pHe). In the present manuscript, we investigated the contribution of mitochondrial sirtuin 3 (SIRT3) to the adaptation and survival of cancer cells to a low pHe. SIRT3-overexpressing and silenced breast cancer cells MDA-MB-231 and human embryonic kidney HEK293 cells were grown in buffered and unbuffered media at pH 7.4 and 6.8 for different times. mRNA expression of SIRT3 and CAVB, was measured by RT-PCR. Protein expression of SIRT3, CAVB and autophagy proteins was estimated by western blot. SIRT3-CAVB interaction was determined by immunoprecipitation and proximity ligation assays (PLA). Induction of autophagy was studied by western blot and TEM. SIRT3 overexpression increases the survival of both cell lines. Moreover, we demonstrated that SIRT3 controls intracellular pH (pHi) through the regulation of mitochondrial carbonic anhydrase VB (CAVB). Interestingly, we obtained similar results by using MC2791, a new SIRT3 activator. Our results point to the possibility of modulating SIRT3 to decrease the response and resistance of tumor cells to the acidic microenvironment and ameliorate the effectiveness of anticancer therapy. Full article
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18 pages, 2560 KiB  
Article
The Influence of an Acute Administration of Cannabidiol or Rivastigmine, Alone and in Combination, on Scopolamine-Provoked Memory Impairment in the Passive Avoidance Test in Mice
by Marta Kruk-Slomka, Tomasz Slomka and Grazyna Biala
Pharmaceuticals 2024, 17(6), 809; https://doi.org/10.3390/ph17060809 - 20 Jun 2024
Viewed by 211
Abstract
Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding environment. However, sometimes there are unfavourable changes in the functioning of the brain and memory [...] Read more.
Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding environment. However, sometimes there are unfavourable changes in the functioning of the brain and memory deficits occur, which may be associated with various diseases. Disturbances in the cholinergic system lead to abnormalities in memory functioning and are an essential part of clinical symptoms of many neurodegenerative diseases. However, their treatment is difficult and still unsatisfactory; thus, it is necessary to search for new drugs and their targets, being an alternative method of mono- or polypharmacotherapy. One of the possible strategies for the modulation of memory-related cognitive disorders is connected with the endocannabinoid system (ECS). The aim of the present study was to determine for the first time the effect of administration of natural cannabinoid compound (cannabidiol, CBD) and rivastigmine alone and in combination on the memory disorders connected with cholinergic dysfunctions in mice, provoked by using an antagonist of muscarinic cholinergic receptor—scopolamine. To assess and understand the memory-related effects in animals, we used the passive avoidance (PA) test, commonly used to examine the different stages of memory. An acute administration of CBD (1 mg/kg) or rivastigmine (0.5 mg/kg) significantly affected changes in scopolamine-induced disturbances in three different memory stages (acquisition, consolidation, and retrieval). Interestingly, co-administration of CBD (1 mg/kg) and rivastigmine (0.5 mg/kg) also attenuated memory impairment provoked by scopolamine (1 mg/kg) injection in the PA test in mice, but at a much greater extent than administered alone. The combination therapy of these two compounds, CBD and rivastigmine, appears to be more beneficial than substances administered alone in reducing scopolamine-induced cognitive impairment. This polytherapy seems to be favourable in the pharmacotherapy of various cognitive disorders, especially those in which cholinergic pathways are implicated. Full article
(This article belongs to the Special Issue Therapeutic Potential for Cannabinoid and Its Receptor)
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17 pages, 4180 KiB  
Article
Amoebicidal Effect of COVID Box Molecules against Acanthamoeba: A Study of Cell Death
by Ines Sifaoui, Rubén L. Rodríguez-Expósito, María Reyes-Batlle, Robert Sutak, José E. Piñero and Jacob Lorenzo-Morales
Pharmaceuticals 2024, 17(6), 808; https://doi.org/10.3390/ph17060808 - 20 Jun 2024
Viewed by 263
Abstract
Acanthamoeba spp. can cause a sight threatening disease. At present, the current treatments used to treat Acanthamoeba spp. Infections, such as biguanide-based antimicrobials, remain inefficacious, with the appearance of resistant forms and high cytotoxicity to host cells. In this study, an initial screening [...] Read more.
Acanthamoeba spp. can cause a sight threatening disease. At present, the current treatments used to treat Acanthamoeba spp. Infections, such as biguanide-based antimicrobials, remain inefficacious, with the appearance of resistant forms and high cytotoxicity to host cells. In this study, an initial screening was conducted against Acanthamoeba castellanii Neff and murine macrophages J774A.1 using alamarBlue™. Among the 160 compounds included in the cited box, 90% exhibited an inhibition of the parasite above 80%, while only 18.75% of the compounds inhibited the parasite with a lethality towards murine macrophage lower than 20%. Based on the amoebicidal activity, the cytotoxicity assay, and availability, Terconazole was chosen for the elucidation of the action mode in two clinical strains, Acanthamoeba culbertsoni and Acanthamoeba castellanii L10. A fluorescence image-based system and proteomic techniques were used to investigate the effect of the present azole on the cytoskeleton network and various programmed cell death features, including chromatin condensation and mitochondria dysfunction. Taking all the results together, we can suggest that Terconazole can induce programmed cell death (PCD) via the inhibition of sterol biosynthesis inhibition. Full article
(This article belongs to the Section Biopharmaceuticals)
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38 pages, 877 KiB  
Review
Pharmacovigilance in Vaccines: Importance, Main Aspects, Perspectives, and Challenges—A Narrative Review
by Katharine Valéria Saraiva Hodel, Bianca Sampaio Dotto Fiuza, Rodrigo Souza Conceição, Augusto Cezar Magalhães Aleluia, Thassila Nogueira Pitanga, Larissa Moraes dos Santos Fonseca, Camila Oliveira Valente, Cintia Silva Minafra-Rezende and Bruna Aparecida Souza Machado
Pharmaceuticals 2024, 17(6), 807; https://doi.org/10.3390/ph17060807 - 19 Jun 2024
Viewed by 270
Abstract
Pharmacovigilance plays a central role in safeguarding public health by continuously monitoring the safety of vaccines, being critical in a climate of vaccine hesitancy, where public trust is paramount. Pharmacovigilance strategies employed to gather information on adverse events following immunization (AEFIs) include pre-registration [...] Read more.
Pharmacovigilance plays a central role in safeguarding public health by continuously monitoring the safety of vaccines, being critical in a climate of vaccine hesitancy, where public trust is paramount. Pharmacovigilance strategies employed to gather information on adverse events following immunization (AEFIs) include pre-registration data, media reports, clinical trials, and societal reporting. Early detection of AEFIs during clinical trials is crucial for thorough safety analysis and preventing serious reactions once vaccines are deployed. This review highlights the importance of societal reporting, encompassing contributions from community members, healthcare workers, and pharmaceutical companies. Technological advancements such as quick response (QR) codes can facilitate prompt AEFI reporting. While vaccines are demonstrably safe, the possibility of adverse events necessitates continuous post-marketing surveillance. However, underreporting remains a challenge, underscoring the critical role of public engagement in pharmacovigilance. This narrative review comprehensively examines and synthesizes key aspects of virus vaccine pharmacovigilance, with special considerations for specific population groups. We explore applicable legislation, the spectrum of AEFIs associated with major vaccines, and the unique challenges and perspectives surrounding pharmacovigilance in this domain. Full article
(This article belongs to the Section Pharmacology)
14 pages, 4397 KiB  
Article
Potential Molecular Mechanism of Illicium simonsii Maxim Petroleum Ether Fraction in the Treatment of Hepatocellular Carcinoma
by Sihua Zou, Yanchun Wu, Meiqi Wen, Jiao Liu, Minghui Chen, Jingquan Yuan and Bei Zhou
Pharmaceuticals 2024, 17(6), 806; https://doi.org/10.3390/ph17060806 - 19 Jun 2024
Viewed by 233
Abstract
Traditional Chinese medicine (TCM) has been considered, for many years, an important source of medicine to treat different diseases. As a type of TCM, Illicium simonsii Maxim (ISM) is used as an anti-inflammatory, anti-bacterial, and anti-virus. Besides, ISM is also used in the [...] Read more.
Traditional Chinese medicine (TCM) has been considered, for many years, an important source of medicine to treat different diseases. As a type of TCM, Illicium simonsii Maxim (ISM) is used as an anti-inflammatory, anti-bacterial, and anti-virus. Besides, ISM is also used in the treatment of cancer. In order to evaluate the anti-hepatocellular carcinoma (HCC) activity, petroleum ether extract was prepared from part of the fruit of ISM. First, the compounds of the petroleum ether fraction of Illicium simonsii Maxim (PEIM) were identified using LC-MS/MS analysis. Next, the cell viability and morphological changes were evaluated by MTT assay and Hoechst staining. In addition, the effect of PEIM on the levels of inflammatory factors (TNF-α, IL-1β, and IL-6) was determined using the ELISA kit. Furthermore, apoptosis was evaluated by flow cytometry, and gene expression and the regulation of signaling pathways were investigated, respectively, by real-time fluorescence quantitative PCR (RT-qPCR) and western blot. Results showed that a total of 64 compounds were identified in the PEIM. Additionally, the PEIM had anti-HCC activity against HepG2 cells, in which the half maximal inhibitory concentration (IC50) was 55.03 μg·mL−1. As well, the PEIM was able to modulate the expression of TNF-α, IL-1β, and IL-6, while we also found that it induced HepG2 cell apoptosis through the activation of P53 mRNA and caspase-3 mRNA. Finally, the PEIM possibly downregulated the expression of TLR4, MyD88, p-NF-κBp65, TNF-α, IL-1β, INOS, IL-6, JAK2, STAT3, CyclinD1, CDK4, MDM2, and Bcl-2, and upregulated the expression of P53, P21, Bax, Cytochrome-C, Caspase-9, and Caspase-3 in HepG2 cells. These findings may confirm that the PEIM has possible anti-HCC effects. However, additional studies are required to fully understand the mechanisms of action of the PEIM and the signaling pathways involved in its effects. Moreover, the anti-HCC activity of the PEIM should be studied in vivo, and signaling pathways involved in its effects should be explored to develop the anti-HCC drug. Full article
(This article belongs to the Section Natural Products)
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24 pages, 4807 KiB  
Article
Sulfated Laminarin Polysaccharides Reduce the Adhesion of Nano-COM Crystals to Renal Epithelial Cells by Inhibiting Oxidative and Endoplasmic Reticulum Stress
by Tian-Qu He, Zhi Wang, Chuang-Ye Li, Yao-Wang Zhao, Xin-Yi Tong, Jing-Hong Liu and Jian-Ming Ouyang
Pharmaceuticals 2024, 17(6), 805; https://doi.org/10.3390/ph17060805 - 19 Jun 2024
Viewed by 187
Abstract
Purpose: Adhesion between calcium oxalate crystals and renal tubular epithelial cells is a vital cause of renal stone formation; however, the drugs that inhibit crystal adhesion and the mechanism of inhibition have yet to be explored. Methods: The cell injury model was constructed [...] Read more.
Purpose: Adhesion between calcium oxalate crystals and renal tubular epithelial cells is a vital cause of renal stone formation; however, the drugs that inhibit crystal adhesion and the mechanism of inhibition have yet to be explored. Methods: The cell injury model was constructed using nano-COM crystals, and changes in oxidative stress levels, endoplasmic reticulum (ER) stress levels, downstream p38 MAPK protein expression, apoptosis, adhesion protein osteopontin expression, and cell–crystal adhesion were examined in the presence of Laminarin polysaccharide (DLP) and sulfated DLP (SDLP) under protected and unprotected conditions. Results: Both DLP and SDLP inhibited nano-COM damage to human kidney proximal tubular epithelial cell (HK-2), increased cell viability, decreased ROS levels, reduced the opening of mitochondrial membrane permeability transition pore, markedly reduced ER Ca2+ ion concentration and adhesion molecule OPN expression, down-regulated the expression of ER stress signature proteins including CHOP, Caspase 12, and p38 MAPK, and decreased the apoptosis rate of cells. SDLP has a better protective effect on cells than DLP. Conclusions: SDLP protects HK-2 cells from nano-COM crystal-induced apoptosis by reducing oxidative and ER stress levels and their downstream factors, thereby reducing crystal–cell adhesion interactions and the risks of kidney stone formation. Full article
(This article belongs to the Special Issue Therapeutic Potential of Natural Products in Urolithiasis)
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15 pages, 1843 KiB  
Article
The Effectiveness of a Dietary Supplement with Honey, Propolis, Pelargonium sidoides Extract, and Zinc in Children Affected by Acute Tonsillopharyngitis: An Open, Randomized, and Controlled Trial
by Fabio Cardinale, Dionisio Franco Barattini, Valentina Martinucci, Maria Morariu Bordea, Luca Barattini and Serban Rosu
Pharmaceuticals 2024, 17(6), 804; https://doi.org/10.3390/ph17060804 - 19 Jun 2024
Viewed by 267
Abstract
Physicians are currently finding products for pediatric respiratory diseases of viral etiology to reduce the inappropriate use of antibiotic therapy. This study evaluated PediaFlù (Pediatrica S.r.l.), a dietary supplement already on the market composed of honey, propolis, Pelargonium sidoides extract, and zinc (DSHPP), [...] Read more.
Physicians are currently finding products for pediatric respiratory diseases of viral etiology to reduce the inappropriate use of antibiotic therapy. This study evaluated PediaFlù (Pediatrica S.r.l.), a dietary supplement already on the market composed of honey, propolis, Pelargonium sidoides extract, and zinc (DSHPP), in children affected by acute tonsillopharyngitis (ATR). The open-label, randomized, and controlled study compared DSHPP + standard of care (SoC) versus SoC alone for six days. Children between 3 and 10 years with an ATR ≤ 48 h, a negative rapid test for beta-hemolytic Streptococcus, or a culture identification of nasal and/or pharyngeal exudates were included. A tonsillitis severity score (TSS) and the number of treatment failures (using ibuprofen or high-dose paracetamol as rescue medication) were the primary endpoints. DSHPP+ SoC showed better performance than SoC alone for TSS sub-scores: throat pain and erythema on day 6 (p < 0.001 and p < 0.05), swallowing (p < 0.01 on day 4), and TSS total score on days 4 and 6 (p < 0.05 and p < 0.001). Only one patient (SoC group) had treatment failure for ibuprofen administration. No adverse events were reported. DSHPP is an optimal adjuvant in the treatment of URTI and could potentially be useful in the daily clinical practice of paediatricians evaluating the correct antibiotic prescription. Full article
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24 pages, 3921 KiB  
Article
Development and Optimization of Dipyridamole- and Roflumilast-Loaded Nanoemulsion and Nanoemulgel for Enhanced Skin Permeation: Formulation, Characterization, and In Vitro Assessment
by Zeyad Khalaf Maded, Souad Sfar, Ghada Abd Alrhman Taqa, Mohamed Ali Lassoued, Olfa Ben Hadj Ayed and Hayder Adnan Fawzi
Pharmaceuticals 2024, 17(6), 803; https://doi.org/10.3390/ph17060803 - 19 Jun 2024
Viewed by 248
Abstract
This study explores developing and optimizing a nanoemulsion (NE) system loaded with dipyridamole and roflumilast, aiming to improve skin penetration and retention. The NE formulation was further transformed into a nanoemulgel to enhance its application as a topical treatment for psoriasis. Solubility studies [...] Read more.
This study explores developing and optimizing a nanoemulsion (NE) system loaded with dipyridamole and roflumilast, aiming to improve skin penetration and retention. The NE formulation was further transformed into a nanoemulgel to enhance its application as a topical treatment for psoriasis. Solubility studies were conducted to select the oil, surfactant, and co-surfactant. Phase diagrams were constructed using the aqueous phase titration method. All the formulations were in nanoscale, and Formula (F2) (which contains oleic acid oil as the oil phase, a mixture of Surfactant Tween 80 and co-surfactant (ethanol) at a ratio of 1:2 in addition to distilled water as an aqueous phase in a ratio of 1:5:4, respectively) was the selected formula depending on the particle size, PDI, and zeta potential. Formula (F2) has the best ratio because it gives the smallest nanoemulsion globule size (particle size average of 167.1 nm), the best homogenicity (lowest PDI of 0.195), and the highest stability (higher zeta potential of −32.22). The selected formula was converted into a nanoemulgel by the addition of 0.5% (w/w) xanthan gum (average particle size of 172.7 nm) and the best homogenicity (lowest PDI of 0.121%) and highest stability (higher zeta potential of −28.31). In conclusion, the selected formula has accepted physical and chemical properties, which enhanced skin penetration. Full article
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27 pages, 7085 KiB  
Article
Ceftazidime and Usnic Acid Encapsulated in Chitosan-Coated Liposomes for Oral Administration against Colorectal Cancer-Inducing Escherichia coli
by Jaqueline Barbosa de Souza, Davi de Lacerda Coriolano, Rayza Camila dos Santos Silva, Sérgio Dias da Costa Júnior, Luís André de Almeida Campos, Iago Dillion Lima Cavalcanti, Mariane Cajubá de Britto Lira Nogueira, Valéria Rêgo Alves Pereira, Maria Carolina Accioly Brelaz-de-Castro and Isabella Macário Ferro Cavalcanti
Pharmaceuticals 2024, 17(6), 802; https://doi.org/10.3390/ph17060802 - 19 Jun 2024
Viewed by 253
Abstract
Escherichia coli has been associated with the induction of colorectal cancer (CRC). Thus, combined therapy incorporating usnic acid (UA) and antibiotics such as ceftazidime (CAZ), co-encapsulated in liposomes, could be an alternative. Coating the liposomes with chitosan (Chi) could facilitate the oral administration [...] Read more.
Escherichia coli has been associated with the induction of colorectal cancer (CRC). Thus, combined therapy incorporating usnic acid (UA) and antibiotics such as ceftazidime (CAZ), co-encapsulated in liposomes, could be an alternative. Coating the liposomes with chitosan (Chi) could facilitate the oral administration of this nanocarrier. Liposomes were prepared using the lipid film hydration method, followed by sonication and chitosan coating via the drip technique. Characterization included particle size, polydispersity index, zeta potential, pH, encapsulation efficiency, and physicochemical analyses. The minimum inhibitory concentration and minimum bactericidal concentration were determined against E. coli ATCC 25922, NCTC 13846, and H10407 using the microdilution method. Antibiofilm assays were conducted using the crystal violet method. The liposomes exhibited sizes ranging from 116.5 ± 5.3 to 240.3 ± 3.5 nm and zeta potentials between +16.4 ± 0.6 and +28 ± 0.8 mV. The encapsulation efficiencies were 51.5 ± 0.2% for CAZ and 99.94 ± 0.1% for UA. Lipo-CAZ-Chi and Lipo-UA-Chi exhibited antibacterial activity, inhibited biofilm formation, and preformed biofilms of E. coli. The Lipo-CAZ-UA-Chi and Lipo-CAZ-Chi + Lipo-UA-Chi formulations showed enhanced activities, potentially due to co-encapsulation or combination effects. These findings suggest potential for in vivo oral administration in future antibacterial and antibiofilm therapies against CRC-inducing bacteria. Full article
(This article belongs to the Section Pharmaceutical Technology)
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12 pages, 1252 KiB  
Article
Oral Administration of Efavirenz Dysregulates the Tph2 Gene in Brain Serotonergic Areas and Alters Weight and Mood in Mice
by Sandra Angélica Rojas-Osornio, Minerva Crespo-Ramírez, Vladimir Paredes-Cervantes, Antonio Mata-Marín, Ricardo Martínez-Lara, Miguel Pérez de la Mora and Emiliano Tesoro-Cruz
Pharmaceuticals 2024, 17(6), 801; https://doi.org/10.3390/ph17060801 - 18 Jun 2024
Viewed by 324
Abstract
Most HIV-antiretroviral drugs have adverse effects. Efavirenz (EFV) is an example of a drug with neuropsychiatric effects, such as anxiety, depression, and suicidal thoughts, in people living with HIV (PLWH). The mechanisms by which EFV causes neuropsychiatric alterations in PLWH are complex, multifactorial, [...] Read more.
Most HIV-antiretroviral drugs have adverse effects. Efavirenz (EFV) is an example of a drug with neuropsychiatric effects, such as anxiety, depression, and suicidal thoughts, in people living with HIV (PLWH). The mechanisms by which EFV causes neuropsychiatric alterations in PLWH are complex, multifactorial, and not fully understood, although several studies in animals have reported changes in brain energy metabolism, alterations in monoamine turnover, GABA, and glutamate levels, and changes in 5-HT receptors. In this report, we studied the effects of EFV on the serotonergic system in healthy mice, specifically, whether EFV results in alterations in the levels of the tryptophan hydroxylase 2 (Tph2) gene in the brain. EFV (10 mg/kg) and distilled water (1.5 µL/kg) (control group) were orally administered to the mice for 36 days. At the end of the treatment, Tph2 expression levels in mouse brains were measured, and mood was evaluated by three trials: the forced swim test, elevated plus maze, and open field test. Our results revealed dysregulation of Tph2 expression in the brainstem, amygdala, and hypothalamus in the EFV group, and 5-HT levels increased in the amygdala in the EFV group. In the behavioral tests, mice given EFV exhibited a passive avoidance response in the forced swim test and anxiety-like behavior in the elevated plus maze, and they lost weight. Herein, for the first time, we showed that EFV triggered dysregulation of the Tph2 gene in the three serotonergic areas studied; and 5-HT levels increased in the amygdala using the ELISA method. However, further studies will be necessary to clarify the increase of 5-HT in the amygdala as well as understand the paradoxical decrease in body weight with the simultaneous increase in food consumption. It will also be necessary to measure 5-HT by other techniques different from ELISA, such as HPLC. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Serotonin and Its Receptors)
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29 pages, 4012 KiB  
Review
A Comprehensive Research Review of Herbal Textual Research, Phytochemistry, Pharmacology, Traditional Uses, Clinical Application, Safety Evaluation, and Quality Control of Trollius chinensis Bunge
by Keke Yang, Zhen Wang, Panpan Wang, Lai Wang, Yuanjie Li, Lianqing He, Xiubo Liu, Jiao Xu, Yijin Duan and Wei Ma
Pharmaceuticals 2024, 17(6), 800; https://doi.org/10.3390/ph17060800 - 18 Jun 2024
Viewed by 419
Abstract
Trollius chinensis Bunge (TCB) is a perennial plant of the Ranunculaceae family with medicinal and edible values. It is widely distributed and commonly used in various regions, including Asia, Europe, and North America. The main chemical components of TCB include alkaloids, flavonoids, phenolic [...] Read more.
Trollius chinensis Bunge (TCB) is a perennial plant of the Ranunculaceae family with medicinal and edible values. It is widely distributed and commonly used in various regions, including Asia, Europe, and North America. The main chemical components of TCB include alkaloids, flavonoids, phenolic acids, and volatile oil compounds. TCB is renowned for its anti-inflammatory, heat-clearing, detoxifying, and eyesight-improving properties. Its dried flowers are commonly used as a traditional Chinese medicine indicated for the treatment of upper respiratory tract infections, chronic tonsillitis, pharyngitis, influenza, and bronchitis. Modern pharmacology has demonstrated the anti-cancer, anti-inflammatory, antihypertensive, and antioxidant effects of TCB. This study presents a comprehensive overview of various aspects of TCB, including herbal textual research, botany, phytochemistry, pharmacology, traditional uses, clinical application, and quality control, aiming to provide new ideas on the scientific application of TCB as well as the integration of modern research with traditional medicinal uses. Full article
(This article belongs to the Section Natural Products)
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11 pages, 2563 KiB  
Article
Identification of Benzodiazepine Use Based on Dried Blood Stains Analysis
by Lucía Fernández-López, Sandra Rodríguez, Alberto Cánovas-Cabanes, Francisco-Javier Teruel-Fernández, Pilar Almela, Juan-Pedro Hernández del Rincón, Javier Navarro-Zaragoza and María Falcón
Pharmaceuticals 2024, 17(6), 799; https://doi.org/10.3390/ph17060799 - 18 Jun 2024
Viewed by 310
Abstract
Biological matrices are typically used in forensic toxicological or pharmacological analysis: mainly blood, vitreous humor or urine. However, there are many cases in which crimes are a consequence of drug intoxication or drug abuse and they are not closed because over the months [...] Read more.
Biological matrices are typically used in forensic toxicological or pharmacological analysis: mainly blood, vitreous humor or urine. However, there are many cases in which crimes are a consequence of drug intoxication or drug abuse and they are not closed because over the months or years the samples become altered or decomposed. A dried blood stains test (DBS-MS) has recently been proposed to be used in drug toxicology when blood is found at a crime scene. This test could help an investigator to reveal what a person had consumed before the perpetration of the crime. In order to check the possibilities of this test, we analyzed several dried blood stains located on a cotton fabric. Therefore, the aim of this study was to determine if the analysis of a dried blood spot located on a cotton fabric could be an alternate source of obtaining toxicological results, particularly regarding benzodiazepines. We splashed blood stains on cotton fabric with different concentrations of the following benzodiazepines: alprazolam, bromazepam, clonazepam, diazepam and lorazepam, which were dried for 96 h and subsequently quantified by high-performance liquid chromatography coupled mass spectrometry (HPLC-MS). Our results show that it is possible to identify several benzodiazepines contained in a cotton fabric blood stain; consequently, this method may add another sample option to the toxicological analysis of biological vestiges found at a crime scene. Full article
(This article belongs to the Special Issue Psychiatric Drug Treatment and Drug Addiction)
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12 pages, 4374 KiB  
Article
Assessment of Brain-Derived Neurotrophic Factor on Retinal Structure and Visual Function in Rodent Models of Optic Nerve Crush
by Takazumi Taniguchi, Najam A. Sharif, Takashi Ota, Rafal A. Farjo and Rebecca Rausch
Pharmaceuticals 2024, 17(6), 798; https://doi.org/10.3390/ph17060798 - 18 Jun 2024
Viewed by 423
Abstract
The effects of brain-derived neurotrophic factor (BDNF) on retinal ganglion cell (RGC) survival and visual function were assessed in rat and mouse models of optic nerve (ON) crush. ONs were crushed on Day 1, followed by intravitreal injections of a vehicle or BDNF [...] Read more.
The effects of brain-derived neurotrophic factor (BDNF) on retinal ganglion cell (RGC) survival and visual function were assessed in rat and mouse models of optic nerve (ON) crush. ONs were crushed on Day 1, followed by intravitreal injections of a vehicle or BDNF on Days 1 and 8. The spatial frequency threshold was measured using optokinetic tracking on Days 7 and 14. On Day 15, ganglion cell complex (GCC) thickness was quantified using optical coherence tomography. Furthermore, all eyes were enucleated for immunohistochemical analysis of the surviving RGC somas and axons. BDNF significantly reduced the RGC soma in mice and increased GCC thickness in intact eyes, with apparent axonal swelling in both species. It displayed significantly greater RGC soma survival in eyes with ON injury, with moderately thicker axonal bundles in both species and a thicker GCC in rats. Visual function was significantly reduced in all ON-crushed animals, regardless of BDNF treatment. Thus, we obtained a comprehensive analysis of the structural and functional impact of BDNF in intact and ON-crushed eyes in two rodent models. Our results provide a foundation for further BDNF evaluation and the design of preclinical studies on neuroprotectants using BDNF as a reference positive control. Full article
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22 pages, 722 KiB  
Systematic Review
(3D) Bioprinting—Next Dimension of the Pharmaceutical Sector
by Anna Mihaylova, Dobromira Shopova, Nikoleta Parahuleva, Antoniya Yaneva and Desislava Bakova
Pharmaceuticals 2024, 17(6), 797; https://doi.org/10.3390/ph17060797 - 17 Jun 2024
Viewed by 289
Abstract
To create a review of the published scientific literature on the benefits and potential perspectives of the use of 3D bio-nitrification in the field of pharmaceutics. This work was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [...] Read more.
To create a review of the published scientific literature on the benefits and potential perspectives of the use of 3D bio-nitrification in the field of pharmaceutics. This work was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting meta-analyses and systematic reviews. The scientific databases PubMed, Scopus, Google Scholar, and ScienceDirect were used to search and extract data using the following keywords: 3D bioprinting, drug research and development, personalized medicine, pharmaceutical companies, clinical trials, drug testing. The data points to several aspects of the application of bioprinting in pharmaceutics were reviewed. The main applications of bioprinting are in the development of new drug molecules as well as in the preparation of personalized drugs, but the greatest benefits are in terms of drug screening and testing. Growth in the field of 3D printing has facilitated pharmaceutical applications, enabling the development of personalized drug screening and drug delivery systems for individual patients. Bioprinting presents the opportunity to print drugs on demand according to the individual needs of the patient, making the shape, structure, and dosage suitable for each of the patient’s physical conditions, i.e., print specific drugs for controlled release rates; print porous tablets to reduce swallowing difficulties; make transdermal microneedle patches to reduce patient pain; and so on. On the other hand, bioprinting can precisely control the distribution of cells and biomaterials to build organoids, or an Organ-on-a-Chip, for the testing of drugs on printed organs mimicking specified disease characteristics instead of animal testing and clinical trials. The development of bioprinting has the potential to offer customized drug screening platforms and drug delivery systems meeting a range of individualized needs, as well as prospects at different stages of drug development and patient therapy. The role of bioprinting in preclinical and clinical testing of drugs is also of significant importance in terms of shortening the time to launch a medicinal product on the market. Full article
(This article belongs to the Section Pharmaceutical Technology)
21 pages, 2142 KiB  
Article
Unraveling the Hippocampal Molecular and Cellular Alterations behind Tramadol and Tapentadol Neurobehavioral Toxicity
by Cristiana Soares-Cardoso, Sandra Leal, Susana I. Sá, Rita Dantas-Barros, Ricardo Jorge Dinis-Oliveira, Juliana Faria and Joana Barbosa
Pharmaceuticals 2024, 17(6), 796; https://doi.org/10.3390/ph17060796 - 17 Jun 2024
Viewed by 429
Abstract
Tramadol and tapentadol are chemically related opioids prescribed for the analgesia of moderate to severe pain. Although safer than classical opioids, they are associated with neurotoxicity and behavioral dysfunction, which arise as a concern, considering their central action and growing misuse and abuse. [...] Read more.
Tramadol and tapentadol are chemically related opioids prescribed for the analgesia of moderate to severe pain. Although safer than classical opioids, they are associated with neurotoxicity and behavioral dysfunction, which arise as a concern, considering their central action and growing misuse and abuse. The hippocampal formation is known to participate in memory and learning processes and has been documented to contribute to opioid dependence. Accordingly, the present study assessed molecular and cellular alterations in the hippocampal formation of Wistar rats intraperitoneally administered with 50 mg/kg tramadol or tapentadol for eight alternate days. Alterations were found in serum hydrogen peroxide, cysteine, homocysteine, and dopamine concentrations upon exposure to one or both opioids, as well as in hippocampal 8-hydroxydeoxyguanosine and gene expression levels of a panel of neurotoxicity, neuroinflammation, and neuromodulation biomarkers, assessed through quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of hippocampal formation sections showed increased glial fibrillary acidic protein (GFAP) and decreased cluster of differentiation 11b (CD11b) protein expression, suggesting opioid-induced astrogliosis and microgliosis. Collectively, the results emphasize the hippocampal neuromodulator effects of tramadol and tapentadol, with potential behavioral implications, underlining the need to prescribe and use both opioids cautiously. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of Opioids)
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22 pages, 537 KiB  
Systematic Review
Machine Learning Techniques for Predicting Drug-Related Side Effects: A Scoping Review
by Esmaeel Toni, Haleh Ayatollahi, Reza Abbaszadeh and Alireza Fotuhi Siahpirani
Pharmaceuticals 2024, 17(6), 795; https://doi.org/10.3390/ph17060795 - 17 Jun 2024
Viewed by 448
Abstract
Background: Drug safety relies on advanced methods for timely and accurate prediction of side effects. To tackle this requirement, this scoping review examines machine-learning approaches for predicting drug-related side effects with a particular focus on chemical, biological, and phenotypical features. Methods: This was [...] Read more.
Background: Drug safety relies on advanced methods for timely and accurate prediction of side effects. To tackle this requirement, this scoping review examines machine-learning approaches for predicting drug-related side effects with a particular focus on chemical, biological, and phenotypical features. Methods: This was a scoping review in which a comprehensive search was conducted in various databases from 1 January 2013 to 31 December 2023. Results: The results showed the widespread use of Random Forest, k-nearest neighbor, and support vector machine algorithms. Ensemble methods, particularly random forest, emphasized the significance of integrating chemical and biological features in predicting drug-related side effects. Conclusions: This review article emphasized the significance of considering a variety of features, datasets, and machine learning algorithms for predicting drug-related side effects. Ensemble methods and Random Forest showed the best performance and combining chemical and biological features improved prediction. The results suggested that machine learning techniques have some potential to improve drug development and trials. Future work should focus on specific feature types, selection techniques, and graph-based methods for even better prediction. Full article
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18 pages, 3308 KiB  
Article
Chlorogenic Acid as a Potential Therapeutic Agent for Cholangiocarcinoma
by Jiabao Liang, Tong Wen, Xiaojian Zhang and Xiaoling Luo
Pharmaceuticals 2024, 17(6), 794; https://doi.org/10.3390/ph17060794 - 17 Jun 2024
Viewed by 262
Abstract
Chlorogenic acid (CGA) has demonstrated anti-tumor effects across various cancers, but its role in cholangiocarcinoma (CCA) remains unclear. Our study revealed CGA’s potent anti-tumor effects on CCA, significantly suppressing cell proliferation, migration, colony formation, and invasion while inhibiting the epithelial–mesenchymal transition. CGA induced [...] Read more.
Chlorogenic acid (CGA) has demonstrated anti-tumor effects across various cancers, but its role in cholangiocarcinoma (CCA) remains unclear. Our study revealed CGA’s potent anti-tumor effects on CCA, significantly suppressing cell proliferation, migration, colony formation, and invasion while inhibiting the epithelial–mesenchymal transition. CGA induced apoptosis, modulated cell cycle progression, and exhibited a stable binding affinity to AKR1B10 in CCA. AKR1B10 was highly expressed in RBE cells, and CGA treatment reduced AKR1B10 expression. Knocking out AKR1B10 inhibited the proliferation of RBE cells, whereas the overexpression of AKR1B10 promoted their proliferation. Additionally, CGA suppressed the proliferation of RBE cells with AKR1B10 overexpression. Mechanistically, AKR1B10 activated AKT, and CGA exerted its inhibitory effect by reducing AKR1B10 levels, thereby suppressing AKT activation. Furthermore, CGA facilitated the polarization of tumor-associated macrophages towards an anti-tumor phenotype and enhanced T-cell cytotoxicity. These findings underscore CGA’s potential as a promising therapeutic agent for CCA treatment. Full article
(This article belongs to the Section Natural Products)
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21 pages, 4713 KiB  
Article
Approved and Commercialized Antidiabetic Medicines (Excluding Insulin) in Seven European Countries—A Cross-Sectional Comparison
by Ana-Maria Atănăsoie, Robert Viorel Ancuceanu, Dušanka Krajnović, Magdalena Waszyk-Nowaczyk, Marcin Skotnicki, Dorota Tondowska, Guenka Petrova, Andrei Marian Niculae and Adriana-Elena Tăerel
Pharmaceuticals 2024, 17(6), 793; https://doi.org/10.3390/ph17060793 - 17 Jun 2024
Viewed by 355
Abstract
Diabetes mellitus is a complex, multifactorial, progressive condition with a variety of approved therapeutic options. The purpose of this study was to offer an overview of the authorized antidiabetic medicines (excluding insulin) compared with marketed products in seven European countries. Data were obtained [...] Read more.
Diabetes mellitus is a complex, multifactorial, progressive condition with a variety of approved therapeutic options. The purpose of this study was to offer an overview of the authorized antidiabetic medicines (excluding insulin) compared with marketed products in seven European countries. Data were obtained from primary sources, including the websites of national authorities and directly from specialists in the countries of interest. The range of marketed medicines compared with the authorized group was assessed in terms of active pharmaceutical ingredients (>60% in Bulgaria, France, Serbia), brand names (>70% in Bulgaria, the Czech Republic, Romania, Serbia, Spain), pharmaceutical forms (>60% in all countries), strengths (>60% in Bulgaria, the Czech Republic, Romania, Serbia, Spain), marketing authorization holder (≥50% in all countries) and the status of medicine. Spain was found to have the highest number of products based on most of these attributes. Over 90% of authorized medicines had a pharmacy price in Serbia. Regarding the newer class of GLP-1 receptor agonists, a retail price for all approved substances was available in Bulgaria, Romania, Serbia, and Spain. Only one brand name with one concentration was found available for some agents, being susceptible to drug shortages: glibenclamide (Romania, Serbia, Spain), glipizide (the Czech Republic, Poland, Romania, Spain), glisentide (Spain), acarbose (the Czech Republic), sitagliptin (Bulgaria, Poland), vildagliptin (the Czech Republic, Poland) and saxagliptin (the Czech Republic, France, Romania, Serbia). An overview of the national and international therapeutic options may allow competent authorities and health professionals to take rapid measures in case of supply problems or health crises. Full article
(This article belongs to the Section Pharmacology)
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13 pages, 1874 KiB  
Article
Effects of the DL76 Antagonist/Inverse Agonist of Histamine H3 Receptors on Experimental Periodontitis in Rats: Morphological Studies
by Mariusz Geremek, Bogna Drozdzowska, Dorota Łażewska, Katarzyna Kieć-Kononowicz and Jerzy Jochem
Pharmaceuticals 2024, 17(6), 792; https://doi.org/10.3390/ph17060792 - 17 Jun 2024
Viewed by 343
Abstract
Background: Periodontitis preceded by gingivitis is the most common form of periodontal disease and occurs due to the interaction of microorganisms present in the complex bacterial aggregates of dental plaque biofilm and their metabolism products with periodontal tissues. Histamine is a heterocyclic biogenic [...] Read more.
Background: Periodontitis preceded by gingivitis is the most common form of periodontal disease and occurs due to the interaction of microorganisms present in the complex bacterial aggregates of dental plaque biofilm and their metabolism products with periodontal tissues. Histamine is a heterocyclic biogenic amine acting via four types of receptors. Histamine H3 receptors act as presynaptic auto/heteroreceptors to regulate the release of histamine and other neurotransmitters. Aim: Since the nervous system is able to regulate the progression of the inflammatory process and bone metabolism, the aim of this study was to investigate the effects of DL76, which acts as an antagonist/inverse agonist of H3 receptors, on the course of experimental periodontitis. Materials and methods: This study was conducted in 24 mature male Wistar rats weighing 245–360 g, aged 6–8 weeks. A silk ligature was placed on the second maxillary molar of the right maxilla under general anesthesia. From the day of ligating, DL76 and 0.9% NaCl solutions were administered subcutaneously for 28 days in the experimental and control groups, respectively. After the experiment, histopathological, immunohistochemical and radiological examinations were performed. Results: Ligation led to the development of the inflammatory process with lymphocytic infiltration, increased epithelial RANKL and OPG expression as well as bone resorption. DL76 evoked a reduction in (1) lymphocytic infiltration, (2) RANKL and OPG expression as well as (3) bone resorption since the medians of the mesial and distal interdental spaces in the molars with induced periodontitis were 3.56-fold and 10-fold lower compared to the corresponding values in saline-treated animals with periodontitis. Conclusion: DL76 is able to inhibit the progression of experimental periodontitis in rats, as demonstrated by a reduction in the inflammatory cell infiltration, a decrease in the RANKL/RANK OPG pathway expression and a reduction in the alveolar bone resorption. Full article
(This article belongs to the Special Issue Histamine Receptor Ligands in Medicinal Chemistry)
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32 pages, 5347 KiB  
Review
Swellable Microneedles in Drug Delivery and Diagnostics
by Hossein Omidian and Sumana Dey Chowdhury
Pharmaceuticals 2024, 17(6), 791; https://doi.org/10.3390/ph17060791 - 16 Jun 2024
Viewed by 481
Abstract
This manuscript explores the transformative potential of swellable microneedles (MNs) in drug delivery and diagnostics, addressing critical needs in medical treatment and monitoring. Innovations in hydrogel-integrated MN arrays facilitate controlled drug release, thereby expanding treatment options for chronic diseases and conditions that require [...] Read more.
This manuscript explores the transformative potential of swellable microneedles (MNs) in drug delivery and diagnostics, addressing critical needs in medical treatment and monitoring. Innovations in hydrogel-integrated MN arrays facilitate controlled drug release, thereby expanding treatment options for chronic diseases and conditions that require precise dosage control. The review covers challenges, such as scalability, patient compliance, and manufacturing processes, as well as achievements in advanced manufacturing, biocompatibility, and versatile applications. Nonetheless, limitations in physiological responsiveness and long-term stability remain, necessitating further research in material innovation and integration with digital technologies. Future directions focus on expanding biomedical applications, material advancements, and regulatory considerations for widespread clinical adoption. Full article
(This article belongs to the Special Issue Hydrogels for Pharmaceutical and Biomedical Applications 2024)
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35 pages, 1938 KiB  
Review
White-to-Beige and Back: Adipocyte Conversion and Transcriptional Reprogramming
by Stanislav Boychenko, Vera S. Egorova, Andrew Brovin and Alexander D. Egorov
Pharmaceuticals 2024, 17(6), 790; https://doi.org/10.3390/ph17060790 - 16 Jun 2024
Viewed by 735
Abstract
Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution of hereditary and behavioral factors, such as nutritional inadequacy, along with the influences of environment and reduced [...] Read more.
Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution of hereditary and behavioral factors, such as nutritional inadequacy, along with the influences of environment and reduced physical activity. Two types of adipose tissue widely known are white and brown. While white adipose tissue functions predominantly as a key energy storage, brown adipose tissue has a greater mass of mitochondria and expresses the uncoupling protein 1 (UCP1) gene, which allows thermogenesis and rapid catabolism. Even though white and brown adipocytes are of different origin, activation of the brown adipocyte differentiation program in white adipose tissue cells forces them to transdifferentiate into “beige” adipocytes, characterized by thermogenesis and intensive lipolysis. Nowadays, researchers in the field of small molecule medicinal chemistry and gene therapy are making efforts to develop new drugs that effectively overcome insulin resistance and counteract obesity. Here, we discuss various aspects of white-to-beige conversion, adipose tissue catabolic re-activation, and non-shivering thermogenesis. Full article
(This article belongs to the Special Issue Anti-obesity and Anti-aging Natural Products)
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20 pages, 15838 KiB  
Article
Daphnetin Ameliorates Neuropathic Pain via Regulation of Microglial Responses and Glycerophospholipid Metabolism in the Spinal Cord
by Wulin Liang, Tianrui Zhang, Mingqian Zhang, Jiahui Gao, Rikang Huang, Xiyan Huang, Jianhua Chen, Lu Cheng, Liyuan Zhang, Zhishan Huang, Qiling Tan, Zhanhong Jia and Shuofeng Zhang
Pharmaceuticals 2024, 17(6), 789; https://doi.org/10.3390/ph17060789 - 16 Jun 2024
Viewed by 296
Abstract
Neuropathic pain (NP) is a common type of chronic pain caused by a lesion or disease of the somatosensory nervous system. This condition imposes a considerable economic burden on society and patients. Daphnetin (DAP) is a natural product isolated from a Chinese medicinal [...] Read more.
Neuropathic pain (NP) is a common type of chronic pain caused by a lesion or disease of the somatosensory nervous system. This condition imposes a considerable economic burden on society and patients. Daphnetin (DAP) is a natural product isolated from a Chinese medicinal herb with various pharmacological activities, such as anti-inflammatory and analgesic properties. However, the underlying mechanisms of these effects are not fully understood. In the present study, we aimed to investigate DAP’s anti-inflammatory and analgesic effects and explore the underlying mechanisms of action. The NP model was established as chronic constrictive injury (CCI) of the sciatic nerve, and pain sensitivity was evaluated by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal threshold (TWT). The activation of microglia in the spinal dorsal horn was measured via immunofluorescence staining. Protein levels were measured using a western blot assay. Using a mass-spectrometry proteomics platform and an LC-MS/MS-based metabolomics platform, proteins and metabolites in spinal cord tissues were extracted and analyzed. DAP treatment ameliorated the MWT and TWT in CCI rats. The expression of IL-1β, IL-6, and TNF-α was inhibited by DAP treatment in the spinal cords of CCI rats. Moreover, the activation of microglia was suppressed after DAP treatment. The elevation in the levels of P2X4, IRF8, IRF5, BDNF, and p-P38/P38 in the spinal cord caused by CCI was inhibited by DAP. Proteomics and metabolomics results indicated that DAP ameliorated the imbalance of glycerophospholipid metabolism in the spinal cords of CCI rats. DAP can potentially ameliorate NP by regulating microglial responses and glycerophospholipid metabolism in the CCI model. This study provides a pharmacological justification for using DAP in the management of NP. Full article
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27 pages, 6753 KiB  
Review
Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19-Exacerbated Dementia and Alzheimer’s Disease
by Nikita Navolokin, Viktoria Adushkina, Daria Zlatogorskaya, Valeria Telnova, Arina Evsiukova, Elena Vodovozova, Anna Eroshova, Elina Dosadina, Sergey Diduk and Oxana Semyachkina-Glushkovskaya
Pharmaceuticals 2024, 17(6), 788; https://doi.org/10.3390/ph17060788 - 16 Jun 2024
Viewed by 1109
Abstract
The COVID-19 pandemic, caused by infection with the SARS-CoV-2 virus, is associated with cognitive impairment and Alzheimer’s disease (AD) progression. Once it enters the brain, the SARS-CoV-2 virus stimulates accumulation of amyloids in the brain that are highly toxic to neural cells. These [...] Read more.
The COVID-19 pandemic, caused by infection with the SARS-CoV-2 virus, is associated with cognitive impairment and Alzheimer’s disease (AD) progression. Once it enters the brain, the SARS-CoV-2 virus stimulates accumulation of amyloids in the brain that are highly toxic to neural cells. These amyloids may trigger neurological symptoms in COVID-19. The meningeal lymphatic vessels (MLVs) play an important role in removal of toxins and mediate viral drainage from the brain. MLVs are considered a promising target to prevent COVID-19-exacerbated dementia. However, there are limited methods for augmentation of MLV function. This review highlights new discoveries in the field of COVID-19-mediated amyloid accumulation in the brain associated with the neurological symptoms and the development of promising strategies to stimulate clearance of amyloids from the brain through lymphatic and other pathways. These strategies are based on innovative methods of treating brain dysfunction induced by COVID-19 infection, including the use of photobiomodulation, plasmalogens, and medicinal herbs, which offer hope for addressing the challenges posed by the SARS-CoV-2 virus. Full article
(This article belongs to the Special Issue Multi-target Drug Treatments for Neurodegenerative Disease)
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16 pages, 1968 KiB  
Article
In Vitro/In Vivo Correlation of Two Extended-Release Cilostazol Formulations
by Kyoung Ah Min, Na Young Kim, Min Jeong Jin, Doyeon Kim, Yoonseo Ma, Sandeep Karna and Young-Joon Park
Pharmaceuticals 2024, 17(6), 787; https://doi.org/10.3390/ph17060787 - 16 Jun 2024
Viewed by 241
Abstract
This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using [...] Read more.
This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal® SR 200 mg capsules have higher drug release rates than Cilostan® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC0-t, and AUC0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal® SR 200 mg capsules compared with Cilostan® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan® CR 200 mg tablets. Full article
(This article belongs to the Section Pharmaceutical Technology)
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17 pages, 1844 KiB  
Article
Phenolic Composition of Crataegus monogyna Jacq. Extract and Its Anti-Inflammatory, Hepatoprotective, and Antileukemia Effects
by Fatima Ez-Zahra Amrati, Ibrahim Mssillou, Smahane Boukhira, Mehdi Djiddi Bichara, Youness El Abdali, Renata Galvão de Azevedo, Chebaibi Mohamed, Meryem Slighoua, Raffaele Conte, Sotirios Kiokias, Gemilson Soares Pontes and Dalila Bousta
Pharmaceuticals 2024, 17(6), 786; https://doi.org/10.3390/ph17060786 - 15 Jun 2024
Viewed by 332
Abstract
Crataegus monogyna (C. monogyna) is a prominent plant used in Moroccan traditional medicine. This study investigated the phenolic composition and the anti-inflammatory, the hepatoprotective, and the anticancer activities of a hydroethanolic extract of C. monogyna leaves and stems. Ultra-high-performance liquid chromatography [...] Read more.
Crataegus monogyna (C. monogyna) is a prominent plant used in Moroccan traditional medicine. This study investigated the phenolic composition and the anti-inflammatory, the hepatoprotective, and the anticancer activities of a hydroethanolic extract of C. monogyna leaves and stems. Ultra-high-performance liquid chromatography identified the phenolic profile. The in vitro anticancer activity was evaluated using the MTT assay on HL-60 and K-562 myeloleukemia cells and liver (Huh-7) cell lines. The anti-inflammatory effect was assessed in vivo using carrageenan-induced paw edema in rats. The hepatoprotective effect at 300 and 1000 mg/kg doses against the acetaminophen-induced hepatotoxicity on rats was studied for seven days. Additionally, molecular docking simulations were performed to evaluate the extract’s inhibitory potential against key targets: lipoxygenase, cytochrome P450, tyrosine kinase, and TRADD. The extract exhibited significant cytotoxic activity against K-562 and HL-60 cells, but not against lung cancer cells (Huh-7 line). The 1000 mg/kg dose demonstrated the most potent anti-inflammatory effect, inhibiting edema by 99.10% after 6 h. C. monogyna extract displayed promising hepatoprotective properties. Procyanidin (−7.27 kcal/mol), quercetin (−8.102 kcal/mol), and catechin (−9.037 kcal/mol) were identified as the most active molecules against lipoxygenase, cytochrome P450, and tyrosine kinase, respectively. These findings highlight the untapped potential of C. monogyna for further exploration in treating liver damage, inflammation, and leukemia. Full article
15 pages, 2205 KiB  
Article
Novel Anti-Enterovirus A71 Compounds Discovered by Repositioning Antivirals from the Open-Source MMV Pandemic Response Box
by Nattinee Lochaiyakun, Potjanee Srimanote, Onruedee Khantisitthiporn and Jeeraphong Thanongsaksrikul
Pharmaceuticals 2024, 17(6), 785; https://doi.org/10.3390/ph17060785 - 14 Jun 2024
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Abstract
The open-source drug library, namely, MMV Pandemic Response Box, contains 153 antiviral agents, a chemically and pharmacologically diverse mixture of early-stage, emerging anti-infective scaffolds, and mature compounds currently undergoing clinical development. Hence, the Pandemic Response Box might contain compounds that bind and interfere [...] Read more.
The open-source drug library, namely, MMV Pandemic Response Box, contains 153 antiviral agents, a chemically and pharmacologically diverse mixture of early-stage, emerging anti-infective scaffolds, and mature compounds currently undergoing clinical development. Hence, the Pandemic Response Box might contain compounds that bind and interfere with target molecules or cellular pathways that are conserved or shared among the closely related viruses with enterovirus A71 (EV-A71). This study aimed to screen antiviral agents included in the Pandemic Response Box for repurposing to anti-EV-A71 activity and investigate the inhibitory effects of the compounds on viral replication. The compounds’ cytotoxicity and ability to rescue infected cells were determined by % cell survival using an SRB assay. The hit compounds were verified for anti-EV-A71 activity by virus reduction assays for viral RNA copy numbers, viral protein synthesis, and mature particle production using qRT-PCR, Western blot analysis, and CCID50 assay, respectively. It was found that some of the hit compounds could reduce EV-A71 genome replication and protein synthesis. D-D7 (2-pyridone-containing human rhinovirus 3C protease inhibitor) exhibited the highest anti-EV-A71 activity. Even though D-D7 has been originally indicated as a polyprotein processing inhibitor of human rhinovirus 3C protease, it could be repurposed as an anti-EV-A71 agent. Full article
(This article belongs to the Section Pharmacology)
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