Pharmaceuticals

22 pages, 3445 KiB

Open AccessArticle

Pharmacological Profile of the Purinergic P2Y Receptors That Modulate, in Response to ADPβS, the Vasodepressor Sensory CGRPergic Outflow in Pithed Rats

by Alejandro D. Miguel-Martínez, Juan Linares-Bedolla, Belinda Villanueva-Castillo, Kristian A. Haanes, Antoinette MaassenVanDenBrink and Carlos M. Villalón

Pharmaceuticals 2023, 16(3), 475; https://doi.org/10.3390/ph16030475 - 22 Mar 2023

Cited by 1 | Viewed by 1528

Abstract

Calcitonin gene-related peptide (CGRP), an endogenous neuropeptide released from perivascular sensory nerves, exerts a powerful vasodilatation. Interestingly, adenosine triphosphate (ATP) stimulates the release of CGRP by activation of prejunctional P2X_2/3 receptors, and adenosine 5′-O-2-thiodiphosphate (ADPβS), a stable adenosine diphosphate (ADP) analogue, produces [...] Read more.

Calcitonin gene-related peptide (CGRP), an endogenous neuropeptide released from perivascular sensory nerves, exerts a powerful vasodilatation. Interestingly, adenosine triphosphate (ATP) stimulates the release of CGRP by activation of prejunctional P2X_2/3 receptors, and adenosine 5′-O-2-thiodiphosphate (ADPβS), a stable adenosine diphosphate (ADP) analogue, produces vasodilator/vasodepressor responses by endothelial P2Y₁ receptors. Since the role of ADP in the prejunctional modulation of the vasodepressor sensory CGRPergic drive and the receptors involved remain unknown, this study investigated whether ADPβS inhibits this CGRPergic drive. Accordingly, 132 male Wistar rats were pithed and subsequently divided into two sets. In set 1, ADPβS (5.6 and 10 µg/kg·min) inhibited the vasodepressor CGRPergic responses by electrical stimulation of the spinal T₉–T₁₂ segment. This inhibition by ADPβS (5.6 µg/kg·min) was reverted after i.v. administration of the purinergic antagonists MRS2500 (300 µg/kg; P2Y₁) or MRS2211 (3000 µg/kg; P2Y₁₃), but not by PSB0739 (300 µg/kg; P2Y₁₂), MRS2211 (1000 µg/kg; P2Y₁₃) or the K_ATP blocker glibenclamide (20 mg/kg). In set 2, ADPβS (5.6 µg/kg·min) failed to modify the vasodepressor responses to exogenous α-CGRP. These results suggest that ADPβS inhibits CGRP release in perivascular sensory nerves. This inhibition, apparently unrelated to activation of ATP-sensitive K⁺ channels, involves P2Y₁ and probably P2Y₁₃, but not P2Y₁₂ receptors. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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27 pages, 1267 KiB

Open AccessReview

Recent Progress of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers as Ocular Drug Delivery Platforms

by Viliana Gugleva and Velichka Andonova

Pharmaceuticals 2023, 16(3), 474; https://doi.org/10.3390/ph16030474 - 22 Mar 2023

Cited by 12 | Viewed by 3098

Abstract

Sufficient ocular bioavailability is often considered a challenge by the researchers, due to the complex structure of the eye and its protective physiological mechanisms. In addition, the low viscosity of the eye drops and the resulting short ocular residence time further contribute to [...] Read more.

Sufficient ocular bioavailability is often considered a challenge by the researchers, due to the complex structure of the eye and its protective physiological mechanisms. In addition, the low viscosity of the eye drops and the resulting short ocular residence time further contribute to the observed low drug concentration at the target site. Therefore, various drug delivery platforms are being developed to enhance ocular bioavailability, provide controlled and sustained drug release, reduce the number of applications, and maximize therapy outcomes. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) exhibit all these benefits, in addition to being biocompatible, biodegradable, and susceptible to sterilization and scale-up. Furthermore, their successive surface modification contributes to prolonged ocular residence time (by adding cationic compounds), enhanced penetration, and improved performance. The review highlights the salient characteristics of SLNs and NLCs concerning ocular drug delivery, and updates the research progress in this area. Full article

(This article belongs to the Special Issue Current Insights on Lipid-Based Nanosystems 2023)

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20 pages, 5842 KiB

Open AccessArticle

FOXO3-Activated circFGFBP1 Inhibits Extracellular Matrix Degradation and Nucleus Pulposus Cell Death via miR-9-5p/BMP2 Axis in Intervertebral Disc Degeneration In Vivo and In Vitro

by Yanlin Tan, Xiaobin Wang, Yi Zhang, Zhehao Dai, Jing Li, Chuning Dong, Xingwang Yao, Chang Lu and Fei Chen

Pharmaceuticals 2023, 16(3), 473; https://doi.org/10.3390/ph16030473 - 22 Mar 2023

Cited by 1 | Viewed by 1204

Abstract

(1) Background: intervertebral disc degeneration (IVDD) defined as the degenerative changes in intervertebral disc is characterized by extracellular matrix (ECM) degradation and death in nucleus pulposus (NP) cells. (2) Methods: The model of IVDD was established in male Sprague Dawley rats using a [...] Read more.

(1) Background: intervertebral disc degeneration (IVDD) defined as the degenerative changes in intervertebral disc is characterized by extracellular matrix (ECM) degradation and death in nucleus pulposus (NP) cells. (2) Methods: The model of IVDD was established in male Sprague Dawley rats using a puncture of a 21-gauge needle at the endplates located in the L4/5 intervertebral disc. Primary NP cells were stimulated by 10 ng/mL IL-1β for 24 h to mimic IVDD impairment in vitro. (3) Results: circFGFBP1 was downregulated in the IVDD samples. circFGFBP1 upregulation inhibited apoptosis and extracellular matrix (ECM) degradation and promoted proliferation in IL-1β-stimulated NP cells. Additionally, circFGFBP1 upregulation mitigated the loss of NP tissue and the destruction of the intervertebral disc structure in vivo during IVDD. FOXO3 could bind to the circFGFBP1 promoter to enhance its expression. circFGFBP1 upregulated BMP2 expression in NP via sponging miR-9-5p. FOXO3 enhanced the protection of circFGFBP1 in IL-1β-stimulated NP cells, whereas a miR-9-5p increase partly reversed the protection. miR-9-5p downregulation contributed to the survival of IL-1β-stimulated NP cells, which was partially reversed by BMP2 silence. (4) Conclusions: FOXO3 could activate the transcription of circFGFBP1 via binding to its promoter, which resulted in the enhancement of BMP2 via sponging miR-9-5p and then inhibited apoptosis and ECM degradation in NP cells during IVDD. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 868 KiB

Open AccessBrief Report

Plasma and Cerebrospinal Fluid Concentrations of Micafungin Administered at High Doses in Critically Ill Infants with Systemic Candidiasis: A Pooled Analysis of Two Studies

by Domenico Umberto De Rose, Iliana Bersani, Maria Paola Ronchetti, Fiammetta Piersigilli, Sara Cairoli, Andrea Dotta, Amit Desai, Laura Lynn Kovanda, Bianca Maria Goffredo and Cinzia Auriti

Pharmaceuticals 2023, 16(3), 472; https://doi.org/10.3390/ph16030472 - 22 Mar 2023

Cited by 1 | Viewed by 1510

Abstract

Background: Neonates may require higher doses of micafungin than adults to reach the therapeutic effect for increased plasma clearance. Only poor and inconclusive data are available still now to support this hypothesis, especially with regard to central nervous system micafungin concentrations. To [...] Read more.

Background: Neonates may require higher doses of micafungin than adults to reach the therapeutic effect for increased plasma clearance. Only poor and inconclusive data are available still now to support this hypothesis, especially with regard to central nervous system micafungin concentrations. To assess the pharmacokinetics of increased doses (8 to 15 mg/kg/day) of micafungin in preterm and term neonates with invasive candidiasis and to complete previously presented results, we analyzed the pharmacokinetic data on a total of 53 newborns treated with micafungin, whereby 3 of them had Candida meningitis and hydrocephalus. Methods: Fifty-three neonates with systemic candidiasis, three of them with meningitis, were treated for at least 14 days with intravenous micafungin (Mycamine^®) at a dosage ranging from 8 to 15 mg/kg/day. Plasma and cerebrospinal fluid (CSF) concentrations of micafungin were measured before the drug administration and at 1, 2, and 8 h after the end of the infusion using high-performance liquid chromatography (HPLC). Systemic exposure was assessed according to AUC_0–24, plasma clearance (CL), and half-life measured in 52/53 patients, divided by chronological age. Results and conclusions: The mean micafungin clearance is higher in neonates than in older infants (0.036 L/h/kg before 28 days of life versus 0.028 L/h/kg after 120 days). The drug half-life is shorter in neonates than in older patients (13.5 h before 28 days of life versus 14.4 h after 120 days). With doses ranging between 8 and 15 mg/kg/day, micafungin crosses the blood–brain barrier reaching therapeutic levels in CSF. Full article

(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)

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9 pages, 1112 KiB

Open AccessOpinion

Heparin Mimetics and Their Impact on Extracellular Matrix Protein Assemblies

by Fabian Heide, Manuel Koch and Jörg Stetefeld

Pharmaceuticals 2023, 16(3), 471; https://doi.org/10.3390/ph16030471 - 22 Mar 2023

Viewed by 1555

Abstract

Heparan sulfate is a crucial extracellular matrix component that organizes structural features and functional protein processes. This occurs through the formation of protein–heparan sulfate assemblies around cell surfaces, which allow for the deliberate local and temporal control of cellular signaling. As such, heparin-mimicking [...] Read more.

Heparan sulfate is a crucial extracellular matrix component that organizes structural features and functional protein processes. This occurs through the formation of protein–heparan sulfate assemblies around cell surfaces, which allow for the deliberate local and temporal control of cellular signaling. As such, heparin-mimicking drugs can directly affect these processes by competing with naturally occurring heparan sulfate and heparin chains that then disturb protein assemblies and decrease regulatory capacities. The high number of heparan-sulfate-binding proteins that are present in the extracellular matrix can cause obscure pathological effects that should be considered and examined in more detail, especially when developing novel mimetics for clinical use. The objective of this article is to investigate recent studies that present heparan-sulfate-mediated protein assemblies and the impact of heparin mimetics on the assembly and function of these protein complexes. Full article

(This article belongs to the Special Issue Medicinal Chemistry and Pharmacological Activities of Heparin and Related Drugs)

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17 pages, 2907 KiB

Open AccessArticle

Suramin Affects the Renal VEGF-A/VEGFR Axis in Short-Term Streptozotocin-Induced Diabetes

by Gabriela Chyła-Danił, Kornelia Sałaga-Zaleska, Ewelina Kreft, Aleksandra Krzesińska, Sylwia Herman, Agnieszka Kuchta, Monika Sakowicz-Burkiewicz, Małgorzata Lenartowicz and Maciej Jankowski

Pharmaceuticals 2023, 16(3), 470; https://doi.org/10.3390/ph16030470 - 22 Mar 2023

Cited by 1 | Viewed by 2204

Abstract

Diabetic nephropathy (DN) accounts for approximately 50% of end-stage renal diseases. Vascular endothelial growth factor A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in DN, but its role is unclear. The lack of pharmacological tools to modify renal concentrations [...] Read more.

Diabetic nephropathy (DN) accounts for approximately 50% of end-stage renal diseases. Vascular endothelial growth factor A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in DN, but its role is unclear. The lack of pharmacological tools to modify renal concentrations further hinders the understanding of its role in DN. In this study, rats were evaluated after 3 weeks of streptozotocin-induced diabetes and two suramin treatments (10 mg/kg, ip). Vascular endothelial growth factor A expression was evaluated by western blot of glomeruli and immunofluorescence of the renal cortex. RT-PCR for receptors Vegfr1 mRNA and Vegfr2 mRNA quantitation was performed. The soluble adhesive molecules (sICAM-1, sVCAM-1) in blood were measured by ELISA and the vasoreactivity of interlobar arteries to acetylcholine was evaluated using wire myography. Suramin administration reduced the expression and intraglomerular localisation of VEGF-A. Increased VEGFR-2 expression in diabetes was reduced by suramin to non-diabetic levels. Diabetes reduced the sVCAM-1 concentrations. Suramin in diabetes restored acetylcholine relaxation properties to non-diabetic levels. In conclusion, suramin affects the renal VEGF-A/VEGF receptors axis and has a beneficial impact on endothelium-dependent relaxation of renal arteries. Thus, suramin may be used as a pharmacological agent to investigate the potential role of VEGF-A in the pathogenesis of renal vascular complications in short-term diabetes. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF) and VEGF Receptor Inhibitors in Health and Disease)

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26 pages, 8067 KiB

Open AccessArticle

Amphiphilic Cell-Penetrating Peptides Containing Arginine and Hydrophobic Residues as Protein Delivery Agents

by Jonathan Moreno, Khalid Zoghebi, David Salehi, Lois Kim, Sorour Khayyatnejad Shoushtari, Rakesh K. Tiwari and Keykavous Parang

Pharmaceuticals 2023, 16(3), 469; https://doi.org/10.3390/ph16030469 - 22 Mar 2023

Viewed by 1993

Abstract

The entry of proteins through the cell membrane is challenging, thus limiting their use as potential therapeutics. Seven cell-penetrating peptides, designed in our laboratory, were evaluated for the delivery of proteins. Fmoc solid-phase peptide synthesis was utilized for the synthesis of seven cyclic [...] Read more.

The entry of proteins through the cell membrane is challenging, thus limiting their use as potential therapeutics. Seven cell-penetrating peptides, designed in our laboratory, were evaluated for the delivery of proteins. Fmoc solid-phase peptide synthesis was utilized for the synthesis of seven cyclic or hybrid cyclic–linear amphiphilic peptides composed of hydrophobic (tryptophan (W) or 3,3-diphenylalanine (Dip) and positively-charged arginine (R) residues, such as [WR]₄, [WR]₉, [WWRR]₄, [WWRR]₅, [(RW)₅K](RW)₅, [R₅K]W₇, and [DipR]₅. Confocal microscopy was used to screen the peptides as a protein delivery system of model cargo proteins, green and red fluorescein proteins (GFP and RFP). Based on the confocal microscopy results, [WR]₉ and [DipR]₅ were found to be more efficient among all the peptides and were selected for further studies. [WR]₉ (1–10 µM) + protein (GFP and RFP) physical mixture did not show high cytotoxicity (>90% viability) in triple-negative breast cancer cells (MDA-MB-231) after 24 h, while [DipR]₅ (1–10 µM) physical mixture with GFP exhibited more than 81% cell viability. Confocal microscopy images revealed internalization of GFP and RFP in MDA-MB-231 cells using [WR]₉ (2–10 μM) and [DipR]₅ (1–10 µM). Fluorescence-activated cell sorting (FACS) analysis indicated that the cellular uptake of GFP was concentration-dependent in the presence of [WR]₉ in MDA-MB-231 cells after 3 h of incubation at 37 °C. The concentration-dependent uptake of GFP and RFP was also observed in the presence of [DipR₅] in SK-OV-3 and MDA-MB-231 cells after 3 h of incubation at 37 °C. FACS analysis indicated that the cellular uptake of GFP in the presence of [WR]₉ was partially decreased by methyl-β-cyclodextrin and nystatin as endocytosis inhibitors after 3 h of incubation in MDA-MB-231 cells, whereas nystatin and chlorpromazine as endocytosis inhibitors slightly reduced the uptake of GFP in the presence of [DipR]₅ after 3 h of incubation in MDA-MB-231. [WR]₉ was able to deliver therapeutically relevant proteins (Histone H2A) at different concentrations. These results provide insight into the use of amphiphilic cyclic peptides in the delivery of protein-related therapeutics. Full article

(This article belongs to the Special Issue Recent Trends in Cyclic Peptides as Therapeutic Agents)

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13 pages, 814 KiB

Open AccessArticle

Development and Characterization of Hydroxyethyl Cellulose-Based Gels Containing Lactobacilli Strains: Evaluation of Antimicrobial Effects in In Vitro and Ex Vivo Models

by Marcela Almeida dos Santos de Sousa, Alexia Figueiredo Ferreira, Camila Caetano da Silva, Marcos Andrade Silva, Tamyris Alicely Xavier Nogueira Bazan, Cristina de Andrade Monteiro, Andrea de Souza Monteiro, Joicy Cortez de Sá Sousa, Luís Cláudio Nascimento da Silva and Adrielle Zagmignan

Pharmaceuticals 2023, 16(3), 468; https://doi.org/10.3390/ph16030468 - 22 Mar 2023

Cited by 2 | Viewed by 2230

Abstract

This study aimed to develop a hydroxyethyl cellulose-based topical formulation containing probiotics and to evaluate its antimicrobial action using in vivo and ex vivo models. Initially, the antagonistic effects of Lacticaseibacillus rhamnosus ATCC 10863, Limosilactobacillus fermentum ATCC 23271, Lactiplantibacillus plantarum ATCC 8014 and Lactiplantibacillus plantarum [...] Read more.

This study aimed to develop a hydroxyethyl cellulose-based topical formulation containing probiotics and to evaluate its antimicrobial action using in vivo and ex vivo models. Initially, the antagonistic effects of Lacticaseibacillus rhamnosus ATCC 10863, Limosilactobacillus fermentum ATCC 23271, Lactiplantibacillus plantarum ATCC 8014 and Lactiplantibacillus plantarum LP-G18-A11 were analyzed against Enterococcus faecalis ATCC 29212, Klebsiella pneumoniae ATCC 700603, Staphylococcus aureus ATCC 27853 and Pseudomonas aeruginosa ATCC 2785. The best action was seen for L. plantarum LP-G18-A11, which presented high inhibition against S. aureus and P. aeruginosa. Then, lactobacilli strains were incorporated into hydroxyethyl cellulose-based gels (natrosol); however, only the LP-G18-A11-incorporated gels (5% and 3%) showed antimicrobial effects. The LP-G18-A11 gel (5%) maintained its antimicrobial effects and viability up to 14 and 90 days at 25 °C and 4 °C, respectively. In the ex vivo assay using porcine skin, the LP-G18-A11 gel (5%) significantly reduced the skin loads of S. aureus and P. aeruginosa after 24 h, while only P. aeruginosa was reduced after 72 h. Moreover, the LP-G18-A11 gel (5%) showed stability in the preliminary and accelerated assays. Taken together, the results show the antimicrobial potential of L. plantarum LP-G18-A11, which may be applied in the development of new dressings for the treatment of infected wounds. Full article

(This article belongs to the Special Issue Antibiodegenerative and Antimicrobial Effects of Natural Products)

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17 pages, 3435 KiB

Open AccessArticle

One-Pot Synthesis of 1-Thia-4-azaspiro[4.4/5]alkan-3-ones via Schiff Base: Design, Synthesis, and Apoptotic Antiproliferative Properties of Dual EGFR/BRAF^V600E Inhibitors

by Lamya H. Al-Wahaibi, Essmat M. El-Sheref, Mohamed M. Hammouda and Bahaa G. M. Youssif

Pharmaceuticals 2023, 16(3), 467; https://doi.org/10.3390/ph16030467 - 22 Mar 2023

Cited by 3 | Viewed by 1579

Abstract

In this investigation, novel 4-((quinolin-4-yl)amino)-thia-azaspiro[4.4/5]alkan-3-ones were synthesized via interactions between 4-(2-cyclodenehydrazinyl)quinolin-2(1H)-one and thioglycolic acid catalyzed by thioglycolic acid. We prepared a new family of spiro-thiazolidinone derivatives in a one-step reaction with excellent yields (67–79%). The various NMR, mass spectra, and elemental [...] Read more.

In this investigation, novel 4-((quinolin-4-yl)amino)-thia-azaspiro[4.4/5]alkan-3-ones were synthesized via interactions between 4-(2-cyclodenehydrazinyl)quinolin-2(1H)-one and thioglycolic acid catalyzed by thioglycolic acid. We prepared a new family of spiro-thiazolidinone derivatives in a one-step reaction with excellent yields (67–79%). The various NMR, mass spectra, and elemental analyses verified the structures of all the newly obtained compounds. The antiproliferative effects of 6a–e, 7a, and 7b against four cancer cells were investigated. The most effective antiproliferative compounds were 6b, 6e, and 7b. Compounds 6b and 7b inhibited EGFR with IC₅₀ values of 84 and 78 nM, respectively. Additionally, 6b and 7b were the most effective inhibitors of BRAF^V600E (IC₅₀ = 108 and 96 nM, respectively) and cancer cell proliferation (GI₅₀ = 35 and 32 nM against four cancer cell lines, respectively). Finally, the apoptosis assay results revealed that compounds 6b and 7b had dual EGFR/BRAF^V600E inhibitory properties and showed promising antiproliferative and apoptotic activity. Full article

(This article belongs to the Special Issue Novel Anti-proliferative Agents)

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10 pages, 651 KiB

Open AccessCommunication

Cost-Effectiveness of Targeted Prophylaxis among Allogenic Stem Cell Transplant Recipients

by Nour Shbaklo, Costanza Vicentini, Alessandro Busca, Luisa Giaccone, Chiara Dellacasa, Irene Dogliotti, Tommaso Lupia, Carla M. Zotti, Silvia Corcione and Francesco Giuseppe De Rosa

Pharmaceuticals 2023, 16(3), 466; https://doi.org/10.3390/ph16030466 - 21 Mar 2023

Cited by 4 | Viewed by 1303

Abstract

Bloodstream infections (BSI) are life-threatening complications for onco-hematologic patients. Fluoroquinolones prophylaxis (FQP) was recommended for patients with neutropenia. Later, it was correlated with increased resistance rates among this population and its role became debated. While the role of FQ prophylaxis is still being [...] Read more.

Bloodstream infections (BSI) are life-threatening complications for onco-hematologic patients. Fluoroquinolones prophylaxis (FQP) was recommended for patients with neutropenia. Later, it was correlated with increased resistance rates among this population and its role became debated. While the role of FQ prophylaxis is still being studied, its cost-effectiveness is also unknown. The objective of this study was to evaluate the costs and effects associated with two alternative strategies (FQP vs. no prophylaxis) for patients with hematological malignancies undergoing allogenic stem cell transplant (HSCT). A decision-tree model was built integrating retrospectively collected data from a single transplant center, part of a tertiary teaching hospital in Northern Italy. Probabilities, costs and effects were considered in the assessment of the two alternative strategies. Probabilities of colonization, BSIs, extended-spectrum beta lactamase (ESBL) and Klebsiella pneumoniae carbapenemase (KPC) BSIs and mortality associated with infection, as well as median duration of length of stay (LOS) were calculated based on data collected between 2013 and 2021. The center applied the strategy of FQP between 2013 and 2016, and of no prophylaxis between 2016 and 2021. Data on 326 patients were collected during the considered time period. Overall, the rates of colonization, BSI, KPC/ESBL BSI, and mortality were 6.8% (95% confidence interval (CI) 2.7–13.5), 42% (9.9–81.4) and 20.72 (16.67–25.26), respectively. A mean bed-day cost of 132€ was estimated. Considering no prophylaxis vs. prophylaxis, the difference in costs ranged between additional 33.61 and 80.59€ per patient, whereas the difference in effects ranged between 0.11 and 0.03 life-years (LYs) lost (around 40 and 11 days). Given the small differences in terms of costs and effects between the two strategies, no prophylaxis seems an appropriate choice. Furthermore, this analysis did not consider the broader effect on hospital ecology of multiple doses of FQP, which could provide further support for the strategy of no prophylaxis. Our results suggest that the necessity for FQP in onco-hematologic setting should be determined based on local antibiotic resistance patterns. Full article

(This article belongs to the Special Issue Multi-Drug Resistance)

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11 pages, 271 KiB

Open AccessArticle

Drug-Utilization, Healthcare Facilities Accesses and Costs of the First Generation of JAK Inhibitors in Rheumatoid Arthritis

by Irma Convertino, Valentina Lorenzoni, Rosa Gini, Giuseppe Turchetti, Elisabetta Fini, Sabrina Giometto, Claudia Bartolini, Olga Paoletti, Sara Ferraro, Emiliano Cappello, Giulia Valdiserra, Marco Bonaso, Corrado Blandizzi, Marco Tuccori and Ersilia Lucenteforte

Pharmaceuticals 2023, 16(3), 465; https://doi.org/10.3390/ph16030465 - 21 Mar 2023

Cited by 2 | Viewed by 1548

Abstract

This study is aimed at describing tofacitinib and baricitinib users by characterizing their prescription and healthcare histories, drug and healthcare utilization patterns, and direct costs from a healthcare system perspective. This retrospective cohort study was performed using Tuscan administrative healthcare databases, which selected [...] Read more.

This study is aimed at describing tofacitinib and baricitinib users by characterizing their prescription and healthcare histories, drug and healthcare utilization patterns, and direct costs from a healthcare system perspective. This retrospective cohort study was performed using Tuscan administrative healthcare databases, which selected two groups of Janus kinase inhibitors (JAKi) incident users (index date) from 1st January 2018 to 31 December 2019 and from 1 January 2018 to 30 June 2019. We included patients ≥18 years old, at least 10 years of data, and six months of follow-up. In the first analysis, we describe mean time, standard deviation (SD), from the first-ever disease-modifying antirheumatic drug (DMARD) to the JAKi, and costs of healthcare facilities and drugs in the 5 years preceding the index date. In the second analysis, we assessed Emergency Department (ED) accesses and hospitalizations for any causes, visits, and costs in the follow-up. In the first analysis, 363 incident JAKi users were included (mean age 61.5, SD 13.6; females 80.7%, baricitinib 78.5%, tofacitinib 21.5%). The time to the first JAKi was 7.2 years (SD 3.3). The mean costs from the fifth to the second year before JAKi increased from 4325 € (0; 24,265) to 5259 € (0; 41,630) per patient/year, driven by hospitalizations. We included 221 incident JAKi users in the second analysis. We observed 109 ED accesses, 39 hospitalizations, and 64 visits. Injury and poisoning (18.3%) and skin (13.8%) caused ED accesses, and cardiovascular (69.2%) and musculoskeletal (64.1%) caused hospitalizations. The mean costs were 4819 € (607.5; 50,493) per patient, mostly due to JAKi. In conclusion, the JAKi introduction in therapy occurred in compliance with RA guidelines and the increase in costs observed could be due to a possible selective prescription. Full article

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

13 pages, 2091 KiB

Open AccessArticle

Model-Informed Target Morning 17α-Hydroxyprogesterone Concentrations in Dried Blood Spots for Pediatric Congenital Adrenal Hyperplasia Patients

by Viktoria Stachanow, Uta Neumann, Oliver Blankenstein, Nele Alder-Baerens, Davide Bindellini, Peter Hindmarsh, Richard J. Ross, Martin J. Whitaker, Johanna Melin, Wilhelm Huisinga, Robin Michelet and Charlotte Kloft

Pharmaceuticals 2023, 16(3), 464; https://doi.org/10.3390/ph16030464 - 21 Mar 2023

Cited by 1 | Viewed by 1550

Abstract

Monitoring cortisol replacement therapy in congenital adrenal hyperplasia (CAH) patients is vital to avoid serious adverse events such as adrenal crises due to cortisol underexposure or metabolic consequences due to cortisol overexposure. The less invasive dried blood spot (DBS) sampling is an advantageous [...] Read more.

Monitoring cortisol replacement therapy in congenital adrenal hyperplasia (CAH) patients is vital to avoid serious adverse events such as adrenal crises due to cortisol underexposure or metabolic consequences due to cortisol overexposure. The less invasive dried blood spot (DBS) sampling is an advantageous alternative to traditional plasma sampling, especially in pediatric patients. However, target concentrations for important disease biomarkers such as 17α-hydroxyprogesterone (17-OHP) are unknown using DBS. Therefore, a modeling and simulation framework, including a pharmacokinetic/pharmacodynamic model linking plasma cortisol concentrations to DBS 17-OHP concentrations, was used to derive a target morning DBS 17-OHP concentration range of 2–8 nmol/L in pediatric CAH patients. Since either capillary or venous DBS sampling is becoming more common in the clinics, the clinical applicability of this work was shown by demonstrating the comparability of capillary and venous cortisol and 17-OHP concentrations collected by DBS sampling, using a Bland-Altman and Passing-Bablok analysis. The derived target morning DBS 17-OHP concentration range is a first step towards providing improved therapy monitoring using DBS sampling and adjusting hydrocortisone (synthetic cortisol) dosing in children with CAH. In the future, this framework can be used to assess further research questions, e.g., target replacement ranges for the entire day. Full article

(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)

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23 pages, 4540 KiB

Open AccessArticle

Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential

by Arafa Musa, Hamada S. Abulkhair, Ateyatallah Aljuhani, Nadjet Rezki, Mohamed A. Abdelgawad, Khaled Shalaby, Ahmed H. El-Ghorab and Mohamed R. Aouad

Pharmaceuticals 2023, 16(3), 463; https://doi.org/10.3390/ph16030463 - 20 Mar 2023

Cited by 11 | Viewed by 2148

Abstract

COVID-19 infection is now considered one of the leading causes of human death. As an attempt towards the discovery of novel medications for the COVID-19 pandemic, nineteen novel compounds containing 1,2,3-triazole side chains linked to phenylpyrazolone scaffold and terminal lipophilic aryl parts with [...] Read more.

COVID-19 infection is now considered one of the leading causes of human death. As an attempt towards the discovery of novel medications for the COVID-19 pandemic, nineteen novel compounds containing 1,2,3-triazole side chains linked to phenylpyrazolone scaffold and terminal lipophilic aryl parts with prominent substituent functionalities were designed and synthesized via a click reaction based on our previous work. The novel compounds were assessed using an in vitro effect on the growth of SARS-CoV-2 virus-infested Vero cells with different compound concentrations: 1 and 10 μM. The data revealed that most of these derivatives showed potent cellular anti-COVID-19 activity and inhibited viral replication by more than 50% with no or weak cytotoxic effect on harboring cells. In addition, in vitro assay employing the SARS-CoV-2-Main protease inhibition assay was done to test the inhibitors’ ability to block the common primary protease of the SARS-CoV-2 virus as a mode of action. The obtained results show that the one non-linker analog 6h and two amide-based linkers 6i and 6q were the most active compounds with IC₅₀ values of 5.08, 3.16, and 7.55 μM, respectively, against the viral protease in comparison to data of the selective antiviral agent GC-376. Molecular modeling studies were done for compound placement within the binding pocket of protease which reveal conserved residues hydrogen bonding and non-hydrogen interactions of 6i analog fragments: triazole scaffold, aryl part, and linker. Moreover, the stability of compounds and their interactions with the target pocket were also studied and analyzed by molecular dynamic simulations. The physicochemical and toxicity profiles were predicted, and the results show that compounds behave as an antiviral activity with low or no cellular or organ toxicity. All research results point to the potential usage of new chemotype potent derivatives as promising leads to be explored in vivo that might open the door to rational drug development of SARS-CoV-2 Main protease potent medicines. Full article

(This article belongs to the Special Issue Small Molecules Targeting Viral Polymerases)

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20 pages, 6088 KiB

Open AccessArticle

A Combination of Deep-Sea Water and Fucoidan Alleviates T2DM through Modulation of Gut Microbiota and Metabolic Pathways

by Shan He, Wei-Bing Peng, Hong-Lei Zhou, Xian-Jun Fu, Yan-Hua Sun and Zhen-Guo Wang

Pharmaceuticals 2023, 16(3), 462; https://doi.org/10.3390/ph16030462 - 20 Mar 2023

Cited by 3 | Viewed by 1561

Abstract

Fucoidan and deep-sea water (DSW) are attractive marine resources for treating type 2 diabetes (T2DM). In this study, the regulation and mechanism associated with the co-administration of the two were first studied using T2DM rats, induced by a high fat diet (HFD) and [...] Read more.

Fucoidan and deep-sea water (DSW) are attractive marine resources for treating type 2 diabetes (T2DM). In this study, the regulation and mechanism associated with the co-administration of the two were first studied using T2DM rats, induced by a high fat diet (HFD) and streptozocin (STZ) injection. Results demonstrate that, compared to those with DSW or FPS alone, the orally administered combination of DSW and FPS (CDF), especially the high dose (H-CDF), could preferably inhibit weight loss, decrease levels of fasting blood glucose (FBG) and lipids, and improve hepatopancreatic pathology and the abnormal Akt/GSK-3β signaling pathway. The fecal metabolomics data show that H-CDF could regulate the abnormal levels of metabolites mainly through the regulation of linoleic acid (LA) metabolism, bile acid (BA) metabolism, and other related pathways. Moreover, H-CDF could adjust the diversity and richness of bacterial flora and enrich bacterial groups, such as Lactobacillaceae and Ruminococcaceae UCG-014. In addition, Spearman correlation analysis illustrated that the interaction between the gut microbiota and BAs plays an essential role in the action of H-CDF. In the ileum, H-CDF was verified to inhibit activation of the farnesoid X receptor (FXR)–fibroblast growth factor 15 (FGF15) pathway, which is regulated by the microbiota–BA–axis. In conclusion, H-CDF enriched Lactobacillaceae and Ruminococcaceae UCG-014, thereby changing BA metabolism, linoleic acid metabolism, and other related pathways, as well as enhancing insulin sensitivity and improving glucose and lipid metabolism. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)

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22 pages, 5762 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Sulfonamide Methoxypyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors

by Haotian Gao, Zaolin Li, Kai Wang, Yuhan Zhang, Tong Wang, Fang Wang and Youjun Xu

Pharmaceuticals 2023, 16(3), 461; https://doi.org/10.3390/ph16030461 - 20 Mar 2023

Cited by 2 | Viewed by 1634

Abstract

Phosphatidylinositol 3-kinase (PI3K) plays an important role in cell proliferation, survival, migration, and metabolism, and has become an effective target for cancer treatment. Meanwhile, inhibiting both PI3K and mammalian rapamycin receptor (mTOR) can simultaneously improve the efficiency of anti-tumor therapy. Herein, a series [...] Read more.

Phosphatidylinositol 3-kinase (PI3K) plays an important role in cell proliferation, survival, migration, and metabolism, and has become an effective target for cancer treatment. Meanwhile, inhibiting both PI3K and mammalian rapamycin receptor (mTOR) can simultaneously improve the efficiency of anti-tumor therapy. Herein, a series of 36 sulfonamide methoxypyridine derivatives with three different aromatic skeletons were synthesized as novel potent PI3K/mTOR dual inhibitors based on a scaffold hopping strategy. Enzyme inhibition assay and cell anti-proliferation assay were employed to assess all derivatives. Then, the effects of the most potent inhibitor on cell cycle and apoptosis were performed. Furthermore, the phosphorylation level of AKT, an important downstream effector of PI3K, was evaluated by Western blot assay. Finally, molecular docking was used to confirm the binding mode with PI3Kα and mTOR. Among them, 22c with the quinoline core showed strong PI3Kα kinase inhibitory activity (IC₅₀ = 0.22 nM) and mTOR kinase inhibitory activity (IC₅₀ = 23 nM). 22c also showed a strong proliferation inhibitory activity, both in MCF-7 cells (IC₅₀ = 130 nM) and HCT-116 cells (IC₅₀ = 20 nM). 22c could effectively cause cell cycle arrest in G0/G1 phase and induce apoptosis of HCT-116 cells. Western blot assay showed that 22c could decrease the phosphorylation of AKT at a low concentration. The results of the modeling docking study also confirmed the binding mode of 22c with PI3Kα and mTOR. Hence, 22c is a promising PI3K/mTOR dual inhibitor, which is worthy of further research in the area. Full article

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

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12 pages, 342 KiB

Open AccessReview

Food By-Products and Agro-Industrial Wastes as a Source of β-Glucans for the Formulation of Novel Nutraceuticals

by Diego Morales

Pharmaceuticals 2023, 16(3), 460; https://doi.org/10.3390/ph16030460 - 20 Mar 2023

Cited by 1 | Viewed by 1537

Abstract

Food and agro-industrial by-products provoke a great environmental and economic impact that must be minimized by adding value to these wastes within the framework of circular economy. The relevance of β-glucans obtained from natural sources (cereals, mushrooms, yeasts, algae, etc.), in terms of [...] Read more.

Food and agro-industrial by-products provoke a great environmental and economic impact that must be minimized by adding value to these wastes within the framework of circular economy. The relevance of β-glucans obtained from natural sources (cereals, mushrooms, yeasts, algae, etc.), in terms of their interesting biological activities (hypocholesterolemic, hypoglycemic, immune-modulatory, antioxidant, etc.), has been validated by many scientific publications. Since most of these by-products contain high levels of these polysaccharides or can serve as a substrate of β-glucan-producing species, this work reviewed the scientific literature, searching for studies that utilized food and agro-industrial wastes to obtain β-glucan fractions, attending to the applied procedures for extraction and/or purification, the characterization of the glucans and the tested biological activities. Although the results related to β-glucan production or extraction using wastes are promising, it can be concluded that further research on the glucans’ characterization, and particularly on the biological activities in vitro and in vivo (apart from antioxidant capacity), is required to reach the final goal of formulating novel nutraceuticals based on these molecules and these raw materials. Full article

(This article belongs to the Special Issue Recent Advances in Drug Discovery Based on β-Glucans)

5 pages, 212 KiB

Open AccessEditorial

Special Issue “In Vivo Nuclear Molecular Imaging in Drug Development and Pharmacological Research”

by Xuyi Yue

Pharmaceuticals 2023, 16(3), 459; https://doi.org/10.3390/ph16030459 - 20 Mar 2023

Viewed by 1052

Abstract

Nuclear molecular imaging is increasingly important in aiding diagnosis, monitoring disease progression, and assessing response to treatment [...] Full article

(This article belongs to the Special Issue In Vivo Nuclear Molecular Imaging in Drug Development and Pharmacological Research)

13 pages, 2934 KiB

Open AccessArticle

The Negative Impact of Triptolide on the Immune Function of Human Natural Killer Cells

by Na Wang, Xiaoyun Min, Ning Ma, Zhuoran Zhu, Bo Cao, Yuan Wang, Qing Yong, Jingjin Huang and Ke Li

Pharmaceuticals 2023, 16(3), 458; https://doi.org/10.3390/ph16030458 - 18 Mar 2023

Viewed by 1313

Abstract

Triptolide (TP), a bioactive compound extracted the from traditional Chinese medicine Tripterygium wilfordii Hook F (TwHF), has been shown to be effective in treating several autoimmune diseases, and has suppressive effects in several key immune cells such as dendritic cells, T cells, and [...] Read more.

Triptolide (TP), a bioactive compound extracted the from traditional Chinese medicine Tripterygium wilfordii Hook F (TwHF), has been shown to be effective in treating several autoimmune diseases, and has suppressive effects in several key immune cells such as dendritic cells, T cells, and macrophages. However, it is unknown whether TP has an impact on natural killer (NK) cells. Here, we report that TP has suppressive effects on human NK cell activity and effector functions. The suppressive effects were observed in human peripheral blood mononuclear cell cultures and purified NK cells from healthy donors, as well as in purified NK cells from patients with rheumatoid arthritis. TP treatment induced downregulation of NK-activating receptor (CD54, CD69) expression and IFN-gamma secretion, in a dose-dependent manner. When exposed to K562 target cells, TP treatment induced inhibition of surface expression of CD107a and IFN-gamma synthesis in NK cells. Furthermore, TP treatment induced activation of inhibitory signaling (SHIP, JNK) and inhibition of MAPK signaling (p38). Thus, our findings demonstrate a previously unknown role for TP in NK cell functional suppression and reveal several key intracellular signaling that can be regulated by TP. Our findings also offer new insight into mechanisms of TP therapeutic treatment in autoimmune disease. Full article

(This article belongs to the Section Natural Products)

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7 pages, 640 KiB

Open AccessBrief Report

The Influence of Protein Charge and Molecular Weight on the Affinity of Aptamers

by Alissa Drees, Tung Lam Trinh and Markus Fischer

Pharmaceuticals 2023, 16(3), 457; https://doi.org/10.3390/ph16030457 - 18 Mar 2023

Cited by 1 | Viewed by 1621

Abstract

Aptamers offer several advantages over antibodies. However, to ensure high affinity and specificity, a better understanding of the interactions between the nucleic-acid-based aptamers and their targets is mandatory. Therefore, we investigated the influence of two physical properties of proteins—molecular mass and charge—on the [...] Read more.

Aptamers offer several advantages over antibodies. However, to ensure high affinity and specificity, a better understanding of the interactions between the nucleic-acid-based aptamers and their targets is mandatory. Therefore, we investigated the influence of two physical properties of proteins—molecular mass and charge—on the affinity of nucleic-acid-based aptamers. For this purpose, first, the affinity of two random oligonucleotides towards twelve proteins was determined. No binding was observed for proteins with a negative net charge towards the two oligonucleotides, while up to nanomolar affinity was determined for positively charged proteins with a high pI value. Second, a literature analysis comprising 369 aptamer–peptide/protein pairs was performed. The dataset included 296 different target peptides and proteins and is thus currently one of the largest databases for aptamers for proteins and peptides. The targets considered covered isoelectric points of 4.1–11.8 and a molecular weight range of 0.7–330 kDa, while the dissociation constants ranged from 50 fM to 29.5 µM. This also revealed a significant inverse correlation between the protein’s isoelectric point and the affinity of aptamers. In contrast, no trend was observed between the affinity and the molecular weight of the target protein with either approach. Full article

(This article belongs to the Special Issue Potential of the Aptamers to Fill Therapeutic and Diagnostic Gaps)

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12 pages, 273 KiB

Open AccessArticle

Co-Developing Patient-Centered Information: A Focus Group Study of Asthma Patients’ Preferences and Attitudes towards New Medical Treatment Guidelines

by Sara Sommer Holst and Charlotte Vermehren

Pharmaceuticals 2023, 16(3), 456; https://doi.org/10.3390/ph16030456 - 17 Mar 2023

Viewed by 1431

Abstract

Studies have suggested patient involvement as an important factor when seeking to improve patient-centered information. The objective of this study was to explore asthma patients’ preferences regarding information when co-developing patient-centered information and how they evaluate the material as a supportive initiative when [...] Read more.

Studies have suggested patient involvement as an important factor when seeking to improve patient-centered information. The objective of this study was to explore asthma patients’ preferences regarding information when co-developing patient-centered information and how they evaluate the material as a supportive initiative when they are deciding whether to switch to the new MART approach. The study was performed as a case study involving qualitative semi-structured focus group interviews inspired by the theoretical framework for supporting patient involvement in research. Two focus group interviews were held, with a total of nine interviewees. Three main interview themes were found: the identification of important topics about the new MART approach, feedback on the design and the preferred implementation of written patient-centered information. The asthma patients preferred written patient-centered material to be short and to be presented briefly at the local community pharmacy, and then discussed more thoroughly with their general practitioner (GP) at a consultation. In conclusion, this study identified asthma patients’ preferences when co-developing written patient-centered information and how the patients favored the material to be implemented as a support to them in their decision on whether to change asthma treatment. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 2804 KiB

Open AccessArticle

A Descriptive Analysis of Direct Oral Anticoagulant Drugs Dosing Errors Based on Spontaneous Reports from the EudraVigilance Database

by Claudiu Morgovan, Carmen Maximiliana Dobrea, Adriana Aurelia Chis, Anca Maria Juncan, Anca Maria Arseniu, Luca Liviu Rus, Felicia Gabriela Gligor, Simona Alexandrina Ardelean, Laurentiu Stoicescu, Steliana Ghibu and Adina Frum

Pharmaceuticals 2023, 16(3), 455; https://doi.org/10.3390/ph16030455 - 17 Mar 2023

Cited by 3 | Viewed by 2014

Abstract

Direct oral anticoagulant drugs (DOACs) interfere with the coagulation process, thus improving patient care for those who require anticoagulant treatment. This study presents a descriptive analysis of adverse reactions (ADRs) attributed to DOAC dosage errors (overdose, underdose, and improper dose). The analysis was [...] Read more.

Direct oral anticoagulant drugs (DOACs) interfere with the coagulation process, thus improving patient care for those who require anticoagulant treatment. This study presents a descriptive analysis of adverse reactions (ADRs) attributed to DOAC dosage errors (overdose, underdose, and improper dose). The analysis was performed based on the Individual Case Safety Reports from the EudraVigilance (EV) database. Results show that data reported for rivaroxaban, apixaban, edoxaban, and dabigatran are mostly regarding underdosing (51.56%) compared to overdosing (18.54%). The most dosage error reports were identified for rivaroxaban (54.02%), followed by apixaban (33.61%). Dabigatran and edoxaban had similar percentages (6.26% and 6.11%, respectively) regarding dosage error reports. Since coagulation issues can become life-threatening events, and factors such as advanced age and renal failure can influence the pharmacokinetics of drugs, the correct usage of DOACs is of utmost importance for the management and prevention of venous thromboembolism. Thus, the collaboration and the complementarity of knowledge of physicians and pharmacists may offer a reliable solution for DOAC dose management and improve patient care. Full article

(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)

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20 pages, 4188 KiB

Open AccessReview

Properties of Poly (Lactic-co-Glycolic Acid) and Progress of Poly (Lactic-co-Glycolic Acid)-Based Biodegradable Materials in Biomedical Research

by Yue Lu, Dongfang Cheng, Baohua Niu, Xiuzhi Wang, Xiaxia Wu and Aiping Wang

Pharmaceuticals 2023, 16(3), 454; https://doi.org/10.3390/ph16030454 - 17 Mar 2023

Cited by 28 | Viewed by 6239

Abstract

In recent years, biodegradable polymers have gained the attention of many researchers for their promising applications, especially in drug delivery, due to their good biocompatibility and designable degradation time. Poly (lactic-co-glycolic acid) (PLGA) is a biodegradable functional polymer made from the polymerization of [...] Read more.

In recent years, biodegradable polymers have gained the attention of many researchers for their promising applications, especially in drug delivery, due to their good biocompatibility and designable degradation time. Poly (lactic-co-glycolic acid) (PLGA) is a biodegradable functional polymer made from the polymerization of lactic acid (LA) and glycolic acid (GA) and is widely used in pharmaceuticals and medical engineering materials because of its biocompatibility, non-toxicity, and good plasticity. The aim of this review is to illustrate the progress of research on PLGA in biomedical applications, as well as its shortcomings, to provide some assistance for its future research development. Full article

(This article belongs to the Section Pharmaceutical Technology)

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16 pages, 3485 KiB

Open AccessArticle

Cyclocreatine Phosphate: A Novel Bioenergetic/Anti-Inflammatory Drug That Resuscitates Poorly Functioning Hearts and Protects against Development of Heart Failure

by Salwa A. Elgebaly, Charles Van Buren, Robert Todd, Robert Poston, Reem K. Arafa, Nashwa El-Khazragy, Donald Kreutzer, Mostafa A. Rabie, Ahmed F. Mohamed, Lamiaa A. Ahmed and Nesrine S. El Sayed

Pharmaceuticals 2023, 16(3), 453; https://doi.org/10.3390/ph16030453 - 16 Mar 2023

Cited by 1 | Viewed by 1895

Abstract

Irreversible myocardial injury causes the exhaustion of cellular adenosine triphosphate (ATP) contributing to heart failure (HF). Cyclocreatine phosphate (CCrP) was shown to preserve myocardial ATP during ischemia and maintain cardiac function in various animal models of ischemia/reperfusion. We tested whether CCrP administered prophylactically/therapeutically [...] Read more.

Irreversible myocardial injury causes the exhaustion of cellular adenosine triphosphate (ATP) contributing to heart failure (HF). Cyclocreatine phosphate (CCrP) was shown to preserve myocardial ATP during ischemia and maintain cardiac function in various animal models of ischemia/reperfusion. We tested whether CCrP administered prophylactically/therapeutically prevents HF secondary to ischemic injury in an isoproterenol (ISO) rat model. Thirty-nine rats were allocated into five groups: control/saline, control/CCrP, ISO/saline (85 and 170 mg/kg/day s.c. for 2 consecutive days), and ISO/CCrP (0.8 g/kg/day i.p.) either administrated 24 h or 1 h before ISO administration (prophylactic regimen) or 1 h after the last ISO injection (therapeutic regimen) and then daily for 2 weeks. CCrP protected against ISO-induced CK-MB elevation and ECG/ST changes when administered prophylactically or therapeutically. CCrP administered prophylactically decreased heart weight, hs-TnI, TNF-α, TGF-β, and caspase-3, as well as increased EF%, eNOS, and connexin-43, and maintained physical activity. Histology indicated a marked decrease in cardiac remodeling (fibrin and collagen deposition) in the ISO/CCrP rats. Similarly, therapeutically administered CCrP showed normal EF% and physical activity, as well as normal serum levels of hs-TnI and BNP. In conclusion, the bioenergetic/anti-inflammatory CCrP is a promising safe drug against myocardial ischemic sequelae, including HF, promoting its clinical application to salvage poorly functioning hearts. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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11 pages, 1589 KiB

Open AccessArticle

Spiroleiferthione A and Oleiferthione A: Two Unusual Isothiocyanate-Derived Thioketone Alkaloids from Moringa oleifera Lam. Seeds

by Yueping Jiang, Rong Liu, Ling Huang, Qi Huang, Min Liu, Shao Liu and Jing Li

Pharmaceuticals 2023, 16(3), 452; https://doi.org/10.3390/ph16030452 - 16 Mar 2023

Cited by 1 | Viewed by 1217

Abstract

Spiroleiferthione A (1), with a 2-thiohydantoin a heterocyclic spiro skeleton, and oleiferthione A (2), an imidazole-2-thione derivative, were isolated from the aqueous extract of Moringa oleifera Lam. seeds. The unprecedented structures of 1 and 2 were elucidated by extensive [...] Read more.

Spiroleiferthione A (1), with a 2-thiohydantoin a heterocyclic spiro skeleton, and oleiferthione A (2), an imidazole-2-thione derivative, were isolated from the aqueous extract of Moringa oleifera Lam. seeds. The unprecedented structures of 1 and 2 were elucidated by extensive spectroscopic data, X-ray diffraction, and gauge-independent atomic orbital (GIAO) NMR calculation, as well as electronic circular dichroism (ECD) calculation. The structures of 1 and 2 were determined to be (5R,7R,8S)-8-hydroxy-3-(4′-hydroxybenzyl)-7-methyl-2-thioxo-6-oxa-1, 3-diazaspiro [4.4] nonan-4-one, and 1-(4′-hydroxybenzyl)-4,5-dimethyl-1,3-dihydro-2H-imidazole-2-thione, respectively. Biosynthetic pathways for 1 and 2 have been proposed. Compounds 1 and 2 are considered to have originated from isothiocyanate and then undergone a series of oxidation and cyclization reactions to form 1 and 2. Compounds 1 and 2 demonstrated weak inhibition rates of NO production, 42.81 ± 1.56% and 33.53 ± 2.34%, respectively, at a concentration of 50 μM. Additionally, Spiroleiferthione A demonstrated moderate inhibitory activity against high glucose-induced human renal mesangial cell proliferation in a dosage-dependent manner. A wider range of biological activities, and the diabetic nephropathy protective activity of Compound 1 in vivo and its mechanism of action, need further investigation after the sufficient enrichment of Compound 1 or total synthesis. Full article

(This article belongs to the Special Issue Bioactive Compounds from Plants and Foods with Pharmaceutical Interest 2023)

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30 pages, 2210 KiB

Open AccessReview

Targeting Inflammation in Non-Small Cell Lung Cancer through Drug Repurposing

by Thiviyadarshini Rajasegaran, Chee Wun How, Anoosha Saud, Azhar Ali and Jonathan Chee Woei Lim

Pharmaceuticals 2023, 16(3), 451; https://doi.org/10.3390/ph16030451 - 16 Mar 2023

Cited by 10 | Viewed by 5040

Abstract

Lung cancer is the most common cause of cancer-related deaths. Lung cancers can be classified as small-cell (SCLC) or non-small cell (NSCLC). About 84% of all lung cancers are NSCLC and about 16% are SCLC. For the past few years, there have been [...] Read more.

Lung cancer is the most common cause of cancer-related deaths. Lung cancers can be classified as small-cell (SCLC) or non-small cell (NSCLC). About 84% of all lung cancers are NSCLC and about 16% are SCLC. For the past few years, there have been a lot of new advances in the management of NSCLC in terms of screening, diagnosis and treatment. Unfortunately, most of the NSCLCs are resistant to current treatments and eventually progress to advanced stages. In this perspective, we discuss some of the drugs that can be repurposed to specifically target the inflammatory pathway of NSCLC utilizing its well-defined inflammatory tumor microenvironment. Continuous inflammatory conditions are responsible to induce DNA damage and enhance cell division rate in lung tissues. There are existing anti-inflammatory drugs which were found suitable for repurposing in non-small cell lung carcinoma (NSCLC) treatment and drug modification for delivery via inhalation. Repurposing anti-inflammatory drugs and their delivery through the airway is a promising strategy to treat NSCLC. In this review, suitable drug candidates that can be repurposed to treat inflammation-mediated NSCLC will be comprehensively discussed together with their administration via inhalation from physico-chemical and nanocarrier perspectives. Full article

(This article belongs to the Special Issue Advances in Non-small Cell Lung Cancer Treatment - Current and Future)

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28 pages, 2106 KiB

Open AccessReview

Propolis: A Detailed Insight of Its Anticancer Molecular Mechanisms

by Suhib Altabbal, Khawla Athamnah, Aaesha Rahma, Adil Farooq Wali, Ali H. Eid, Rabah Iratni and Yusra Al Dhaheri

Pharmaceuticals 2023, 16(3), 450; https://doi.org/10.3390/ph16030450 - 16 Mar 2023

Cited by 7 | Viewed by 8084

Abstract

Cancer is the second most life-threatening disease and has become a global health and economic problem worldwide. Due to the multifactorial nature of cancer, its pathophysiology is not completely understood so far, which makes it hard to treat. The current therapeutic strategies for [...] Read more.

Cancer is the second most life-threatening disease and has become a global health and economic problem worldwide. Due to the multifactorial nature of cancer, its pathophysiology is not completely understood so far, which makes it hard to treat. The current therapeutic strategies for cancer lack the efficacy due to the emergence of drug resistance and the toxic side effects associated with the treatment. Therefore, the search for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Propolis is a mixture of resinous compounds containing beeswax and partially digested exudates from plants leaves and buds. Its chemical composition varies widely depending on the bee species, geographic location, plant species, and weather conditions. Since ancient times, propolis has been used in many conditions and aliments for its healing properties. Propolis has well-known therapeutic actions including antioxidative, antimicrobial, anti-inflammatory, and anticancer properties. In recent years, extensive in vitro and in vivo studies have suggested that propolis possesses properties against several types of cancers. The present review highlights the recent progress made on the molecular targets and signaling pathways involved in the anticancer activities of propolis. Propolis exerts anticancer effects primarily by inhibiting cancer cell proliferation, inducing apoptosis through regulating various signaling pathways and arresting the tumor cell cycle, inducing autophagy, epigenetic modulations, and further inhibiting the invasion and metastasis of tumors. Propolis targets numerous signaling pathways associated with cancer therapy, including pathways mediated by p53, β-catenin, ERK1/2, MAPK, and NF-κB. Possible synergistic actions of a combination therapy of propolis with existing chemotherapies are also discussed in this review. Overall, propolis, by acting on diverse mechanisms simultaneously, can be considered to be a promising, multi-targeting, multi-pathways anticancer agent for the treatment of various types of cancers. Full article

(This article belongs to the Special Issue Molecular and Cellular Studies of Natural Antioxidants as Potential Therapeutics for Cancer)

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13 pages, 2838 KiB

Open AccessArticle

Novel ⁶⁸Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast

by Arsyangela Verena, Hsiou-Ting Kuo, Helen Merkens, Jutta Zeisler, Shreya Bendre, Antonio A. W. L. Wong, François Bénard and Kuo-Shyan Lin

Pharmaceuticals 2023, 16(3), 449; https://doi.org/10.3390/ph16030449 - 16 Mar 2023

Cited by 3 | Viewed by 2295

Abstract

Compared to quinoline-based fibroblast activation protein (FAP)-targeted radiotracers, pyridine-based FAP-targeted tracers are expected to have faster pharmacokinetics due to their smaller molecular size and higher hydrophilicity, which we hypothesize would improve the tumor-to-background image contrast. We aim to develop ⁶⁸Ga-labeled pyridine-based FAP-targeted [...] Read more.

Compared to quinoline-based fibroblast activation protein (FAP)-targeted radiotracers, pyridine-based FAP-targeted tracers are expected to have faster pharmacokinetics due to their smaller molecular size and higher hydrophilicity, which we hypothesize would improve the tumor-to-background image contrast. We aim to develop ⁶⁸Ga-labeled pyridine-based FAP-targeted tracers for cancer imaging with positron emission tomography (PET), and compare their imaging potential with the clinically validated [⁶⁸Ga]Ga-FAPI-04. Two DOTA-conjugated pyridine-based AV02053 and AV02070 were synthesized through multi-step organic synthesis. IC₅₀(FAP) values of Ga-AV02053 and Ga-AV02070 were determined by an enzymatic assay to be 187 ± 52.0 and 17.1 ± 4.60 nM, respectively. PET imaging and biodistribution studies were conducted in HEK293T:hFAP tumor-bearing mice at 1 h post-injection. The HEK293T:hFAP tumor xenografts were clearly visualized with good contrast on PET images by [⁶⁸Ga]Ga-AV02053 and [⁶⁸Ga]Ga-AV02070, and both tracers were excreted mainly through the renal pathway. The tumor uptake values of [⁶⁸Ga]Ga-AV02070 (7.93 ± 1.88%ID/g) and [⁶⁸Ga]Ga-AV02053 (5.6 ± 1.12%ID/g) were lower than that of previously reported [⁶⁸Ga]Ga-FAPI-04 (12.5 ± 2.00%ID/g). However, both [⁶⁸Ga]Ga-AV02070 and [⁶⁸Ga]Ga-AV02053 showed higher tumor-to-background (blood, muscle, and bone) uptake ratios than [⁶⁸Ga]Ga-FAPI-04. Our data suggests that pyridine-based pharmacophores are promising for the design of FAP-targeted tracers. Future optimization on the selection of a linker will be explored to increase tumor uptake while maintaining or even further improving the high tumor-to-background contrast. Full article

(This article belongs to the Special Issue Novel Imaging Probes: From Design to Applications)

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15 pages, 705 KiB

Open AccessReview

A Systematic Review of In Vivo Studies of the Efficacy of Herbal Medicines for Anti-Aging in the Last Five Years

by Seung-Yeon Cho, Han-Gyul Lee, Seungwon Kwon, Seong-Uk Park, Woo-Sang Jung, Sang-Kwan Moon, Jung-Mi Park and Chang-Nam Ko

Pharmaceuticals 2023, 16(3), 448; https://doi.org/10.3390/ph16030448 - 16 Mar 2023

Viewed by 2562

Abstract

Background: The world’s population is rapidly aging, and attention to and research on the increase in life expectancy and age-related diseases are needed. This study aimed to review the in vivo studies on the anti-aging effects of herbal medicines. Methods: In vivo studies [...] Read more.

Background: The world’s population is rapidly aging, and attention to and research on the increase in life expectancy and age-related diseases are needed. This study aimed to review the in vivo studies on the anti-aging effects of herbal medicines. Methods: In vivo studies of single or complex herbal medicines for anti-aging that were published in the last five years were included in this review. The following databases were used: PubMed, Scopus, ScienceDirect, Web of Science and EMBASE. Results: A total of 41 studies were considered eligible for the review. The articles were classified into body organs and functions, experimental country, herbal medicine, extraction method, administration route, dosage, duration, animal model, aging-induced method, sex, number of animals per group, and outcomes and mechanisms A single herbal extract was used in a total of 21 studies including Alpinia oxyphylla Miq., Acanthopanax senticosus and Lyceum barbarum, and a multi-compound herbal prescription was used in a total of 20 studies, including Modified Qiongyu paste, Wuzi Yanzong recipe, etc. Each herbal medicine had anti-aging effects on learning and memory, cognition, emotion, internal organs, gastrointestinal tracts, sexual functions, musculoskeletal function and so on. The common mechanisms of action were antioxidant and anti-inflammatory, and various effects and mechanisms for each organ and function were identified. Conclusions: Herbal medicine exhibited beneficial effects on anti-aging in various parts of the body and its function. Further investigation of the appropriate herbal medicine prescriptions and their components is recommended. Full article

(This article belongs to the Section Natural Products)

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18 pages, 8448 KiB

Open AccessArticle

The In Vitro Anti-Parasitic Activities of Emodin toward Toxoplasma gondii

by Oluyomi Stephen Adeyemi, Kosei Ishii and Kentaro Kato

Pharmaceuticals 2023, 16(3), 447; https://doi.org/10.3390/ph16030447 - 16 Mar 2023

Viewed by 1549

Abstract

Currently, toxoplasmosis affects nearly one-third of the world’s population, but the available treatments have several limitations. This factor underscores the search for better therapy for toxoplasmosis. Therefore, in the current investigation, we investigated the potential of emodin as a new anti-Toxoplasma gondii [...] Read more.

Currently, toxoplasmosis affects nearly one-third of the world’s population, but the available treatments have several limitations. This factor underscores the search for better therapy for toxoplasmosis. Therefore, in the current investigation, we investigated the potential of emodin as a new anti-Toxoplasma gondii while exploring its anti-parasitic mechanism of action. We explored the mechanisms of action of emodin in the presence and absence of an in vitro model of experimental toxoplasmosis. Emodin showed strong anti-T. gondii action with an EC₅₀ value of 0.03 µg/mL; at this same effective anti-parasite concentration, emodin showed no appreciable host cytotoxicity. Likewise, emodin showed a promising anti-T. gondii specificity with a selectivity index (SI) of 276. Pyrimethamine, a standard drug for toxoplasmosis, had an SI of 2.3. The results collectively imply that parasite damage was selective rather than as a result of a broad cytotoxic effect. Furthermore, our data confirm that emodin-induced parasite growth suppression stems from parasite targets and not host targets, and indicate that the anti-parasite action of emodin precludes oxidative stress and ROS production. Emodin likely mediates parasite growth suppression through means other than oxidative stress, ROS production, or mitochondrial toxicity. Collectively, our findings support the potential of emodin as a promising and novel anti-parasitic agent that warrants further investigation. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals 2022)

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13 pages, 3083 KiB

Open AccessArticle

Histone Deacetylase 6 Inhibitor CKD-WID Suppressed Monosodium Urate-Induced Osteoclast Formation by Blocking Calcineurin-NFAT Pathway in RAW 264.7 Cells

by Seong-Kyu Kim, Jung-Yoon Choe, Ji-Won Kim and Ki-Yeun Park

Pharmaceuticals 2023, 16(3), 446; https://doi.org/10.3390/ph16030446 - 16 Mar 2023

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Abstract

Histone deacetylase (HDAC) has been found to play a crucial role in the regulation of osteoclast differentiation and formation. This study was designed to identify the effect of the HDAC6 inhibitor CKD-WID on the receptor for the activation of nuclear factor-κB ligand (RANKL)-mediated [...] Read more.

Histone deacetylase (HDAC) has been found to play a crucial role in the regulation of osteoclast differentiation and formation. This study was designed to identify the effect of the HDAC6 inhibitor CKD-WID on the receptor for the activation of nuclear factor-κB ligand (RANKL)-mediated osteoclast formation in the presence of monosodium urate (MSU) in RAW 264.7 murine macrophage cells. The expression of osteoclast-specific target genes, calcineurin, and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) was evaluated in RAW 264.7 murine macrophages treated with MSU, RANKL, or CKD-WID by real-time quantitative polymerase chain reaction and Western blot assay. The effect of CKD-WID on osteoclast formation was measured by tartrate-resistant acid phosphatase (TRAP) staining, F-actin ring formation staining, and assays for bone resorption activity. RANKL in the presence of MSU significantly induced HDAC6 gene and protein expression in RAW 264.7 cells. CKD-WID markedly suppressed the expression of osteoclast-related markers such as c-Fos, TRAP, cathepsin K, and carbonic anhydrase II induced by co-stimulation with RANKL and MSU in RAW 264.7 cells. Transcription factor NFATc1 mRNA expression and nuclear NFATc1 protein expression induced by co-stimulation with RANKL and MSU were significantly inhibited by CKD-WID treatment. CKD-WID also decreased the number of TRAP-positive multinuclear cells and F-actin ring-positive cells and attenuated bone resorption activity. Co-stimulation with RANKL and MSU increased calcineurin gene and protein expression, which was significantly blocked by CKD-WID treatment. The HDAC6 inhibitor CKD-WID suppressed MSU-induced osteoclast formation through blocking the calcineurin-NFAT pathway in RAW 264.7 cells. This suggests that HDAC6 is considered a therapeutic target in uric acid-mediated osteoclastogenesis. Full article

(This article belongs to the Section Biopharmaceuticals)

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Pharmaceuticals, Volume 16, Issue 3 (March 2023) – 148 articles

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