Subjects -> CHEMISTRY (Total: 928 journals)
    - ANALYTICAL CHEMISTRY (59 journals)
    - CHEMISTRY (661 journals)
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CHEMISTRY (661 journals)            First | 1 2 3 4 | Last

Showing 401 - 600 of 735 Journals sorted alphabetically
Journal of Molecular Liquids     Hybrid Journal   (Followers: 3)
Journal of Molecular Modeling     Hybrid Journal   (Followers: 5)
Journal of Molecular Recognition     Hybrid Journal   (Followers: 2)
Journal of Molecular Spectroscopy     Hybrid Journal   (Followers: 6)
Journal of Molecular Structure     Hybrid Journal   (Followers: 6)
Journal of Nanoparticles     Open Access   (Followers: 4)
Journal of Nanostructure in Chemistry     Open Access   (Followers: 8)
Journal of Organometallic Chemistry     Hybrid Journal   (Followers: 25)
Journal of Photochemistry and Photobiology     Open Access  
Journal of Photochemistry and Photobiology A: Chemistry     Hybrid Journal   (Followers: 3)
Journal of Photochemistry and Photobiology B: Biology     Hybrid Journal   (Followers: 4)
Journal of Photochemistry and Photobiology C: Photochemistry Reviews     Full-text available via subscription   (Followers: 3)
Journal of Polymer & Composites     Full-text available via subscription   (Followers: 17)
Journal of Polymer and Biopolymer Physics Chemistry     Open Access   (Followers: 7)
Journal of Polymer Science Part A: Polymer Chemistry     Hybrid Journal   (Followers: 92)
Journal of Polymers     Open Access   (Followers: 7)
Journal of Porphyrins and Phthalocyanines     Hybrid Journal   (Followers: 1)
Journal of Progressive Research in Chemistry     Open Access  
Journal of Pure and Applied Chemistry Research     Open Access   (Followers: 3)
Journal of Raman Spectroscopy     Hybrid Journal   (Followers: 14)
Journal of Research and Education Chemistry     Open Access   (Followers: 1)
Journal of Research Updates in Polymer Science     Hybrid Journal   (Followers: 2)
Journal of Rubber Research     Hybrid Journal   (Followers: 1)
Journal of Saudi Chemical Society     Open Access  
Journal of Solid State Chemistry     Hybrid Journal   (Followers: 13)
Journal of Solution Chemistry     Hybrid Journal   (Followers: 1)
Journal of Structural Chemistry     Hybrid Journal   (Followers: 1)
Journal of Sulfur Chemistry     Hybrid Journal   (Followers: 1)
Journal of Supercritical Fluids     Hybrid Journal   (Followers: 3)
Journal of Superhard Materials     Hybrid Journal  
Journal of Surface Science and Technology     Hybrid Journal  
Journal of Surfactants and Detergents     Hybrid Journal   (Followers: 3)
Journal of Taibah University for Science     Open Access  
Journal of the American Chemical Society     Hybrid Journal   (Followers: 321)
Journal of the American Society for Mass Spectrometry     Hybrid Journal   (Followers: 32)
Journal of the American Society of Brewing Chemists     Full-text available via subscription   (Followers: 2)
Journal of the Chilean Chemical Society     Open Access   (Followers: 2)
Journal of the Chinese Chemical Society     Hybrid Journal  
Journal of the Indian Chemical Society     Hybrid Journal  
Journal of The Indonesian Society of Integrated Chemistry     Open Access  
Journal of the Iranian Chemical Society     Hybrid Journal   (Followers: 1)
Journal of the Korean Society for Applied Biological Chemistry     Hybrid Journal  
Journal of the Mexican Chemical Society     Open Access   (Followers: 1)
Journal of the Serbian Chemical Society     Open Access  
Journal of the Turkish Chemical Society, Section A : Chemistry     Open Access  
Journal of Theoretical and Computational Chemistry     Hybrid Journal   (Followers: 9)
Jurnal Inovasi Pendidikan Kimia     Open Access  
Jurnal Kimia (Journal of Chemistry)     Open Access  
Jurnal Kimia Riset     Open Access  
Jurnal Pendidikan Kimia     Open Access  
Jurnal Penelitian Sains (JPS)     Open Access  
Karbala International Journal of Modern Science     Open Access  
Kinetics and Catalysis     Hybrid Journal   (Followers: 4)
Konfigurasi : Jurnal Pendidikan Kimia dan Terapan     Open Access  
Korea-Australia Rheology Journal     Hybrid Journal   (Followers: 1)
Langmuir     Hybrid Journal   (Followers: 58)
Lebensmittelchemie     Hybrid Journal   (Followers: 1)
Lipid Insights     Open Access  
Luminescence     Hybrid Journal   (Followers: 2)
Macromolecular Materials & Engineering     Hybrid Journal   (Followers: 5)
Macromolecular Rapid Communications     Hybrid Journal   (Followers: 10)
Macromolecular Research     Hybrid Journal   (Followers: 2)
Macromolecular Symposia     Hybrid Journal   (Followers: 3)
Macromolecular Theory and Simulations     Hybrid Journal   (Followers: 2)
Macromolecules     Hybrid Journal   (Followers: 48)
Magnetic Resonance in Chemistry     Hybrid Journal   (Followers: 8)
Magnetochemistry     Open Access  
Marine Chemistry     Hybrid Journal   (Followers: 6)
Marine Drugs     Open Access   (Followers: 1)
MATEC Web of Conferences     Open Access  
Materials Advances     Open Access   (Followers: 2)
Materials and Devices     Open Access  
Materials Characterization     Hybrid Journal   (Followers: 32)
Materials Chemistry Frontiers     Hybrid Journal   (Followers: 4)
Materials Horizons     Hybrid Journal   (Followers: 6)
Materials Research Bulletin     Hybrid Journal   (Followers: 25)
Materials Science-Poland     Open Access   (Followers: 1)
Materials Sciences and Applications     Open Access   (Followers: 2)
Medicinal Chemistry Research     Hybrid Journal   (Followers: 9)
Mediterranean Journal of Chemistry     Open Access  
Metallography, Microstructure, and Analysis     Hybrid Journal   (Followers: 1)
Micro and Nano Systems Letters     Open Access   (Followers: 6)
Microchimica Acta     Hybrid Journal   (Followers: 2)
Microporous and Mesoporous Materials     Hybrid Journal   (Followers: 9)
Modern Chemistry & Applications     Open Access   (Followers: 1)
Modern Research in Catalysis     Open Access  
Molbank     Open Access  
Molecular Catalysis     Hybrid Journal   (Followers: 6)
Molecules     Open Access   (Followers: 4)
Molecules and Cells     Hybrid Journal   (Followers: 1)
Monatshefte für Chemie - Chemical Monthly     Hybrid Journal   (Followers: 4)
Mongolian Journal of Chemistry     Open Access  
Moscow University Chemistry Bulletin     Hybrid Journal   (Followers: 1)
MRS Bulletin     Full-text available via subscription   (Followers: 4)
Nachrichten aus der Chemie     Hybrid Journal   (Followers: 18)
Nano Convergence     Open Access   (Followers: 1)
Nano Materials Science     Open Access   (Followers: 1)
Nano Reviews & Experiments     Open Access   (Followers: 14)
Nano Select     Open Access  
Nanochemistry Research     Open Access   (Followers: 1)
Nanoscale     Hybrid Journal   (Followers: 18)
Nanoscale Advances     Open Access  
Nanoscale Horizons     Hybrid Journal  
Nanoscale Research Letters     Open Access   (Followers: 8)
Nanoscience and Nanotechnology Letters     Full-text available via subscription   (Followers: 24)
Natural Product Communications     Open Access  
Natural Product Reports     Hybrid Journal   (Followers: 10)
Natural Science     Open Access   (Followers: 8)
Natural Volatiles & Essential Oils     Open Access  
Nature Chemistry     Full-text available via subscription   (Followers: 97)
Nature Protocols     Full-text available via subscription   (Followers: 72)
Nature Reviews Chemistry     Hybrid Journal   (Followers: 17)
New Journal of Chemistry     Hybrid Journal   (Followers: 17)
Nitric Oxide     Hybrid Journal  
Nitrogen     Open Access  
Nukleonika     Open Access  
Open Chemistry Journal     Open Access  
Open Conference Proceedings Journal     Open Access  
Open Journal of Chemistry     Open Access  
Open Journal of Composite Materials     Open Access   (Followers: 21)
Open Journal of Inorganic Non-metallic Materials     Open Access   (Followers: 2)
Open Journal of Medicinal Chemistry     Open Access   (Followers: 4)
Open Journal of Polymer Chemistry     Open Access   (Followers: 12)
Open Journal of Synthesis Theory and Applications     Open Access  
Open Medicinal Chemistry Journal     Open Access  
Orbital - The Electronic Journal of Chemistry     Open Access   (Followers: 1)
Organic & Biomolecular Chemistry     Hybrid Journal   (Followers: 57)
Organometallics     Hybrid Journal   (Followers: 19)
Oxidation of Metals     Hybrid Journal   (Followers: 16)
Passer Journal of Basic and Applied Sciences     Open Access  
Peptide Science     Full-text available via subscription  
Pharmaceuticals     Open Access   (Followers: 4)
Pharmaceutics     Open Access   (Followers: 5)
Phosphorus, Sulfur, and Silicon and the Related Elements     Hybrid Journal   (Followers: 2)
Photochemistry and Photobiology     Hybrid Journal   (Followers: 3)
Physical Science International Journal     Open Access  
Physics and Materials Chemistry     Open Access   (Followers: 1)
Phytochemistry     Hybrid Journal   (Followers: 4)
Phytochemistry Letters     Full-text available via subscription   (Followers: 1)
Plasma     Open Access   (Followers: 3)
Plasma Chemistry and Plasma Processing     Hybrid Journal   (Followers: 3)
Polycyclic Aromatic Compounds     Hybrid Journal  
Polyhedron     Hybrid Journal   (Followers: 4)
Polymer Chemistry     Hybrid Journal   (Followers: 24)
Polymer crystallization     Hybrid Journal  
Polymer Degradation and Stability     Hybrid Journal   (Followers: 23)
Polymer Engineering & Science     Hybrid Journal   (Followers: 14)
Polymer Reviews     Hybrid Journal   (Followers: 32)
Polymer Science Series D     Hybrid Journal   (Followers: 3)
Polymer Testing     Hybrid Journal   (Followers: 192)
Polymer-Plastics Technology and Materials     Hybrid Journal   (Followers: 5)
Polymers     Open Access   (Followers: 21)
Polymers from Renewable Resources     Hybrid Journal  
Proceedings of the Combustion Institute     Full-text available via subscription   (Followers: 8)
Processes     Open Access  
Progress in Lipid Research     Hybrid Journal   (Followers: 3)
Progress in Organic Coatings     Hybrid Journal   (Followers: 7)
Progress in Polymer Science     Full-text available via subscription   (Followers: 36)
Progress in Reaction Kinetics and Mechanism     Open Access  
Progress in Solid State Chemistry     Full-text available via subscription   (Followers: 3)
Progress in Surface Science     Full-text available via subscription   (Followers: 3)
Protein Science     Hybrid Journal   (Followers: 45)
Radiochemistry     Hybrid Journal   (Followers: 1)
Rapid Communications in Mass Spectrometry     Hybrid Journal   (Followers: 33)
Reaction Chemistry & Engineering     Hybrid Journal  
Reaction Kinetics, Mechanisms and Catalysis     Hybrid Journal   (Followers: 3)
Reactions     Open Access  
Reportes Científicos de la FaCEN     Open Access  
Research Journal of Phytochemistry     Open Access   (Followers: 1)
Resources Chemicals and Materials     Full-text available via subscription   (Followers: 2)
Results in Chemistry     Open Access  
Results in Geochemistry     Open Access  
Results in Surfaces and Interfaces     Open Access  
Review Journal of Chemistry     Hybrid Journal   (Followers: 1)
Reviews in Mineralogy and Geochemistry     Hybrid Journal   (Followers: 4)
Revista Boliviana de Química     Open Access  
Revista CENIC. Ciencias Quimicas     Open Access  
Revista Colombiana de Ciencias Químico-Farmacéuticas     Open Access  
Revista Colombiana de Química     Open Access  
Revista Cubana de Química     Open Access  
Revista de Ciencia y Tecnología     Open Access  
Revista de Ciencias     Open Access  
Revista de la Academia Colombiana de Ciencias Exactas, Físicas y Naturales     Open Access  
Revista de la Sociedad Química del Perú     Open Access  
Revista de la Societat Catalana de Química     Open Access  
Revista de Química     Open Access   (Followers: 3)
Revista Debates em Ensino de Química     Open Access  
Revista ION     Open Access  
RSC Advances     Open Access   (Followers: 27)
RSC Chemical Biology     Open Access  
RSC Medicinal Chemistry     Hybrid Journal   (Followers: 6)
Russian Journal of Bioorganic Chemistry     Hybrid Journal   (Followers: 1)
Russian Journal of Coordination Chemistry     Hybrid Journal   (Followers: 1)
Russian Journal of General Chemistry     Hybrid Journal   (Followers: 1)
Russian Journal of Inorganic Chemistry     Hybrid Journal  
Sainstek : Jurnal Sains dan Teknologi     Open Access  
Science China Chemistry     Hybrid Journal   (Followers: 2)
Science Talks     Full-text available via subscription   (Followers: 2)
Sciences & Technologie A : sciences exactes     Open Access  
Scientific Journal of Frontier Chemical Development     Open Access   (Followers: 2)

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Journal Prestige (SJR): 0.949
Citation Impact (citeScore): 4
Number of Followers: 5  

  This is an Open Access Journal Open Access journal
ISSN (Print) 1999-4923
Published by MDPI Homepage  [84 journals]
  • Pharmaceutics, Vol. 14, Pages 959: Inhalable Mannosylated
           Rifampicin–Curcumin Co-Loaded Nanomicelles with Enhanced In Vitro
           Antimicrobial Efficacy for an Optimized Pulmonary Tuberculosis Therapy

    • Authors: Juan M. Galdopórpora, Camila Martinena, Ezequiel Bernabeu, Jennifer Riedel, Lucia Palmas, Ines Castangia, Maria Letizia Manca, Mariana Garcés, Juan Lázaro-Martinez, Maria Jimena Salgueiro, Pablo Evelson, Nancy Liliana Tateosian, Diego Andres Chiappetta, Marcela Analia Moretton
      First page: 959
      Abstract: Among respiratory infections, tuberculosis was the second deadliest infectious disease in 2020 behind COVID-19. Inhalable nanocarriers offer the possibility of actively targeting anti-tuberculosis drugs to the lungs, especially to alveolar macrophages (cellular reservoirs of the Mycobacterium tuberculosis). Our strategy was based on the development of a mannose-decorated micellar nanoformulation based in Soluplus® to co-encapsulate rifampicin and curcumin. The former is one of the most effective anti-tuberculosis first-line drugs, while curcumin has demonstrated potential anti-mycobacterial properties. Mannose-coated rifampicin (10 mg/mL)–curcumin (5 mg/mL)-loaded polymeric micelles (10% w/v) demonstrated excellent colloidal properties with micellar size ~108 ± 1 nm after freeze-drying, and they remain stable under dilution in simulated interstitial lung fluid. Drug-loaded polymeric micelles were suitable for drug delivery to the deep lung with lung accumulation, according to the in vitro nebulization studies and the in vivo biodistribution assays of radiolabeled (99mTc) polymeric micelles, respectively. Hence, the nanoformulation did not exhibit hemolytic potential. Interestingly, the addition of mannose significantly improved (5.2-fold) the microbicidal efficacy against Mycobacterium tuberculosis H37Rv of the drug-co-loaded systems in comparison with their counterpart mannose-free polymeric micelles. Thus, this novel inhaled nanoformulation has demonstrated its potential for active drug delivery in pulmonary tuberculosis therapy.
      Citation: Pharmaceutics
      PubDate: 2022-04-28
      DOI: 10.3390/pharmaceutics14050959
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 960: Liposome-Encapsulated Tobramycin and
           IDR-1018 Peptide Mediated Biofilm Disruption and Enhanced Antimicrobial
           Activity against Pseudomonas aeruginosa

    • Authors: Nouf M. Alzahrani, Rayan Y. Booq, Ahmad M. Aldossary, Abrar A. Bakr, Fahad A. Almughem, Ahmed J. Alfahad, Wijdan K. Alsharif, Somayah J. Jarallah, Waleed S. Alharbi, Samar A. Alsudir, Essam J. Alyamani, Essam A. Tawfik, Abdullah A. Alshehri
      First page: 960
      Abstract: The inadequate eradication of pulmonary infections and chronic inflammation are significant complications in cystic fibrosis (CF) patients, who usually suffer from persistent and frequent lung infections caused by several pathogens, particularly Pseudomonas aeruginosa (P. aeruginosa). The ability of pathogenic microbes to protect themselves from biofilms leads to the development of an innate immune response and antibiotic resistance. In the present work, a reference bacterial strain of P. aeruginosa (PA01) and a multidrug-resistant isolate (MDR 7067) were used to explore the microbial susceptibility to three antibiotics (ceftazidime, imipenem, and tobramycin) and an anti-biofilm peptide (IDR-1018 peptide) using the minimum inhibition concentration (MIC). The most effective antibiotic was then encapsulated into liposomal nanoparticles and the IDR-1018 peptide with antibacterial activity, and the ability to disrupt the produced biofilm against PA01 and MDR 7067 was assessed. The MIC evaluation of the tobramycin antibacterial activity showed an insignificant effect on the liposomes loaded with tobramycin and liposomes encapsulating tobramycin and IDR-1018 against both P. aeruginosa strains to free tobramycin. Nevertheless, the biofilm formation was significantly reduced (p < 0.05) at concentrations of ≥4 μg/mL and ≤32 μg/mL for PA01 and ≤32 μg/mL for MDR 7067 when loading tobramycin into liposomes, with or without the anti-biofilm peptide compared to the free antibiotic, empty liposomes, and IDR-1018-loaded liposomes. A tobramycin concentration of ≤256 µg/mL was safe when exposed to a lung carcinoma cell line upon its encapsulation into the liposomal formulation. Tobramycin-loaded liposomes could be a potential candidate for treating lung-infected animal models owing to the high therapeutic efficacy and safety profile of this system compared to the free administration of the antibiotic.
      Citation: Pharmaceutics
      PubDate: 2022-04-28
      DOI: 10.3390/pharmaceutics14050960
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 961: In Silico Prediction of Skin
           Permeability Using a Two-QSAR Approach

    • Authors: Yu-Wen Wu, Giang Huong Ta, Yi-Chieh Lung, Ching-Feng Weng, Max K. Leong
      First page: 961
      Abstract: Topical and transdermal drug delivery is an effective, safe, and preferred route of drug administration. As such, skin permeability is one of the critical parameters that should be taken into consideration in the process of drug discovery and development. The ex vivo human skin model is considered as the best surrogate to evaluate in vivo skin permeability. This investigation adopted a novel two-QSAR scheme by collectively incorporating machine learning-based hierarchical support vector regression (HSVR) and classical partial least square (PLS) to predict the skin permeability coefficient and to uncover the intrinsic permeation mechanism, respectively, based on ex vivo excised human skin permeability data compiled from the literature. The derived HSVR model functioned better than PLS as represented by the predictive performance in the training set, test set, and outlier set in addition to various statistical estimations. HSVR also delivered consistent performance upon the application of a mock test, which purposely mimicked the real challenges. PLS, contrarily, uncovered the interpretable relevance between selected descriptors and skin permeability. Thus, the synergy between interpretable PLS and predictive HSVR models can be of great use for facilitating drug discovery and development by predicting skin permeability.
      Citation: Pharmaceutics
      PubDate: 2022-04-28
      DOI: 10.3390/pharmaceutics14050961
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 962: The Bacillary Postbiotics, Including
           2-Undecanone, Suppress the Virulence of Pathogenic Microorganisms

    • Authors: Satish Kumar Rajasekharan, Moshe Shemesh
      First page: 962
      Abstract: Secreted molecules from probiotic Bacilli have often been considered potential pharmaceuticals to fight infections caused by bacterial or yeast pathogens. In the present study, we investigated the antagonistic potential of secreted probiotic filtrates (hereafter, postbiotics) derived from Lactobacillus plantarum cells against pathogenic microorganisms, such as Escherichia coli, Staphylococcus aureus, and Candida albicans. We found that the postbiotics mitigate the biofilms of the tested pathogens with no notable effect on their planktonic growth. In addition, the postbiotics suppressed some virulence traits, for instance, the dendrite swarming motility of E. coli and yeast-to-hyphal switch in C. albicans. Further assays with an active constituent produced by the L. plantarum cells–2-undecanone revealed two significant findings: (i) 2-undecanone inhibits C. albicans biofilms and hyphae in vitro and in a Caenorhabditis elegans model, and (ii) it interacts specifically with Gln 58 amino acid residue of hyphal wall protein-1 (Hwp-1) in molecular docking analysis. The results suggest the targeted mode of antagonistic action of 2-undecanone against C. albicans biofilm. In total, the findings of the study depict an appealing strategy to use postbiotics, including specific ketone molecules, produced by L. plantarum for developing novel antibiofilm and anti-hyphal pharmaceuticals.
      Citation: Pharmaceutics
      PubDate: 2022-04-29
      DOI: 10.3390/pharmaceutics14050962
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 963: The Antitumoral/Antimetastatic Action
           of the Flavonoid Brachydin A in Metastatic Prostate Tumor Spheroids In
           Vitro Is Mediated by (Parthanatos) PARP-Related Cell Death

    • Authors: Diego Luis Ribeiro, Katiuska Tuttis, Larissa Cristina Bastos de Oliveira, Juliana Mara Serpeloni, Izabela Natalia Faria Gomes, André van Helvoort Lengert, Cláudia Quintino da Rocha, Rui Manuel Reis, Ilce Mara de Syllos Cólus, Lusânia Maria Greggi Antunes
      First page: 963
      Abstract: Metastatic prostate cancer (mPCa) is resistant to several chemotherapeutic agents. Brachydin A (BrA), a glycosylated flavonoid extracted from Fridericia platyphylla, displays a remarkable antitumoral effect against in vitro mPCa cells cultured as bidimensional (2D) monolayers. Considering that three-dimensional (3D) cell cultures provide a more accurate response to chemotherapeutic agents, this study investigated the antiproliferative/antimetastatic effects of BrA and the molecular mechanisms underlying its action in mPCa spheroids (DU145) in vitro. BrA at 60–100 μM was cytotoxic, altered spheroid morphology/volume, and suppressed cell migration and tumor invasiveness. High-content analysis revealed that BrA (60–100 µM) reduced mitochondrial membrane potential and increased apoptosis and necrosis markers, indicating that it triggered cell death mechanisms. Molecular analysis showed that (i) 24-h treatment with BrA (80–100 µM) increased the protein levels of DNA disruption markers (cleaved-PARP and p-γ-H2AX) as well as decreased the protein levels of anti/pro-apoptotic (BCL-2, BAD, and RIP3K) and cell survival markers (p-AKT1 and p-44/42 MAPK); (ii) 72-h treatment with BrA increased the protein levels of effector caspases (CASP3, CASP7, and CASP8) and inflammation markers (NF-kB and TNF-α). Altogether, our results suggest that PARP-mediated cell death (parthanatos) is a potential mechanism of action. In conclusion, BrA confirms its potential as a candidate drug for preclinical studies against mPCa.
      Citation: Pharmaceutics
      PubDate: 2022-04-29
      DOI: 10.3390/pharmaceutics14050963
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 964: Development and Evaluation of a
           PSMA-Targeted Nanosystem Co-Packaging Docetaxel and Androgen Receptor
           siRNA for Castration-Resistant Prostate Cancer Treatment

    • Authors: Yingying Zhang, Hongxia Duan, Heming Zhao, Lingling Qi, Yanhong Liu, Zheao Zhang, Chao Liu, Liqing Chen, Mingji Jin, Youyan Guan, Zhonggao Gao, Wei Huang
      First page: 964
      Abstract: Primary prostate cancer (PC) progresses to castration-resistant PC (CRPC) during androgen deprivation therapy (ADR) in early stages of prostate cancer. Thus, rather than blocking the androgen-related pathway further, docetaxel (DTX)-based therapy has become the most effective and standard first-line chemotherapy for CRPC. Although the therapy is successful in prolonging the survival of patients with CRPC, chemotherapy resistance develops due to the abnormal activation of the androgen receptor (AR) signaling pathway. Thus, to optimize DTX efficacy, continued maximum suppression of androgen levels and AR signaling is required. Here, we designed a prostate-specific membrane antigen (PSMA)-targeted nanosystem to carry both DTX and AR siRNA (Di-PP/AR-siRNA/DTX) for CRPC treatment. Specifically, DTX was encapsulated into the hydrophobic inner layer, and the AR siRNA was then condensed with the cationic PEI block in the hydrophilic outer layer of the PEI-PLGA polymeric micelles. The micelles were further coated with PSMA-targeted anionic polyethylene glycol-polyaspartic acid (Di-PEG-PLD). In vitro and in vivo results demonstrated that the resulting Di-PP/AR-siRNA/DTX exhibited prolonged blood circulation, selective targeting, and enhanced antitumor effects. Consequently, Di-PP/AR-siRNA/DTX holds great potential for efficient CRPC treatment by combining chemotherapy and siRNA silencing of androgen-related signaling pathways.
      Citation: Pharmaceutics
      PubDate: 2022-04-29
      DOI: 10.3390/pharmaceutics14050964
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 965: Ciprofloxacin in Patients Undergoing
           Extracorporeal Membrane Oxygenation (ECMO): A Population Pharmacokinetic

    • Authors: Dzenefa Alihodzic, Sebastian G. Wicha, Otto R. Frey, Christina König, Michael Baehr, Dominik Jarczak, Stefan Kluge, Claudia Langebrake
      First page: 965
      Abstract: Extracorporeal membrane oxygenation (ECMO) is utilized to temporarily sustain respiratory and/or cardiac function in critically ill patients. Ciprofloxacin is used to treat nosocomial infections, but data describing the effect of ECMO on its pharmacokinetics is lacking. Therefore, a prospective, observational trial including critically ill adults (n = 17), treated with ciprofloxacin (400 mg 8–12 hourly) during ECMO, was performed. Serial blood samples were collected to determine ciprofloxacin concentrations to assess their pharmacokinetics. The pharmacometric modeling was performed (NONMEM®) and utilized for simulations to evaluate the probability of target attainment (PTA) to achieve an AUC0–24/MIC of 125 mg·h/L for ciprofloxacin. A two-compartment model most adequately described the concentration-time data of ciprofloxacin. Significant covariates on ciprofloxacin clearance (CL) were plasma bicarbonate and the estimated glomerular filtration rate (eGFR). For pathogens with an MIC of ≤0.25 mg/L, a PTA of ≥90% was attained. However, for pathogens with an MIC of ≥0.5 mg/L, plasma bicarbonate ≥ 22 mmol/L or eGFR ≥ 10 mL/min PTA decreased below 90%, steadily declining to 7.3% (plasma bicarbonate 39 mmol/L) and 21.4% (eGFR 150 mL/min), respectively. To reach PTAs of ≥90% for pathogens with MICs ≥ 0.5 mg/L, optimized dosing regimens may be required.
      Citation: Pharmaceutics
      PubDate: 2022-04-29
      DOI: 10.3390/pharmaceutics14050965
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 966: Essential Oils of Gardenia jasminoides
           J. Ellis and Gardenia jasminoides f. longicarpa Z.W. Xie & M. Okada
           Flowers: Chemical Characterization and Assessment of Anti-Inflammatory
           Effects in Alveolar Macrophage

    • Authors: Nan Zhang, Ying Bian, Lei Yao
      First page: 966
      Abstract: Alveolar macrophage is the predominant cell type in the lung and is thought to be the major target for anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Aromatherapy using natural essential oils with anti-inflammatory effects for inhalable administration is a potential complementary and alternative therapy for COPD treatment. The Gardenia jasminoides flower is famous for its fragrance in East Asia and is used for treating colds and lung problems in folk medicine. Therefore, in the present study, flower essential oils from two main medicinal gardenia varieties (G. jasminoides J. Ellis and G. jasminoides f. longicarpa Z.W. Xie & M. Okada) were extracted by hydro-distillation, and their chemical components were analyzed by GC-MS. The anti-inflammatory effects of the two essential oils and their main ingredients were further studied on lipopolysaccharide (LPS)-induced models in murine alveolar macrophages (MH-S). The results indicated that the chemical constituents of the two gardenia varieties were quite different. Alcohol accounted for 53.8% of the G. jasminoides essential oil, followed by terpenes (16.01%). Terpenes accounted for 34.32% of the G. jasminoides f. longicarpa essential oil, followed by alcohols (19.6%) and esters (13.85%). Both the two gardenia essential oils inhibited the LPS-induced nitric oxide (NO) release and reduced the production of tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) in the MH-S cells. Linalool and α-farnesene dose-dependently reduced the NO release in the MH-S cells. Linalool and α-farnesene did not affect the PGE2 production but regulated the expression of TNF- α. In addition to linalool and α-farnesene, other components in the gardenia flower essential oils appeared to be able to act as anti-inflammatory agents and influence the PGE2 pathway.
      Citation: Pharmaceutics
      PubDate: 2022-04-29
      DOI: 10.3390/pharmaceutics14050966
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 967: Anti-Virulence Activity of
           3,3′-Diindolylmethane (DIM): A Bioactive Cruciferous Phytochemical
           with Accelerated Wound Healing Benefits

    • Authors: Karina Golberg, Victor Markus, Bat-el Kagan, Sigalit Barzanizan, Karin Yaniv, Kerem Teralı, Esti Kramarsky-Winter, Robert S. Marks, Ariel Kushmaro
      First page: 967
      Abstract: Antimicrobial resistance is among the top global health problems with antibacterial resistance currently representing the major threat both in terms of occurrence and complexity. One reason current treatments of bacterial diseases are ineffective is the occurrence of protective and resistant biofilm structures. Phytochemicals are currently being reviewed for newer anti-virulence agents. In the present study, we aimed to investigate the anti-virulence activity of 3,3′-diindolylmethane (DIM), a bioactive cruciferous phytochemical. Using a series of in vitro assays on major Gram-negative pathogens, including transcriptomic analysis, and in vivo porcine wound studies as well as in silico experiments, we show that DIM has anti-biofilm activity. Following DIM treatment, our findings show that biofilm formation of two of the most prioritized bacterial pathogens Acinetobacter baumannii and Pseudomonas aeruginosa was inhibited respectively by 65% and 70%. Combining the antibiotic tobramycin with DIM enabled a high inhibition (94%) of P. aeruginosa biofilm. A DIM-based formulation, evaluated for its wound-healing efficacy on P. aeruginosa-infected wounds, showed a reduction in its bacterial bioburden, and wound size. RNA-seq was used to evaluate the molecular mechanism underlying the bacterial response to DIM. The gene expression profile encompassed shifts in virulence and biofilm-associated genes. A network regulation analysis showed the downregulation of 14 virulence-associated super-regulators. Quantitative real-time PCR verified and supported the transcriptomic results. Molecular docking and interaction profiling indicate that DIM can be accommodated in the autoinducer- or DNA-binding pockets of the virulence regulators making multiple non-covalent interactions with the key residues that are involved in ligand binding. DIM treatment prevented biofilm formation and destroyed existing biofilm without affecting microbial death rates. This study provides evidence for bacterial virulence attenuation by DIM.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050967
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 968: The Potential Anti-Photoaging Effect of
           Photodynamic Therapy Using Chlorin e6-Curcumin Conjugate in UVB-Irradiated
           Fibroblasts and Hairless Mice

    • Authors: Ga-Hee Hur, A-Reum Ryu, Yong-Wan Kim, Mi-Young Lee
      First page: 968
      Abstract: Photodynamic therapy (PDT) has been used to treat cancers and non-malignant skin diseases. In this study, a chlorin e6–curcumin conjugate (Ce6-PEG-Cur), a combination of chlorin e6 (Ce6) and curcumin via a PEG linker, was used as a photosensitizer. The in vitro and in vivo effects of PDT using Ce6-PEG-Cur were analyzed in UVB-irradiated fibroblasts and hairless mice. The UVB-induced expression of MMPs was reduced in Hs68 fibroblast cells, and procollagen type Ⅰ expression was enhanced by Ce6-PEG-Cur-mediated PDT on a Western blotting gel. Moreover, UVB-induced collagen levels were restored upon application of Ce6-PEG-Cur-mediated PDT. Ce6-PEG-Cur-mediated PDT inhibited the expression of phosphorylated p38 in the MAPK signaling pathway, and it reduced the expression of phosphorylated NF-κB. In animal models, Ce6-PEG-Cur-mediated PDT inhibited the expression of MMPs, whereas procollagen type Ⅰ levels were enhanced in the dorsal skin of UVB-irradiated mice. Moreover, UVB-induced dorsal roughness was significantly reduced following Ce6-PEG-Cur-mediated PDT treatment. H&E staining and Masson’s trichrome staining showed that the thickness of the epidermal region was reduced, and the density of collagen fibers increased. Taken together, Ce6-PEG-Cur-mediated PDT might delay and improve skin photoaging by ultraviolet light, suggesting its potential for use as a more effective photo-aging treatment.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050968
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 969: Toxicity Assessment of Mesoporous
           Silica Nanoparticles upon Intravenous Injection in Mice: Implications for
           Drug Delivery

    • Authors: William M. MacCuaig, Abhilash Samykutty, Jeremy Foote, Wenyi Luo, Alexander Filatenkov, Min Li, Courtney Houchen, William E. Grizzle, Lacey R. McNally
      First page: 969
      Abstract: Nanoparticles are popular tools utilized to selectively deliver drugs and contrast agents for identification and treatment of disease. To determine the usefulness and translational potential of mesoporous silica nanoparticles (MSNs), further evaluations of toxicity are required. MSNs are among the most utilized nano-delivery systems due to ease of synthesis, pore structure, and functionalization. This study aims to elucidate toxicity as a result of intravenous injection of 25 nm MSNs coated with chitosan (C) or polyethylene glycol (PEG) in mice. Following acute and chronic injections, blood was evaluated for standard blood chemistry and complete blood count analyses. Blood chemistry results primarily indicated that no abnormalities were present following acute or chronic injections of MSNs, or C/PEG-coated MSNs. After four weekly administered treatments, vital organs showed minor exacerbation of pre-existing lesions in the 35KPEG-MSN and moderate exacerbation of pre-existing lesions in uncoated MSN and 2KPEG-MSN treatment groups. In contrast, C-MSN treatment groups had minimal changes compared to controls. This study suggests 25 nm MSNs coated with chitosan should elicit minimal toxicity when administered as either single or multiple intravenous injections, but MSNs coated with PEG, especially 2KPEG may exacerbate pre-existing vascular conditions. Further studies should evaluate varying sizes and types of nanoparticles to provide a better overall understanding on the relation between nanoparticles and in vivo toxicity.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050969
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 970: Nonclinical Pharmacokinetics and
           Pharmacodynamics Characterization of Anti-CD79b/CD3 T Cell-Dependent
           Bispecific Antibody Using a Surrogate Molecule: A Potential Therapeutic
           Agent for B Cell Malignancies

    • Authors: Rajbharan Yadav, Siddharth Sukumaran, Tanja S. Zabka, Jinze Li, Amy Oldendorp, Gary Morrow, Arthur Reyes, Melissa Cheu, Jessica Li, Jeffrey J. Wallin, Siao Tsai, Laura Sun, Peiyin Wang, Diego Ellerman, Christoph Spiess, Andy Polson, Eric G. Stefanich, Amrita V. Kamath, Meric A. Ovacik
      First page: 970
      Abstract: The T cell-dependent bispecific (TDB) antibody, anti-CD79b/CD3, targets CD79b and CD3 cell-surface receptors expressed on B cells and T cells, respectively. Since the anti-CD79b arm of this TDB binds only to human CD79b, a surrogate TDB that binds to cynomolgus monkey CD79b (cyCD79b) was used for preclinical characterization. To evaluate the impact of CD3 binding affinity on the TDB pharmacokinetics (PK), we utilized non-tumor-targeting bispecific anti-gD/CD3 antibodies composed of a low/high CD3 affinity arm along with a monospecific anti-gD arm as controls in monkeys and mice. An integrated PKPD model was developed to characterize PK and pharmacodynamics (PD). This study revealed the impact of CD3 binding affinity on anti-cyCD79b/CD3 PK. The surrogate anti-cyCD79b/CD3 TDB was highly effective in killing CD79b-expressing B cells and exhibited nonlinear PK in monkeys, consistent with target-mediated clearance. A dose-dependent decrease in B cell counts in peripheral blood was observed, as expected. Modeling indicated that anti-cyCD79b/CD3 TDB’s rapid and target-mediated clearance may be attributed to faster internalization of CD79b, in addition to enhanced CD3 binding. The model yielded unbiased and precise curve fits. These findings highlight the complex interaction between TDBs and their targets and may be applicable to the development of other biotherapeutics.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050970
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 971: A Single-Cell Network-Based Drug
           Repositioning Strategy for Post-COVID-19 Pulmonary Fibrosis

    • Authors: Albert Li, Jhih-Yu Chen, Chia-Lang Hsu, Yen-Jen Oyang, Hsuan-Cheng Huang, Hsueh-Fen Juan
      First page: 971
      Abstract: Post-COVID-19 pulmonary fibrosis (PCPF) is a long-term complication that appears in some COVID-19 survivors. However, there are currently limited options for treating PCPF patients. To address this problem, we investigated COVID-19 patients’ transcriptome at single-cell resolution and combined biological network analyses to repurpose the drugs treating PCPF. We revealed a novel gene signature of PCPF. The signature is functionally associated with the viral infection and lung fibrosis. Further, the signature has good performance in diagnosing and assessing pulmonary fibrosis. Next, we applied a network-based drug repurposing method to explore novel treatments for PCPF. By quantifying the proximity between the drug targets and the signature in the interactome, we identified several potential candidates and provided a drug list ranked by their proximity. Taken together, we revealed a novel gene expression signature as a theragnostic biomarker for PCPF by integrating different computational approaches. Moreover, we showed that network-based proximity could be used as a framework to repurpose drugs for PCPF.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050971
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 972: Citric Acid: A Multifunctional
           Pharmaceutical Excipient

    • Authors: Maria Lambros, Thac (Henry) Tran, Qinqin Fei, Mike Nicolaou
      First page: 972
      Abstract: Citric acid, a tricarboxylic acid, has found wide application in the chemical and pharmaceutical industry due to its biocompatibility, versatility, and green, environmentally friendly chemistry. This review emphasizes the pharmaceutical uses of citric acid as a strategic ingredient in drug formulation while focusing on the impact of its physicochemical properties. The functionality of citric acid is due to its three carboxylic groups and one hydroxyl group. These allow it to be used in many ways, including its ability to be used as a crosslinker to form biodegradable polymers and as a co-former in co-amorphous and co-crystal applications. This paper also analyzes the effect of citric acid in physiological processes and how this effect can be used to enhance the attributes of pharmaceutical preparations, as well as providing a critical discussion on the issues that may arise out of the presence of citric acid in formulations.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050972
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 973: Ionizable Lipid Nanoparticles Enhanced
           the Synergistic Adjuvant Effect of CpG ODNs and QS21 in a Varicella Zoster
           Virus Glycoprotein E Subunit Vaccine

    • Authors: Ning Luan, Han Cao, Yunfei Wang, Kangyang Lin, Cunbao Liu
      First page: 973
      Abstract: Varicella zoster virus (VZV) causes two diseases: varicella upon primary infection and herpes zoster when latent viruses in the sensory ganglia reactivate. While varicella vaccines depend on humoral immunity to prevent VZV infection, cell-mediated immunity (CMI), which plays a therapeutic role in the control or elimination of reactivated VZV in infected cells, is decisive for zoster vaccine efficacy. As one of the most abundant glycoproteins of VZV, conserved glycoprotein E (gE) is essential for viral replication and transmission between ganglion cells, thus making it an ideal target subunit vaccine antigen; gE has been successfully used in the herpes zoster vaccine ShingrixTM on the market. In this report, we found that ionizable lipid nanoparticles (LNPs) approved by the Food and Drug Administration (FDA) as vectors for coronavirus disease 2019 (COVID-19) mRNA vaccines could enhance the synergistic adjuvant effect of CpG oligodeoxynucleotides (CpG ODNs) and QS21 on VZV-gE, affecting both humoral immunity and CMI. Vaccines made with these LNPs showed promise as varicella vaccines without a potential risk of herpes zoster, which identifies them as a novel type of herpes zoster vaccine similar to ShingrixTM. All of the components in this LNP-CpG-QS21 adjuvant system were proven to be safe after mass vaccination, and the high proportion of cholesterol contained in the LNPs was helpful for limiting the cytotoxicity induced by QS21, which may lead to the development of a novel herpes zoster subunit vaccine for clinical application.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050973
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 974: Impaired Pharmacokinetics of Amiodarone
           under Veno-Venous Extracorporeal Membrane Oxygenation: From Bench to

    • Authors: Mickaël Lescroart, Claire Pressiat, Benjamin Péquignot, N’Guyen Tran, Jean-Louis Hébert, Nassib Alsagheer, Nicolas Gambier, Bijan Ghaleh, Julien Scala-Bertola, Bruno Levy
      First page: 974
      Abstract: Background: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both in vitro and in vivo. Methods: In vitro: Amiodarone concentration decays were compared between closed-loop ECMO and control stirring containers over a 24 h period. In vivo: Potassium-induced cardiac arrest in 10 pigs with ARDS, assigned to either control or VV ECMO groups, was treated with 300 mg amiodarone injection under continuous cardiopulmonary resuscitation. Pharmacokinetic parameters Cmax, Tmax AUC and F were determined from both direct amiodarone plasma concentrations observation and non-linear mixed effects modeling estimation. Results: An in vitro study revealed a rapid and significant decrease in amiodarone concentrations in the closed-loop ECMO circuitry whereas it remained stable in control experiment. In vivo study revealed a 32% decrease in the AUC and a significant 42% drop of Cmax in the VV ECMO group as compared to controls. No difference in Tmax was observed. VV ECMO significantly modified both central distribution volume and amiodarone clearance. Monte Carlo simulations predicted that a 600 mg bolus of amiodarone under VV ECMO would achieve the amiodarone bioavailability observed in the control group. Conclusions: This is the first study to report decreased amiodarone bioavailability under VV ECMO. Higher doses of amiodarone should be considered for effective amiodarone exposure under VV ECMO.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050974
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 975: Synthesis and Characterization of
           Antibiotic–Loaded Biodegradable Citrate Functionalized Mesoporous
           Hydroxyapatite Nanocarriers as an Alternative Treatment for Bone

    • Authors: Nasser H. Alotaibi, Muhammad Usman Munir, Nabil K. Alruwaili, Khalid Saad Alharbi, Ayesha Ihsan, Alanood S. Almurshedi, Ikram Ullah Khan, Syed Nasir Abbas Bukhari, Mubashar Rehman, Naveed Ahmad
      First page: 975
      Abstract: The continuing growth of bacterial resistance makes the top challenge for the healthcare system especially in bone–infections treatment. Current estimates reveal that in 2050 the death ratio caused by bacterial infections can be higher than cancer. The aim of this study is to provide an alternative to currently available bone–infection treatments. Here we designed mesoporous hydroxyapatite nanocarriers functionalized with citrate (Ctr–mpHANCs). Amoxicillin (AMX) is used as a model drug to load in Ctr–mpHANCs, and the drug loading was more than 90% due to the porous nature of nanocarriers. Scanning electron microscopy shows the roughly spherical morphology of nanocarriers, and the DLS study showed the approximate size of 92 nm. The Brunauer–Emmett–Teller (BET) specific surface area and pore diameter was found to be about 182.35 m2/g and 4.2 nm, respectively. We noticed that almost 100% of the drug is released from the AMX loaded Ctr–mpHANCs (AMX@Ctr–mpHANCs) in a pH–dependent manner within 3 d and 5 d at pH 2.0 and 4.5, respectively. The sustained drug release behaviour was observed for 15 d at pH 7.4 and no RBCs hemolysis by AMX@Ctr–mpHANCs. The broth dilution and colony forming unit (CFU) assays were used to determine the antimicrobial potential of AMX@Ctr–mpHANCs. It was observed in both studies that AMX@Ctr–mpHANCs showed a significant reduction in the bacterial growth of S.aureus, E. coli, and P. aeruginosa as compared to Ctr–mpHANCs with no bacteria–killing. Thus, we proposed that Ctr–mpHANCs can be used as a drug carrier and a treatment option for bone infections caused by bacteria.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050975
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 976: Transdermal Delivery of High Molecular
           Weight Antibiotics to Deep Tissue Infections via Droplette Micromist
           Technology Device (DMTD)

    • Authors: Lakshmi Pulakat, Howard H. Chen, Madhavi P. Gavini, Lauren A. Ling, Yinian Tang, Alexander Mehm, Gregory L. Martin, Corinna N. Beale, Brian P. Mooney, Hongmin Sun
      First page: 976
      Abstract: Wound infection by multidrug-resistant (MDR) bacteria is a major disease burden. Systemic administration of broad-spectrum antibiotics colistin methanesulfonate (CMS) and vancomycin are the last lines of defense against deep wound infections by MDR bacteria. However, systemic administration of CMS and vancomycin are linked to life-threatening vital organ damage. Currently there are no effective topical application strategies to deliver these high molecular weight antibiotics across the stratum corneum. To overcome this difficulty, we tested if high molecular weight antibiotics delivered by Droplette micromist technology device (DMTD), a transdermal delivery device that generates a micromist capable of packaging large molecules, could attenuate deep skin tissue infections. Using green fluorescent protein-tagged E. coli and live tissue imaging, we show that (1) the extent of attenuation of deep-skin E. coli infection was similar when treated with topical DMTD- or systemic IP (intraperitoneal)-delivered CMS; (2) DMTD-delivered micromist did not spread the infection deeper; (3) topical DMTD delivery and IP delivery resulted in similar levels of vancomycin in the skin after a 2 h washout period; and (4) IP-delivered vancomycin was about 1000-fold higher in kidney and plasma than DMTD-delivered vancomycin indicating systemic toxicity. Thus, topical DMTD delivery of these antibiotics is a safe treatment for the difficult-to-treat deep skin tissue infections by MDR bacteria.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050976
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 977: Activity-Based Probes for Proteases
           Pave the Way to Theranostic Applications

    • Authors: Georgia Sotiropoulou, Eleni Zingkou, Evangelos Bisyris, Georgios Pampalakis
      First page: 977
      Abstract: Proteases are important enzymes in health and disease. Their activities are regulated at multiple levels. In fact, proteases are synthesized as inactive proenzymes (zymogens) that are activated by proteolytic removal of their pro-peptide sequence and can remain active or their activity can be attenuated by complex formation with specific endogenous inhibitors or by limited proteolysis or degradation. Consequently, quite often, only a fraction of the protease molecules is in the active/functional form, thus, the abundance of a protease is not always linearly proportional to the (patho)physiological function(s). Therefore, assays to determine the active forms of proteases are needed, not only in research but also in molecular diagnosis and therapy. Activity-based probes (ABPs) are chemical entities that bind covalently to the active enzyme/protease. ABPs carry a detection tag to enable localization and quantification of specific enzymatic/proteolytic activities with applications in molecular imaging and diagnosis. Moreover, ABPs act as suicide inhibitors of proteases, which can be exploited for delineation of the functional role(s) of a given protease in (patho) biological context and as potential therapeutics. In this sense, ABPs represent new theranostic agents. We outline recent developments pertaining to ABPs for proteases with potential therapeutic applications, with the aim to highlight their importance in theranostics.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050977
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 978: Brain-Targeted Intranasal Delivery of
           Zotepine Microemulsion: Pharmacokinetics and Pharmacodynamics

    • Authors: Sravanthi Reddy Pailla, Sunitha Sampathi, Vijayabhaskarreddy Junnuthula, Sravya Maddukuri, Sujatha Dodoala, Sathish Dyawanapelly
      First page: 978
      Abstract: The purpose of our study was to improve the solubility, bioavailability, and efficacy of zotepine (ZTP) by brain-targeted intranasal delivery of microemulsion (ME) and its physicochemical properties, the pharmacokinetic and pharmacodynamic parameters were evaluated. The optimized ME formulations contain 10% w/w of oil (Capmul MCM C8, monoglycerides, and diglycerides of caprylic acid), 50% w/w of Smix (Labrasol and Transcutol HP, and 40% w/w of water resulting in a globule size of 124.6 ±3.52 nm with low polydispersity index (PDI) (0.212 ± 0.013) and 2.8-fold higher permeation coefficient through porcine nasal mucosa compared to pure drug. In vitro cell line studies on RPMI 2650, Beas-2B, and Neuro-2A revealed ZTP-ME as safe. ZTP-ME administered intranasally showed higher AUC0-t24 (18.63 ± 1.33 h x µg/g) in the brain by approximately 4.3-fold than oral ME (4.30 ± 0.92 h × µg/g) and 7.7-fold than intravenous drug solutions (2.40 ± 0.36 h × µg/g). In vivo anti-schizophrenic activity was conducted using catalepsy test scores, the formulation showed better efficacy via the intranasal route; furthermore, there was no inflammation or hemorrhage in the nasal cavity. The results concluded that the ZTP microemulsion as a safe and effective strategy could greatly enhance brain distribution by intranasal administration.
      Citation: Pharmaceutics
      PubDate: 2022-04-30
      DOI: 10.3390/pharmaceutics14050978
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 979: Benchmarking the Solubility Enhancement
           and Storage Stability of Amorphous Drug–Polyelectrolyte Nanoplex
           against Co-Amorphous Formulation of the Same Drug

    • Authors: Li Ming Lim, Jin-Won Park, Kunn Hadinoto
      First page: 979
      Abstract: Amorphization, typically in the form of amorphous solid dispersion (ASD), represents a well-established solubility enhancement strategy for poorly soluble drugs. Recently, two amorphous drug formulations, i.e., the amorphous drug–polyelectrolyte nanoparticle complex (nanoplex) and co-amorphous system, have emerged as promising alternatives to circumvent the issues faced by ASD (i.e., large dosage requirement, high hygroscopicity). In the present work, the nanoplex was benchmarked against the co-amorphous system in terms of the preparation efficiency, drug payload, thermal stability, dissolution rate, supersaturation generation, and accelerated storage stability. Weakly acidic curcumin (CUR) and weakly basic ciprofloxacin (CIP) were used as the model poorly soluble drugs. The CUR and CIP nanoplexes were prepared using chitosan and sodium dextran sulfate as the polyelectrolytes, respectively. The co-amorphous CUR and CIP were prepared using tannic acid and tryptophan as the co-formers, respectively. The benchmarking results showed that the amorphous drug nanoplex performed as well as, if not better than, the co-amorphous system depending on the drug in question and the aspects being compared. The present work successfully established the nanoplex as an equally viable amorphous drug formulation as the more widely studied co-amorphous system to potentially serve as an alternative to ASD.
      Citation: Pharmaceutics
      PubDate: 2022-05-02
      DOI: 10.3390/pharmaceutics14050979
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 980: A Comparative Study on Inhibition of
           Breast Cancer Cells and Tumors in Mice by Carotenoid Extract and
           Nanoemulsion Prepared from Sweet Potato (Ipomoea batatas L.) Peel

    • Authors: Hsin-Yen Hsu, Bing-Huei Chen
      First page: 980
      Abstract: The objectives of this study were to determine carotenoid composition in sweet potato (TNG66) peel and prepare carotenoid nanoemulsion to study its inhibition effect on breast cancer cells MCF-7 and tumors in mice. Results showed that a total of 10 carotenoids were separated within 30 min by employing a YMC C30 column and a gradient mobile phase of methanol/acetonitrile/water (74:14:12, v/v/v) and dichloromethane (B) with a flow rate of 1 mL/min, column temperature of 25 °C, and detection wavelength of 450 nm. Following quantitation, all-trans-β-carotene was present in the highest amount (663.8 μg/g). The method validation data demonstrated a high accuracy and precision of this method. The carotenoid nanoemulsion was prepared by mixing an appropriate proportion of carotenoid extract, Tween 80, PEG 400, soybean oil and deionized water with the mean particle size being 15.7 nm (transmission electron microscope (TEM)), polydispersity index 0.238, encapsulation efficiency 97% and zeta potential −69.8 mV. A high stability of carotenoid nanoemulsion was shown over a 90-day storage period at 25 °C and during heating at 100 °C for 2 h. The release percentage of total carotenoids from carotenoid nanoemulsion under gastric and intestinal condition was 18.3% and 49.1%, respectively. An antiproliferation study revealed that carotenoid nanoemulsion was more effective than carotenoid extract in inhibiting the growth of human breast cancer cells MCF-7. Following treatments of paclitaxel (10 μg/mL), carotenoid nanoemulsion (20 and 10 μg/mL) and carotenoid extract (20 and 10 μg/mL), the tumor weight of mice respectively decreased by 77.4, 56.2, 40.3, 36.1 and 18.7%, as well as tumor volume of mice by 75.4, 65.0, 49.7, 46.7 and 26.5%. Also, both carotenoid extract and nanoemulsion could reduce the levels of epidermal growth factor (EGF) and (vascular endothelial growth factor (VEGF) in serum, with the latter being more effective. This finding suggested that carotenoid nanoemulsion was more effective than carotenoid extract in inhibiting tumor growth in mice.
      Citation: Pharmaceutics
      PubDate: 2022-05-02
      DOI: 10.3390/pharmaceutics14050980
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 981: Metallic Engineered Nanomaterials and
           Ocular Toxicity: A Current Perspective

    • Authors: Krista M. Cosert, Soohyun Kim, Iman Jalilian, Maggie Chang, Brooke L. Gates, Kent E. Pinkerton, Laura S. Van Winkle, Vijay Krishna Raghunathan, Brian C. Leonard, Sara M. Thomasy
      First page: 981
      Abstract: The ocular surface, comprised of the transparent cornea, conjunctiva, and protective tear film, forms a protective barrier defending deeper structures of the eye from particulate matter and mechanical trauma. This barrier is routinely exposed to a multitude of naturally occurring and engineered nanomaterials (ENM). Metallic ENMs are particularly ubiquitous in commercial products with a high risk of ocular exposure, such as cosmetics and sunscreens. Additionally, there are several therapeutic uses for metallic ENMs owing to their attractive magnetic, antimicrobial, and functionalization properties. The increasing commercial and therapeutic applications of metallic ENMs come with a high risk of ocular exposure with poorly understood consequences to the health of the eye. While the toxicity of metallic ENMs exposure has been rigorously studied in other tissues and organs, further studies are necessary to understand the potential for adverse effects and inform product usage for individuals whose ocular health may be compromised by injury, disease, or surgical intervention. This review provides an update of current literature on the ocular toxicity of metallic ENMs in vitro and in vivo, as well as the risks and benefits of therapeutic applications of metallic ENMs in ophthalmology.
      Citation: Pharmaceutics
      PubDate: 2022-05-03
      DOI: 10.3390/pharmaceutics14050981
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 982: Curcumin as a Natural Approach of
           Periodontal Adjunctive Treatment and Its Immunological Implications: A
           Narrative Review

    • Authors: Sorina Mihaela Solomon, Celina Silvia Stafie, Irina-Georgeta Sufaru, Silvia Teslaru, Cristina Mihaela Ghiciuc, Florin Dumitru Petrariu, Oana Tanculescu
      First page: 982
      Abstract: Scaling and root planing represent the gold standard in the treatment of periodontal disease, but these therapeutic methods cannot eliminate the remaining periodontopathogenic bacteria in cement, tubules, and periodontal soft tissue. Thus, a number of additional therapeutic means have been adopted, including local and systemic antibiotic therapy, as well as the use of photodynamic therapy techniques. Recently, special attention has been paid to potential phytotherapeutic means in the treatment of periodontal disease. In this review, we aim to present the effects generated by the extract of Curcuma longa, the various forms of application of turmeric as an additional therapeutic means, as well as the aspects related to its biotolerance.
      Citation: Pharmaceutics
      PubDate: 2022-05-03
      DOI: 10.3390/pharmaceutics14050982
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 983: Amorphization of Drugs for Transdermal
           Delivery-a Recent Update

    • Authors: Bappaditya Chatterjee, Abhishek Reddy, Moushami Santra, Sandile Khamanga
      First page: 983
      Abstract: Amorphous solid dispersion is a popular formulation approach for orally administered poorly water-soluble drugs, especially for BCS class II. But oral delivery could not be an automatic choice for some drugs with high first-pass metabolism susceptibility. In such cases, transdermal delivery is considered an alternative if the drug is potent and the dose is less than 10 mg. Amorphization of drugs causes supersaturation and enhances the thermodynamic activity of the drugs. Hence, drug transport through the skin could be improved. The stabilization of amorphous system is a persistent challenge that restricts its application. A polymeric system, where amorphous drug is dispersed in a polymeric carrier, helps its stability. However, high excipient load often becomes problematic for the polymeric amorphous system. Coamorphous formulation is another approach, where one drug is mixed with another drug or low molecular weight compound, which stabilizes each other, restricts crystallization, and maintains a single-phase homogenous amorphous system. Prevention of recrystallization along with enhanced skin permeation has been observed by the transdermal coamorphous system. But scalable manufacturing methods, extensive stability study and in-depth in vivo evaluation are lacking. This review has critically studied the mechanistic aspects of amorphization and transdermal permeation by analyzing recent researches in this field to propose a future direction.
      Citation: Pharmaceutics
      PubDate: 2022-05-03
      DOI: 10.3390/pharmaceutics14050983
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 984: Development of Tea Seed Oil
           Nanostructured Lipid Carriers and In Vitro Studies on Their Applications
           in Inducing Human Hair Growth

    • Authors: Pornthida Riangjanapatee, Mattaka Khongkow, Alongkot Treetong, Onuma Unger, Chutikorn Phungbun, Supatchaya Jaemsai, Chatchaya Bootsiri, Siriporn Okonogi
      First page: 984
      Abstract: Synthetic drugs used to treat hair loss cause many side-effects. Natural tea seed oil possesses many activities that can suppress hair loss. However, it is oily and sticky in direct application. In this study, tea seed oil loaded nanostructured lipid carriers (NLC) using Tween 80 (NLC-T), Varisoft 442 (NLC-V), and a combination of both surfactants (NLC-C) was developed. The obtained nanoformulations showed spherical particles in the size range 130–430 nm. Particle size and size distribution of NLC-C and NLC-T after storage at 4, 25, and 40 °C for 90 days were unchanged, indicating their excellent stability. The pH of NLC-T, NLC-V, and NLC-C throughout 90 days remained at 3, 4, and 3.7, respectively. NLC-C showed significantly greater nontoxicity and growth-stimulating effect on human follicle dermal papilla (HFDP) cells than the intact oil. NLC-T and NLC-V could not stimulate cell growth and showed high cytotoxicity. NLC-C showed melting point at 52 ± 0.02 °C and its entrapment efficiency was 96.26 ± 2.26%. The prepared hair serum containing NLC-C showed better spreading throughout the formulation than that containing the intact oil. Using 5% NLC-C showed a 78.8% reduction in firmness of the hair serum while enhancing diffusion efficiency by reducing shear forces up to 81.4%. In conclusion, the developed NLC-C of tea seed oil is an effective alternative in stimulating hair growth. Hair serum containing NLC-C obviously reduces sticky, oily, and greasy feeling after use.
      Citation: Pharmaceutics
      PubDate: 2022-05-04
      DOI: 10.3390/pharmaceutics14050984
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 985: Dexamethasone-Loaded Radially
           Mesoporous Silica Nanoparticles for Sustained Anti-Inflammatory Effects in
           Rheumatoid Arthritis

    • Authors: Sang Jun Kim, Youngbo Choi, Khee Tae Min, Surin Hong
      First page: 985
      Abstract: Radially mesoporous silica nanoparticles (RMSNs) with protonated amine functionality are proposed to be a dexamethasone (Dex) carrier that could achieve a sustained anti-inflammatory effect in rheumatoid arthritis (RA). High-capacity loading and a sustained release of target drugs were achieved by radially oriented mesopores and surface functionality. The maximum loading efficiency was confirmed to be about 76 wt%, which is about two times greater than that of representative mesopores silica, SBA-15. In addition, Dex-loaded RMSNs allow a sustained-release profile with about 92% of the loaded Dex for 100 h in vitro, resulting in 2.3-fold better delivery efficiency of Dex than that of the SBA-15 over the same period. In vivo evaluation of the inhibitory effects on inflammation in a RA disease rat model showed that, compared with the control groups, the group treated with Dex-loaded RMSNs sustained significant anti-inflammatory effects and recovery of cartilage over a period of 8 weeks. The in vivo effects were confirmed via micro-computed tomography, bone mineral density measurements, and modified Mankin scoring. The proposed Dex-loaded RMSNs prolonged the life of the in vivo concentrations of therapeutic agents and maximized their effect, which should encourage its application.
      Citation: Pharmaceutics
      PubDate: 2022-05-04
      DOI: 10.3390/pharmaceutics14050985
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 986: Formulation and Biological Evaluation
           of Mesoporous Silica Nanoparticles Loaded with Combinations of Sortase A
           Inhibitors and Antimicrobial Peptides

    • Authors: Alharthi, Ziora, Janjua, Popat, Moyle
      First page: 986
      Abstract: This study aimed to develop synergistic therapies to treat superbug infections through the encapsulation of sortase A inhibitors (SrtAIs; trans-chalcone (TC), curcumin (CUR), quercetin (QC), or berberine chloride (BR)) into MCM-41 mesoporous silica nanoparticles (MSNs) or a phosphonate-modified analogue (MCM-41-PO3−) to overcome their poor aqueous solubility. A resazurin-modified minimum inhibitory concentration (MIC) and checkerboard assays, to measure SrtAI synergy in combination with leading antimicrobial peptides (AMPs; pexiganan (PEX), indolicidin (INDO), and [I5, R8] mastoparan (MASTO)), were determined against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The results demonstrated that the MCM-41 and MCM-41-PO3− formulations significantly improved the aqueous solubility of each SrtAI. The MICs for SrtAI/MCM-41-PO3− formulations were lower compared to the SrtAI/MCM-41 formulations against tested bacterial strains, except for the cases of BR/MCM-41 and QC/MCM-41 against P. aeruginosa. Furthermore, the following combinations demonstrated synergy: PEX with TC/MCM-41 (against all strains) or TC/MCM-41-PO3− (against all strains except P. aeruginosa); PEX with BR/MCM-41 or BR/MCM-41-PO3− (against MSSA and MRSA); INDO with QC/MCM-41 or QC/MCM-41-PO3− (against MRSA); and MASTO with CUR/MCM-41 (against E. coli). These combinations also reduced each components’ toxicity against human embryonic kidney cells. In conclusion, MCM-41 MSNs provide a platform to enhance SrtAI solubility and demonstrated antimicrobial synergy with AMPs and reduced toxicity, providing novel superbug treatment opportunities.
      Citation: Pharmaceutics
      PubDate: 2022-05-04
      DOI: 10.3390/pharmaceutics14050986
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 987: Current Strategies to Enhance Delivery
           of Drugs across the Blood–Brain Barrier

    • Authors: Teleanu, Preda, Niculescu, Vladâcenco, Radu, Grumezescu, Teleanu
      First page: 987
      Abstract: The blood–brain barrier (BBB) has shown to be a significant obstacle to brain medication delivery. The BBB in a healthy brain is a diffusion barrier that prevents most substances from passing from the blood to the brain; only tiny molecules can pass across the BBB. The BBB is disturbed in specific pathological illnesses such as stroke, diabetes, seizures, multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. The goal of this study is to offer a general overview of current brain medication delivery techniques and associated topics from the last five years. It is anticipated that this review will stimulate readers to look into new ways to deliver medications to the brain. Following an introduction of the construction and function of the BBB in both healthy and pathological conditions, this review revisits certain contested questions, such as whether nanoparticles may cross the BBB on their own and if medications are selectively delivered to the brain by deliberately targeted nanoparticles. Current non-nanoparticle options are also discussed, including drug delivery via the permeable BBB under pathological circumstances and the use of non-invasive approaches to improve brain medication absorption.
      Citation: Pharmaceutics
      PubDate: 2022-05-04
      DOI: 10.3390/pharmaceutics14050987
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 988: Persistent Properties of a
           Subpopulation of Cancer Cells Overexpressing the Hedgehog Receptor Patched

    • Authors: Álvaro Javier Feliz Morel, Anida Hasanovic, Aurélie Morin, Chloé Prunier, Virginie Magnone, Kevin Lebrigand, Amaury Aouad, Sarah Cogoluegnes, Judith Favier, Claude Pasquier, Isabelle Mus-Veteau
      First page: 988
      Abstract: Despite the development of new therapeutic strategies, cancer remains one of the leading causes of mortality worldwide. One of the current major challenges is the resistance of cancers to chemotherapy treatments inducing metastases and relapse of the tumor. The Hedgehog receptor Patched (Ptch1) is overexpressed in many types of cancers. We showed that Ptch1 contributes to the efflux of doxorubicin and plays an important role in the resistance to chemotherapy in adrenocortical carcinoma (ACC), a rare cancer which presents strong resistance to the standard of care chemotherapy treatment. In the present study, we isolated and characterized a subpopulation of the ACC cell line H295R in which Ptch1 is overexpressed and more present at the cell surface. This cell subpopulation is more resistant to doxorubicin, grows as spheroids, and has a greater capability of clonogenicity, migration, and invasion than the parental cells. Xenograft experiments performed in mice and in ovo showed that this cell subpopulation is more tumorigenic and metastatic than the parental cells. These results suggest that this cell subpopulation has cancer stem-like or persistent cell properties which were strengthened by RNA-seq. If present in tumors from ACC patients, these cells could be responsible for therapy resistance, relapse, and metastases.
      Citation: Pharmaceutics
      PubDate: 2022-05-05
      DOI: 10.3390/pharmaceutics14050988
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 989: Formulation of Amphotericin B in
           PEGylated Liposomes for Improved Treatment of Cutaneous Leishmaniasis by
           Parenteral and Oral Routes

    • Authors: Guilherme S. Ramos, Virgínia M. R. Vallejos, Gabriel S. M. Borges, Raquel M. Almeida, Izabela M. Alves, Marta M. G. Aguiar, Christian Fernandes, Pedro P. G. Guimarães, Ricardo T. Fujiwara, Philippe M. Loiseau, Lucas A. M. Ferreira, Frédéric Frézard
      First page: 989
      Abstract: Liposomal amphotericin B (AmB) or AmBisome® is the most effective and safe therapeutic agent for visceral leishmaniasis (VL), but its clinical efficacy is limited in cutaneous leishmaniasis (CL) and HIV/VL co-infection. The aim of this work was to develop a formulation of AmB in PEGylated liposomes and compare its efficacy to AmBisome® in a murine model of CL. Formulations of AmB in conventional and PEGylated liposomes were characterized for particle size and morphology, drug encapsulation efficiency and aggregation state. Those were compared to AmBisome® in Leishmania amazonensis-infected BALB/c mice for their effects on the lesion size growth and parasite load. The conventional and PEGylated formulations showed vesicles with 100–130 nm diameter and low polydispersity, incorporating more than 95% of AmB under the non-aggregated form. Following parenteral administration in the murine model of CL, the PEGylated formulation of AmB significantly reduced the lesion size growth and parasite load, in comparison to control groups, in contrast to conventional liposomal AmB. The PEGylated formulation of AmB was also effective when given by oral route on a 2-day regimen. This work reports for the first time that PEGylated liposomal AmB can improve the treatment of experimental cutaneous leishmaniasis by both parenteral and oral routes.
      Citation: Pharmaceutics
      PubDate: 2022-05-05
      DOI: 10.3390/pharmaceutics14050989
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 990: Semi-Automated Therapeutic Drug
           Monitoring as a Pillar toward Personalized Medicine for Tuberculosis

    • Authors: Jayanti, Long, Phat, Cho, Shin
      First page: 990
      Abstract: Standard tuberculosis (TB) management has failed to control the growing number of drug-resistant TB cases worldwide. Therefore, innovative approaches are required to eradicate TB. Model-informed precision dosing and therapeutic drug monitoring (TDM) have become promising tools for adjusting anti-TB drug doses corresponding with individual pharmacokinetic profiles. These are crucial to improving the treatment outcome of the patients, particularly for those with complex comorbidity and a high risk of treatment failure. Despite the actual benefits of TDM at the bedside, conventional TDM encounters several hurdles related to laborious, time-consuming, and costly processes. Herein, we review the current practice of TDM and discuss the main obstacles that impede it from successful clinical implementation. Moreover, we propose a semi-automated TDM approach to further enhance precision medicine for TB management.
      Citation: Pharmaceutics
      PubDate: 2022-05-05
      DOI: 10.3390/pharmaceutics14050990
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 991: Vesicular Nanocarriers for
           Phytocompounds in Wound Care: Preparation and Characterization

    • Authors: Safta, Bogdan, Moldovan
      First page: 991
      Abstract: The need to develop wound healing preparations is a pressing challenge given the limitations of the current treatment and the rising prevalence of impaired healing wounds. Although herbal extracts have been used for many years to treat skin disorders, due to their wound healing, anti-inflammatory, antimicrobial, and antioxidant effects, their efficacy can be questionable because of their poor bioavailability and stability issues. Nanotechnology offers an opportunity to revolutionize wound healing therapies by including herbal compounds in nanosystems. Particularly, vesicular nanosystems exhibit beneficial properties, such as biocompatibility, targeted and sustained delivery capacity, and increased phytocompounds’ bioavailability and protection, conferring them a great potential for future applications in wound care. This review summarizes the beneficial effects of phytocompounds in wound healing and emphasizes the advantages of their entrapment in vesicular nanosystems. Different types of lipid nanocarriers are presented (liposomes, niosomes, transferosomes, ethosomes, cubosomes, and their derivates’ systems), highlighting their applications as carriers for phytocompounds in wound care, with the presentation of the state-of-art in this field. The methods of preparation, characterization, and evaluation are also described, underlining the properties that ensure good in vitro and in vivo performance. Finally, future directions of topical systems in which vesicle-bearing herbal extracts or phytocompounds can be incorporated are pointed out, as their development is emerging as a promising strategy.
      Citation: Pharmaceutics
      PubDate: 2022-05-05
      DOI: 10.3390/pharmaceutics14050991
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 992: Non-Cellular Layers of the Respiratory
           Tract: Protection against Pathogens and Target for Drug Delivery

    • Authors: Fröhlich
      First page: 992
      Abstract: Epithelial barriers separate the human body from the environment to maintain homeostasis. Compared to the skin and gastrointestinal tract, the respiratory barrier is the thinnest and least protective. The properties of the epithelial cells (height, number of layers, intercellular junctions) and non-cellular layers, mucus in the conducting airways and surfactant in the respiratory parts determine the permeability of the barrier. The review focuses on the non-cellular layers and describes the architecture of the mucus and surfactant followed by interaction with gases and pathogens. While the penetration of gases into the respiratory tract is mainly determined by their hydrophobicity, pathogens use different mechanisms to invade the respiratory tract. Often, the combination of mucus adhesion and subsequent permeation of the mucus mesh is used. Similar mechanisms are also employed to improve drug delivery across the respiratory barrier. Depending on the payload and target region, various mucus-targeting delivery systems have been developed. It appears that the mucus-targeting strategy has to be selected according to the planned application.
      Citation: Pharmaceutics
      PubDate: 2022-05-05
      DOI: 10.3390/pharmaceutics14050992
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 993: Advances in Hydrogel-Based Microfluidic
           Blood–Brain-Barrier Models in Oncology Research

    • Authors: Sood, Kumar, Dev, Gupta, Han
      First page: 993
      Abstract: The intrinsic architecture and complexity of the brain restricts the capacity of therapeutic molecules to reach their potential targets, thereby limiting therapeutic possibilities concerning neurological ailments and brain malignancy. As conventional models fail to recapitulate the complexity of the brain, progress in the field of microfluidics has facilitated the development of advanced in vitro platforms that could imitate the in vivo microenvironments and pathological features of the blood–brain barrier (BBB). It is highly desirous that developed in vitro BBB-on-chip models serve as a platform to investigate cancer metastasis of the brain along with the possibility of efficiently screening chemotherapeutic agents against brain malignancies. In order to improve the proficiency of BBB-on-chip models, hydrogels have been widely explored due to their unique physical and chemical properties, which mimic the three-dimensional (3D) micro architecture of tissues. Hydrogel-based BBB-on-chip models serves as a stage which is conducive for cell growth and allows the exchange of gases and nutrients and the removal of metabolic wastes between cells and the cell/extra cellular matrix (ECM) interface. Here, we present recent advancements in BBB-on-chip models targeting brain malignancies and examine the utility of hydrogel-based BBB models that could further strengthen the future application of microfluidic devices in oncology research.
      Citation: Pharmaceutics
      PubDate: 2022-05-05
      DOI: 10.3390/pharmaceutics14050993
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 994: Laser Synthesized Core-Satellite Fe-Au
           Nanoparticles for Multimodal In Vivo Imaging and In Vitro Photothermal

    • Authors: Griaznova, Belyaev, Sogomonyan, Zelepukin, Tikhonowski, Popov, Komlev, Nikitin, Gorin, Kabashin, Deyev
      First page: 994
      Abstract: Hybrid multimodal nanoparticles, applicable simultaneously to the noninvasive imaging and therapeutic treatment, are highly demanded for clinical use. Here, Fe-Au core-satellite nanoparticles prepared by the method of pulsed laser ablation in liquids were evaluated as dual magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents and as sensitizers for laser-induced hyperthermia of cancer cells. The biocompatibility of Fe-Au nanoparticles was improved by coating with polyacrylic acid, which provided excellent colloidal stability of nanoparticles with highly negative ζ-potential in water (−38 ± 7 mV) and retained hydrodynamic size (88 ± 20 nm) in a physiological environment. The ferromagnetic iron cores offered great contrast in MRI images with r2 = 11.8 ± 0.8 mM−1 s−1 (at 1 T), while Au satellites showed X-ray attenuation in CT. The intravenous injection of nanoparticles enabled clear tumor border visualization in mice. Plasmonic peak in the Fe-Au hybrids had a tail in the near-infrared region (NIR), allowing them to cause hyperthermia under 808 nm laser exposure. Under NIR irradiation Fe-Au particles provided 24.1 °C/W heating and an IC50 value below 32 µg/mL for three different cancer cell lines. Taken together, these results show that laser synthesized Fe-Au core-satellite nanoparticles are excellent theranostic agents with multimodal imaging and photothermal capabilities.
      Citation: Pharmaceutics
      PubDate: 2022-05-05
      DOI: 10.3390/pharmaceutics14050994
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 995: Bioactivity of Novel
           Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational
           Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease

    • Authors: Leonardo da Silva Lara, Guilherme Curty Lechuga, Lorraine Martins Rocha Orlando, Byanca Silva Ferreira, Bernardo Araújo Souto, Maurício Silva Dos Santos, Mirian Claudia de Souza Pereira
      First page: 995
      Abstract: Chagas disease, a century-old disease that mainly affects the impoverished population in Latin America, causes high morbidity and mortality in endemic countries. The available drugs, benznidazole (Bz) and nifurtimox, have limited effectiveness and intense side effects. Drug repurposing, and the development of new chemical entities with potent activity against Trypanosoma cruzi, are a potential source of therapeutic options. The present study describes the biological activity of two new series of pyrazole-thiazoline derivatives, based on optimization of a hit system 5-aminopyrazole-imidazoline previously identified, using structure–activity relationship exploration, and computational and phenotype-based strategies. Promising candidates, 2c, 2e, and 2i derivatives, showed good oral bioavailability and ADMET properties, and low cytotoxicity (CC50 > 100 µM) besides potent activity against trypomastigotes (0.4–2.1 µM) compared to Bz (19.6 ± 2.3 µM). Among them, 2c also stands out, with greater potency against intracellular amastigotes (pIC50 = 5.85). The selected pyrazole-thiazoline derivatives showed good permeability and effectiveness in the 3D spheroids system, but did not sustain parasite clearance in a washout assay. The compounds’ mechanism of action is still unknown, since the treatment neither increased reactive oxygen species, nor reduced cysteine protease activity. This new scaffold will be targeted to optimize in order to enhance its biological activity to identify new drug candidates for Chagas disease therapy.
      Citation: Pharmaceutics
      PubDate: 2022-05-05
      DOI: 10.3390/pharmaceutics14050995
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 996: [99mTc]Tc-Labeled Plectin-Targeting
           Peptide as a Novel SPECT Probe for Tumor Imaging

    • Authors: Jiali Gong, Lingzhou Zhao, Jiqin Yang, Meilin Zhu, Jinhua Zhao
      First page: 996
      Abstract: Certain receptors are often overexpressed during tumor occurrence and development and closely correlate with carcinogenesis. Owing to its overexpression on the cell membrane and cytoplasm of various tumors, plectin, which is involved in tumor proliferation, migration, and invasion, has been viewed as a promising target for cancer imaging. Hence, plectin-targeting agents have great potential as imaging probes for tumor diagnosis. In this study, we developed a [99mTc]Tc-labeled plectin-targeted peptide (PTP) as a novel single-photon emission computed tomography (SPECT) probe for tumor imaging and investigated its pharmacokinetics, biodistribution, and targeting ability in several types of tumor-bearing mouse models. The PTP had good biocompatibility and targeting ability to tumor cells in vitro and could be readily labeled with [99mTc]Tc after modification with the bifunctional chelator 6-hydrazino nicotinamide (HYNIC). Furthermore, the prepared [99mTc]Tc-labeled PTP ([99mTc]Tc-HYNIC-PTP) showed high radiochemical purity and excellent stability in vitro. In addition, favorable biodistribution, fast blood clearance, and clear accumulation of [99mTc]Tc-HYNIC-PTP in several types of tumors were observed, with a good correlation between tumor uptake and plectin expression levels. These results indicate the potential of [99mTc]Tc-HYNIC-PTP as a novel SPECT probe for tumor imaging.
      Citation: Pharmaceutics
      PubDate: 2022-05-06
      DOI: 10.3390/pharmaceutics14050996
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 997: Development of Anticancer Peptides
           Using Artificial Intelligence and Combinational Therapy for Cancer

    • Authors: Ji Su Hwang, Seok Gi Kim, Tae Hwan Shin, Yong Eun Jang, Do Hyeon Kwon, Gwang Lee
      First page: 997
      Abstract: Cancer is a group of diseases causing abnormal cell growth, altering the genome, and invading or spreading to other parts of the body. Among therapeutic peptide drugs, anticancer peptides (ACPs) have been considered to target and kill cancer cells because cancer cells have unique characteristics such as a high negative charge and abundance of microvilli in the cell membrane when compared to a normal cell. ACPs have several advantages, such as high specificity, cost-effectiveness, low immunogenicity, minimal toxicity, and high tolerance under normal physiological conditions. However, the development and identification of ACPs are time-consuming and expensive in traditional wet-lab-based approaches. Thus, the application of artificial intelligence on the approaches can save time and reduce the cost to identify candidate ACPs. Recently, machine learning (ML), deep learning (DL), and hybrid learning (ML combined DL) have emerged into the development of ACPs without experimental analysis, owing to advances in computer power and big data from the power system. Additionally, we suggest that combination therapy with classical approaches and ACPs might be one of the impactful approaches to increase the efficiency of cancer therapy.
      Citation: Pharmaceutics
      PubDate: 2022-05-06
      DOI: 10.3390/pharmaceutics14050997
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 998: Ocular Barriers and Their Influence on
           Gene Therapy Products Delivery

    • Authors: Bastien Leclercq, Dan Mejlachowicz, Francine Behar-Cohen
      First page: 998
      Abstract: The eye is formed by tissues and cavities that contain liquids whose compositions are highly regulated to ensure their optical properties and their immune and metabolic functions. The integrity of the ocular barriers, composed of different elements that work in a coordinated fashion, is essential to maintain the ocular homeostasis. Specialized junctions between the cells of different tissues have specific features which guarantee sealing properties and selectively control the passage of drugs from the circulation or the outside into the tissues and within the different ocular compartments. Tissues structure also constitute selective obstacles and pathways for various molecules. Specific transporters control the passage of water, ions, and macromolecules, whilst efflux pumps reject and eliminate toxins, metabolites, or drugs. Ocular barriers, thus, limit the bioavailability of gene therapy products in ocular tissues and cells depending on the route chosen for their administration. On the other hand, ocular barriers allow a real local treatment, with limited systemic side-effects. Understanding the different barriers that limit the accessibility of different types of gene therapy products to the different target cells is a prerequisite for the development of efficient gene delivery systems. This review summarizes actual knowledge on the different ocular barriers that limit the penetration and distribution of gene therapy products using different routes of administration, and it provides a general overview of various methods used to bypass the ocular barriers.
      Citation: Pharmaceutics
      PubDate: 2022-05-06
      DOI: 10.3390/pharmaceutics14050998
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 999: Pharmacogenetic Interventions Improve
           the Clinical Outcome of Treatment-Resistant Autistic Spectrum Disorder

    • Authors: Maria J. Arranz, Juliana Salazar, Valentin Bote, Alicia Artigas-Baleri, Alexandre Serra-LLovich, Emma Triviño, Jordi Roige, Carlos Lombardia, Martha Cancino, Marta Hernandez, Marc Cendros, Enric Duran-Tauleria, Nuria Maraver, Amaia Hervas
      First page: 999
      Abstract: BACKGROUND: Autistic spectrum disorders (ASD) are severe neurodevelopmental alterations characterised by deficits in social communication and repetitive and restricted behaviours. About a third of patients receive pharmacological treatment for comorbid symptoms. However, 30–50% do not respond adequately and/or present severe and long-lasting side effects. METHODS: Genetic variants in CYP1A2, CYP2C19, CYP2D6 and SLC6A4 were investigated in N = 42 ASD sufferers resistant to pharmacological treatment. Clinical recommendations based on their pharmacogenetic profiles were provided within 24–48 h of receiving a biological sample. RESULTS: A total of 39 participants (93%) improved after the pharmacogenetic intervention according to their CGI scores (difference in basal-final scores: 2.26, SD 1.55) and 37 participants (88%) according to their CGAS scores (average improvement of 20.29, SD 11.85). Twenty-three of them (55%) achieved symptom stability (CGI ≤ 3 and CGAS improvement ≥ 20 points), requiring less frequent visits to their clinicians and hospital stays. Furthermore, the clinical improvement was higher than that observed in a control group (N = 62) with no pharmacogenetic interventions, in which 66% responded to treatment (difference in CGI scores: −0.87, SD 9.4, p = 1 × 10−5; difference in CGAS scores: 6.59, SD 7.76, p = 5 × 10−8). CONCLUSIONS: The implementation of pharmacogenetic interventions has the potential to significantly improve the clinical outcomes in severe comorbid ASD populations with drug treatment resistance and poor prognosis.
      Citation: Pharmaceutics
      PubDate: 2022-05-06
      DOI: 10.3390/pharmaceutics14050999
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1000: D-Alpha-Tocopheryl Poly(ethylene
           Glycol 1000) Succinate-Coated Manganese-Zinc Ferrite Nanomaterials for a
           Dual-Mode Magnetic Resonance Imaging Contrast Agent and Hyperthermia

    • Authors: Lin Wang, Syu-Ming Lai, Cun-Zhao Li, Hsiu-Ping Yu, Parthiban Venkatesan, Ping-Shan Lai
      First page: 1000
      Abstract: Manganese-zinc ferrite (MZF) is known as high-performance magnetic material and has been used in many fields and development. In the biomedical applications, the biocompatible MZF formulation attracted much attention. In this study, water-soluble amphiphilic vitamin E (TPGS, d-alpha-tocopheryl poly(ethylene glycol 1000) succinate) formulated MZF nanoparticles were synthesized to serve as both a magnetic resonance imaging (MRI) contrast agent and a vehicle for creating magnetically induced hyperthermia against cancer. The MZF nanoparticles were synthesized from a metallic acetylacetonate in an organic phase and further modified with TPGS using an emulsion and solvent-evaporation method. The resulting TPGS-modified MZF nanoparticles exhibited a dual-contrast ability, with a longitudinal relaxivity (35.22 s−1 mM Fe−1) and transverse relaxivity (237.94 s−1 mM Fe−1) that were both higher than Resovist®. Furthermore, the TPGS-assisted MZF formulation can be used for hyperthermia treatment to successfully suppress cell viability and tumor growth after applying an alternating current (AC) electromagnetic field at lower amplitude. Thus, the TPGS-assisted MZF theranostics can not only be applied as a potential contrast agent for MRI but also has potential for use in hyperthermia treatments.
      Citation: Pharmaceutics
      PubDate: 2022-05-06
      DOI: 10.3390/pharmaceutics14051000
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1001: A Comprehensive Overview of Globally
           Approved JAK Inhibitors

    • Authors: Shawky, Almalki, Abdalla, Abdelazeem, Gouda
      First page: 1001
      Abstract: Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.
      Citation: Pharmaceutics
      PubDate: 2022-05-06
      DOI: 10.3390/pharmaceutics14051001
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1002: Glioblastoma-Derived Exosomes as
           Nanopharmaceutics for Improved Glioma Treatment

    • Authors: Lee, Bae, Baek, Kwon, Kim, Nam, Lee, Chang
      First page: 1002
      Abstract: The use of cancer-derived exosomes has been studied in several cancer types, but the cancer-targeting efficacy of glioma-derived exosomes has not been investigated in depth for malignant glioblastoma (GBM) cells. In this study, exosomes were derived from U87MG human glioblastoma cells, and selumetinib, a new anticancer drug, was loaded into the exosomes. We observed the tropism of GBM-derived exosomes in vitro and in vivo. We found that the tropism of GBM-derived exosomes is in contrast to the behavior of non-exosome-enveloped drugs and non-GBM-specific exosomes in vitro and in vivo in an animal GBM model. We found that the tropism exhibited by GBM-derived exosomes can be utilized to shuttle selumetinib, with no specific targeting moiety, to GBM tumor sites. Therefore, our findings indicated that GBM-derived exosomes loaded with selumetinib had a specific antitumor effect on U87MG cells and were non-toxic to normal brain cells. These exosomes offer improved therapeutic prospects for glioblastoma therapy.
      Citation: Pharmaceutics
      PubDate: 2022-05-06
      DOI: 10.3390/pharmaceutics14051002
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1003: Novel Luteolin-Loaded Chitosan
           Decorated Nanoparticles for Brain-Targeting Delivery in a Sporadic
           Alzheimer’s Disease Mouse Model: Focus on Antioxidant,
           Anti-Inflammatory, and Amyloidogenic Pathways

    • Authors: Haidy Abbas, Nesrine S El Sayed, Nancy Abdel Hamid Abou Youssef, Passent M. E. Gaafar, Mohamed R. Mousa, Ahmed M. Fayez, Manal A Elsheikh
      First page: 1003
      Abstract: Preparation and evaluation of a non-invasive intranasal luteolin delivery for the management of cognitive dysfunction in Alzheimer’s disease (AD) using novel chitosan decorated nanoparticles. Development of luteolin-loaded chitosomes was followed by full in vitro characterization. In vivo efficacy was evaluated using a sporadic Alzheimer’s disease (SAD) animal model via intracerebroventricular injection of 3 mg/kg streptozotocin (ICV-STZ). Treatment groups of luteolin suspension and chitosomes (50 mg/kg) were then intranasally administered after 5 h of ICV-STZ followed by everyday administration for 21 consecutive days. Behavioral, histological, immunohistochemical, and biochemical studies were conducted. Chitosomes yielded promising quality attributes in terms of particle size (PS) (412.8 ± 3.28 nm), polydispersity index (PDI) (0.378 ± 0.07), Zeta potential (ZP) (37.4 ± 2.13 mv), and percentage entrapment efficiency (EE%) (86.6 ± 2.05%). Behavioral findings showed obvious improvement in the acquisition of short-term and long-term spatial memory. Furthermore, histological evaluation revealed an increased neuronal survival rate with a reduction in the number of amyloid plaques. Biochemical results showed improved antioxidant effects and reduced pro-inflammatory mediators’ levels. In addition, a suppression by half was observed in the levels of both Aβ aggregation and hyperphosphorylated-tau protein in comparison to the model control group which in turn confirmed the capability of luteolin-loaded chitosomes (LUT-CHS) in attenuating the pathological changes of AD. The prepared nanoparticles are considered a promising safe, effective, and non-invasive nanodelivery system that improves cognitive function in SAD albino mice as opposed to luteolin suspension.
      Citation: Pharmaceutics
      PubDate: 2022-05-06
      DOI: 10.3390/pharmaceutics14051003
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1004: Two Innovative Approaches to Optimize
           Vancomycin Dosing Using Estimated AUC after First Dose: Validation Using
           Data Generated from Population PK Model Coupled with Monte-Carlo
           Simulation and Comparison with the First-Order PK Equation Approach

    • Authors: Qingxia Liu, Huiping Huang, Baohua Xu, Dandan Li, Maobai Liu, Imam H. Shaik, Xuemei Wu
      First page: 1004
      Abstract: The revised consensus guidelines for optimizing vancomycin doses suggest that maintaining the area under the concentration-time curve to minimal inhibitory concentration ratio (AUC/MIC) of 400–600 mg·h/L is the target pharmacokinetic/pharmacodynamic (PK/PD) index for efficacy. AUC-guided dosing approach uses a first-order pharmacokinetics (PK) equation to estimate AUC using two samples obtained at steady state and one-compartment model, which can cause inaccurate AUC estimation and fail to achieve the effective PK/PD target early in therapy (days 1 and 2). To achieve an efficacy target from the third or fourth dose, two innovative approaches (Method 1 and Method 2) to estimate vancomycin AUC at steady state (AUCSS) using two-compartment model and three or four levels after the first dose are proposed. The feasibility of the proposed methods was evaluated and compared with another published dosing algorithm (Method 3), which uses two samples and a one-compartment approach. Monte Carlo simulation was performed using a well-established population PK model, and concentration-time profiles for virtual patients with various degrees of renal function were generated, with 1000 subjects per group. AUC extrapolated to infinity (AUC0–∞) after the first dose was estimated using the three methods, whereas reference AUC (AUCref) was calculated using the linear-trapezoidal method at steady state after repeated doses. The ratio of AUC0–∞: AUCref and % bias were selected as the indicators to evaluate the accuracy of three methods. Sensitivity analysis was performed to examine the influence of change in each sampling time on the estimated AUC0–∞ using the two proposed approaches. For simulated patients with various creatinine clearance, the mean of AUC0–∞: AUCref obtained from Method 1, Method 2 and Method 3 ranged between 0.98 to 1, 0.96 to 0.99, and 0.44 to 0.69, respectively. The mean bias observed with the three methods was −0.10% to −2.09%, −1.30% to −3.59% and −30.75% to −55.53%, respectively. The largest mean bias observed by changing sampling time while using Method 1 and Method 2 were −4.30% and −10.50%, respectively. Three user-friendly and easy-to-use excel calculators were built based on the two proposed methods. The results showed that our approaches ensured sufficient accuracy and achieved target PK/PD index early and were superior to the published methodologies. Our methodology has the potential to be used for vancomycin dose optimization and can be easily implemented in clinical practice.
      Citation: Pharmaceutics
      PubDate: 2022-05-07
      DOI: 10.3390/pharmaceutics14051004
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1005: New Autonomous Water-Enabled
           Self-Healing Coating Material with Antibacterial-Agent-Releasing

    • Authors: Ki-Hak Kim, Hang-Nga Mai, Dong-Choon Hyun, Du-Hyeong Lee
      First page: 1005
      Abstract: A new autonomous water-enabled self-healing coating with antibacterial-agent-releasing capability was developed for the first time by precipitating an aqueous solution of hydrogen-bonded tannic acid (TA) and polyethylene glycol (PEG) (TA: 5 mg/mL; PEG: 5 mg/mL with MW = 100 kDa) to form a smooth, uniform coating layer with an average roughness of 0.688 nm and thickness of 22.3 μm on a polymethyl methacrylate (PMMA) substrate after 10 min of incubation. Our method is cost- and time-efficient, as the hydrophilic coating (water contact angle = 65.1°) forms rapidly, binding strongly to the PMMA substrate (adhesive energy = 83 mJ/m2), without the need for pretreatment or surface modification, and is capable of rapid self-repair (approximately 5 min) through hydrogen bonding in aqueous media. Furthermore, adding 0.5 mg/mL of chlorhexidine acetate (CHX), a commonly used antibacterial agent in dentistry, into the TA–PEG emulsion allowed the release of 2.89 μg/mL of the drug from the coating layer, which is promising for actively inhibiting the vitality and growth of bacteria around PMMA dental restorations. The use of CHX-loaded TA–PEG hydrogen-bonded complexes is highly favorable for the fabrication of an autonomous self-healing biocoating with active antibacterial-agent-releasing capability, which can be applied not only in dentistry but also in other medical fields.
      Citation: Pharmaceutics
      PubDate: 2022-05-07
      DOI: 10.3390/pharmaceutics14051005
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1006: Translational Value of the Transdermal
           Administration of Bergamot Essential Oil and of Its Fractions

    • Authors: Damiana Scuteri, Laura Rombolà, Michele Crudo, Chizuko Watanabe, Hirokazu Mizoguchi, Shinobu Sakurada, Kengo Hamamura, Tsukasa Sakurada, Luigi Antonio Morrone, Paolo Tonin, Giacinto Bagetta, Maria Tiziana Corasaniti
      First page: 1006
      Abstract: The essential oil of bergamot (BEO) has consistently proven antinociceptive and antiallodynic properties. Accordingly, the analgesic efficacy of the decolored essential oil (DEC), with higher levels of limonene, and the deterpenated (DET) fraction, with higher levels of linalool and linalyl acetate, was investigated using a formalin test after inhalation. The present study was aimed at characterizing the effects of BEO, its components with the highest pharmacological activity (represented by linalool, limonene, and linalyl acetate), and its DEC and DET fractions on the formalin test after transdermal administration relevant to clinical translation through topical application. To this aim, the schedule of intervention involved administration immediately after formalin injection or as a 5 min pretreatment followed by washout in ddY-strain mice. This study demonstrates, for the first time, the significant analgesic effect of all three constituents in the first and second phases, accounting for the efficacy of the essential oil in the formalin test. While all fractions revealed equal activity toward the phytocomplex in the early phase, the reduction in time of licking/biting during the late phase was more markedly induced by DEC. Moreover, pretreatment with BEO and its fractions followed by washout did not produce a significant reduction in licking/biting time in both phases of formalin-induced nociceptive response.
      Citation: Pharmaceutics
      PubDate: 2022-05-07
      DOI: 10.3390/pharmaceutics14051006
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1007: Infrared Thermography for Monitoring
           of Freeze Drying Processes—Part 2: Monitoring of Temperature on the
           Surface and Vertically in Cuvettes during Freeze Drying of a
           Pharmaceutical Formulation

    • Authors: Håkan Emteborg, Jean Charoud-Got, John Seghers
      First page: 1007
      Abstract: The coupling of an infrared (IR) camera to a freeze dryer for monitoring of the temperature of a pharmaceutical formulation (sucrose/mannitol solution, 4:1%, m/m) during freeze-drying has been exploited further. The new development allows monitoring of temperatures simultaneously at the surface as well as vertically, (e.g., in depth) along the side using custom-made cuvettes. The IR camera was placed on the chamber roof of a process-scale freeze dryer. Monitoring of cuvettes containing the formulation took place from above where one side of each cuvette was equipped with a germanium window. The Ge-window was placed next to an IR mirror having a 45° angle. The long-wave infrared radiation (LWIR) coming from the inside of the cuvette was reflected upwards toward the IR camera. Accurate recording of the temperature along the cuvettes’ depth profile was therefore possible. Direct imaging from −40 °C to 30 °C took place every 60 s on the surface and on the side with a 2 × 2 mm resolution per IR pixel for 45 h resulting in 2700 thermograms. Results are presented for freeze-drying of a pharmaceutical formulation as a function of time and spatially for the entire side (depth) of the cuvette. As the sublimation process was progressing, the spatial resolution (84 IR pixels for the side-view and 64 pixels for the surface-view) was more than sufficient to reveal lower temperatures deeper down in the material. The results show that the pharmaceutical formulation (a true solution at the onset) dries irregularly and that the sublimation front does not progress evenly through the material. During secondary drying, potential evaporative cooling of upper layers could be detected thanks to the high thermal and spatial resolution.
      Citation: Pharmaceutics
      PubDate: 2022-05-07
      DOI: 10.3390/pharmaceutics14051007
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1008: 123I-BMIPP, a Radiopharmaceutical for
           Myocardial Fatty Acid Metabolism Scintigraphy, Could Be Utilized in
           Bacterial Infection Imaging

    • Authors: Yuka Muranaka, Asuka Mizutani, Masato Kobayashi, Koya Nakamoto, Miki Matsue, Fumika Takagi, Kenichi Okazaki, Kodai Nishi, Kana Yamazaki, Ryuichi Nishii, Naoto Shikano, Shigefumi Okamoto, Hideki Maki, Keiichi Kawai
      First page: 1008
      Abstract: In this study, we evaluated the use of 15-(4-123I-iodophenyl)-3(R,S)-methylpentadecanoic acid (123I-BMIPP) to visualize fatty acid metabolism in bacteria for bacterial infection imaging. We found that 123I-BMIPP, which is used for fatty acid metabolism scintigraphy in Japan, accumulated markedly in Escherichia coli EC-14 similar to 18F-FDG, which has previously been studied for bacterial imaging. To elucidate the underlying mechanism, we evaluated changes in 123I-BMIPP accumulation under low-temperature conditions and in the presence of a CD36 inhibitor. The uptake of 123I-BMIPP by EC-14 was mediated via the CD36-like fatty-acid-transporting membrane protein and accumulated by fatty acid metabolism. In model mice infected with EC-14, the biological distribution and whole-body imaging were assessed using 123I-BMIPP and 18F-FDG. The 123I-BMIPP biodistribution study showed that, 8 h after infection, the ratio of 123I-BMIPP accumulated in infected muscle to that in control muscle was 1.31 at 60 min after 123I-BMIPP injection. In whole-body imaging 1.5 h after 123I-BMIPP administration and 9.5 h after infection, infected muscle exhibited a 1.33-times higher contrast than non-infected muscle. Thus, 123I-BMIPP shows potential for visualizing fatty acid metabolism of bacteria for imaging bacterial infections.
      Citation: Pharmaceutics
      PubDate: 2022-05-07
      DOI: 10.3390/pharmaceutics14051008
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1009: Cost-Effectiveness of Therapeutic Drug
           Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease: A Systematic

    • Authors: Silvia Marquez-Megias, Ricardo Nalda-Molina, Javier Sanz-Valero, Patricio Más-Serrano, Marcos Diaz-Gonzalez, Maria Remedios Candela-Boix, Amelia Ramon-Lopez
      First page: 1009
      Abstract: Infliximab and adalimumab are monoclonal antibodies against tumor necrosis factor (anti-TNF) used to manage inflammatory bowel disease (IBD). Therapeutic Drug Monitoring (TDM) has been proven to prevent immunogenicity, to achieve better long-term clinical results and to save costs in IBD treatment. The aim of this study was to conduct a systematic review on cost-effectiveness analyses of studies that apply TDM of anti-TNF in IBD and to provide a critical analysis of the best scientific knowledge available in the literature. The quality of the included studies was assessed using Consolidated Health Economic Evaluation Reporting Standards (CHEERS). Cost-effectiveness of the TDM strategies was presented as total costs, cost savings, quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER). Thirteen studies that examined the health economics of TDM of anti-TNF in IBD from 2013 to 2021 were included. Eight of them (61.5%) achieved a score between 17 and 23 on the CHEERS checklist. The comparison between the TDM strategy and an empirical strategy was cost saving. The ICER between reactive TDM and an empirical strategy was dominated (favorable) by reactive TDM, whereas the ICER value for proactive TDM compared to an empirical strategy ranged from EUR 56,845 to 3,901,554. This systematic review demonstrated that a TDM strategy is cost-effective or cost-saving in IBD.
      Citation: Pharmaceutics
      PubDate: 2022-05-07
      DOI: 10.3390/pharmaceutics14051009
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1010: Developing Clinically Relevant
           Dissolution Specifications (CRDSs) for Oral Drug Products: Virtual Webinar

    • Authors: Mark McAllister, Talia Flanagan, Susan Cole, Andreas Abend, Evangelos Kotzagiorgis, Jobst Limberg, Heather Mead, Victor Mangas-Sanjuan, Paul A. Dickinson, Andrea Moir, Xavier Pepin, Diansong Zhou, Christophe Tistaert, Aristides Dokoumetzidis, Om Anand, Maxime Le Merdy, David B. Turner, Brendan T. Griffin, Adam Darwich, Jennifer Dressman, Claire Mackie
      First page: 1010
      Abstract: A webinar series that was organised by the Academy of Pharmaceutical Sciences Biopharmaceutics focus group in 2021 focused on the challenges of developing clinically relevant dissolution specifications (CRDSs) for oral drug products. Industrial scientists, together with regulatory and academic scientists, came together through a series of six webinars, to discuss progress in the field, emerging trends, and areas for continued collaboration and harmonisation. Each webinar also hosted a Q&A session where participants could discuss the shared topic and information. Although it was clear from the presentations and Q&A sessions that we continue to make progress in the field of CRDSs and the utility/success of PBBM, there is also a need to continue the momentum and dialogue between the industry and regulators. Five key areas were identified which require further discussion and harmonisation.
      Citation: Pharmaceutics
      PubDate: 2022-05-07
      DOI: 10.3390/pharmaceutics14051010
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1011: Effect of Penetration Enhancers and
           Safety on the Transdermal Delivery of Apremilast in Skin

    • Authors: Paulo Sarango-Granda, Lupe Carolina Espinoza, Natalia Díaz-Garrido, Helen Alvarado, María J. Rodríguez-Lagunas, Laura Baldomá, Ana Calpena
      First page: 1011
      Abstract: The poor water solubility of apremilast (APR) is the main impediment to the penetration of the drug through the skin barrier. The objective of this study was to evaluate the permeability of APR in different solutions enriched with penetration promoters in ex vivo samples of human skin, and additionally assess its tolerance in vivo. To this end, APR solutions with 5% promoter were developed, and the drug’s ability to penetrate human abdominal skin samples was evaluated; the coefficients of permeability, cumulated amounts permeated, and flow were some of the parameters evaluated; likewise, the in vitro and in vivo tolerance of the solutions was evaluated. The results obtained showed that the solutions containing squalene as a promoter improved the penetration of APR compared to the other promoters evaluated; in the same way, on an in vitro scale in HaCaT cells, the promoters were not toxic, finding a cell viability greater than 80% at the different dilutions evaluated. In the in vivo tests carried out with the solution that presented the best results (APR-Squalene solution), it was observed that it does not cause irritation or erythema on the skin after its colorimetric and histological evaluation of the dorsal region of rats after its application. Squalene becomes an excellent candidate to improve the permeability of the drug in the case of the development of a topical formulation; in addition, it was confirmed that this penetration enhancer is neither toxic nor irritating when in contact with the skin in in vivo tests.
      Citation: Pharmaceutics
      PubDate: 2022-05-07
      DOI: 10.3390/pharmaceutics14051011
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1012: Effects of BMSC-Derived EVs on Bone

    • Authors: Xuchang Zhou, Hong Cao, Jianming Guo, Yu Yuan, Guoxin Ni
      First page: 1012
      Abstract: Extracellular vesicles (EVs) are small membrane vesicles that can be secreted by most cells. EVs can be released into the extracellular environment through exocytosis, transporting endogenous cargo (proteins, lipids, RNAs, etc.) to target cells and thereby triggering the release of these biomolecules and participating in various physiological and pathological processes. Among them, EVs derived from bone marrow mesenchymal stem cells (BMSC-EVs) have similar therapeutic effects to BMSCs, including repairing damaged tissues, inhibiting macrophage polarization and promoting angiogenesis. In addition, BMSC-EVs, as efficient and feasible natural nanocarriers for drug delivery, have the advantages of low immunogenicity, no ethical controversy, good stability and easy storage, thus providing a promising therapeutic strategy for many diseases. In particular, BMSC-EVs show great potential in the treatment of bone metabolic diseases. This article reviews the mechanism of BMSC-EVs in bone formation and bone resorption, which provides new insights for future research on therapeutic strategies for bone metabolic diseases.
      Citation: Pharmaceutics
      PubDate: 2022-05-08
      DOI: 10.3390/pharmaceutics14051012
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1013: Photothermal Therapy with
           HER2-Targeted Silver Nanoparticles Leading to Cancer Remission

    • Authors: Victoria O. Shipunova, Mariia M. Belova, Polina A. Kotelnikova, Olga N. Shilova, Aziz B. Mirkasymov, Natalia V. Danilova, Elena N. Komedchikova, Rachela Popovtzer, Sergey M. Deyev, Maxim P. Nikitin
      First page: 1013
      Abstract: Nanoparticles exhibiting the localized surface plasmon resonance (LSPR) phenomenon are promising tools for diagnostics and cancer treatment. Among widely used metal nanoparticles, silver nanoparticles (Ag NPs) possess the strongest light scattering and surface plasmon strength. However, the therapeutic potential of Ag NPs has until now been underestimated. Here we show targeted photothermal therapy of solid tumors with 35 nm HER2-targeted Ag NPs, which were produced by the green synthesis using an aqueous extract of Lavandula angustifolia Mill. Light irradiation tests demonstrated effective hyperthermic properties of these NPs, namely heating by 10 °С in 10 min. To mediate targeted cancer therapy, Ag NPs were conjugated to the scaffold polypeptide, affibody ZHER2:342, which recognizes a clinically relevant oncomarker HER2. The conjugation was mediated by the PEG linker to obtain Ag-PEG-HER2 nanoparticles. Flow cytometry tests showed that Ag-PEG-HER2 particles successfully bind to HER2-overexpressing cells with a specificity comparable to that of full-size anti-HER2 IgGs. A confocal microscopy study showed efficient internalization of Ag-PEG-HER2 into cells in less than 2 h of incubation. Cytotoxicity assays demonstrated effective cell death upon exposure to Ag-PEG-HER2 and irradiation, caused by the production of reactive oxygen species. Xenograft tumor therapy with Ag-PEG-HER2 particles in vivo resulted in full primary tumor regression and the prevention of metastatic spread. Thus, for the first time, we have shown that HER2-directed plasmonic Ag nanoparticles are effective sensitizers for targeted photothermal oncotherapy.
      Citation: Pharmaceutics
      PubDate: 2022-05-08
      DOI: 10.3390/pharmaceutics14051013
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1014: Intranasal Immunization with Zika
           Virus Envelope Domain III-Flagellin Fusion Protein Elicits Systemic and
           Mucosal Immune Responses and Protection against Subcutaneous and
           Intravaginal Virus Challenges

    • Authors: Chi-Hsun Chen, Chung-Chu Chen, Wei-Bo Wang, Vania Lionel, Chia-Chyi Liu, Li-Min Huang, Suh-Chin Wu
      First page: 1014
      Abstract: Zika virus (ZIKV) infections in humans are mainly transmitted by the mosquito vectors, but human-to-human sexual transmission is also another important route. Developing a ZIKV mucosal vaccine that can elicit both systemic and mucosal immune responses is of particular interest. In this study, we constructed a recombinant ZIKV envelope DIII (ZDIII) protein genetically fused with Salmonella typhimurium flagellin (FliC-ZDIII) as a novel mucosal antigen for intranasal immunization. The results indicated that the FliC-ZDIII fusion proteins formulated with E. coli heat-labile enterotoxin B subunit (LTIIb-B5) adjuvant greatly increased the ZDIII-specific IgG, IgA, and neutralizing titers in sera, and the ZDIII-specific IgA titers in bronchoalveolar lavage and vaginal fluids. Protective immunity was further assessed by subcutaneous and intravaginal ZIKV challenges. The second-generation FliCΔD3-2ZDIII was shown to result in a reduced titer of anti-FliC IgG antibodies in sera and still retained the same levels of serum IgG, IgA, and neutralizing antibodies and mucosal IgA antibodies without compromising the vaccine antigenicity. Therefore, intranasal immunization with FliCΔD3-2ZDIII fusion proteins formulated with LTIIb-B5 adjuvant elicited the greatest protective immunity against subcutaneous and intravaginal ZIKV challenges. Our findings indicated that the combination of FliCΔD3-2ZDIII fusion proteins and LTIIb-B5 adjuvant for intranasal immunization can be used for developing ZIKV mucosal vaccines.
      Citation: Pharmaceutics
      PubDate: 2022-05-08
      DOI: 10.3390/pharmaceutics14051014
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1015: Heptamethine Cyanine-Loaded
           Nanomaterials for Cancer Immuno-Photothermal/Photodynamic Therapy: A

    • Authors: Cátia G. Alves, Rita Lima-Sousa, Bruna L. Melo, André F. Moreira, Ilídio J. Correia, Duarte de Melo-Diogo
      First page: 1015
      Abstract: The development of strategies capable of eliminating metastasized cancer cells and preventing tumor recurrence is an exciting and extremely important area of research. In this regard, therapeutic approaches that explore the synergies between nanomaterial-mediated phototherapies and immunostimulants/immune checkpoint inhibitors have been yielding remarkable results in pre-clinical cancer models. These nanomaterials can accumulate in tumors and trigger, after irradiation of the primary tumor with near infrared light, a localized temperature increase and/or reactive oxygen species. These effects caused damage in cancer cells at the primary site and can also (i) relieve tumor hypoxia, (ii) release tumor-associated antigens and danger-associated molecular patterns, and (iii) induced a pro-inflammatory response. Such events will then synergize with the activity of immunostimulants and immune checkpoint inhibitors, paving the way for strong T cell responses against metastasized cancer cells and the creation of immune memory. Among the different nanomaterials aimed for cancer immuno-phototherapy, those incorporating near infrared-absorbing heptamethine cyanines (Indocyanine Green, IR775, IR780, IR797, IR820) have been showing promising results due to their multifunctionality, safety, and straightforward formulation. In this review, combined approaches based on phototherapies mediated by heptamethine cyanine-loaded nanomaterials and immunostimulants/immune checkpoint inhibitor actions are analyzed, focusing on their ability to modulate the action of the different immune system cells, eliminate metastasized cancer cells, and prevent tumor recurrence.
      Citation: Pharmaceutics
      PubDate: 2022-05-08
      DOI: 10.3390/pharmaceutics14051015
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1016: Regeneration of Articular Cartilage
           Using Membranes of Polyester Scaffolds in a Rabbit Model

    • Authors: Maciej Baranowski, Monika Wasyłeczko, Anna Kosowska, Andrzej Plichta, Sebastian Kowalczyk, Andrzej Chwojnowski, Wojciech Bielecki, Jarosław Czubak
      First page: 1016
      Abstract: One promising method for cartilage regeneration involves combining known methods, such as the microfracture technique with biomaterials, e.g., scaffolds (membranes). The most important feature of such implants is their appropriate rate of biodegradation, without the production of toxic metabolites. This study presents work on two different membranes made of polyester (L-lactide-co-ε-caprolactone-PLCA) named “PVP and “Z”. The difference between them was the use of different pore precursors—polyvinylpyrrolidone in the “PVP” scaffold and gelatin in the “Z” scaffold. These were implemented in the articular cartilage defects of rabbit knee joints (defects were created for the purpose of the study). After 8, 16, and 24 weeks of observation, and the subsequent termination of the animals, histopathology and gel permeation chromatography (GPC) examinations were performed. Statistical analysis proved that the membranes support the regeneration process. GPC testing proved that the biodegradation process is progressing exponentially, causing the membranes to degrade at the appropriate time. The surgical technique we used meets all the requirements without causing the membrane to migrate after implantation. The “PVP” membrane is better due to the fact that after 24 weeks of observation there was a statistical trend for higher histological ratings. It is also better because it is easier to implant due to its lower fragility then membrane “Z”. We conclude that the selected membranes seem to support the regeneration of articular cartilage in the rabbit model.
      Citation: Pharmaceutics
      PubDate: 2022-05-08
      DOI: 10.3390/pharmaceutics14051016
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1017: The Use of Probiotics as Adjuvant
           Therapy of Periodontal Treatment: A Systematic Review and Meta-Analysis of
           Clinical Trials

    • Authors: Louis Hardan, Rim Bourgi, Carlos Enrique Cuevas-Suárez, Maythé Flores-Rodríguez, Arianna Omaña-Covarrubias, Marco Nicastro, Florin Lazarescu, Maciej Zarow, Paulo Monteiro, Natalia Jakubowicz, Patrycja Proc, Monika Lukomska-Szymanska
      First page: 1017
      Abstract: For many years, the use of probiotics in periodontitis treatment was reflected in their abilities to control the immune response of the host to the presence of pathogenic microorganisms and to upset periodontopathogens. Accordingly, the aim of the present study was to assess the use of probiotics as adjuvant therapy on clinical periodontal parameters throughout a systematic review and meta-analysis. The literature was screened, up to 4 June 2021, by two independent reviewers (L.H. and R.B.) in four electronic databases: PubMed (MedLine), ISI Web of Science, Scielo, and Scopus. Only clinical trials that report the effect of the use of probiotics as adjuvants in the treatment of periodontal disease were included. Comparisons were carried out using Review Manager Software version 5.3.5 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). A total of 21 studies were considered for the meta-analysis. For the index plaque, the use of probiotics did not improve this clinical parameter (p = 0.16). On the other hand, for the periodontal pocket depth, the clinical attachment loss, the bleeding on probing, and the use of probiotics as adjuvant therapy resulted in an improvement of these parameters, since the control group achieved statistically higher values of this parameter (p < 0.001; p < 0.001; and p = 0.005, respectively). This study suggests that the use of probiotics led to an improvement in periodontal pocket depth, clinical attachment loss, and bleeding on probing parameters. On the other hand, this protocol seems to not be beneficial for the index plaque parameter.
      Citation: Pharmaceutics
      PubDate: 2022-05-09
      DOI: 10.3390/pharmaceutics14051017
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1018: Dual Coating of Chitosan and Albumin
           Negates the Protein Corona-Induced Reduced Vascular Adhesion of Targeted
           PLGA Microparticles in Human Blood

    • Authors: Genesis Lopez-Cazares, Omolola Eniola-Adefeso
      First page: 1018
      Abstract: Vascular-targeted carriers (VTCs) have the potential to localize therapeutics and imaging agents to inflamed, diseased sites. Poly (lactic-co-glycolic acid) (PLGA) is a negatively charged copolymer commonly used to construct VTCs due to its biodegradability and FDA approval. Unfortunately, PLGA VTCs experienced reduced adhesion to inflamed endothelium in the presence of human plasma proteins. In this study, PLGA microparticles were coated with chitosan (CS), human serum albumin (HSA), or both (HSA-CS) to improve adhesion. The binding of sialyl Lewis A (a ligand for E-selectin)-targeted PLGA, HSA-PLGA, CSPLGA, and HSA-CSPLGA to activated endothelial cells was evaluated in red blood cells in buffer or plasma flow conditions. PLGA VTCs with HSA-only coating showed improvement and experienced 35–52% adhesion in plasma compared to plasma-free buffer conditions across all shear rates. PLGA VTCs with dual coating—CS and HSA—maintained 80% of their adhesion after exposure to plasma at low and intermediate shears and ≈50% at high shear. Notably, the protein corona characterization showed increases at the 75 and 150 kDa band intensities for HSA-PLGA and HSA-CSPLGA, which could correlate to histidine-rich glycoprotein and immunoglobulin G. The changes in protein corona on HSA-coated particles seem to positively influence particle binding, emphasizing the importance of understanding plasma protein–particle interactions.
      Citation: Pharmaceutics
      PubDate: 2022-05-09
      DOI: 10.3390/pharmaceutics14051018
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1019: Melatonin-Eluting Contact Lenses
           Effect on Tear Volume: In Vitro and In Vivo Experiments

    • Authors: María Serramito, Ana F. Pereira-da-Mota, Carlos Carpena-Torres, Fernando Huete-Toral, Carmen Alvarez-Lorenzo, Gonzalo Carracedo
      First page: 1019
      Abstract: (1) Background: The purpose of this study was to synthesize melatonin-eluting contact lenses (CLs) and evaluate both the ocular kinetics of the released melatonin and its effect on tear volume and intraocular pressure. (2) Methods: In vitro, melatonin-eluting CLs were synthesized by using non-functionalized (HEMA) and functionalized (HEMA/APMA) monomers. In vivo, a short-term prospective and randomized study was performed on 15 rabbits divided into two groups: 12 rabbits wearing functionalized CLs and 3 rabbits without CLs as a control. The melatonin levels in tears, aqueous humor, vitreous body and retina, tear volume, and intraocular pressure were measured for 8 h. (3) Results: In vitro, both monomers did not show differences in terms of melatonin loading and release (p ≥ 0.05). In vivo, the melatonin concentration was elevated in tears and aqueous humor after 2 and 4 h of wearing CLs, respectively (p < 0.05). Additionally, the CLs increased tear volume for 2 h (p < 0.05). (4) Conclusions: The melatonin-eluting CLs released their content over the ocular surface for at least 2 h, which was associated with a secretagogue effect on tear volume. However, the increased amount of melatonin found in the aqueous humor had no effect on intraocular pressure.
      Citation: Pharmaceutics
      PubDate: 2022-05-09
      DOI: 10.3390/pharmaceutics14051019
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1020: Convalescent Plasma Therapy,
           Therapeutic Formulations of Repurposed Drugs in 20th Century Epidemics
           against COVID-19: A Systematic Review

    • Authors: Diego Fernández-Lázaro, Carlos Domínguez Ortega, Nerea Sánchez-Serrano, Fahd Beddar Chaib, David Jerves Donoso, Elena Jiménez-Callejo, Saray Rodríguez-García
      First page: 1020
      Abstract: Coronavirus 2019 disease (COVID-19) represents one of the largest pandemics the world has faced, and it is producing a global health crisis. To date, the availability of drugs to treat COVID-19 infections remains limited to supportive care although therapeutic options are being explored. Some of them are old strategies for treating infectious diseases. convalescent plasma (CP) therapy has been used successfully in other viral outbreaks in the 20th century. In this study, we systematically evaluated the effect and safety of CP therapy on hospitalized COVID-19 patients. A structured search was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines using Medline (PubMed), SciELO, Cochrane Library Plus, Web of Science, and Scopus. The search included articles published up to January 2022 and was restricted to English- and Spanish-language publications. As such, investigators identified six randomized controlled trials that met the search criteria. The results determined that in hospitalized COVID-19 patients the administration of CP therapy with a volume between 200–500 mL and a single transfusion performed in 1–2 h, compared to the control group, decreased viral load, symptomatology, the period of infection, and mortality, without serious adverse effects. CP did influence clinical outcomes and may be a possible treatment option, although further studies will be necessary.
      Citation: Pharmaceutics
      PubDate: 2022-05-09
      DOI: 10.3390/pharmaceutics14051020
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1021: Antibiotics-Free Compounds for Chronic
           Wound Healing

    • Authors: David O. Oluwole, Lucy Coleman, William Buchanan, Tao Chen, Roberto M. La Ragione, Lian X. Liu
      First page: 1021
      Abstract: The rapid rise in the health burden associated with chronic wounds is of great concern to policymakers, academia, and industry. This could be attributed to the devastating implications of this condition, and specifically, chronic wounds which have been linked to invasive microbial infections affecting patients’ quality of life. Unfortunately, antibiotics are not always helpful due to their poor penetration of bacterial biofilms and the emergence of antimicrobial resistance. Hence, there is an urgent need to explore antibiotics-free compounds/formulations with proven or potential antimicrobial, anti-inflammatory, antioxidant, and wound healing efficacy. The mechanism of antibiotics-free compounds is thought to include the disruption of the bacteria cell structure, preventing cell division, membrane porins, motility, and the formation of a biofilm. Furthermore, some of these compounds foster tissue regeneration by modulating growth factor expression. In this review article, the focus is placed on a number of non-antibiotic compounds possessing some of the aforementioned pharmacological and physiological activities. Specific interest is given to Aloevera, curcumin, cinnamaldehyde, polyhexanide, retinoids, ascorbate, tocochromanols, and chitosan. These compounds (when alone or in formulation with other biologically active molecules) could be a dependable alternative in the management or prevention of chronic wounds.
      Citation: Pharmaceutics
      PubDate: 2022-05-09
      DOI: 10.3390/pharmaceutics14051021
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1022: A Real-Time Sensing System for
           Monitoring Neural Network Degeneration in an Alzheimer’s
           Disease-on-a-Chip Model

    • Authors: Nien-Che Liu, Chu-Chun Liang, Yi-Chen Ethan Li, I-Chi Lee
      First page: 1022
      Abstract: Stem cell-based in vitro models may provide potential therapeutic strategies and allow drug screening for neurodegenerative diseases, including Alzheimer’s disease (AD). Herein, we develop a neural stem cell (NSC) spheroid-based biochip that is characterized by a brain-like structure, well-defined neural differentiation, and neural network formation, representing a brain-on-a-chip. This system consisted of microelectrode arrays with a multichannel platform and allowed the real-time monitoring of network formation and degeneration by impedance analysis. The parameters of this platform for the real-time tracking of network development and organization were established based on our previous study. Subsequently, β-amyloid (Aβ) was added into the brain-on-a-chip system to generate an AD-on-a-chip model, and toxic effects on neurons and the degeneration of synapses were observed. The AD-on-a-chip model may help us to investigate the neurotoxicity of Aβ on neurons and neural networks in real time. Aβ causes neural damage and accumulates around neurites or inside neurospheroids, as observed by immunostaining and scanning electron microscopy (SEM). After incubation with Aβ, reactive oxygen species (ROS) increased, synapse function decreased, and the neurotransmitter-acetylcholine (ACh) concentration decreased were observed. Most importantly, the real-time analysis system monitored the impedance value variation in the system with Aβ incubation, providing consecutive network disconnection data that are consistent with biological data. This platform provides simple, real-time, and convenient sensing to monitor the network microenvironment. The proposed AD-on-a-chip model enhances the understanding of neurological pathology, and the development of this model provides an alternative for the study of drug discovery and cell–protein interactions in the brain.
      Citation: Pharmaceutics
      PubDate: 2022-05-09
      DOI: 10.3390/pharmaceutics14051022
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1023: Application of Machine Learning
           Classification to Improve the Performance of Vancomycin Therapeutic Drug

    • Authors: Sooyoung Lee, Moonsik Song, Jongdae Han, Donghwan Lee, Bo-Hyung Kim
      First page: 1023
      Abstract: Bayesian therapeutic drug monitoring (TDM) software uses a reported pharmacokinetic (PK) model as prior information. Since its estimation is based on the Bayesian method, the estimation performance of TDM software can be improved using a PK model with characteristics similar to those of a patient. Therefore, we aimed to develop a classifier using machine learning (ML) to select a more suitable vancomycin PK model for TDM in a patient. In our study, nine vancomycin PK studies were selected, and a classifier was created to choose suitable models among them for patients. The classifier was trained using 900,000 virtual patients, and its performance was evaluated using 9000 and 4000 virtual patients for internal and external validation, respectively. The accuracy of the classifier ranged from 20.8% to 71.6% in the simulation scenarios. TDM using the ML classifier showed stable results compared with that using single models without the ML classifier. Based on these results, we have discussed further development of TDM using ML. In conclusion, we developed and evaluated a new method for selecting a PK model for TDM using ML. With more information, such as on additional PK model reporting and ML model improvement, this method can be further enhanced.
      Citation: Pharmaceutics
      PubDate: 2022-05-09
      DOI: 10.3390/pharmaceutics14051023
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1024: Merging Experimental Design and
           Nanotechnology for the Development of Optimized Simvastatin Spanlastics: A
           Promising Combined Strategy for Augmenting the Suppression of Various
           Human Cancer Cells

    • Authors: Shaimaa M. Badr-Eldin, Hibah M. Aldawsari, Nabil A. Alhakamy, Usama A. Fahmy, Osama A. A. Ahmed, Thikryat Neamatallah, Singkome Tima, Raghad H. Almaghrabi, Fayda M. Alkudsi, Asmaa A. Alamoudi, Amjad A. Alzahrani, Sabna Kotta, Omar D. Al-hejaili
      First page: 1024
      Abstract: Simvastatin (SMV) is an antihyperlipidemic agent that has been investigated as a possible anti-cancer agent. An obstacle to malignant tumor therapy using drugs is the delivery of adequate levels to the cancer cells while minimizing side effects following their systemic administration. To circumvent this challenge, the researchers directed towards the field of nanotechnology to benefit from the nano-size of the formulation in passively targeting the tumor cells. Thus, our study aimed at investigating the potential of a combined mixture–process variable design for optimization of SMV spanlastics (SMV-SPNs) with minimized particle size and maximized zeta potential to enhance the anticancer activity of the drug. The study investigated the effects of Span® 20 and Tween® 80 as mixture components and sonication time as a process variable on particle size, polydispersity index, and zeta potential as responses. SPNs were prepared using an ethanol injection method. Combining the predicted optimized variables’ levels is supposed to achieve the set goals with a desirability of 0.821. The optimized spanlastics exhibited a measured globule size of 128.50 nm, PDI of 0.329, and ZP of −29.11 mV. The percentage relative error between predicted responses and the observed ones were less than 5% for the three responses, indicating the optimization technique credibility. A significant improvement in the cytotoxicity of the optimized formulation against three different cancerous cell lines was observed in comparison with SMV. The inhibitory concentration (IC50) values of MCF-7, HCT-116, and HEPG2 were found to be 0.89, 0.39, and 0.06 μM at 24 h incubation. The enhanced cytotoxicity could be assigned to the possible improved permeation and preferential build-up within the cancerous cells by virtue of the minimized size. These findings imply that SMV-SPNs could be an ideal strategy to combat cancer.
      Citation: Pharmaceutics
      PubDate: 2022-05-09
      DOI: 10.3390/pharmaceutics14051024
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1025: Combination of DNA Vaccine and Immune
           Checkpoint Blockades Improves the Immune Response in an Orthotopic
           Unresectable Glioblastoma Model

    • Authors: Mathilde Bausart, Kevin Vanvarenberg, Bernard Ucakar, Alessandra Lopes, Gaëlle Vandermeulen, Alessio Malfanti, Véronique Préat
      First page: 1025
      Abstract: Combination immunotherapy has emerged as a promising strategy to increase the immune response in glioblastoma (GBM) and overcome the complex immunosuppression occurring in its microenvironment. In this study, we hypothesized that combining DNA vaccines—to stimulate a specific immune response—and dual immune checkpoint blockade (ICB)—to decrease the immunosuppression exerted on T cells—will improve the immune response and the survival in an orthotopic unresectable GL261 model. We first highlighted the influence of the insertion position of a GBM epitope sequence in a plasmid DNA vaccine encoding a vesicular stomatitis virus glycoprotein (VSV-G) (here referred to as pTOP) in the generation of a specific and significant IFN-γ response against the GBM antigen TRP2 by inserting a CD8 epitope sequence in specific permissive sites. Then, we combined the pTOP vaccine with anti-PD-1 and anti-CTLA-4 ICBs. Immune cell analysis revealed an increase in effector T cell to Treg ratios in the spleens and an increase in infiltrated IFN-γ-secreting CD8 T cell frequency in the brains following combination therapy. Even if the survival was not significantly different between dual ICB and combination therapy, we offer a new immunotherapeutic perspective by improving the immune landscape in an orthotopic unresectable GBM model.
      Citation: Pharmaceutics
      PubDate: 2022-05-10
      DOI: 10.3390/pharmaceutics14051025
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1026: Indirect SPECT Imaging Evaluation for
           Possible Nose-to-Brain Drug Delivery Using a Compound with Poor
           Blood–Brain Barrier Permeability in Mice

    • Authors: Asuka Mizutani, Masato Kobayashi, Makoto Ohuchi, Keita Sasaki, Yuka Muranaka, Yusuke Torikai, Shota Fukakusa, Chie Suzuki, Ryuichi Nishii, Shunji Haruta, Yasuhiro Magata, Keiichi Kawai
      First page: 1026
      Abstract: Single-photon emission computed tomography (SPECT) imaging using intravenous radioactive ligand administration to indirectly evaluate the time-dependent effect of intranasal drugs with poor blood-brain barrier permeability on brain drug distributions in mice was evaluated. The biodistribution was examined using domperidone, a dopamine D2 receptor ligand, as the model drug, with intranasal administration at 0, 15, or 30 min before intravenous [123I]IBZM administration. In the striatum, [123I]IBZM accumulation was significantly lower after intranasal (IN) domperidone administration than in controls 15 min after intravenous [125I]IBZM administration. [123I]IBZM SPECT was acquired with intravenous (IV) or IN domperidone administration 15 min before [123I]IBZM, and time–activity curves were obtained. In the striatum, [123I]IBZM accumulation was clearly lower in the IN group than in the control and IV groups. Time–activity curves showed no significant difference between the control and IV groups in the striatum, and values were significantly lowest during the first 10 min in the IN group. In the IN group, binding potential and % of receptor occupancy were significantly lower and higher, respectively, compared to the control and IV groups. Thus, brain-migrated domperidone inhibited D2R binding of [123I]IBZM. SPECT imaging is suitable for research to indirectly explore nose-to-brain drug delivery and locus-specific biological distribution.
      Citation: Pharmaceutics
      PubDate: 2022-05-10
      DOI: 10.3390/pharmaceutics14051026
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1027: Dexamethasone-Loaded Ureasil
           Hydrophobic Membrane for Bone Guided Regeneration

    • Authors: Rafaella Moreno Barros, Camila Garcia Da Silva, Kammila Martins Nicolau Costa, Arnóbio A. Da Silva-Junior, Cássio Rocha Scardueli, Rosemary Adriana Chiérici Marcantonio, Leila Aparecida Chiavacci, João Augusto Oshiro-Junior
      First page: 1027
      Abstract: Physical barrier membranes have been used to release active substances to treat critical bone defects; however, hydrophilic membranes do not present a prolonged release capacity. In this sense, hydrophobic membranes have been tested. Thus, this study aimed to develop hydrophobic membranes based on mixtures of ureasil–polyether-type materials containing incorporated dexamethasone (DMA) for the application in guided bone regeneration. The physicochemical characterization and biological assays were carried out using small-angle X-ray scattering (SAXS), an in vitro DMA release study, atomic force microscopy (AFM), a hemolysis test, and in vivo bone formation. The swelling degree, SAXS, and release results revealed that the u-PPO400/2000 membrane in the proportion of 70:30 showed swelling (4.69% ± 0.22) similar to the proportions 90:10 and 80:20, and lower than the proportion 60:40 (6.38% ± 0.49); however, an equal release percentage after 134 h was observed between the proportions 70:30 and 60:40. All u-PPO materials presented hemocompatibility (hemolysis ≤2.8%). AFM results showed that the treatments with or without DMA did not present significant differences, revealing a flat/smooth surface, with no pores and/or crystalline precipitates. Finally, in vivo results revealed that for both the commercial hydrophilic membrane and u-PPO400/2000 (70:30) after 60 days, the bone formation volume was 21%. In conclusion, hybrid membranes present unique characteristics for treating critical bone defects, considering the delayed and prolonged release results associated with the physical barrier capacity.
      Citation: Pharmaceutics
      PubDate: 2022-05-10
      DOI: 10.3390/pharmaceutics14051027
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1028: Tissue Adhesive, Self-Healing,
           Biocompatible, Hemostasis, and Antibacterial Properties of Fungal-Derived
           Carboxymethyl Chitosan-Polydopamine Hydrogels

    • Authors: Kummara Madhusudana Rao, Kannan Badri Narayanan, Uluvangada Thammaiah Uthappa, Pil-Hoon Park, Inho Choi, Sung Soo Han
      First page: 1028
      Abstract: In this work, fungal mushroom-derived carboxymethyl chitosan-polydopamine hydrogels (FCMCS-PDA) with multifunctionality (tissue adhesive, hemostasis, self-healing, and antibacterial properties) were developed for wound dressing applications. The hydrogel is obtained through dynamic Schiff base cross-linking and hydrogen bonds between FCMCS-PDA and covalently cross-linked polyacrylamide (PAM) networks. The FCMCS-PDA-PAM hydrogels have a good swelling ratio, biodegradable properties, excellent mechanical properties, and a highly interconnected porous structure with PDA microfibrils. Interestingly, the PDA microfibrils were formed along with FCMCS fibers in the hydrogel networks, which has a high impact on the biological performance of hydrogels. The maximum adhesion strength of the hydrogel to porcine skin was achieved at about 29.6 ± 2.9 kPa. The hydrogel had good self-healing and recoverable properties. The PDA-containing hydrogels show good antibacterial properties on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) bacteria. Moreover, the adhesive hydrogels depicted good viability and attachment of skin fibroblasts and keratinocyte cells. Importantly, FCMCS and PDA combined resulted in fast blood coagulation within 60 s. Hence, the adhesive hydrogel with multifunctionality has excellent potential as a wound dressing material for infected wounds.
      Citation: Pharmaceutics
      PubDate: 2022-05-10
      DOI: 10.3390/pharmaceutics14051028
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1029: Formulation and Evaluation of SNEDDS
           Loaded with Original Lipophenol for the Oral Route to Prevent Dry AMD and
           Stragardt’s Disease

    • Authors: Maxime Vincent, Laurianne Simon, Philippe Brabet, Philippe Legrand, Christophe Dorandeu, Josephine Lai Kee Him, Thierry Durand, Céline Crauste, Sylvie Begu
      First page: 1029
      Abstract: Dry age-related macular degeneration (Dry AMD) and Stargardt’s disease (STGD1) are common eye diseases, characterized by oxidative and carbonyl stress (COS)-inducing photoreceptor degeneration and vision loss. Previous studies have demonstrated the protective effect of photoreceptors after the intravenous administration of a new lipophenol drug, phloroglucinol-isopropyl-DHA (IP-DHA). In this study, we developed an oral formulation of IP-DHA (BCS Class IV) relying on a self-nanoemulsifying drug delivery system (SNEDDS). SNEDDS, composed of Phosal® 53 MCT, Labrasol®, and Transcutol HP® at a ratio of 25/60/15 (w/w/w), led to a homogeneous nanoemulsion (NE) with a mean size of 53.5 ± 4.5 nm. The loading of IP-DHA in SNEDDS (SNEDDS-IP-DHA) was successful, with a percentage of IP-DHA of 99.7% in nanoemulsions. The in vivo study of the therapeutic potency of SNEDDS-IP-DHA after oral administration on mice demonstrated photoreceptor protection after the induction of retinal degeneration with acute light stress (73–80%) or chronic light stress (52–69%). Thus, SNEDDS formulation proved to increase the solubility of IP-DHA, improving its stability in intestinal media and allowing its passage through the intestinal barrier after oral force-fed administration, while maintaining its biological activity. Therefore, SNEDDS-IP-DHA is a promising future preventive treatment for dry AMD and STGD1.
      Citation: Pharmaceutics
      PubDate: 2022-05-10
      DOI: 10.3390/pharmaceutics14051029
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1030: Sex Differences in Intestinal
           P-Glycoprotein Expression in Wistar versus Sprague Dawley Rats

    • Authors: Christine M. Madla, Yujia Qin, Francesca K. H. Gavins, Jing Liu, Liu Dou, Mine Orlu, Sudaxshina Murdan, Yang Mai, Abdul W. Basit
      First page: 1030
      Abstract: Wistar and Sprague Dawley are the most common strains of rat used in pharmaceutical research and are used interchangeably in pre-clinical drug development. No studies have assessed whether Wistar and Sprague Dawley rats are equivalent in the gastrointestinal factors that influence oral drug absorption, specifically in relation to intestinal transporters. Enzyme-linked immunosorbent assay (ELISA) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) are two reliable methods for quantifying intestinal protein levels with their own distinct advantages and limitations. In this study, P-glycoprotein (P-gp), a key efflux transporter, was quantified using ELISA and LC-MS/MS along the complete intestinal tract of male and female Wistar and Sprague Dawley rats. This work presents that Sprague Dawley rats have innately higher baseline P-gp expression than Wistar rats. Significant sex differences in P-gp expression were identified in the jejunum, ileum and colon between male and female Wistar rats using both techniques, with males exhibiting higher P-gp levels. Sprague Dawley rats showed no sex differences in P-gp expression through ELISA and LC-MS/MS. Both methods demonstrated similar trends for P-gp quantification, but ELISA could offer faster data acquisition. Our findings report significant sex differences between the strains and highlight that Wistar and Sprague Dawley rats are not equivalent in their P-gp expression. As humans exhibit distinct sex differences in intestinal P-gp levels, Wistar rats may therefore be a more suitable pre-clinical animal strain to model oral drug absorption of P-gp substrates in male and female subjects.
      Citation: Pharmaceutics
      PubDate: 2022-05-10
      DOI: 10.3390/pharmaceutics14051030
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1031: Physics of Brain Cancer: Multiscale
           Alterations of Glioblastoma Cells under Extracellular Matrix Stiffening

    • Authors: Mohammad Khoonkari, Dong Liang, Marleen Kamperman, Frank A. E. Kruyt, Patrick van Rijn
      First page: 1031
      Abstract: The biology and physics underlying glioblastoma is not yet completely understood, resulting in the limited efficacy of current clinical therapy. Recent studies have indicated the importance of mechanical stress on the development and malignancy of cancer. Various types of mechanical stress activate adaptive tumor cell responses that include alterations in the extracellular matrix (ECM) which have an impact on tumor malignancy. In this review, we describe and discuss the current knowledge of the effects of ECM alterations and mechanical stress on GBM aggressiveness. Gradual changes in the brain ECM have been connected to the biological and physical alterations of GBM cells. For example, increased expression of several ECM components such as glycosaminoglycans (GAGs), hyaluronic acid (HA), proteoglycans and fibrous proteins result in stiffening of the brain ECM, which alters inter- and intracellular signaling activity. Several mechanosensing signaling pathways have been identified that orchestrate adaptive responses, such as Hippo/YAP, CD44, and actin skeleton signaling, which remodel the cytoskeleton and affect cellular properties such as cell–cell/ECM interactions, growth, and migration/invasion of GBM cells. In vitro, hydrogels are used as a model to mimic the stiffening of the brain ECM and reconstruct its mechanics, which we also discuss. Overall, we provide an overview of the tumor microenvironmental landscape of GBM with a focus on ECM stiffening and its associated adaptive cellular signaling pathways and their possible therapeutic exploitation.
      Citation: Pharmaceutics
      PubDate: 2022-05-10
      DOI: 10.3390/pharmaceutics14051031
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1032: Compounded Nonsterile Preparations and
           FDA-Approved Commercially Available Liquid Products for Children: A North
           American Update

    • Authors: Richard H. Parrish, Lisa D. Ashworth, Raimar Löbenberg, Sandra Benavides, Jeffrey J. Cies, Robert B. MacArthur
      First page: 1032
      Abstract: The purpose of this work was to evaluate the suitability of recent US Food and Drug Administration (US-FDA)-approved and marketed oral liquid, powder, or granule products for children in North America, to identify the next group of Active Pharmaceutical Ingredients (APIs) that have high potential for development as commercially available FDA-approved finished liquid dosage forms, and to propose lists of compounded nonsterile preparations (CNSPs) that should be developed as commercially available FDA-approved finished liquid dosage forms, as well as those that pharmacists should continue to compound extemporaneously. Through this identification and categorization process, the pharmaceutical industry, government, and professionals are encouraged to continue to work together to improve the likelihood that patients will receive high-quality standardized extemporaneously compounded CNSPs and US-FDA-approved products.
      Citation: Pharmaceutics
      PubDate: 2022-05-10
      DOI: 10.3390/pharmaceutics14051032
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1033: Population Pharmacokinetics and Dosing
           Regimen Optimization of Latamoxef in Chinese Children

    • Authors: Yang Wang, Dan Sun, Yan Mei, Sanlan Wu, Xinlin Li, Sichan Li, Jun Wang, Liuliu Gao, Hua Xu, Yali Tuo
      First page: 1033
      Abstract: The present study aimed to establish population pharmacokinetic models of latamoxef, as well as its R- and S-epimers, and generate findings to guide the individualized administration of latamoxef in pediatric patients. A total of 145 in-hospital children aged 0.08–10.58 years old were included in this study. Three population pharmacokinetic models of latamoxef and its R- and S-epimers were established. The stability and predictive ability of the final models were evaluated by utilizing goodness-of-fit plots, nonparametric bootstrapping, and normalized prediction distribution errors. The final model of total latamoxef was considered as a basis for the dosing regimen. A two-compartment model with first-order elimination best described the pharmacokinetics of total latamoxef. The population typical values of total latamoxef were as follows: central compartment distribution volume (V1) of 4.84 L, peripheral compartment distribution volume (V2) of 16.18 L, clearance (CL) of 1.00 L/h, and inter-compartmental clearance (Q) of 0.97 L/h. Moreover, R-epimer has a higher apparent volume of distribution and lower clearance than S-epimer. Body surface area (BSA) was identified as the most significant covariate to V, CL, and Q. Specific recommendations are given for dosage adjustment in pediatric patients based on BSA. This study highlights that a BSA-normalized dose of latamoxef was required when treating different bacteria to reach the therapeutic target more effectively.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051033
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1034: Development of α-Tocopherol
           Succinate-Based Nanostructured Lipid Carriers for Delivery of Paclitaxel

    • Authors: Sushrut Marathe, Gauri Shadambikar, Tabish Mehraj, Suresh P. Sulochana, Narendar Dudhipala, Soumyajit Majumdar
      First page: 1034
      Abstract: The management of retinoblastoma (RB) involves the use of invasive treatment regimens. Paclitaxel (PTX), an effective antineoplastic compound used in the treatment of a wide range of malignant tumors, poses treatment challenges due to systemic toxicity, rapid elimination, and development of resistance. The goal of this work was to develop PTX-loaded, α-tocopherol succinate (αTS)-based, nanostructured lipid carrier (NLCs; αTS-PTX-NLC) and PEGylated αTS-PTX-NLC (αTS-PTX-PEG-NLC) to improve ocular bioavailability. The hot homogenization method was used to prepare the NLCs, and repeated measures ANOVA analysis was used for formulation optimization. αTS-PTX-NLC and αTS-PTX-PEG-NLC had a mean particle size, polydispersity index and zeta potential of 186.2 ± 3.9 nm, 0.17 ± 0.03, −33.2 ± 1.3 mV and 96.2 ± 3.9 nm, 0.27 ± 0.03, −39.15 ± 3.2 mV, respectively. The assay and entrapment efficiency of both formulations was >95.0%. The NLC exhibited a spherical shape, as seen from TEM images. Sterilized (autoclaved) formulations were stable for up to 60 days (last time point checked) under refrigerated conditions. PTX-NLC formulations exhibited an initial burst release and 40% drug release, overall, in 48 h. The formulations exhibited desirable physicochemical properties and could lead to an effective therapeutic option in the management of RB.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051034
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1035: Development of New Drugs for
           Autoimmune Hemolytic Anemia

    • Authors: Zhengrui Xiao, Irina Murakhovskaya
      First page: 1035
      Abstract: Autoimmune hemolytic anemia (AIHA) is a rare disorder characterized by the autoantibody-mediated destruction of red blood cells, and treatments for it still remain challenging. Traditional first-line immunosuppressive therapy, which includes corticosteroids and rituximab, is associated with adverse effects as well as treatment failures, and relapses are common. Subsequent lines of therapy are associated with higher rates of toxicity, and some patients remain refractory to currently available treatments. Novel therapies have become promising for this vulnerable population. In this review, we will discuss the mechanism of action, existing data, and ongoing clinical trials of current novel therapies for AIHA, including B-cell-directed therapy, phagocytosis inhibition, plasma cell-directed therapy, and complement inhibition.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051035
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1036: A Small Peptide Increases Drug
           Delivery in Human Melanoma Cells

    • Authors: Shirley Tong, Shaban Darwish, Hanieh Hossein Nejad Ariani, Kate Alison Lozada, David Salehi, Maris A. Cinelli, Richard B. Silverman, Kamaljit Kaur, Sun Yang
      First page: 1036
      Abstract: Melanoma is the most fatal type of skin cancer and is notoriously resistant to chemotherapies. The response of melanoma to current treatments is difficult to predict. To combat these challenges, in this study, we utilize a small peptide to increase drug delivery to melanoma cells. A peptide library array was designed and screened using a peptide array-whole cell binding assay, which identified KK-11 as a novel human melanoma-targeting peptide. The peptide and its D-amino acid substituted analogue (VPWxEPAYQrFL or D-aa KK-11) were synthesized via a solid-phase strategy. Further studies using FITC-labeled KK-11 demonstrated dose-dependent uptake in human melanoma cells. D-aa KK-11 significantly increased the stability of the peptide, with 45.3% remaining detectable after 24 h with human serum incubation. Co-treatment of KK-11 with doxorubicin was found to significantly enhance the cytotoxicity of doxorubicin compared to doxorubicin alone, or sequential KK-11 and doxorubicin treatment. In vivo and ex vivo imaging revealed that D-aa KK-11 distributed to xenografted A375 melanoma tumors as early as 5 min and persisted up to 24 h post tail vein injection. When co-administered, D-aa KK-11 significantly enhanced the anti-tumor activity of a novel nNOS inhibitor (MAC-3-190) in an A375 human melanoma xenograft mouse model compared to MAC-3-190 treatment alone. No apparent systemic toxicities were observed. Taken together, these results suggest that KK-11 may be a promising human melanoma-targeted delivery vector for anti-melanoma cargo.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051036
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1037: Enhancing Dissolution and Oral
           Bioavailability of Ursodeoxycholic Acid with a Spray-Dried pH-Modified
           Extended Release Formulation

    • Authors: Jaehyeok Lee, Chul Haeng Lee, Jong-Geon Lee, So Yeon Jeon, Min-Koo Choi, Im-Sook Song
      First page: 1037
      Abstract: Ursodeoxycholate (UDCA) has low oral bioavailability and pH-dependent solubility and permeability. Thus, we developed a pH-modified extended-release formulation of UDCA using Na2CO3 as the alkalizing agent and hydroxypropyl methylcellulose (HPMC) as the release-modifying agent. The optimized pH-modified controlled-release UDCA formulation, with the UDCA:HPMC:Na2CO3 ratio of 200:600:150 (w/w/w), was prepared using a spray-drying method. Then, the formulation’s solubility, dissolution, and pharmacokinetic properties were characterized. In a pH-modified extended-release formulation of UDCA, the solubility of UDCA was increased to 8 mg/mL with a sustained dissolution for 12 h. Additionally, the spray-dried formulation exhibited amorphous states without molecular interaction among UDCA, Na2CO3, and HPMC. Moreover, the plasma UDCA concentration of the formulation maintained a higher UDCA concentration for up to 48 h than that of UDCA itself or the non-extended-release UDCA formulation. Consequently, the formulation significantly increased the AUC compared to UDCA or the non-extended-release UDCA formulation in rats. In conclusion, we have improved UDCA’s solubility and dissolution profile by preparing a pH-modified extended-release formulation with the UDCA:HPMC:Na2CO3 ratio of 200:600:150 (w/w/w), which effectively increased the oral bioavailability of UDCA by 251% in rats.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051037
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1038: Ethosomes and Transethosomes as
           Cutaneous Delivery Systems for Quercetin: A Preliminary Study on Melanoma

    • Authors: Francesca Ferrara, Mascia Benedusi, Maddalena Sguizzato, Rita Cortesi, Anna Baldisserotto, Raissa Buzzi, Giuseppe Valacchi, Elisabetta Esposito
      First page: 1038
      Abstract: The present study is aimed to design ethosomes and transethosomes for topical administration of quercetin. To overcome quercetin low bioavailability, scarce solubility and poor permeability that hamper its pharmaceutical use, the drug was loaded in ethosomes and transethosomes based on different concentrations of phosphatidylcholine. Vesicle morphology was studied by cryogenic transmission electron microscopy, while size distribution and quercetin entrapment capacity were evaluated up to 3 months, respectively, by photon correlation spectroscopy and high-performance liquid chromatography. The antioxidant property was studied by photochemiluminescence test. Quercetin release and permeation was investigated in vitro, using Franz cells associated to different membranes. In vitro assays were conducted on human keratinocytes and melanoma cells to study the behavior of quercetin-loaded nano-vesicular forms with respect to cell migration and proliferation. The results evidenced that both phosphatidylcholine concentration and quercetin affected the vesicle size. Quercetin entrapment capacity, antioxidant activity and size stability were controlled using transethosomes produced by the highest amount of phosphatidylcholine. In vitro permeation studies revealed an enhancement of quercetin permeation in the case of transethosomes with respect to ethosomes. Notably, scratch wound and migration assays suggested the potential of quercetin loaded-transethosomes as adjuvant strategy for skin conditions.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051038
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1039: Particle-Assisted Dermal
           Penetration—A Simple Formulation Strategy to Foster the Dermal
           Penetration Efficacy

    • Authors: Sabrina Wiemann, Cornelia M. Keck
      First page: 1039
      Abstract: (1) Background: The study systematically investigated the influence of dispersed particles within a topical formulation on the dermal penetration efficacy of active compounds that are dissolved in the water phase of this formulation. The aim was to prove or disprove if particle-assisted dermal penetration can be used for improved dermal drug delivery. (2) Methods: Fluorescein was used as a surrogate for a hydrophilic active ingredient (AI). It was dissolved in the water phase of different formulations with and without particles. Two different types of particles (titanium dioxide and nanostructured lipid carriers (NLC)) were used. The influence of particle size and number of particles and the influence of skin hydrating excipients was also investigated. (3) Results demonstrate that the addition of particles can strongly increase the dermal penetration efficacy of AI. The effect depends on the size of the particles and the number of particles in the formulation, where smaller sizes and higher numbers resulted in higher penetration parameters. Formulations with NLC that contained 20% w/w or 40% w/w particles resulted in an about 2-fold higher amount of penetrated AI and increased the penetration depth about 2.5-fold. The penetration-enhancing effect was highly significant (p < 0.001) and allowed for an efficient delivery of the AI in the viable dermis. In contrast, the penetration-enhancing effect of excipients that increase the skin hydration was found to be very limited and not significant (≤5%, p > 0.05). (4) Conclusions: Based on the results, it can be concluded that particle-assisted dermal penetration can be considered to be a simple but highly efficient and industrially feasible formulation principle for improved and tailor-made dermal drug delivery of active compounds.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051039
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1040: The Role of the Kinase Inhibitors in
           Thyroid Cancers

    • Authors: Cuomo, Giani, Cobellis
      First page: 1040
      Abstract: Thyroid cancer is the most common endocrine malignancy, accounting for about 3% of all cancer cases each year worldwide with increasing incidence, but with the mortality remaining stable at low levels. This contradiction is due to overdiagnosis of indolent neoplasms identified by neck ultrasound screening that would remain otherwise asymptomatic. Differentiated thyroid carcinomas (DTCs) are almost curable for 95% with a good prognosis. However, 5% of these tumours worsened toward aggressive forms: large tumours with extravasal invasion, either with regional lymph node or distant metastasis, that represent a serious clinical challenge. The unveiling of the genomic landscape of these tumours shows that the most frequent mutations occur in tyrosine kinase receptors (RET), in components of the MAPK/PI3K signalling pathway (RAS and BRAF) or chromosomal rearrangements (RET/PTC and NTRK hybrids); thus, tyrosine-kinase inhibitor (TKI) treatments arose in the last decade as the most effective therapeutic option for these aggressive tumours to mitigate the MAPK/PI3K activation. In this review, we summarize the variants of malignant thyroid cancers, the molecular mechanisms and factors known to contribute to thyroid cell plasticity and the approved drugs in the clinical trials and those under investigation, providing an overview of available treatments toward a genome-driven oncology, the only opportunity to beat cancer eventually through tailoring the therapy to individual genetic alterations. However, radiotherapeutic and chemotherapeutic resistances to these anticancer treatments are common and, wherever possible, we discuss these issues.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051040
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1041: Click-Chemistry Cross-Linking of
           Hyaluronan Graft Copolymers

    • Authors: Saletti, Paolino, Ballerini, Giuliani, Leone, Lamponi, Andreassi, Bonechi, Donati, Piovani, Schieroni, Magnani, Cappelli
      First page: 1041
      Abstract: An easy and viable crosslinking procedure by click-chemistry (click-crosslinking) of hyaluronic acid (HA) was developed. In particular, the clickable propargyl groups of hyaluronane-based HA-FA-Pg graft copolymers showing low and medium molecular weight values were exploited in crosslinking by click-chemistry by using a hexa(ethylene glycol) spacer. The resulting HA-FA-HEG-CL materials showed an apparent lack of in vitro cytotoxic effects, tuneable water affinity, and rheological properties according to the crosslinking degree that suggests their applicability in different biomedical fields.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051041
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1042: 3D Spheroids of Human Primary
           Urine-Derived Stem Cells in the Assessment of Drug-Induced Mitochondrial

    • Authors: Ding, Jambunathan, Jiang, Margolis, Leng, Ihnat, Ma, Mirsalis, Zhang
      First page: 1042
      Abstract: Mitochondrial toxicity (Mito-Tox) risk has increased due to the administration of several classes of drugs, particularly some life-long antiretroviral drugs for HIV+ individuals. However, no suitable in vitro assays are available to test long-term Mito-Tox (≥4 weeks). The goal of this study is to develop a 3D spheroid system of human primary urine-derived stem cells (USC) for the prediction of drug-induced delayed Mito-Tox. The cytotoxicity and Mito-Tox were assessed in 3D USC spheroids 4 weeks after treatment with antiretroviral drugs: zalcitabine (ddC; 0.1, 1 and 10 µM), tenofovir (TFV; 3, 30 and 300 µM) or Raltegravir (RAL; 2, 20 and 200 µM). Rotenone (RTNN, 10 µM) and 0.1% DMSO served as positive and negative controls. Despite only mild cytotoxicity, ddC significantly inhibited the expression of oxidative phosphorylation enzyme Complexes I, III, and IV; and RAL transiently reduced the level of Complex IV. A significant increase in caspase 3 and ROS/RNS level but a decrease in total ATP were observed in USC treated with ddC, TFV, RAL, and RTNN. Levels of mtDNA content and mitochondrial mass were decreased in ddC but minimally or not in TFV- and RAL-treated spheroids. Thus, 3D USC spheroid using antiretroviral drugs as a model offers an alternative platform to assess drug-induced late Mito-Tox.
      Citation: Pharmaceutics
      PubDate: 2022-05-11
      DOI: 10.3390/pharmaceutics14051042
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1043: Evaluation of the Anti-Histoplasma
           capsulatum Activity of Indole and Nitrofuran Derivatives and Their
           Pharmacological Safety in Three-Dimensional Cell Cultures

    • Authors: Carolina Orlando Vaso, Níura Madalena Bila, Fabiana Pandolfi, Daniela De Vita, Martina Bortolami, Jean Lucas Carvalho Bonatti, Rosângela Aparecida De Moraes Silva, Larissa Naiara Carvalho Gonçalves, Valeria Tudino, Roberta Costi, Roberto Di Santo, Maria José Soares Mendes-Giannini, Caroline Barcelos Costa-Orlandi, Luigi Scipione, Ana Marisa Fusco-Almeida
      First page: 1043
      Abstract: Histoplasma capsulatum is a fungus that causes histoplasmosis. The increased evolution of microbial resistance and the adverse effects of current antifungals help new drugs to emerge. In this work, fifty-four nitrofurans and indoles were tested against the H. capsulatum EH-315 strain. Compounds with a minimum inhibitory concentration (MIC90) equal to or lower than 7.81 µg/mL were selected to evaluate their MIC90 on ATCC G217-B strain and their minimum fungicide concentration (MFC) on both strains. The quantification of membrane ergosterol, cell wall integrity, the production of reactive oxygen species, and the induction of death by necrosis–apoptosis was performed to investigate the mechanism of action of compounds 7, 11, and 32. These compounds could reduce the extracted sterol and induce necrotic cell death, similarly to itraconazole. Moreover, 7 and 11 damaged the cell wall, causing flaws in the contour (11), or changing the size and shape of the fungal cell wall (7). Furthermore, 7 and 32 induced reactive oxygen species (ROS) formation higher than 11 and control. Finally, the cytotoxicity was measured in two models of cell culture, i.e., monolayers (cells are flat) and a three-dimensional (3D) model, where they present a spheroidal conformation. Cytotoxicity assays in the 3D model showed a lower toxicity in the compounds than those performed on cell monolayers. Overall, these results suggest that derivatives of nitrofurans and indoles are promising compounds for the treatment of histoplasmosis.
      Citation: Pharmaceutics
      PubDate: 2022-05-12
      DOI: 10.3390/pharmaceutics14051043
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1044: A Hot-Melt Extrusion Risk Assessment
           Classification System for Amorphous Solid Dispersion Formulation

    • Authors: Samuel O. Kyeremateng, Kristin Voges, Stefanie Dohrn, Ekaterina Sobich, Ute Lander, Stefan Weber, David Gessner, Rachel C. Evans, Matthias Degenhardt
      First page: 1044
      Abstract: Several literature publications have described the potential application of active pharmaceutical ingredient (API)–polymer phase diagrams to identify appropriate temperature ranges for processing amorphous solid dispersion (ASD) formulations via the hot-melt extrusion (HME) technique. However, systematic investigations and reliable applications of the phase diagram as a risk assessment tool for HME are non-existent. Accordingly, within AbbVie, an HME risk classification system (HCS) based on API–polymer phase diagrams has been developed as a material-sparing tool for the early risk assessment of especially high melting temperature APIs, which are typically considered unsuitable for HME. The essence of the HCS is to provide an API risk categorization framework for the development of ASDs via the HME process. The proposed classification system is based on the recognition that the manufacture of crystal-free ASD using the HME process fundamentally depends on the ability of the melt temperature to reach the API’s thermodynamic solubility temperature or above. Furthermore, we explored the API–polymer phase diagram as a simple tool for process design space selection pertaining to API or polymer thermal degradation regions and glass transition temperature-related dissolution kinetics limitations. Application of the HCS was demonstrated via HME experiments with two high melting temperature APIs, sulfamerazine and telmisartan, with the polymers Copovidone and Soluplus. Analysis of the resulting ASDs in terms of the residual crystallinity and degradation showed excellent agreement with the preassigned HCS class. Within AbbVie, the HCS concept has been successfully applied to more than 60 different APIs over the last 8 years as a robust validated risk assessment and quality-by-design (QbD) tool for the development of HME ASDs.
      Citation: Pharmaceutics
      PubDate: 2022-05-12
      DOI: 10.3390/pharmaceutics14051044
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1045: Swine as the Animal Model for Testing
           New Formulations of Anti-Inflammatory Drugs: Carprofen Pharmacokinetics
           and Bioavailability of the Intramuscular Route

    • Authors: Lidia Gómez-Segura, Antoni Boix-Montañes, Mireia Mallandrich, Alexander Parra-Coca, José L. Soriano-Ruiz, Ana Cristina Calpena, Álvaro Gimeno, David Bellido, Helena Colom
      First page: 1045
      Abstract: Carprofen (CP) is a non-steroidal anti-inflammatory drug (NSAID) frequently used to treat respiratory diseases in numerous small animals, but also in large species. CP is a formidable candidate for further therapeutic research of human inflammatory diseases using the pig as an animal model. However, CP administration in swine is very uncommon and respective pharmacokinetics/bioavailability studies are scarce. A simultaneous population pharmacokinetic analysis after CP intravenous and intramuscular administrations in pigs has shown high extent and rate of absorption and a similar distribution profile with respect to man and other mammals. However, clearance and half-life values found in swine suggest a slower elimination process than that observed in man and some other animal species. Although not reported in other species, liver and kidney concentrations achieved at 48 h post-intramuscular administration in pigs were ten times lower than those found in plasma. Simulations pointed to 4 mg/kg every 24 h as the best dosage regimen to achieve similar therapeutic levels to those observed in other animal species. All these findings support the use of pig as an animal model to study the anti-inflammatory effects of CP in humans.
      Citation: Pharmaceutics
      PubDate: 2022-05-12
      DOI: 10.3390/pharmaceutics14051045
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1046: Chitooligosaccharides Improve the
           Efficacy of Checkpoint Inhibitors in a Mouse Model of Lung Cancer

    • Authors: Astrid Zedlitz Johansen, Marco Carretta, Marie-Louise Thorseth, Shawez Khan, Klaire Yixin Fjæstad, Christian Beltoft Brøchner, Hannes Linder, Christina Ankjærgaard, Marco Donia, Inna Chen, Dorte Lisbet Nielsen, Claus Preibisch Behrens, Daniel Hargbøl Madsen
      First page: 1046
      Abstract: YKL-40 (also named chitinase 3 like-1 protein [CHI3L1]) is a secreted chitinase-like protein which is upregulated in cancers and suggested to have pro-tumorigenic activity. YKL-40 lacks enzymatic function, but it can bind carbohydrates such as chitin. Chitooligosaccharides (COS) derived from deacetylation and hydrolysis of chitin might be used for the blockade of YKL-40 function. Here, public single-cell RNA sequencing datasets were used to elucidate the cellular source of YKL-40 gene expression in human tumors. Fibroblasts and myeloid cells were the primary sources of YKL-40. Screening of YKL-40 gene expression in syngeneic mouse cancer models showed the highest expression in the Lewis lung carcinoma (LL2) model. LL2 was used to investigate COS monotherapy and combinations with immune checkpoint inhibitors (anti-PD-L1 and anti-CTLA-4) (ICIs) and radiotherapy (8 Gy × 3) (RT). COS tended to reduce plasma YKL-40 levels, but it did not affect tumor growth. LL2 showed minimal responses to ICIs, or to RT alone. Interestingly, ICIs combined with COS led to delayed tumor growth. RT also enhanced the efficacy of ICIs; however, the addition of COS did not further delay the tumor growth. COS may exert their anti-tumorigenic effects through the inhibition of YKL-40, but additional functions of COS should be investigated.
      Citation: Pharmaceutics
      PubDate: 2022-05-12
      DOI: 10.3390/pharmaceutics14051046
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1047: Phytopigment Alizarin Inhibits
           Multispecies Biofilm Development by Cutibacterium acnes, Staphylococcus
           aureus, and Candida albicans

    • Authors: Jin-Hyung Lee, Yong-Guy Kim, Sunyoung Park, Liangbin Hu, Jintae Lee
      First page: 1047
      Abstract: Acne vulgaris is a common chronic inflammatory skin disease involving Cutibacterium acnes with other skin commensals such as Staphylococcus aureus and Candida albicans in the anaerobic and lipid-rich conditions of pilosebaceous units. These microbes readily form multispecies biofilms that are tolerant of traditional antibiotics as well as host immune systems. The phytopigment alizarin was previously found to prevent biofilm formation by S. aureus and C. albicans strains under aerobic conditions. Hence, we hypothesized that alizarin might control C. acnes and multispecies biofilm development. We found that under anaerobic conditions, alizarin efficiently inhibited single biofilm formation and multispecies biofilm development by C. acnes, S. aureus, and C. albicans without inhibiting planktonic cell growth. Alizarin increased the hydrophilicities of S. aureus and C. albicans cells, decreased lipase production by S. aureus, diminished agglutination by C. acnes, and inhibited the aggregation of C. albicans cells. Furthermore, the co-administration of alizarin and antibiotics enhanced the antibiofilm efficacies of alizarin against C. acnes. A transcriptomic study showed that alizarin repressed the transcriptions of various biofilm-related genes such as lipase, hyaluronate lyase, adhesin/invasion-related, and virulence-related genes of C. acnes. Furthermore, alizarin at 100 µg/mL prevented C. acnes biofilm development on porcine skin. Our results show that alizarin inhibits multispecies biofilm development by acne-causing microbes and suggest it might be a useful agent for treating or preventing C. acnes-causing skin diseases.
      Citation: Pharmaceutics
      PubDate: 2022-05-12
      DOI: 10.3390/pharmaceutics14051047
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1048: Efficacy of Polymer-Based Nanomedicine
           for the Treatment of Brain Cancer

    • Authors: Tobeka Naki, Blessing A. Aderibigbe
      First page: 1048
      Abstract: Malignant brain tumor is a life-threatening disease with a low survival rate. The therapies available for the treatment of brain tumor is limited by poor uptake via the blood–brain barrier. The challenges with the chemotherapeutics used for the treatment of brain tumors are poor distribution, drug toxicity, and their inability to pass via the blood–brain barrier, etc. Several researchers have investigated the potential of nanomedicines for the treatment of brain cancer. Nanomedicines are designed with nanosize particle sizes with a large surface area and are loaded with bioactive agents via encapsulation, immersion, conjugation, etc. Some nanomedicines have been approved for clinical use. The most crucial part of nanomedicine is that they promote drug delivery across the blood–brain barrier, display excellent specificity, reduce drug toxicity, enhance drug bioavailability, and promote targeted drug release mechanisms. The aforementioned features make them promising therapeutics for brain targeting. This review reports the in vitro and in vivo results of nanomedicines designed for the treatment of brain cancers.
      Citation: Pharmaceutics
      PubDate: 2022-05-13
      DOI: 10.3390/pharmaceutics14051048
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1049: An Advanced Bioreactor Simulating
           Dynamic Physiological Conditions in the Human Ascending Colon: MimiCol3

    • Authors: Regine Beeck, Annemarie Dols, Felix Schneider, Dariah-Sohreh Seradj, Julius Krause, Philipp Schick, Werner Weitschies
      First page: 1049
      Abstract: In recent years, the colon has become a hot topic in biopharmaceutical research as several in vitro models of the human colon have been presented. A major focus is on the characterization of the microbiota and its capabilities. The aim of the present study was to further develop the MimiCol, preserving its properties and accelerating data acquisition. Emphasis was placed on the simplicity of its design and easy scalability. To prove the viability of the concept, degradation of sulfasalazine was investigated, and the bacterial composition during the experiment was assessed by 16S rRNA sequencing. The transfer of the experimental conditions to the new model was successful. Commercially available components were implemented in the setup. The model MimiCol3 represented the colon ascendens satisfactorily in its properties regarding volume, pH value, and redox potential. 16S rRNA sequencing led to further insights into the bacterial composition in the vessels. Degradation of sulfasalazine was in good agreement with in vivo data. The new model of the colon ascendens MimiCol3 enabled us to collect more reliable data, as three experiments were conducted simultaneously under the same conditions.
      Citation: Pharmaceutics
      PubDate: 2022-05-13
      DOI: 10.3390/pharmaceutics14051049
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1050: Poly
           (N-Vinylcaprolactam-Grafted-Sodium Alginate) Based Injectable pH/Thermo
           Responsive In Situ Forming Depot Hydrogels for Prolonged Controlled
           Anticancer Drug Delivery; In Vitro, In Vivo Characterization and Toxicity

    • Authors: Samiullah Khan, Muhammad Usman Minhas, Muhammad Tahir Aqeel, Ihsan Shah, Shahzeb Khan, Mohsin Kazi, Zachary N. Warnken
      First page: 1050
      Abstract: This study was aimed to develop novel in situ forming gels based on N-vinylcaprolactam, sodium alginate, and N,N-methylenebisacrylamide. The in situ Poly (NVRCL-g-NaAlg) gels were developed using the cold and free radical polymerization method. The structure formation, thermal stability, and porous nature of gels was confirmed by FTIR, NMR, DSC, TGA, and SEM. The tunable gelation temperature was evaluated by tube titling and rheological analysis. Optical transmittance showed that all formulations demonstrated phase transition around 33 °C. The swelling and release profile showed that gels offered maximum swelling and controlled 5-FU release at 25 °C and pH (7.4), owing to a relaxed state. Porosity and mesh size showed an effect on swelling and drug release. The in vitro degradation profile demonstrated a controlled degradation rate. An MTT assay confirmed that formulations are safe tested against Vero cells. In vitro cytotoxicity showed that 5-FU loaded gels have controlled cytotoxic potential against HeLa and MCF-7 cells (IC50 = 39.91 µg/mL and 46.82 µg/mL) compared to free 5-FU (IC50 = 50.52 µg/mL and 53.58 µg/mL). Histopathological study demonstrated no harmful effects of gels on major organs. The in vivo bioavailability in rabbits showed a controlled release in gel form (Cmax, 1433.59 ± 45.09 ng/mL) compared to a free drug (Cmax, 2263.31 ± 13.36 ng/mL) after the subcutaneous injection.
      Citation: Pharmaceutics
      PubDate: 2022-05-13
      DOI: 10.3390/pharmaceutics14051050
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1051: Current Approaches to Monitor
           Macromolecules Directly from the Cerebral Interstitial Fluid

    • Authors: Marie-Laure Custers, Liam Nestor, Dimitri De Bundel, Ann Van Eeckhaut, Ilse Smolders
      First page: 1051
      Abstract: Gaining insights into the pharmacokinetic and pharmacodynamic properties of lead compounds is crucial during drug development processes. When it comes to the treatment of brain diseases, collecting information at the site of action is challenging. There are only a few techniques available that allow for the direct sampling from the cerebral interstitial space. This review concerns the applicability of microdialysis and other approaches, such as cerebral open flow microperfusion and electrochemical biosensors, to monitor macromolecules (neuropeptides, proteins, …) in the brain. Microdialysis and cerebral open flow microperfusion can also be used to locally apply molecules at the same time at the site of sampling. Innovations in the field are discussed, together with the pitfalls. Moreover, the ‘nuts and bolts’ of the techniques and the current research gaps are addressed. The implementation of these techniques could help to improve drug development of brain-targeted drugs.
      Citation: Pharmaceutics
      PubDate: 2022-05-13
      DOI: 10.3390/pharmaceutics14051051
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1052: Raman Mapping-Based Reverse
           Engineering Facilitates Development of Sustained-Release Nifedipine Tablet

    • Authors: Ningyun Sun, Liang Chang, Yi Lu, Wei Wu
      First page: 1052
      Abstract: The development of generic preparations that are bioequivalent to a reference listed drug (RLD) is faced with challenges because some critical attributes of RLDs are commonly unknown to developers. In order to determine these attributes, Raman mapping-based reverse engineering in this study to analyze a model sustained-release tablet of nifedipine. The Raman mapping results indicate that the size and size distribution of nifedipine are critical to its release pattern and bioavailability. The tablets with a particle size of nifedipine comparable to that of a commercial product, Adalat®-L, showed similar in vitro release profiles to the RLD. Moreover, a pharmacokinetic study in human volunteers proved the bioequivalence of the two preparations. In conclusion, Raman mapping-based reverse engineering has the potential to facilitate the development of generic preparations.
      Citation: Pharmaceutics
      PubDate: 2022-05-13
      DOI: 10.3390/pharmaceutics14051052
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1053: Integrin-αvβ3 as a
           Therapeutic Target in Glioblastoma: Back to the Future'

    • Authors: William Echavidre, Vincent Picco, Marc Faraggi, Christopher Montemagno
      First page: 1053
      Abstract: Glioblastoma (GBM), the most common primary malignant brain tumor, is associated with a dismal prognosis. Standard therapies including maximal surgical resection, radiotherapy, and temozolomide chemotherapy remain poorly efficient. Improving GBM treatment modalities is, therefore, a paramount challenge for researchers and clinicians. GBMs exhibit the hallmark feature of aggressive invasion into the surrounding tissue. Among cell surface receptors involved in this process, members of the integrin family are known to be key actors of GBM invasion. Upregulation of integrins was reported in both tumor and stromal cells, making them a suitable target for innovative therapies targeting integrins in GBM patients, as their impairment disrupts tumor cell proliferation and invasive capacities. Among them, integrin-αvβ3 expression correlates with high-grade GBM. Driven by a plethora of preclinical biological studies, antagonists of αvβ3 rapidly became attractive therapeutic candidates to impair GBM tumorigenesis. In this perspective, the advent of nuclear medicine is currently one of the greatest components of the theranostic concept in both preclinical and clinical research fields. In this review, we provided an overview of αvβ3 expression in GBM to emphasize the therapeutic agents developed. Advanced current and future developments in the theranostic field targeting αvβ3 are finally discussed.
      Citation: Pharmaceutics
      PubDate: 2022-05-13
      DOI: 10.3390/pharmaceutics14051053
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1054: Plasma-Enabled Smart Nanoexosome
           Platform as Emerging Immunopathogenesis for Clinical Viral Infection

    • Authors: Mousavi, Hashemi, Gholami, Kalashgrani, Vijayakameswara Rao, Omidifar, Hsiao, Lai, Chiang
      First page: 1054
      Abstract: Smart nanoexosomes are nanosized structures enclosed in lipid bilayers that are structurally similar to the viruses released by a variety of cells, including the cells lining the respiratory system. Of particular importance, the interaction between smart nanoexosomes and viruses can be used to develop antiviral drugs and vaccines. It is possible that nanoexosomes will be utilized and antibodies will be acquired more successfully for the transmission of an immune response if reconvalescent plasma (CP) is used instead of reconvalescent plasma exosomes (CPExo) in this concept. Convalescent plasma contains billions of smart nanoexosomes capable of transporting a variety of molecules, including proteins, lipids, RNA and DNA among other viral infections. Smart nanoexosomes are released from virus-infected cells and play an important role in mediating communication between infected and uninfected cells. Infections use the formation, production and release of smart nanoexosomes to enhance the infection, transmission and intercellular diffusion of viruses. Cell-free smart nanoexosomes produced by mesenchymal stem cells (MSCs) could also be used as cell-free therapies in certain cases. Smart nanoexosomes produced by mesenchymal stem cells can also promote mitochondrial function and heal lung injury. They can reduce cytokine storms and restore the suppression of host antiviral defenses weakened by viral infections. This study examines the benefits of smart nanoexosomes and their roles in viral transmission, infection, treatment, drug delivery and clinical applications. We also explore some potential future applications for smart nanoexosomes in the treatment of viral infections.
      Citation: Pharmaceutics
      PubDate: 2022-05-13
      DOI: 10.3390/pharmaceutics14051054
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1055: Introducing Fiber-Assisted
           Colorimetric Measurements as a Quality Control Tool of Hot Melt Extruded

    • Authors: Rebecca Chamberlain, Eirini Mangiorou, Björn Fischer
      First page: 1055
      Abstract: Pharmaceutical and medicinal printing technologies allow personalization and on-demand manufacturing of drug and medicinal products. Being able to manufacture patient tailored dosage forms or medical devices in a pharmacy, medical office, dental laboratory, or hospital at the point of care raises new demands on quality control procedures. For Fused Deposition Modeling, for example, it must be ensured that the starting materials, the (drug-loaded) filaments, are not accidentally exchanged by the operator. This study investigated the potential of colorimetric measurements for direct and indirect determination of the identity of extruded filaments consisting of polymer matrix, different API and/or coloring agents. Since reflection measurements were affected by surface properties of the filaments, a self-constructed filament holder was utilized with an optical fiber positioned in a 180° angle to a white light LED to perform transmission measurements. It was possible to distinguish filaments with different API concentrations by their color values, taking into account that transmission partially decreased by increased API concentration. Therefore, the intensity of the light source had to be adjusted depending on the transparency of the filament. It was shown that colorimetry can be used as a quality control tool to detect differences in drug-loading and is able to distinguish various extruded batches. Additionally, if differences in API/polymer concentrations do not lead to significant changes in L*a*b values, coloring agents were used as additives in low concentrations to color code filaments. In future studies, the setup must be supplemented with a standardized light source and obscuring filters for light intensity adjustments.
      Citation: Pharmaceutics
      PubDate: 2022-05-14
      DOI: 10.3390/pharmaceutics14051055
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1056: Renal Artery Catheterization for
           Microcapsules’Targeted Delivery to the Mouse Kidney

    • Authors: Olga I. Gusliakova, Ekaterina S. Prikhozhdenko, Valentina O. Plastun, Oksana A. Mayorova, Natalia A. Shushunova, Arkady S. Abdurashitov, Oleg A. Kulikov, Maxim A. Abakumov, Dmitry A. Gorin, Gleb B. Sukhorukov, Olga A. Sindeeva
      First page: 1056
      Abstract: The problem of reducing the side effects associated with drug distribution throughout the body in the treatment of various kidney diseases can be solved by effective targeted drug delivery. The method described herein involves injection of a drug encapsulated in polyelectrolyte capsules to achieve prolonged local release and long-term capillary retention of several hours while these capsules are administered via the renal artery. The proposed method does not imply disruption (puncture) of the renal artery or aorta and is suitable for long-term chronic experiments on mice. In this study, we compared how capsule size and dosage affect the target kidney blood flow. It has been established that an increase in the diameter of microcapsules by 29% (from 3.1 to 4.0 μm) requires a decrease in their concentration by at least 50% with the same suspension volume. The photoacoustic method, along with laser speckle contrast imaging, was shown to be useful for monitoring blood flow and selecting a safe dose. Capsules contribute to a longer retention of a macromolecular substance in the target kidney compared to its free form due to mechanical retention in capillaries and slow impregnation into surrounding tissues during the first 1–3 h, which was shown by fluorescence tomography and microscopy. At the same time, the ability of capillaries to perform almost complete “self-cleaning” from capsular shells during the first 12 h leads to the preservation of organ tissues in a normal state. The proposed strategy, which combines endovascular surgery and the injection of polymer microcapsules containing the active substance, can be successfully used to treat a wide range of nephropathies.
      Citation: Pharmaceutics
      PubDate: 2022-05-14
      DOI: 10.3390/pharmaceutics14051056
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1057: Dextran-Coated Iron Oxide
           Nanoparticles Loaded with Curcumin for Antimicrobial Therapies

    • Authors: Cristina Chircov, Raluca-Elena Ștefan, Georgiana Dolete, Adriana Andrei, Alina Maria Holban, Ovidiu-Cristian Oprea, Bogdan Stefan Vasile, Ionela Andreea Neacșu, Bianca Tihăuan
      First page: 1057
      Abstract: The current trend in antimicrobial-agent development focuses on the use of natural compounds that limit the toxicity of conventional drugs and provide a potential solution to the antimicrobial resistance crisis. Curcumin represents a natural bioactive compound with well-known antimicrobial, anticancer, and antioxidant properties. However, its hydrophobicity considerably limits the possibility of body administration. Therefore, dextran-coated iron oxide nanoparticles can be used as efficient drug-delivery supports that could overcome this limitation. The iron oxide nanoparticles were synthesized through the microwave-assisted hydrothermal method by varying the treatment parameters (pressure and reaction time). The nanoparticles were subsequently coated with dextran and used for the loading of curcumin (in various concentrations). The drug-delivery systems were characterized through X-ray diffraction (XRD) coupled with Rietveld refinement, transmission electron microscopy (TEM), high-resolution TEM (HR-TEM), selected area electron diffraction (SAED), dynamic light scattering (DLS) and zeta potential, thermogravimetry and differential scanning calorimetry (TG-DSC), vibrating sample magnetometry (VSM), and UV-Vis spectrophotometry, as well as regarding their antimicrobial efficiency and biocompatibility using the appropriate assays. The results demonstrate a promising antimicrobial efficiency, as well as an increased possibility of controlling the properties of the resulted nanosystems. Thus, the present study represents an important step forward toward the development of highly efficient antimicrobial drug-delivery systems.
      Citation: Pharmaceutics
      PubDate: 2022-05-14
      DOI: 10.3390/pharmaceutics14051057
      Issue No: Vol. 14, No. 5 (2022)
  • Pharmaceutics, Vol. 14, Pages 1058: Integrated Purification and
           Formulation of an Active Pharmaceutical Ingredient via Agitated Bed
           Crystallization and Fluidized Bed Processing

    • Authors: Michael W. Stocker, Matthew J. Harding, Valerio Todaro, Anne Marie Healy, Steven Ferguson
      First page: 1058
      Abstract: Integrated API and drug product processing enable molecules with high clinical efficacy but poor physicochemical characteristics to be commercialized by direct co-processing with excipients to produce advanced multicomponent intermediates. Furthermore, developing isolation-free frameworks would enable end-to-end continuous processing of drugs. The aim of this work was to purify a model API (sodium ibuprofen) and impurity (ibuprofen ethyl ester) system and then directly process it into a solid-state formulation without isolating a solid API phase. Confined agitated bed crystallization is proposed to purify a liquid stream of impure API from 4% to 0.2% w/w impurity content through periodic or parallelized operations. This stream is combined with a polymer solution in an intermediary tank, enabling the API to be spray coated directly onto microcrystalline cellulose beads. The spray coating process was developed using a Design of Experiments approach, allowing control over the drug loading efficiency and the crystallinity of the API on the beads by altering the process parameters. The DoE study indicated that the solvent volume was the dominant factor controlling the drug loading efficiency, while a combination of factors influenced the crystallinity. The products from the fluidized bed are ideal for processing into final drug products and can subsequently be coated to control drug release.
      Citation: Pharmaceutics
      PubDate: 2022-05-14
      DOI: 10.3390/pharmaceutics14051058
      Issue No: Vol. 14, No. 5 (2022)
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