Pharmaceutics

16 pages, 2466 KiB

Open AccessArticle

Antimicrobial Peptides and Biomarkers Induced by Ultraviolet Irradiation Have the Potential to Reduce Endodontic Inflammation and Facilitate Tissue Healing

by Kimberly A. Morio, Robert H. Sternowski, Erliang Zeng and Kim A. Brogden

Pharmaceutics 2022, 14(9), 1979; https://doi.org/10.3390/pharmaceutics14091979 - 19 Sep 2022

Cited by 4 | Viewed by 1938

Abstract

Background: Ultraviolet (UV) irradiation can modulate host immune responses and this approach is a novel application for treating endodontic infections and inflammation in root canals. Methods: A dataset of UV-induced molecules was compiled from a literature search. A subset of this dataset was [...] Read more.

Background: Ultraviolet (UV) irradiation can modulate host immune responses and this approach is a novel application for treating endodontic infections and inflammation in root canals. Methods: A dataset of UV-induced molecules was compiled from a literature search. A subset of this dataset was used to calculate expression log2 ratios of endodontic tissue molecules from HEPM cells and gingival fibroblasts after 255, 405, and 255/405 nm UV irradiation. Both datasets were analyzed using ingenuity pathway analysis (IPA, Qiagen, Germantown, MD, USA). Statistical significance was calculated using Fisher’s exact test and z-scores were calculated for IPA comparison analysis. Results: The dataset of 32 UV-induced molecules contained 9 antimicrobial peptides, 10 cytokines, 6 growth factors, 3 enzymes, 2 transmembrane receptors, and 2 transcription regulators. These molecules were in the IPA canonical pathway annotations for the wound healing signaling pathway (9/32, p = 3.22 × 10⁻¹¹) and communication between immune cells (6/32, p = 8.74 × 10⁻¹¹). In the IPA disease and function annotations, the 32 molecules were associated with an antimicrobial response, cell-to-cell signaling and interaction, cellular movement, hematological system development and function, immune cell trafficking, and inflammatory response. In IPA comparison analysis of the 13 molecules, the predicted activation or inhibition of pathways depended upon the cell type exposed, the wavelength of the UV irradiation used, and the time after exposure. Conclusions: UV irradiation activates and inhibits cellular pathways and immune functions. These results suggested that UV irradiation can activate innate and adaptive immune responses, which may supplement endodontic procedures to reduce infection, inflammation, and pain and assist tissues to heal. Full article

(This article belongs to the Special Issue Special Issue in Honor of Dr. Marie-Hélène Metz-Boutigue 75th Birthday: “Recent Advances in Multifunctional Antimicrobial Peptides as Preclinical Therapeutic Studies and Clinical Future Applications”)

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35 pages, 8382 KiB

Open AccessReview

3D Bioprinted Chitosan-Based Hydrogel Scaffolds in Tissue Engineering and Localised Drug Delivery

by Maria Lazaridou, Dimitrios N. Bikiaris and Dimitrios A. Lamprou

Pharmaceutics 2022, 14(9), 1978; https://doi.org/10.3390/pharmaceutics14091978 - 19 Sep 2022

Cited by 51 | Viewed by 9002

Abstract

Bioprinting is an emerging technology with various applications in developing functional tissue constructs for the replacement of harmed or damaged tissues and simultaneously controlled drug delivery systems (DDSs) for the administration of several active substances, such as growth factors, proteins, and drug molecules. [...] Read more.

Bioprinting is an emerging technology with various applications in developing functional tissue constructs for the replacement of harmed or damaged tissues and simultaneously controlled drug delivery systems (DDSs) for the administration of several active substances, such as growth factors, proteins, and drug molecules. It is a novel approach that provides high reproducibility and precise control over the fabricated constructs in an automated way. An ideal bioink should possess proper mechanical, rheological, and biological properties essential to ensure proper function. Chitosan is a promising natural-derived polysaccharide to be used as ink because of its attractive properties, such as biodegradability, biocompatibility, low cost, and non-immunogenicity. This review focuses on 3D bioprinting technology for the preparation of chitosan-based hydrogel scaffolds for the regeneration of tissues delivering either cells or active substances to promote restoration. Full article

(This article belongs to the Special Issue New Pharmaceutical Applications through 3D Printing Processes)

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18 pages, 5097 KiB

Open AccessArticle

Vitamin E TPGS-Poloxamer Nanoparticles Entrapping a Novel PI3Kα Inhibitor Potentiate Its Activity against Breast Cancer Cell Lines

by Suhair Sunoqrot, Sundos Aliyeh, Samah Abusulieh and Dima Sabbah

Pharmaceutics 2022, 14(9), 1977; https://doi.org/10.3390/pharmaceutics14091977 - 19 Sep 2022

Cited by 8 | Viewed by 2892

Abstract

N-(2-fluorphenyl)-6-chloro-4-hydroxy-2-quinolone-3-carboxamide (R19) is a newly synthesized phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor with promising activity against cancer cells. The purpose of this study was to develop a polymeric nanoparticle (NP) formulation for R19 to address its poor aqueous solubility and to facilitate its future [...] Read more.

N-(2-fluorphenyl)-6-chloro-4-hydroxy-2-quinolone-3-carboxamide (R19) is a newly synthesized phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor with promising activity against cancer cells. The purpose of this study was to develop a polymeric nanoparticle (NP) formulation for R19 to address its poor aqueous solubility and to facilitate its future administration in preclinical and clinical settings. NPs were prepared by nanoprecipitation using two polymers: D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and the poloxamer Pluronic P123 in different ratios. Physicochemical characterization of the NPs revealed them to be around 100 nm in size with high monodispersity, a spherical morphology, and an almost neutral surface charge. The NPs achieved ~60% drug loading efficiency and sustained release of R19 for up to 96 h, with excellent colloidal stability in serum-containing cell culture media. NPs containing TPGS enhanced R19’s potency against MCF-7 and MDA-MB-231 breast cancer cells in vitro, with half-maximal inhibitory concentrations (IC₅₀) ranging between 1.8 and 4.3 µM compared to free R19, which had an IC₅₀ of 14.7–17.0 µM. The NPs also demonstrated low cytotoxicity against human dermal fibroblasts and more significant induction of apoptosis compared to the free drug, which was correlated with their cellular uptake efficiency. Our findings present a biocompatible NP formulation for the delivery of a cancer-targeted PI3Kα inhibitor, R19, which can further enhance its potency for the treatment of breast cancer and potentially other cancer types. Full article

(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)

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19 pages, 3444 KiB

Open AccessEditor’s ChoiceArticle

Curcumin-Loaded Mesoporous Silica Nanoparticles Dispersed in Thermo-Responsive Hydrogel as Potential Alzheimer Disease Therapy

by Tais de Cassia Ribeiro, Rafael Miguel Sábio, Marcela Tavares Luiz, Lucas Canto de Souza, Bruno Fonseca-Santos, Luis Carlos Cides da Silva, Márcia Carvalho de Abreu Fantini, Cleopatra da Silva Planeta and Marlus Chorilli

Pharmaceutics 2022, 14(9), 1976; https://doi.org/10.3390/pharmaceutics14091976 - 19 Sep 2022

Cited by 38 | Viewed by 4335

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) can overcome the drawbacks related to the free curcumin (CCM) clinical application, such as water insolubility and low bioavailability, besides acting over the main causes [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) can overcome the drawbacks related to the free curcumin (CCM) clinical application, such as water insolubility and low bioavailability, besides acting over the main causes associated to AD. A thermo-responsive hydrogel is an interesting approach for facilitating the administration of the nanosystem via a nasal route, as well as for overcoming mucociliary clearance mechanisms. In light of this, MSN-CCM were dispersed in the hydrogel and evaluated through in vitro and in vivo assays. The MSNs and MSN-CCM were successfully characterized by physicochemical analysis and a high value of the CCM encapsulation efficiency (EE%, 87.70 ± 0.05) was achieved. The designed thermo-responsive hydrogel (HG) was characterized by rheology, texture profile analysis, and ex vivo mucoadhesion, showing excellent mechanical and mucoadhesive properties. Ex vivo permeation studies of MSN-CCM and HG@MSN-CCM showed high permeation values (12.46 ± 1.08 and 28.40 ± 1.88 μg cm⁻² of CCM, respectively) in porcine nasal mucosa. In vivo studies performed in a streptozotocin-induced AD model confirmed that HG@MSN-CCM reverted the cognitive deficit in mice, acting as a potential formulation in the treatment of AD. Full article

(This article belongs to the Special Issue Silica-Based Carriers for Drug Delivery)

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36 pages, 6609 KiB

Open AccessArticle

Microemulsions as Lipid Nanosystems Loaded into Thermoresponsive In Situ Microgels for Local Ocular Delivery of Prednisolone

by Rania Hamed, Amani D. Abu Kwiak, Yasmeen Al-Adhami, Alaa M. Hammad, Rana Obaidat, Osama H. Abusara and Rana Abu Huwaij

Pharmaceutics 2022, 14(9), 1975; https://doi.org/10.3390/pharmaceutics14091975 - 19 Sep 2022

Cited by 15 | Viewed by 2355

Abstract

This study aimed to develop and evaluate thermoresponsive in situ microgels for the local ocular delivery of prednisolone (PRD) (PRD microgels) to improve drug bioavailability and prolong ocular drug residence time. Lipid nanosystems of PRD microemulsions (PRD-MEs) were prepared and evaluated at a [...] Read more.

This study aimed to develop and evaluate thermoresponsive in situ microgels for the local ocular delivery of prednisolone (PRD) (PRD microgels) to improve drug bioavailability and prolong ocular drug residence time. Lipid nanosystems of PRD microemulsions (PRD-MEs) were prepared and evaluated at a drug concentration of 0.25–0.75%. PRD microgels were prepared by incorporating PRD-MEs into 10 and 12% Pluronic^® F127 (F127) or combinations of 12% F127 and 1–10% Kolliphor^®P188 (F68). PRD microgels were characterized for physicochemical, rheological, and mucoadhesive properties, eye irritation, and stability. Results showed that PRD-MEs were clear, miscible, thermodynamically stable, and spherical with droplet size (16.4 ± 2.2 nm), polydispersity index (0.24 ± 0.01), and zeta potential (−21.03 ± 1.24 mV). The PRD microgels were clear with pH (5.37–5.81), surface tension (30.96–38.90 mN/m), size, and zeta potential of mixed polymeric micelles (20.1–23.9 nm and −1.34 to −10.25 mV, respectively), phase transition temperature (25.3–36 °C), and gelation time (1.44–2.47 min). The FTIR spectra revealed chemical compatibility between PRD and microgel components. PRD microgels showed pseudoplastic flow, viscoelastic and mucoadhesive properties, absence of eye irritation, and drug content (99.3 to 106.3%) with a sustained drug release for 16–24 h. Microgels were physicochemically and rheologically stable for three to six months. Therefore, PRD microgels possess potential vehicles for local ocular delivery. Full article

(This article belongs to the Special Issue Lipid Nanosystems for Local Drug Delivery)

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26 pages, 7515 KiB

Open AccessReview

A Review of Non-Invasive Drug Delivery through Respiratory Routes

by Yong-Bo Zhang, Dong Xu, Lu Bai, Yan-Ming Zhou, Han Zhang and Yuan-Lu Cui

Pharmaceutics 2022, 14(9), 1974; https://doi.org/10.3390/pharmaceutics14091974 - 19 Sep 2022

Cited by 16 | Viewed by 4993

Abstract

With rapid and non-invasive characteristics, the respiratory route of administration has drawn significant attention compared with the limitations of conventional routes. Respiratory delivery can bypass the physiological barrier to achieve local and systemic disease treatment. A scientometric analysis and review were used to [...] Read more.

With rapid and non-invasive characteristics, the respiratory route of administration has drawn significant attention compared with the limitations of conventional routes. Respiratory delivery can bypass the physiological barrier to achieve local and systemic disease treatment. A scientometric analysis and review were used to analyze how respiratory delivery can contribute to local and systemic therapy. The literature data obtained from the Web of Science Core Collection database showed an increasing worldwide tendency toward respiratory delivery from 1998 to 2020. Keywords analysis suggested that nasal and pulmonary drug delivery are the leading research topics in respiratory delivery. Based on the results of scientometric analysis, the research hotspots mainly included therapy for central nervous systems (CNS) disorders (Parkinson’s disease, Alzheimer’s disease, depression, glioblastoma, and epilepsy), tracheal and bronchial or lung diseases (chronic obstructive pulmonary disease, asthma, acute lung injury or respiratory distress syndrome, lung cancer, and idiopathic pulmonary fibrosis), and systemic diseases (diabetes and COVID-19). The study of advanced preparations contained nano drug delivery systems of the respiratory route, drug delivery barriers investigation (blood-brain barrier, BBB), and chitosan-based biomaterials for respiratory delivery. These results provided researchers with future research directions related to respiratory delivery. Full article

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21 pages, 2053 KiB

Open AccessReview

Immune Responses to Gene Editing by Viral and Non-Viral Delivery Vectors Used in Retinal Gene Therapy

by Duohao Ren, Sylvain Fisson, Deniz Dalkara and Divya Ail

Pharmaceutics 2022, 14(9), 1973; https://doi.org/10.3390/pharmaceutics14091973 - 19 Sep 2022

Cited by 19 | Viewed by 3823

Abstract

Inherited retinal diseases (IRDs) are a leading cause of blindness in industrialized countries, and gene therapy is quickly becoming a viable option to treat this group of diseases. Gene replacement using a viral vector has been successfully applied and advanced to commercial use [...] Read more.

Inherited retinal diseases (IRDs) are a leading cause of blindness in industrialized countries, and gene therapy is quickly becoming a viable option to treat this group of diseases. Gene replacement using a viral vector has been successfully applied and advanced to commercial use for a rare group of diseases. This, and the advances in gene editing, are paving the way for the emergence of a new generation of therapies that use CRISPR–Cas9 to edit mutated genes in situ. These CRISPR-based agents can be delivered to the retina as transgenes in a viral vector, unpackaged transgenes or as proteins or messenger RNA using non-viral vectors. Although the eye is considered to be an immune-privileged organ, studies in animals, as well as evidence from clinics, have concluded that ocular gene therapies elicit an immune response that can under certain circumstances result in inflammation. In this review, we evaluate studies that have reported on pre-existing immunity, and discuss both innate and adaptive immune responses with a specific focus on immune responses to gene editing, both with non-viral and viral delivery in the ocular space. Lastly, we discuss approaches to prevent and manage the immune responses to ensure safe and efficient gene editing in the retina. Full article

(This article belongs to the Special Issue Gene- and Cell-Based Therapies for Retinal Diseases)

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20 pages, 8780 KiB

Open AccessReview

Application of DFT Calculations in Designing Polymer-Based Drug Delivery Systems: An Overview

by Oluwasegun Chijioke Adekoya, Gbolahan Joseph Adekoya, Emmanuel Rotimi Sadiku, Yskandar Hamam and Suprakas Sinha Ray

Pharmaceutics 2022, 14(9), 1972; https://doi.org/10.3390/pharmaceutics14091972 - 19 Sep 2022

Cited by 33 | Viewed by 8788

Abstract

Drug delivery systems transfer medications to target locations throughout the body. These systems are often made up of biodegradable and bioabsorbable polymers acting as delivery components. The introduction of density functional theory (DFT) has tremendously aided the application of computational material science in [...] Read more.

Drug delivery systems transfer medications to target locations throughout the body. These systems are often made up of biodegradable and bioabsorbable polymers acting as delivery components. The introduction of density functional theory (DFT) has tremendously aided the application of computational material science in the design and development of drug delivery materials. The use of DFT and other computational approaches avoids time-consuming empirical processes. Therefore, this review explored how the DFT computation may be utilized to explain some of the features of polymer-based drug delivery systems. First, we went through the key aspects of DFT and provided some context. Then we looked at the essential characteristics of a polymer-based drug delivery system that DFT simulations could predict. We observed that the Gaussian software had been extensively employed by researchers, particularly with the B3LYP functional and 6-31G(d, p) basic sets for polymer-based drug delivery systems. However, to give researchers a choice of basis set for modelling complicated organic systems, such as polymer–drug complexes, we then offered possible resources and presented the future trend. Full article

(This article belongs to the Special Issue Sustainable Materials and Technologies for Drug Delivery and Tissue Engineering)

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14 pages, 1138 KiB

Open AccessArticle

Fabrication, In Vitro, and In Vivo Assessment of Eucalyptol-Loaded Nanoemulgel as a Novel Paradigm for Wound Healing

by Anis Rehman, Muhammad Iqbal, Barkat A. Khan, Muhammad Khalid Khan, Bader Huwaimel, Sameer Alshehri, Ali H. Alamri, Rami M. Alzhrani, Deena M. Bukhary, Awaji Y. Safhi and Khaled M. Hosny

Pharmaceutics 2022, 14(9), 1971; https://doi.org/10.3390/pharmaceutics14091971 - 19 Sep 2022

Cited by 24 | Viewed by 2844

Abstract

Wounds are the most common causes of mortality all over the world. Topical drug delivery systems are more efficient in treating wounds as compared to oral delivery systems because they bypass the disadvantages of the oral route. The aim of the present study [...] Read more.

Wounds are the most common causes of mortality all over the world. Topical drug delivery systems are more efficient in treating wounds as compared to oral delivery systems because they bypass the disadvantages of the oral route. The aim of the present study was to formulate and evaluate in vitro in vivo nanoemulgels loaded with eucalyptol for wound healing. Nanoemulsions were prepared using the solvent emulsification diffusion method by mixing an aqueous phase and an oil phase, and a nanoemulgel was then fabricated by mixing nanoemulsions with a gelling agent (Carbopol 940) in a 1:1 ratio. The nanoemulgels were evaluated regarding stability, homogeneity, pH, viscosity, Fourier-transform infrared spectroscopy (FTIR), droplet size, zeta potential, polydispersity index (PDI), spreadability, drug content, in vitro drug release, and in vivo study. The optimized formulation, F5, exhibited pH values between 5 and 6, with no significant variations at different temperatures, and acceptable homogeneity and spreadability. F5 had a droplet size of 139 ± 5.8 nm, with a low polydispersity index. FTIR studies showed the compatibility of the drug with the excipients. The drug content of F5 was 94.81%. The percentage of wound contraction of the experimental, standard, and control groups were 100% ± 0.015, 98.170% ± 0.749, and 70.846% ± 0.830, respectively. Statistically, the experimental group showed a significant difference (p < 0.03) from the other two groups. The results suggest that the formulated optimized dosage showed optimum stability, and it can be considered an effective wound healing alternative. Full article

(This article belongs to the Special Issue Sustainable Materials and Technologies for Drug Delivery and Tissue Engineering)

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17 pages, 8359 KiB

Open AccessArticle

Molecular Mechanisms of Cassia fistula against Epithelial Ovarian Cancer Using Network Pharmacology and Molecular Docking Approaches

by Aqsa Kanwal, Farrukh Azeem, Habibullah Nadeem, Usman Ali Ashfaq, Rana Muhammad Aadil, A. K. M. Humayun Kober, Muhammad Shahid Riaz Rajoka and Ijaz Rasul

Pharmaceutics 2022, 14(9), 1970; https://doi.org/10.3390/pharmaceutics14091970 - 19 Sep 2022

Cited by 5 | Viewed by 3125

Abstract

Epithelial ovarian cancer (EOC) is one of the deadliest reproductive tract malignancies that form on the external tissue covering of an ovary. Cassia fistula is popular for its anti-inflammatory and anticarcinogenic properties in conventional medications. Nevertheless, its molecular mechanisms are still unclear. The [...] Read more.

Epithelial ovarian cancer (EOC) is one of the deadliest reproductive tract malignancies that form on the external tissue covering of an ovary. Cassia fistula is popular for its anti-inflammatory and anticarcinogenic properties in conventional medications. Nevertheless, its molecular mechanisms are still unclear. The current study evaluated the potential of C. fistula for the treatment of EOC using network pharmacology approach integrated with molecular docking. Eight active constituents of C. fistula were obtained from two independent databases and the literature, and their targets were retrieved from the SwissTargetPrediction. In total, 1077 EOC associated genes were retrieved from DisGeNET and GeneCardsSuite databases, and 800 potential targets of eight active constituents of C. fistula were mapped to the 1077 EOC targets and intersected targets from two databases. Ultimately, 98 potential targets were found from C. fistula for EOC. Finally, the protein–protein interaction network (PPI) topological interpretation revealed AKT1, CTNNB1, ESR1, and CASP3 as key targets. This is the first time four genes have been found against EOC from C. fistula. The major enriched pathways of these candidate genes were established by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) investigations. To confirm the network pharmacology findings, the molecular docking approach demonstrated that active molecules have higher affinity for binding to putative targets for EOC suppression. More pharmacological and clinical research is required for the development of a drug to treat EOC. Full article

(This article belongs to the Special Issue Natural and Synthesized Anticancer Bioactive Compounds in Drug Discovery, Formulations and Delivery)

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21 pages, 3603 KiB

Open AccessReview

Oral Nanomedicines for siRNA Delivery to Treat Inflammatory Bowel Disease

by Jongyoon Shinn, Juyeon Lee, Seon Ah Lee, Seon Ju Lee, Ah Hyun Choi, Jung Seo Kim, Su Jin Kim, Hyo Jin Kim, Cherin Lee, Yejin Kim, Joohyeon Kim, Jonghee Choi, Byungchae Jung, Taeho Kim, HyeonTaek Nam, Hyungjun Kim and Yonghyun Lee

Pharmaceutics 2022, 14(9), 1969; https://doi.org/10.3390/pharmaceutics14091969 - 19 Sep 2022

Cited by 9 | Viewed by 3169

Abstract

RNA interference (RNAi) therapies have significant potential for the treatment of inflammatory bowel diseases (IBD). Although administering small interfering RNA (siRNA) via an oral route is desirable, various hurdles including physicochemical, mucus, and cellular uptake barriers of the gastrointestinal tract (GIT) impede both [...] Read more.

RNA interference (RNAi) therapies have significant potential for the treatment of inflammatory bowel diseases (IBD). Although administering small interfering RNA (siRNA) via an oral route is desirable, various hurdles including physicochemical, mucus, and cellular uptake barriers of the gastrointestinal tract (GIT) impede both the delivery of siRNA to the target site and the action of siRNA drugs at the target site. In this review, we first discuss various physicochemical and biological barriers in the GI tract. Furthermore, we present recent strategies and the progress of oral siRNA delivery strategies to treat IBD. Finally, we consider the challenges faced in the use of these strategies and future directions of oral siRNA delivery strategies. Full article

(This article belongs to the Special Issue Drug Delivery Systems for Oral Immunotherapy)

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18 pages, 3990 KiB

Open AccessArticle

Insight into the Formation of Cocrystal and Salt of Tenoxicam from the Isomer and Conformation

by Yifei Xie, Penghui Yuan, Tianyu Heng, Lida Du, Qi An, Baoxi Zhang, Li Zhang, Dezhi Yang, Guanhua Du and Yang Lu

Pharmaceutics 2022, 14(9), 1968; https://doi.org/10.3390/pharmaceutics14091968 - 19 Sep 2022

Cited by 11 | Viewed by 2284

Abstract

Tenoxicam (TNX) is a new non-steroidal anti-inflammatory drug that shows a superior anti-inflammatory effect and has the advantages of a long half-life period, a fast onset of action, a small dose, complete metabolism, and good tolerance. Some compounds often have tautomerism, and different [...] Read more.

Tenoxicam (TNX) is a new non-steroidal anti-inflammatory drug that shows a superior anti-inflammatory effect and has the advantages of a long half-life period, a fast onset of action, a small dose, complete metabolism, and good tolerance. Some compounds often have tautomerism, and different tautomers exist in different crystalline forms. TNX is such a compound and has three tautomers. TNX always exists as the zwitterionic form in cocrystals. When the salt is formed, TNX exists in the enol form, which exhibits two conformations depending on whether a proton is gained or lost. Currently, the crystal structure of the keto form is not in the Cambridge Structural Database (CSD). Based on the analysis of existing crystal structures, we derived a simple rule for what form of TNX exists according to the pKa value of the cocrystal coformer (CCF) and carried out validation tests using three CCFs with different pKa values, including p-aminosalicylic acid (PAS), 3,5-dinitrobenzoic acid (DNB), and 2,6-dihydroxybenzoic acid (DHB). The molecular surface electrostatic potential (MEPS) was combined with the pKa rule to predict the interaction sites. Finally, two new cocrystals (TNX-PAS and TNX-DNB) and one salt (TNX-DHB) of TNX were obtained as expected. The differences between the cocrystals and salt were distinguished by X-ray diffraction, vibration spectra, thermal analysis, and dissolution measurements. To further understand the intermolecular interactions in these cocrystals and salt, the lattice energy and energy decomposition analysis (EDA) were used to explain them from the perspective of energy. The results suggest that the melting point of the CCF determines that of the cocrystal or salt, the solubility of the CCF itself plays an important role, and the improvement of the solubility after salt formation is not necessarily better than that of API or its cocrystals. Full article

(This article belongs to the Special Issue Applications of Crystal Engineering in Drug Delivery)

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17 pages, 3193 KiB

Open AccessArticle

Stability Study of Alpinia galanga Constituents and Investigation of Their Membrane Permeability by ChemGPS-NP and the Parallel Artificial Membrane Permeability Assay

by Alexandra Simon, Kim Szofi Nghiem, Nóra Gampe, Zsófia Garádi, Imre Boldizsár, Anders Backlund, András Darcsi, Andrea Nagyné Nedves and Eszter Riethmüller

Pharmaceutics 2022, 14(9), 1967; https://doi.org/10.3390/pharmaceutics14091967 - 18 Sep 2022

Cited by 4 | Viewed by 2987

Abstract

Alpinia galanga Willd., greater galangal, has been used for thousands of years as a spice as well as in traditional medicine. Its central nervous system (CNS) stimulant activity and neuroprotective effects have been proved both in animal models and human trials. However, the [...] Read more.

Alpinia galanga Willd., greater galangal, has been used for thousands of years as a spice as well as in traditional medicine. Its central nervous system (CNS) stimulant activity and neuroprotective effects have been proved both in animal models and human trials. However, the compounds responsible for these effects have not been identified yet. Therefore, the main constituents (p-OH-benzaldehyde (1), trans-p-coumaryl-alcohol (2), p-coumaryl-aldehyde (4), galanganol A (5), galanganol B (6), trans-p-acetoxycinnamyl alcohol (7), 1′S-1′-acetoxychavicol acetate (ACA, 9), and 1′S-1′-acetoxyeugenol acetate (AEA, 10)) were isolated to investigate their aqueous stability and passive diffusion across the gastro-intestinal tract (GIT) membrane and the blood–brain barrier (BBB) by the parallel artificial membrane permeability assay (PAMPA). Our positive results for compounds 1, 2, 4, 7, 9, and 10 suggest good permeability, thus potential contribution to the effects of greater galangal in the CNS. The results of the PAMPA-BBB were corroborated by in silico chemography-based ChemGPS-NP framework experiments. In addition, examination of the chemical space position of galangal compounds in relation to known psychostimulants revealed that all the molecules in proximity are NET/SERT inhibitors. As ACA and AEA did not show much proximity to either compound, the importance of further investigation of their degradation products becomes more pronounced. Full article

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

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17 pages, 3885 KiB

Open AccessArticle

Novel 3D-Printed Dressings of Chitosan–Vanillin-Modified Chitosan Blends Loaded with Fluticasone Propionate for Treatment of Atopic Dermatitis

by Georgia Michailidou and Dimitrios N. Bikiaris

Pharmaceutics 2022, 14(9), 1966; https://doi.org/10.3390/pharmaceutics14091966 - 18 Sep 2022

Cited by 6 | Viewed by 2076

Abstract

In the present study, the blends of CS and Vanillin–CS derivative (VACS) were utilized for the preparation of printable inks for their application in three-dimensional (3D) printing procedures. Despite the synergic interaction between the blends, the addition of ι-carrageenan (iCR) as a thickening [...] Read more.

In the present study, the blends of CS and Vanillin–CS derivative (VACS) were utilized for the preparation of printable inks for their application in three-dimensional (3D) printing procedures. Despite the synergic interaction between the blends, the addition of ι-carrageenan (iCR) as a thickening agent was mandatory. Their viscosity analysis was conducted for the evaluation of the optimum CS/VACS ratio. The shear thinning behavior along with the effect of the temperature on viscosity values were evident. Further characterization of the 3D-printed structures was conducted. The effect of the CS/VACS ratio was established through swelling and contact angle measurements. An increasing amount of VACS resulted in lower swelling ability along with higher hydrophobicity. Fluticasone propionate (FLU), a crystalline synthetic corticosteroid, was loaded into the CS/VACS samples. The drug was loaded in its amorphous state, and consequently, its in vitro release was significantly enhanced. An initial burst release, followed by a sustained release profile, was observed. Full article

(This article belongs to the Special Issue Development of Chitosan/Cyclodextrins in Drug Delivery Field)

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24 pages, 2865 KiB

Open AccessReview

Nanocarriers as a Delivery Platform for Anticancer Treatment: Biological Limits and Perspectives in B-Cell Malignancies

by Sara Bozzer, Michele Dal Bo, Maria Cristina Grimaldi, Giuseppe Toffoli and Paolo Macor

Pharmaceutics 2022, 14(9), 1965; https://doi.org/10.3390/pharmaceutics14091965 - 17 Sep 2022

Cited by 8 | Viewed by 2160

Abstract

Nanoparticle-based therapies have been proposed in oncology research using various delivery methods to increase selectivity toward tumor tissues. Enhanced drug delivery through nanoparticle-based therapies could improve anti-tumor efficacy and also prevent drug resistance. However, there are still problems to overcome, such as the [...] Read more.

Nanoparticle-based therapies have been proposed in oncology research using various delivery methods to increase selectivity toward tumor tissues. Enhanced drug delivery through nanoparticle-based therapies could improve anti-tumor efficacy and also prevent drug resistance. However, there are still problems to overcome, such as the main biological interactions of nanocarriers. Among the various nanostructures for drug delivery, drug delivery based on polymeric nanoparticles has numerous advantages for controlling the release of biological factors, such as the ability to add a selective targeting mechanism, controlled release, protection of administered drugs, and prolonging the circulation time in the body. In addition, the functionalization of nanoparticles helps to achieve the best possible outcome. One of the most promising applications for nanoparticle-based drug delivery is in the field of onco-hematology, where there are many already approved targeted therapies, such as immunotherapies with monoclonal antibodies targeting specific tumor-associated antigens; however, several patients have experienced relapsed or refractory disease. This review describes the major nanocarriers proposed as new treatments for hematologic cancer, describing the main biological interactions of these nanocarriers and the related limitations of their use as drug delivery strategies. Full article

(This article belongs to the Special Issue Nanoparticle Delivery to Tumors: Challenges and Advances)

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26 pages, 442 KiB

Open AccessReview

Modern Approaches for the Treatment of Heart Failure: Recent Advances and Future Perspectives

by Irene Paula Popa, Mihai Ștefan Cristian Haba, Minela Aida Mărănducă, Daniela Maria Tănase, Dragomir N. Șerban, Lăcrămioara Ionela Șerban, Radu Iliescu and Ionuț Tudorancea

Pharmaceutics 2022, 14(9), 1964; https://doi.org/10.3390/pharmaceutics14091964 - 17 Sep 2022

Cited by 6 | Viewed by 5111

Abstract

Heart failure (HF) is a progressively deteriorating medical condition that significantly reduces both the patients’ life expectancy and quality of life. Even though real progress was made in the past decades in the discovery of novel pharmacological treatments for HF, the prevention of [...] Read more.

Heart failure (HF) is a progressively deteriorating medical condition that significantly reduces both the patients’ life expectancy and quality of life. Even though real progress was made in the past decades in the discovery of novel pharmacological treatments for HF, the prevention of premature deaths has only been marginally alleviated. Despite the availability of a plethora of pharmaceutical approaches, proper management of HF is still challenging. Thus, a myriad of experimental and clinical studies focusing on the discovery of new and provocative underlying mechanisms of HF physiopathology pave the way for the development of novel HF therapeutic approaches. Furthermore, recent technological advances made possible the development of various interventional techniques and device-based approaches for the treatment of HF. Since many of these modern approaches interfere with various well-known pathological mechanisms in HF, they have a real ability to complement and or increase the efficiency of existing medications and thus improve the prognosis and survival rate of HF patients. Their promising and encouraging results reported to date compel the extension of heart failure treatment beyond the classical view. The aim of this review was to summarize modern approaches, new perspectives, and future directions for the treatment of HF. Full article

(This article belongs to the Special Issue Modern Pharmaceutics for Cardiovascular Diseases)

27 pages, 5845 KiB

Open AccessArticle

New Diarylamine K_V10.1 Inhibitors and Their Anticancer Potential

by Špela Gubič, Žan Toplak, Xiaoyi Shi, Jaka Dernovšek, Louise Antonia Hendrickx, Ernesto Lopes Pinheiro-Junior, Steve Peigneur, Jan Tytgat, Luis A. Pardo, Lucija Peterlin Mašič and Tihomir Tomašič

Pharmaceutics 2022, 14(9), 1963; https://doi.org/10.3390/pharmaceutics14091963 - 17 Sep 2022

Cited by 4 | Viewed by 2143

Abstract

Expression of the voltage-gated potassium channel K_V10.1 (Eag1) has been detected in over 70% of human cancers, making the channel a promising new target for new anticancer drug discovery. A new structural class of K_V10.1 inhibitors was prepared by [...] Read more.

Expression of the voltage-gated potassium channel K_V10.1 (Eag1) has been detected in over 70% of human cancers, making the channel a promising new target for new anticancer drug discovery. A new structural class of K_V10.1 inhibitors was prepared by structural optimisation and exploration of the structure–activity relationship of the previously published hit compound ZVS-08 (1) and its optimised analogue 2. The potency and selectivity of the new inhibitors between K_V10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised K_V10.1 inhibitors, 17a and 18b, with improved nanomolar IC₅₀ values of 568 nM and 214 nM, respectively. Compound 17a exhibited better ratio between IC₅₀ values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds 17a and 18b moderately inhibited the growth of the K_V10.1-expressing cell line MCF-7 in two independent assays. In addition, 17a and 18b also inhibited the growth of hERG-expressing Panc-1 cells with higher potency compared with MCF-7 cells. The main obstacle for newly developed diarylamine K_V10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future. Full article

(This article belongs to the Special Issue Advances in Anticancer Agent)

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10 pages, 2339 KiB

Open AccessArticle

Biodegradation of HA and β-TCP Ceramics Regulated by T-Cells

by Zifan Zhao, Jing Zhang, Zaibo Yang and Qin Zhao

Pharmaceutics 2022, 14(9), 1962; https://doi.org/10.3390/pharmaceutics14091962 - 16 Sep 2022

Cited by 6 | Viewed by 2189

Abstract

Biodegradability is one of the most important properties of implantable bone biomaterials, which is directly related to material bioactivity and the osteogenic effect. How foreign body giant cells (FBGC) involved in the biodegradation of bone biomaterials are regulated by the immune system is [...] Read more.

Biodegradability is one of the most important properties of implantable bone biomaterials, which is directly related to material bioactivity and the osteogenic effect. How foreign body giant cells (FBGC) involved in the biodegradation of bone biomaterials are regulated by the immune system is poorly understood. Hence, this study found that β-tricalcium phosphate (β-TCP) induced more FBGCs formation in the microenvironment (p = 0.0061) accompanied by more TNFα (p = 0.0014), IFNγ (p = 0.0024), and T-cells (p = 0.0029) than hydroxyapatite (HA), resulting in better biodegradability. The final use of T-cell depletion in mice confirmed that T-cell-mediated immune responses play a decisive role in the formation of FBGCs and promote bioceramic biodegradation. This study reveals the biological mechanism of in vivo biodegradation of implantable bone tissue engineering materials from the perspective of material-immune system interaction, which complements the mechanism of T-cells’ adaptive immunity in bone immune regulation and can be used as a theoretical basis for rational optimization of implantable material properties. Full article

(This article belongs to the Special Issue Sustainable Materials and Technologies for Drug Delivery and Tissue Engineering)

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24 pages, 5531 KiB

Open AccessEditor’s ChoiceArticle

Optimization of Lipid Nanoparticles by Response Surface Methodology to Improve the Ocular Delivery of Diosmin: Characterization and In-Vitro Anti-Inflammatory Assessment

by Elide Zingale, Salvatore Rizzo, Angela Bonaccorso, Valeria Consoli, Luca Vanella, Teresa Musumeci, Angelo Spadaro and Rosario Pignatello

Pharmaceutics 2022, 14(9), 1961; https://doi.org/10.3390/pharmaceutics14091961 - 16 Sep 2022

Cited by 12 | Viewed by 3339

Abstract

Diosmin is a flavonoid with a great variety of biological activities including antioxidant and anti-inflammatory ones. Its cytoprotective effect in retinal pigment epithelium cells under high glucose conditions makes it a potential support in the treatment of diabetic retinopathy. Despite its benefits, poor [...] Read more.

Diosmin is a flavonoid with a great variety of biological activities including antioxidant and anti-inflammatory ones. Its cytoprotective effect in retinal pigment epithelium cells under high glucose conditions makes it a potential support in the treatment of diabetic retinopathy. Despite its benefits, poor solubility in water reduces its potential for therapeutic use, making it the biggest biopharmaceutical challenge. The design of diosmin-loaded nanocarriers for topical ophthalmic application represents a novelty that has not been yet explored. For this purpose, the response surface methodology (RSM) was used to optimize nanostructured lipid carriers (NLCs), compatible for ocular administration, to encapsulate diosmin and improve its physicochemical issues. NLCs were prepared by a simple and scalable technique: a melt emulsification method followed by ultrasonication. The experimental design was composed of four independent variables (solid lipid concentration, liquid lipid concentration, surfactant concentration and type of solid lipid). The effect of the factors was assessed on NLC size and PDI (responses) by analysis of variance (ANOVA). The optimized formulation was selected according to the desirability function (0.993). Diosmin at two different concentrations (80 and 160 µM) was encapsulated into NLCs. Drug-loaded nanocarriers (D-NLCs) were subjected to a physicochemical and technological investigation revealing a mean particle size of 83.58 ± 0.77 nm and 82.21 ± 1.12 nm, respectively for the D-NLC formulation prepared with diosmin at the concentration of 80 µM or 160 µM, and a net negative surface charge (−18.5 ± 0.60 and −18.0 ± 1.18, respectively for the two batches). The formulations were analyzed in terms of pH (6.5), viscosity, and adjusted for osmolarity, making them more compatible with the ocular environment. Subsequently, stability studies were carried out to assess D-NLC behavior under different storage conditions up to 60 days, indicating a good stability of NLC samples at room temperature. In-vitro studies on ARPE-19 cells confirmed the cytocompatibility of NLCs with retinal epithelium. The effect of D-NLCs was also evaluated in-vitro on a model of retinal inflammation, demonstrating the cytoprotective effect of D-NLCs at various concentrations. RSM was found to be a reliable model to optimize NLCs for diosmin encapsulation. Full article

(This article belongs to the Special Issue Advances in Formulation of Poorly Soluble Bioactive Compounds)

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13 pages, 3000 KiB

Open AccessArticle

Complexation: An Interesting Pathway for Combining Two APIs at the Solid State

by Fucheng Leng, Oleksii Shemchuk, Koen Robeyns and Tom Leyssens

Pharmaceutics 2022, 14(9), 1960; https://doi.org/10.3390/pharmaceutics14091960 - 16 Sep 2022

Cited by 2 | Viewed by 1846

Abstract

Combining different drugs into a single crystal form is one of the current challenges in crystal engineering, with the number of reported multi-drug solid forms remaining limited. This paper builds upon an efficient approach to combining Active Pharmaceutical Ingredients (APIs) containing carboxylic groups [...] Read more.

Combining different drugs into a single crystal form is one of the current challenges in crystal engineering, with the number of reported multi-drug solid forms remaining limited. This paper builds upon an efficient approach to combining Active Pharmaceutical Ingredients (APIs) containing carboxylic groups in their structure with APIs containing pyridine moieties. By transforming the former into their zinc salts, they can be successfully combined with the pyridine-containing APIs. This work highlights the successfulness of this approach, as well as the improvement in the physical properties of the obtained solid forms. Full article

(This article belongs to the Collection Feature Papers in Pharmaceutical Technology)

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21 pages, 3745 KiB

Open AccessArticle

Gene Electrotransfer into Mammalian Cells Using Commercial Cell Culture Inserts with Porous Substrate

by Tina Vindiš, Anja Blažič, Diaa Khayyat, Tjaša Potočnik, Shaurya Sachdev and Lea Rems

Pharmaceutics 2022, 14(9), 1959; https://doi.org/10.3390/pharmaceutics14091959 - 16 Sep 2022

Cited by 3 | Viewed by 2491

Abstract

Gene electrotransfer is one of the main non-viral methods for intracellular delivery of plasmid DNA, wherein pulsed electric fields are used to transiently permeabilize the cell membrane, allowing enhanced transmembrane transport. By localizing the electric field over small portions of the cell membrane [...] Read more.

Gene electrotransfer is one of the main non-viral methods for intracellular delivery of plasmid DNA, wherein pulsed electric fields are used to transiently permeabilize the cell membrane, allowing enhanced transmembrane transport. By localizing the electric field over small portions of the cell membrane using nanostructured substrates, it is possible to increase considerably the gene electrotransfer efficiency while preserving cell viability. In this study, we expand the frontier of localized electroporation by designing an electrotransfer approach based on commercially available cell culture inserts with polyethylene-terephthalate (PET) porous substrate. We first use multiscale numerical modeling to determine the pulse parameters, substrate pore size, and other factors that are expected to result in successful gene electrotransfer. Based on the numerical results, we design a simple device combining an insert with substrate containing pores with 0.4 µm or 1.0 µm diameter, a multiwell plate, and a pair of wire electrodes. We test the device in three mammalian cell lines and obtain transfection efficiencies similar to those achieved with conventional bulk electroporation, but at better cell viability and with low-voltage pulses that do not require the use of expensive electroporators. Our combined theoretical and experimental analysis calls for further systematic studies that will investigate the influence of substrate pore size and porosity on gene electrotransfer efficiency and cell viability. Full article

(This article belongs to the Special Issue Plasmid DNA for Gene Therapy and DNA Vaccine Applications)

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12 pages, 1326 KiB

Open AccessArticle

Monitoring of Ex Vivo Cyclosporin a Activity in Healthy Volunteers Using T Cell Function Assays in Relation to Whole Blood and Cellular Pharmacokinetics

by Aliede E. in ’t Veld, Manon A. A. Jansen, Bertine W. Huisman, Mascha Schoonakker, Marieke L. de Kam, Dirk Jan A. R. Moes, Mariëtte I. E. van Poelgeest, Jacobus Burggraaf and Matthijs Moerland

Pharmaceutics 2022, 14(9), 1958; https://doi.org/10.3390/pharmaceutics14091958 - 16 Sep 2022

Cited by 3 | Viewed by 1930

Abstract

Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has strongly decreased, there are still many patients who experience severe side effects or rejection after long-term [...] Read more.

Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has strongly decreased, there are still many patients who experience severe side effects or rejection after long-term treatment. In this healthy volunteer study we therefore aimed to identify biomarkers to move from a pharmacokinetic-based towards a pharmacodynamic-based monitoring approach for calcineurin inhibitor treatment. Healthy volunteers received a single dose of cyclosporine A (CsA) or placebo, after which whole blood samples were stimulated to measure ex vivo T cell functionality, including proliferation, cytokine production, and activation marker expression. The highest whole blood concentration of CsA was found at 2 h post-dose, which resulted in a strong inhibition of interferon gamma (IFNy) and interleukin-2 (IL-2) production and expression of CD154 and CD71 on T cells. Moreover, the in vitro effect of CsA was studied by incubation of pre-dose whole blood samples with a concentration range of CsA. The average in vitro and ex vivo CsA activity overlapped, making the in vitro dose–effect relationship an interesting method for prediction of post-dose drug effect. The clinical relevance of the results is to be explored in transplantation patients on calcineurin inhibitor treatment. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring as a Useful Tool in Therapy Improvement, 2nd Edition)

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12 pages, 1105 KiB

Open AccessArticle

The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling

by Karel Allegaert, Mohammad Yaseen Abbasi, Robin Michelet and Olusola Olafuyi

Pharmaceutics 2022, 14(9), 1957; https://doi.org/10.3390/pharmaceutics14091957 - 16 Sep 2022

Cited by 3 | Viewed by 2385

Abstract

Background: pathophysiological changes such as low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO [...] Read more.

Background: pathophysiological changes such as low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp^® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, manual infusion dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80–125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80–125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40–50%, a dose reduction of 15% is warranted in neonates, infants and children, and 25% in adolescents and adults. Conclusions: PBPK-driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, and proportionally greater in adults. Consequently, age group-specific dose reductions for propofol are required in LCO conditions. Full article

(This article belongs to the Special Issue Dosing Strategies for Protecting the Vulnerable)

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23 pages, 2248 KiB

Open AccessReview

Acyldepsipeptide Analogues: A Future Generation Antibiotics for Tuberculosis Treatment

by Sinazo Z. Z. Cobongela, Maya M. Makatini, Phumlane S. Mdluli and Nicole R. S. Sibuyi

Pharmaceutics 2022, 14(9), 1956; https://doi.org/10.3390/pharmaceutics14091956 - 15 Sep 2022

Cited by 5 | Viewed by 2572

Abstract

Acyldepsipeptides (ADEPs) are a new class of emerging antimicrobial peptides (AMPs), which are currently explored for treatment of pathogenic infections, including tuberculosis (TB). These cyclic hydrophobic peptides have a unique bacterial target to the conventional anti-TB drugs, and present a therapeutic window to [...] Read more.

Acyldepsipeptides (ADEPs) are a new class of emerging antimicrobial peptides (AMPs), which are currently explored for treatment of pathogenic infections, including tuberculosis (TB). These cyclic hydrophobic peptides have a unique bacterial target to the conventional anti-TB drugs, and present a therapeutic window to overcome Mycobacterium Tuberculosis (M. tb) drug resistance. ADEPs exerts their antibacterial activity on M. tb strains through activation of the protein homeostatic regulatory protease, the caseinolytic protease (ClpP1P2). ClpP1P2 is normally regulated and activated by the ClpP-ATPases to degrade misfolded and toxic peptides and/or short proteins. ADEPs bind and dysregulate all the homeostatic capabilities of ClpP1P2 while inducing non-selective proteolysis. The uncontrolled proteolysis leads to M. tb cell death within the host. ADEPs analogues that have been tested possess cytotoxicity and poor pharmacokinetic and pharmacodynamic properties. However, these can be improved by drug design techniques. Moreover, the use of nanomaterial in conjunction with ADEPs would yield effective synergistic effect. This new mode of action has potential to combat and eradicate the extensive multi-drug resistance (MDR) problem that is currently faced by the public health pertaining bacterial infections, especially TB. Full article

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15 pages, 3122 KiB

Open AccessArticle

In Vivo Skin Regeneration and Wound Healing Using Cell Micro-Transplantation

by Lucia Nanić, Andrea Cedilak, Nikolina Škrobot Vidaček, Florian Gruber, Miljenko Huzak, Michael Bader and Ivica Rubelj

Pharmaceutics 2022, 14(9), 1955; https://doi.org/10.3390/pharmaceutics14091955 - 15 Sep 2022

Cited by 1 | Viewed by 2231

Abstract

Background: The accumulation of senescent cells in tissues alters tissue homeostasis and affects wound healing. It is also considered to be the main contributing factor to aging. In addition to losing their ability to divide, senescent cells exert detrimental effects on surrounding tissues [...] Read more.

Background: The accumulation of senescent cells in tissues alters tissue homeostasis and affects wound healing. It is also considered to be the main contributing factor to aging. In addition to losing their ability to divide, senescent cells exert detrimental effects on surrounding tissues through their senescence-associated secretory phenotype (SASP). They also affect stem cells and their niche, reducing their capacity to divide which increasingly reduces tissue regenerative capacity over time. The aim of our study was to restore aged skin by increasing the fraction of young cells in vivo using a young cell micro-transplantation technique on Fischer 344 rats. Employing the same technique, we also used wild-type skin fibroblasts and stem cells in order to heal Dominant Dystrophic Epidermolysis Bulosa (DDEB) wounds and skin blistering. Results: We demonstrate that implantation of young fibroblasts restores cell density, revitalizes cell proliferation in the dermis and epidermis, rejuvenates collagen I and III matrices, and boosts epidermal stem cell proliferation in rats with advancing age. We were also able to reduce blistering in DDEB rats by transplantation of skin stem cells but not skin fibroblasts. Conclusions: Our intervention proves that a local increase of young cells in the dermis changes tissue homeostasis well enough to revitalize the stem cell niche, ensuring overall skin restoration and rejuvenation as well as healing DDEB skin. Our method has great potential for clinical applications in skin aging, as well as for the treatment of various skin diseases. Full article

(This article belongs to the Special Issue Emerging and Innovative Approaches for Wound Healing and Skin Regeneration: Current Status and Advances)

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17 pages, 3876 KiB

Open AccessArticle

Scaffold Repurposing Reveals New Nanomolar Phosphodiesterase Type 5 (PDE5) Inhibitors Based on Pyridopyrazinone Scaffold: Investigation of In Vitro and In Silico Properties

by Kamelia M. Amin, Ossama M. El-Badry, Doaa E. Abdel Rahman, Magda H. Abdellattif, Mohammed A. S. Abourehab, Mahmoud H. El-Maghrabey, Fahmy G. Elsaid, Mohamed A. El Hamd, Ahmed Elkamhawy and Usama M. Ammar

Pharmaceutics 2022, 14(9), 1954; https://doi.org/10.3390/pharmaceutics14091954 - 15 Sep 2022

Cited by 4 | Viewed by 2057

Abstract

Inhibition of PDE5 results in elevation of cGMP leading to vascular relaxation and reduction in the systemic blood pressure. Therefore, PDE5 inhibitors are used as antihypertensive and antianginal agents in addition to their major use as male erectile dysfunction treatments. Previously, we developed [...] Read more.

Inhibition of PDE5 results in elevation of cGMP leading to vascular relaxation and reduction in the systemic blood pressure. Therefore, PDE5 inhibitors are used as antihypertensive and antianginal agents in addition to their major use as male erectile dysfunction treatments. Previously, we developed a novel series of 34 pyridopyrazinone derivatives as anticancer agents (series A–H). Herein, a multi-step in silico approach was preliminary conducted to evaluate the predicted PDE5 inhibitory activity, followed by an in vitro biological evaluation over the enzymatic level and a detailed SAR study. The designed 2D-QSAR model which was carried out to predict the IC₅₀ of the tested compounds revealed series B, D, E and G with nanomolar range of IC₅₀ values (6.00–81.56 nM). A further docking simulation model was performed to investigate the binding modes within the active site of PDE5. Interestingly, most of the tested compounds showed almost the same binding modes of that of reported PDE5 inhibitors. To validate the in silico results, an in vitro enzymatic assay over PDE5 enzyme was performed for a number of the promising candidates with different substitutions. Both series E and G exhibited a potent inhibitory activity (IC₅₀ = 18.13–41.41 nM). Compound 11b (series G, oxadiazole-based derivatives with terminal 4-NO₂ substituted phenyl ring and rigid linker) was the most potent analogue with IC₅₀ value of 18.13 nM. Structure–activity relationship (SAR) data attained for various substitutions were rationalized. Furthermore, a molecular dynamic simulation gave insights into the inhibitory activity of the most active compound (11b). Accordingly, this report presents a successful scaffold repurposing approach that reveals compound 11b as a highly potent nanomolar PDE5 inhibitor worthy of further investigation. Full article

(This article belongs to the Special Issue Computer Simulation for Drug Design and Medical Bioengineering)

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14 pages, 1077 KiB

Open AccessArticle

Anti PD-1/Anti PDL-1 Inhibitors in Advanced Gastroesophageal Cancers: A Systematic Review and Meta-Analysis of Phase 2/3 Randomized Controlled Trials

by Kanak Parmar, Sai Subramanyam, Kristopher Attwood, Duke Appiah, Christos Fountzilas and Sarbajit Mukherjee

Pharmaceutics 2022, 14(9), 1953; https://doi.org/10.3390/pharmaceutics14091953 - 15 Sep 2022

Cited by 4 | Viewed by 3126

Abstract

Importance: Immune checkpoint inhibitors (ICI) have revolutionized the treatment for gastroesophageal cancers (GEC). It is important to investigate the factors that influence the response to anti-PD-1/PD-L1 ICIs. Objective: To assess the benefits of PD-1/PD-L1 ICIs in advanced GEC and perform subgroup analysis to [...] Read more.

Importance: Immune checkpoint inhibitors (ICI) have revolutionized the treatment for gastroesophageal cancers (GEC). It is important to investigate the factors that influence the response to anti-PD-1/PD-L1 ICIs. Objective: To assess the benefits of PD-1/PD-L1 ICIs in advanced GEC and perform subgroup analysis to identify patient populations who would benefit from ICI. Data sources: PubMed, Embase, Scopus, and the Cochrane Library databases were systematically searched from database inception to September 2021 for all relevant articles. We also reviewed abstracts and presentations from all major conference proceedings including relevant meetings of the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO) during the last four years (2018 to 2021) and reviewed citation lists. Study selection, data extraction, and synthesis: Full articles and presentations were further assessed if the information suggested that the study was a phase 2/3 randomized controlled trial (RCT) comparing PD-1/PD-L1 inhibitor either alone, or in combination with standard therapy vs. standard therapy in advanced GEC. The full text of the resulting studies/presentations and extracted data were reviewed independently according to PRISMA guidelines. Main outcomes and measures: The main outcomes were OS, PFS, and treatment-related adverse events (TRAEs). Results: A total of 168 studies were assessed for eligibility, and 17 RCTs with 12,312 patients met the inclusion criteria. There was an OS benefit in the overall population with ICIs (HR 0.78; 95% CI 0.73–0.83 p < 0.001). Immunotherapy showed better OS benefit in males (HR 0.77 95% CI 0.72–0.83; p < 0.001) than females (HR 0.89; 95% CI 0.80–0.99 p < 0.03), esophageal primary tumors (HR 0.70 95% CI 0.64–0.76 p < 0.001) vs. gastric cancer (HR 0.84 95% CI 0.74–0.94 p 0.002) or GEJ cancer (HR 0.84 95% CI 0.72–0.98 p 0.024) and in squamous cell carcinoma (HR 0.71 95% CI 0.66–0.77 p < 0.001) vs. adenocarcinoma (HR 0.85 95% CI 0.78–0.93 p < 0.001). PD-L1 positive patients seemed to benefit more (HR 0.74 95% CI 0.67–0.82 p < 0.001) compared to PD-L1 negative patients (HR 0.86 95% CI 0.74–1.00 p < 0.043), and Asians showed OS benefit (HR 0.76 95% CI 0.67–0.87 p < 0.001) compared to their White counterparts (HR 0.92 95% CI 0.74–1.14; p 0.424). Conclusions and relevance: ICIs improve survival in advanced GEC without significantly increasing the side effects. However, certain subgroups of patients such as males, Asians, and those with esophageal primary, PD-L1 positive tumors and squamous cell carcinoma benefit more from such treatments. Further translational research is needed to understand the mechanistic links and develop new biomarkers. Full article

(This article belongs to the Special Issue Drug Repurposing and Delivery Systems for Immunotherapy)

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17 pages, 3630 KiB

Open AccessArticle

In Vitro Antibacterial and Anti-Inflammatory Activity of Arctostaphylos uva-ursi Leaf Extract against Cutibacterium acnes

by Federica Dell’Annunziata, Stefania Cometa, Roberta Della Marca, Francesco Busto, Veronica Folliero, Gianluigi Franci, Massimiliano Galdiero, Elvira De Giglio and Anna De Filippis

Pharmaceutics 2022, 14(9), 1952; https://doi.org/10.3390/pharmaceutics14091952 - 15 Sep 2022

Cited by 7 | Viewed by 3257

Abstract

Cutibacterium acnes (C. acnes) is the main causative agent of acne vulgaris. The study aims to evaluate the antimicrobial activity of a natural product, Arctostaphylos uva-ursi leaf extract, against C. acnes. Preliminary chemical–physical characterization of the extract was carried out [...] Read more.

Cutibacterium acnes (C. acnes) is the main causative agent of acne vulgaris. The study aims to evaluate the antimicrobial activity of a natural product, Arctostaphylos uva-ursi leaf extract, against C. acnes. Preliminary chemical–physical characterization of the extract was carried out by means of FT-IR, TGA and XPS analyses. Skin permeation kinetics of the extract conveyed by a toning lotion was studied in vitro by Franz diffusion cell, monitoring the permeated arbutin (as the target component of the extract) and the total phenols by HPLC and UV-visible spectrophotometry, respectively. Antimicrobial activity and time-killing assays were performed to evaluate the effects of Arctostaphylos uva-ursi leaf extract against planktonic C. acnes. The influence of different Arctostaphylos uva-ursi leaf extract concentrations on the biofilm biomass inhibition and degradation was evaluated by the crystal violet (CV) method. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test was used to determine the viability of immortalized human keratinocytes (HaCaT) after exposure to Arctostaphylos uva-ursi leaf extract for 24 and 48 h. Levels of interleukin (IL)-1β, IL-6, IL-8 and tumour necrosis factor (TNF)-α were quantified after HaCaT cells cotreatment with Arctostaphylos uva-ursi leaf extract and heat-killed C. acnes. The minimum inhibitory concentration (MIC) which exerted a bacteriostatic action on 90% of planktonic C. acnes (MIC₉₀) was 0.6 mg/mL. Furthermore, MIC and sub-MIC concentrations influenced the biofilm formation phases, recording a percentage of inhibition that exceeded 50 and 40% at 0.6 and 0.3 mg/mL. Arctostaphylos uva-ursi leaf extract disrupted biofilm biomass of 57 and 45% at the same concentrations mentioned above. Active Arctostaphylos uva-ursi leaf extract doses did not affect the viability of HaCaT cells. On the other hand, at 1.25 and 0.6 mg/mL, complete inhibition of the secretion of pro-inflammatory cytokines was recorded. Taken together, these results indicate that Arctostaphylos uva-ursi leaf extract could represent a natural product to counter the virulence of C. acnes, representing a new alternative therapeutic option for the treatment of acne vulgaris. Full article

(This article belongs to the Special Issue Natural Products for Antimicrobial and Antibiofilm Application)

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18 pages, 6664 KiB

Open AccessReview

Chiral Biomaterials for Nanomedicines: From Molecules to Supraparticles

by Wookjin Jung, Junyoung Kwon, Wonjoon Cho and Jihyeon Yeom

Pharmaceutics 2022, 14(9), 1951; https://doi.org/10.3390/pharmaceutics14091951 - 15 Sep 2022

Cited by 6 | Viewed by 2645

Abstract

Chirality, the property whereby an object or a system cannot be superimposed on its mirror image, prevails amongst nature over various scales. Especially in biology, numerous chiral building blocks and chiral-specific interactions are involved in many essential biological activities. Despite the prevalence of [...] Read more.

Chirality, the property whereby an object or a system cannot be superimposed on its mirror image, prevails amongst nature over various scales. Especially in biology, numerous chiral building blocks and chiral-specific interactions are involved in many essential biological activities. Despite the prevalence of chirality in nature, it has been no longer than 70 years since the mechanisms of chiral-specific interactions drew scientific attention and began to be studied. Owing to the advent of chiral-sensitive equipment such as circular dichroism spectrometers or chiral liquid columns for chromatography, it has recently been possible to achieve a deeper understanding of the chiral-specific interactions and consequential impacts on the functionality and efficiency of nanomedicine. From this point of view, it is worthwhile to examine previously reported chiral biomaterials with their compositions and possible applications to achieve new paradigms of biomaterials. This review discusses chiral materials on various scales and their biological applications. Full article

(This article belongs to the Special Issue Advanced Technologies for Developing the State-of-the-Art Nanomedicines)

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23 pages, 4704 KiB

Open AccessArticle

Oxime Therapy for Brain AChE Reactivation and Neuroprotection after Organophosphate Poisoning

by Darya A. Kuznetsova, Gulnara A. Gaynanova, Elmira A. Vasilieva, Rais V. Pavlov, Irina V. Zueva, Vasily M. Babaev, Denis M. Kuznetsov, Alexandra D. Voloshina, Konstantin A. Petrov, Lucia Y. Zakharova and Oleg G. Sinyashin

Pharmaceutics 2022, 14(9), 1950; https://doi.org/10.3390/pharmaceutics14091950 - 15 Sep 2022

Cited by 15 | Viewed by 2606

Abstract

One of the main problems in the treatment of poisoning with organophosphorus (OPs) inhibitors of acetylcholinesterase (AChE) is low ability of existing reactivators of AChE that are used as antidotes to cross the blood-brain barrier (BBB). In this work, modified cationic liposomes were [...] Read more.

One of the main problems in the treatment of poisoning with organophosphorus (OPs) inhibitors of acetylcholinesterase (AChE) is low ability of existing reactivators of AChE that are used as antidotes to cross the blood-brain barrier (BBB). In this work, modified cationic liposomes were developed that can penetrate through the BBB and deliver the reactivator of AChE pralidoxime chloride (2-PAM) into the brain. Liposomes were obtained on the basis of phosphatidylcholine and imidazolium surfactants. To obtain the composition optimized in terms of charge, stability, and toxicity, the molar ratio of surfactant/lipid was varied. For the systems, physicochemical parameters, release profiles of the substrates (rhodamine B, 2-PAM), hemolytic activity and ability to cause hemagglutination were evaluated. Screening of liposome penetration through the BBB, analysis of 2-PAM pharmacokinetics, and in vivo AChE reactivation showed that modified liposomes readily pass into the brain and reactivate brain AChE in rats poisoned with paraoxon (POX) by 25%. For the first time, an assessment was made of the ability of imidazolium liposomes loaded with 2-PAM to reduce the death of neurons in the brains of mice. It was shown that intravenous administration of liposomal 2-PAM can significantly reduce POX-induced neuronal death in the hippocampus. Full article

(This article belongs to the Special Issue Liposomal and Lipid-Based Drug Delivery Systems and Vaccines)

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Pharmaceutics, Volume 14, Issue 9 (September 2022) – 228 articles

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