Pharmaceuticals

9 pages, 596 KiB

Open AccessCommunication

Photoprotective Effects of Selected Amino Acids on Naproxen Photodegradation in Aqueous Media

by Kohei Kawabata, Momoka Kanoh, Mayu Okazaki, Rina Maeda, Satomi Mori, Shiori Akimoto, Masanori Inagaki and Hiroyuki Nishi

Pharmaceuticals 2020, 13(6), 135; https://doi.org/10.3390/ph13060135 - 26 Jun 2020

Cited by 9 | Viewed by 2923

Abstract

It is important to develop a photostabilization strategy to ensure the quality of photosensitive compounds, including pharmaceuticals. This study focused on the protective effects of 20 amino acids on the photodegradation of naproxen (NX), a photosensitive pharmaceutical, to clarify the important nature of [...] Read more.

It is important to develop a photostabilization strategy to ensure the quality of photosensitive compounds, including pharmaceuticals. This study focused on the protective effects of 20 amino acids on the photodegradation of naproxen (NX), a photosensitive pharmaceutical, to clarify the important nature of a good photostabilizer. Our previous report indicated the photodegradability of NX and the protective effects of some antioxidants on its photodegradation, therefore, this compound was used as a model compound. The degradation of NX in aqueous media during ultraviolet light (UV) irradiation and the protective effects of selected amino acids were monitored through high-performance liquid chromatography (HPLC), equipped with a reverse-phase column. Addition of cysteine, tryptophan, and tyrosine induced the significant suppression of NX photodegradation after UV irradiation for 3 h (residual amount of NX; 15.35%, 6.82%, and 15.64%, respectively). Evaluation of the antioxidative activity and UV absorption spectrum showed that cysteine suppressed NX degradation through its antioxidative ability, while tryptophan and tyrosine suppressed it through their UV filtering ability. Furthermore, three amino acids at higher concentrations (more than 100 µmol/L) showed more protective effects on NX photodegradation. For 10 mmol/L, residual amounts of NX with cysteine, tryptophan, and tyrosine were 58.51%, 69.34%, and 82.40%, respectively. These results showed the importance of both photoprotective potencies (antioxidative potency and UV filtering potency) and stability to UV irradiation for a good photostabilizer of photosensitive pharmaceuticals. Full article

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10 pages, 1537 KiB

Open AccessArticle

Probing the Kinetic and Thermodynamic Fingerprints of Anti-EGF Nanobodies by Surface Plasmon Resonance

by Salvador Guardiola, Monica Varese, Marta Taulés, Mireia Díaz-Lobo, Jesús García and Ernest Giralt

Pharmaceuticals 2020, 13(6), 134; https://doi.org/10.3390/ph13060134 - 26 Jun 2020

Cited by 6 | Viewed by 3809

Abstract

Despite the widespread use of antibodies in clinical applications, the precise molecular mechanisms underlying antibody–antigen (Ab–Ag) interactions are often poorly understood. In this study, we exploit the technical features of a typical surface plasmon resonance (SPR) biosensor to dissect the kinetic and thermodynamic [...] Read more.

Despite the widespread use of antibodies in clinical applications, the precise molecular mechanisms underlying antibody–antigen (Ab–Ag) interactions are often poorly understood. In this study, we exploit the technical features of a typical surface plasmon resonance (SPR) biosensor to dissect the kinetic and thermodynamic components that govern the binding of single-domain Ab or nanobodies to their target antigen, epidermal growth factor (EGF), a key oncogenic protein that is involved in tumour progression. By carefully tuning the experimental conditions and transforming the kinetic data into equilibrium constants, we reveal the complete picture of binding thermodynamics, including the energetics of the complex-formation transition state. This approach, performed using an experimentally simple and high-throughput setup, is expected to facilitate mechanistic studies of Ab-based therapies and, importantly, promote the rational development of new biological drugs with suitable properties. Full article

(This article belongs to the Section Pharmaceutical Technology)

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12 pages, 2186 KiB

Open AccessArticle

Antibacterial and Antibiofilm Activity of Myrtenol against Staphylococcus aureus

by Laísa Cordeiro, Pedro Figueiredo, Helivaldo Souza, Aleson Sousa, Francisco Andrade-Júnior, José Barbosa-Filho and Edeltrudes Lima

Pharmaceuticals 2020, 13(6), 133; https://doi.org/10.3390/ph13060133 - 25 Jun 2020

Cited by 33 | Viewed by 4192

Abstract

The increase in Staphylococcus aureus resistance to conventional antibacterials and persistent infections related to biofilms, as well as the low availability of new antibacterial drugs, has made the development of new therapeutic alternatives necessary. Medicinal plants are one of the main sources of [...] Read more.

The increase in Staphylococcus aureus resistance to conventional antibacterials and persistent infections related to biofilms, as well as the low availability of new antibacterial drugs, has made the development of new therapeutic alternatives necessary. Medicinal plants are one of the main sources of bioactive molecules and myrtenol is a natural product with several biological activities, although its antimicrobial activity is little explored. Based on this, the objective of this study was to evaluate the antibacterial activity of myrtenol against S. aureus, determining the minimum inhibitory and bactericidal concentrations (MIC and MBC), investigating the possible molecular target through the analysis of molecular docking. It also aimed to evaluate the effect of its combination with antibacterial drugs and its activity against S. aureus biofilms, in addition to performing an in silico analysis of its pharmacokinetic parameters. Myrtenol showed MIC and MBC of 128 µg/mL (bactericidal action) and probably acts by interfering with the synthesis of the bacterial cell wall. The effects of the association with antibacterials demonstrate favorable results. Myrtenol has remarkable antibiofilm activity and in silico results indicate a good pharmacokinetic profile, which make myrtenol a potential drug candidate for the treatment of infections caused by S. aureus. Full article

(This article belongs to the Section Natural Products)

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13 pages, 1520 KiB

Open AccessCommunication

Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection

by Andreia Palmeira, Emília Sousa, Aylin Köseler, Ramazan Sabirli, Tarık Gören, İbrahim Türkçüer, Özgür Kurt, Madalena M. Pinto and M. Helena Vasconcelos

Pharmaceuticals 2020, 13(6), 132; https://doi.org/10.3390/ph13060132 - 25 Jun 2020

Cited by 52 | Viewed by 6771 | Correction

Abstract

SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus [...] Read more.

SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (−) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (−) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compounds were identified with potential as GRP78 inhibitors. In conclusion, we found preliminary evidence that further proposes GRP78 as a possible molecular target to treat Covid-19 and that many clinically approved drugs bind GRP78 as an off-target effect. We suggest that further work should be urgently carried out to confirm if GRP78 is indeed a good molecular target and if some of those drugs have potential to be repurposed for SARS-CoV-2 antiviral activity. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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22 pages, 4469 KiB

Open AccessArticle

Development, Optimization and Characterization of Eudraguard^®-Based Microparticles for Colon Delivery

by Claudia Curcio, Antonio S. Greco, Salvatore Rizzo, Lorena Saitta, Teresa Musumeci, Barbara Ruozi and Rosario Pignatello

Pharmaceuticals 2020, 13(6), 131; https://doi.org/10.3390/ph13060131 - 24 Jun 2020

Cited by 9 | Viewed by 3446

Abstract

Development of pH-dependent systems for colon delivery of natural active ingredients is an attractive area of research in the field of nutraceutical products. This study was focused on Eudraguard^® resins, that are methacrylate copolymers approved as “food grade” by European Commission and [...] Read more.

Development of pH-dependent systems for colon delivery of natural active ingredients is an attractive area of research in the field of nutraceutical products. This study was focused on Eudraguard^® resins, that are methacrylate copolymers approved as “food grade” by European Commission and useful for the production of food supplements. In particular, Eudraguard^® Biotic (EUG-B), characterized by a pH-dependent solubility and Eudraguard^® Control (EUG-C), whose chemical properties support a prolonged release of the encapsulated compounds, were tested. To obtain EUG microparticles, different preparation techniques were tested, in order to optimize the preparation method and observe the effect upon drug encapsulation and specific colonic release. Unloaded microparticles were initially produced to evaluate the influence of polymer characteristics on the formulation process; subsequently microparticles loaded with quercetin (QUE) as a low solubility model drug were prepared. The characterization of microparticles in the solid-state (FT-IR spectroscopy, differential scanning calorimetry and X-ray diffractometry) indicated that QUE was uniformly dispersed in a non-crystalline state in the polymeric network, without strong signs of chemical interactions. Finally, to assess the ability of EUG-C and EUG-B to control the drug release in the gastric environment, and to allow an increased release at a colonic level, suitable in vitro release tests were carried out by simulating the pH variations along the gastro-intestinal tract. Among the evaluated preparation methods, those in which an aqueous phase was not present, and in particular the emulsion-solvent evaporation method produced the best microparticle systems. The in vitro tests showed a limited drug release at a gastric level and a good specific colon release. Full article

(This article belongs to the Section Pharmaceutical Technology)

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20 pages, 4110 KiB

Open AccessFeature PaperArticle

Differential Expression of Kinin Receptors in Human Wet and Dry Age-Related Macular Degeneration Retinae

by Rahmeh Othman, Simon Berbari, Elvire Vaucher and Réjean Couture

Pharmaceuticals 2020, 13(6), 130; https://doi.org/10.3390/ph13060130 - 24 Jun 2020

Cited by 6 | Viewed by 3416

Abstract

Kinins are vasoactive peptides and mediators of inflammation, which signal through two G protein-coupled receptors, B1 and B2 receptors (B1R, B2R). Recent pre-clinical findings suggest a primary role for B1R in a rat model of wet age-related macular degeneration (AMD). The aim of [...] Read more.

Kinins are vasoactive peptides and mediators of inflammation, which signal through two G protein-coupled receptors, B1 and B2 receptors (B1R, B2R). Recent pre-clinical findings suggest a primary role for B1R in a rat model of wet age-related macular degeneration (AMD). The aim of the present study was to investigate whether kinin receptors are differentially expressed in human wet and dry AMD retinae. The cellular distribution of B1R and B2R was examined by immunofluorescence and in situ hybridization in post-mortem human AMD retinae. The association of B1R with inflammatory proteins (inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor A (VEGFA)), fibrosis markers and glial cells was also studied. While B2R mRNA and protein expression was not affected by AMD, a significant increase of B1R mRNA and immunoreactivity was measured in wet AMD retinae when compared to control and dry AMD retinae. B1R was expressed by Müller cells, astrocytes, microglia and endothelial/vascular smooth muscle cells, and colocalized with iNOS and fibrosis markers, but not with VEGFA. In conclusion, the induction and upregulation of the pro-inflammatory and pro-fibrotic kinin B1R in human wet AMD retinae support previous pre-clinical studies and provide a clinical proof-of-concept that B1R represents an attractive therapeutic target worth exploring in this retinal disease. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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15 pages, 316 KiB

Open AccessArticle

Wheatgrass Juice Administration and Immune Measures during Adjuvant Chemotherapy in Colon Cancer Patients: Preliminary Results

by Adva Avisar, Miri Cohen, Rina Katz, Talia Shentzer Kutiel, Anat Aharon and Gil Bar-Sela

Pharmaceuticals 2020, 13(6), 129; https://doi.org/10.3390/ph13060129 - 23 Jun 2020

Cited by 15 | Viewed by 6033

Abstract

Adjuvant chemotherapy is recommended in high-risk stage II–III colorectal cancer (CC). We examine the effect of daily wheatgrass juice (WGJ) intake in addition to chemotherapy on immune parameters, including IL-6, IL-8, IL-10, IL-12, and white blood cells (WBCs) among CC patients. In a [...] Read more.

Adjuvant chemotherapy is recommended in high-risk stage II–III colorectal cancer (CC). We examine the effect of daily wheatgrass juice (WGJ) intake in addition to chemotherapy on immune parameters, including IL-6, IL-8, IL-10, IL-12, and white blood cells (WBCs) among CC patients. In a controlled prospective trial, 100 stage II–III CC patients were enrolled. According to patient preference, they were divided into two subgroups, control group and intervention group, 50 patients each, all of whom received the same standard postoperative adjuvant chemotherapy, plus consumption of 60 cc WGJ daily in the intervention group. Blood samples were collected at baseline (T0) and upon treatment termination, 5–6 months later (T1). Cytokine concentrations were assessed using ELISA kits. Anti-inflammatory cytokine IL-10 concentrations were significantly higher in the WGJ group than in the control group at T1. The decline in WBC counts between T0 and T1 was significantly lower in the WGJ group. No significant differences were observed in IL-6, IL-8, and IL-12 concentrations between the study groups. The higher levels of IL-10 and the attenuating of WBC decline during chemotherapy may constitute preliminary evidence of the beneficial effects of WGJ on immune parameters, when given as a supplement to standard care. In light of these preliminary results, WGJ supports immunological parameters during adjuvant chemotherapy. Nevertheless, future studies are needed in order to translate those results to clinical recommendations for cancer survivors. Full article

(This article belongs to the Section Pharmacology)

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14 pages, 1703 KiB

Open AccessReview

Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation

by Hikaru Tsuchiya, Akinori Endo and Yasushi Saeki

Pharmaceuticals 2020, 13(6), 128; https://doi.org/10.3390/ph13060128 - 23 Jun 2020

Cited by 10 | Viewed by 5856

Abstract

The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes [...] Read more.

The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes in cell homeostasis. A major function of ubiquitylation is to target proteins for proteasomal degradation. Accompanied by deciphering the structural diversity of ubiquitin chains with eight linkages and chain lengths, the ubiquitin code for proteasomal degradation has been expanding beyond the best-characterized Lys48-linked ubiquitin chains. Whereas polyubiquitylated proteins can be directly recognized by the proteasome, in several cases, these proteins need to be extracted or segregated by the conserved ATPases associated with diverse cellular activities (AAA)-family ATPase p97/valosin-containing protein (VCP) complex and escorted to the proteasome by ubiquitin-like (UBL)–ubiquitin associated (UBA) proteins; these are called substrate-shuttling factors. Furthermore, proteasomes are highly mobile and are appropriately spatiotemporally regulated in response to different cellular environments and stresses. In this review, we highlight an emerging key link between p97, shuttling factors, and proteasome for efficient proteasomal degradation. We also present evidence that proteasome-containing nuclear foci form by liquid–liquid phase separation under acute hyperosmotic stress. Full article

(This article belongs to the Special Issue Targeted Protein Degradation: From Chemical Biology to Drug Discovery)

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17 pages, 1406 KiB

Open AccessArticle

Phytochemicals and Enzyme Inhibitory Capacities of the Methanolic Extracts from the Italian Apple Cultivar Mela Rosa dei Monti Sibillini

by Víctor López, Francisco Les, Serena Mevi, Joice Guileine Nkuimi Wandjou, Guillermo Cásedas, Giovanni Caprioli and Filippo Maggi

Pharmaceuticals 2020, 13(6), 127; https://doi.org/10.3390/ph13060127 - 22 Jun 2020

Cited by 8 | Viewed by 3324

Abstract

The phytochemical profile of the methanolic extracts (pulp and peel) obtained from two dehydration methods (drying and freeze-lyophilization) of the traditional Italian apple Mela Rosa dei Monti Sibillini, as well as their inhibitory properties against some biological enzymes (α-glucosidase, lipase, monoamine oxidase A, [...] Read more.

The phytochemical profile of the methanolic extracts (pulp and peel) obtained from two dehydration methods (drying and freeze-lyophilization) of the traditional Italian apple Mela Rosa dei Monti Sibillini, as well as their inhibitory properties against some biological enzymes (α-glucosidase, lipase, monoamine oxidase A, tyrosinase and acetylcholinesterase) were assessed in this study. HPLC-DAD-MS technique was used for the determination of polyphenolic and triterpenic compounds. The determination of the enzymes inhibitory effect was made through spectrophotometric techniques. The peel extracts were richer in bioactive compounds than the pulp. In this regard, the extracts from freeze-lyophilization displayed higher levels of flavan-3-ols, flavonol glycosides and dihydrochalcones. However, the extracts obtained from dried material displayed a stronger enzyme inhibition. Notably, the peel extracts showed a higher activity than the pulp ones, especially in terms of α-glucosidase whereby some samples exerted a similar enzymatic inhibition than acarbose (100% inhibition) at high concentrations (1 mg/mL). These results encourage thus further studies on this traditional Italian apple as a potential source of nutraceuticals helpful to prevent the insurgence of some pathologies. Full article

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

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13 pages, 2594 KiB

Open AccessArticle

Ocular Co-Delivery of Timolol and Brimonidine from a Self-Assembling Peptide Hydrogel for the Treatment of Glaucoma: In Vitro and Ex Vivo Evaluation

by Elissavet Taka, Christina Karavasili, Nikolaos Bouropoulos, Thomas Moschakis, Dimitrios D. Andreadis, Constantinos K. Zacharis and Dimitrios G. Fatouros

Pharmaceuticals 2020, 13(6), 126; https://doi.org/10.3390/ph13060126 - 21 Jun 2020

Cited by 23 | Viewed by 3909

Abstract

Effective pharmacotherapy during glaucoma treatment depends on interventions that reduce intraocular pressure (IOP) and retain the IOP lowering effect for sufficient time so as to reduce dosing frequency and enhance patient adherence. Combination anti-glaucoma therapy and dosage forms that increase precorneal residence time [...] Read more.

Effective pharmacotherapy during glaucoma treatment depends on interventions that reduce intraocular pressure (IOP) and retain the IOP lowering effect for sufficient time so as to reduce dosing frequency and enhance patient adherence. Combination anti-glaucoma therapy and dosage forms that increase precorneal residence time could therefore constitute a promising therapeutic intervention. The in-situ gel forming self-assembling peptide ac-(RADA)₄-CONH₂ was evaluated as carrier for the ocular co-delivery of timolol maleate (TM) and brimonidine tartrate (BR). The hydrogel’s microstructure and mechanical properties were assessed with atomic force microscopy and rheology, respectively. Drug diffusion from the hydrogel was evaluated in vitro in simulated tear fluid and ex vivo across porcine corneas and its effect on the treated corneas was assessed through physicochemical characterization and histological analysis. Results indicated that TM and BR co-delivery affected hydrogel’s microstructure resulting in shorter nanofibers and a less rigid hydrogel matrix. Rapid and complete release of both drugs was achieved within 8 h, while a 2.8-fold and 5.4-fold higher corneal permeability was achieved for TM and BR, respectively. No significant alterations were induced in the structural integrity of the corneas treated with the hydrogel formulation, suggesting that self-assembling peptide hydrogels might serve as promising systems for combination anti-glaucoma therapy. Full article

(This article belongs to the Special Issue Advances in Ocular Pharmacology)

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16 pages, 553 KiB

Open AccessArticle

Echinacea purpurea (L.) Moench: Chemical Characterization and Bioactivity of Its Extracts and Fractions

by Joana Coelho, Lillian Barros, Maria Inês Dias, Tiane C. Finimundy, Joana S. Amaral, Maria José Alves, Ricardo C. Calhelha, P. F. Santos and Isabel C.F.R. Ferreira

Pharmaceuticals 2020, 13(6), 125; https://doi.org/10.3390/ph13060125 - 20 Jun 2020

Cited by 37 | Viewed by 5691

Abstract

Echinacea purpurea (L.) Moench is widely known for its medicinal properties, being one of the most used medicinal plants for its immunostimulant properties. Nevertheless, there is still scarce information on its cytotoxic activity. Thus, this study aims at evaluating the cytotoxicity and antimicrobial [...] Read more.

Echinacea purpurea (L.) Moench is widely known for its medicinal properties, being one of the most used medicinal plants for its immunostimulant properties. Nevertheless, there is still scarce information on its cytotoxic activity. Thus, this study aims at evaluating the cytotoxicity and antimicrobial activity of several aqueous and organic extracts of the aerial parts of this plant and chemically characterizing the obtained extracts. The analysis was performed by HPLC–DAD–ESI/MS. Fifteen compounds were identified; of these, seven were phenolic acids and eight were flavonoids. Non-polar compounds were evaluated by GC/MS, with a total of sixty-four compounds identified, and the most abundant groups were the sterols, fatty acids and long-chain hydrocarbons. The highest antimicrobial activity was exhibited by the dichloromethane, ethyl acetate, and acetone extracts. Dichloromethane and n-hexane extracts showed the highest cytotoxic activity. Therefore, they were fractionated, and the obtained fractions were also assessed for their cytotoxicity. Notwithstanding, the cytotoxicity of the extracts was superior to that of the obtained fractions, evidencing a possible synergistic effect of different compounds in the whole extracts. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants)

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6 pages, 213 KiB

Open AccessCommunication

Frontline Blinatumomab in Older Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

by Sandrine Niyongere, Gabriela Sanchez-Petitto, Jack Masur, Maria R. Baer, Vu H. Duong and Ashkan Emadi

Pharmaceuticals 2020, 13(6), 124; https://doi.org/10.3390/ph13060124 - 16 Jun 2020

Cited by 7 | Viewed by 3603

Abstract

Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, [...] Read more.

Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, including in older patients. We retrospectively analyzed outcomes of blinatumomab monotherapy in five newly diagnosed Philadelphia chromosome-negative B-cell ALL patients over 70 years. Three had cytokine release syndrome, treated with dexamethasone and/or tocilizumab, and four patients had neurotoxicity, treated with dexamethasone, without blinatumomab interruption. All five achieved complete remission (CR) after cycle one, three with undetectable MRD. All five were alive at 8 to 15 months. Three remained in MRD-negative CR. Two relapsed after cycle 3, one with extramedullary disease. In our small cohort of patients over 70 years, blinatumomab was safe initial therapy and produced a high response rate. Full article

(This article belongs to the Section Pharmacology)

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16 pages, 4726 KiB

Open AccessArticle

Diterpenoids from Plectranthus spp. as Potential Chemotherapeutic Agents via Apoptosis

by Tomasz Śliwiński, Przemysław Sitarek, Ewa Skała, Vera M. S. Isca, Ewelina Synowiec, Tomasz Kowalczyk, Michał Bijak and Patrícia Rijo

Pharmaceuticals 2020, 13(6), 123; https://doi.org/10.3390/ph13060123 - 16 Jun 2020

Cited by 16 | Viewed by 3397

Abstract

Plectranthus spp. is widely known for its medicinal properties and bioactive metabolites. The cytotoxic and genotoxic properties of the four known abietane diterpenoids: 7α-Acetoxy-6β-hydroxyroyleanone (Roy), 6,7-dehydroroyleanone (Deroy), 7β,6β-dihydroxyroyleanone6 (Diroy), and Parvifloron D (Parv), isolated from P. madagascariensis (Roy, DeRoy, and Diroy) and P. [...] Read more.

Plectranthus spp. is widely known for its medicinal properties and bioactive metabolites. The cytotoxic and genotoxic properties of the four known abietane diterpenoids: 7α-Acetoxy-6β-hydroxyroyleanone (Roy), 6,7-dehydroroyleanone (Deroy), 7β,6β-dihydroxyroyleanone6 (Diroy), and Parvifloron D (Parv), isolated from P. madagascariensis (Roy, DeRoy, and Diroy) and P. ecklonii (Parv) were evaluated. The tested compounds showed cytotoxic effects against the human leukemia cell line CCRF-CEM and the lung adenocarcinoma cell line A549. All tested compounds induced apoptosis by altering the level of pro- and anti-apoptotic genes. The results show that from the tested diterpenoids, Roy and Parv demonstrated the strongest activity in both human cancer cell lines, changing the permeability mitochondrial membrane potential and reactive oxygen species (ROS) levels, and possibly inducing mtDNA or nDNA damage. In conclusion, the abietane diterpenoids tested may be used in the future as potential natural chemotherapeutic agents Full article

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

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26 pages, 4807 KiB

Open AccessReview

Non-Nucleoside Reverse Transcriptase Inhibitors Join Forces with Integrase Inhibitors to Combat HIV

by Daniel M. Himmel and Eddy Arnold

Pharmaceuticals 2020, 13(6), 122; https://doi.org/10.3390/ph13060122 - 11 Jun 2020

Cited by 14 | Viewed by 5486

Abstract

In the treatment of acquired immune deficiency syndrome (AIDS), the diarylpyrimidine (DAPY) analogs etravirine (ETR) and rilpivirine (RPV) have been widely effective against human immunodeficiency virus (HIV) variants that are resistant to other non-nucleoside reverse transcriptase inhibitors (NNRTIs). With non-inferior or improved efficacy, [...] Read more.

In the treatment of acquired immune deficiency syndrome (AIDS), the diarylpyrimidine (DAPY) analogs etravirine (ETR) and rilpivirine (RPV) have been widely effective against human immunodeficiency virus (HIV) variants that are resistant to other non-nucleoside reverse transcriptase inhibitors (NNRTIs). With non-inferior or improved efficacy, better safety profiles, and lower doses or pill burdens than other NNRTIs in the clinic, combination therapies including either of these two drugs have led to higher adherence than other NNRTI-containing treatments. In a separate development, HIV integrase strand transfer inhibitors (INSTIs) have shown efficacy in treating AIDS, including raltegravir (RAL), elvitegravir (EVG), cabotegravir (CAB), bictegravir (BIC), and dolutegravir (DTG). Of these, DTG and BIC perform better against a wide range of resistance mutations than other INSTIs. Nevertheless, drug-resistant combinations of mutations have begun to emerge against all DAPYs and INSTIs, attributable in part to non-adherence. New dual therapies that may promote better adherence combine ETR or RPV with an INSTI and have been safer and non-inferior to more traditional triple-drug treatments. Long-acting dual- and triple-therapies combining ETR or RPV with INSTIs are under study and may further improve adherence. Here, highly resistant emergent mutations and efficacy data on these novel treatments are reviewed. Overall, ETR or RPV, in combination with INSTIs, may be treatments of choice as long-term maintenance therapies that optimize efficacy, adherence, and safety. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 3011 KiB

Open AccessArticle

Copolymeric Micelles Overcome the Oral Delivery Challenges of Amphotericin B

by Pataranapa Nimtrakul, Desmond B. Williams, Waree Tiyaboonchai and Clive A. Prestidge

Pharmaceuticals 2020, 13(6), 121; https://doi.org/10.3390/ph13060121 - 11 Jun 2020

Cited by 18 | Viewed by 3740

Abstract

Classified as a Biopharmaceutical Classification System (BCS) class IV drug, amphotericin B (AmB) has low aqueous solubility and low permeability leading to low oral bioavailability. To improve these limitations, this study investigated the potential of AmB-loaded polymeric micelles (AmB-PM) to increase intestinal absorption. [...] Read more.

Classified as a Biopharmaceutical Classification System (BCS) class IV drug, amphotericin B (AmB) has low aqueous solubility and low permeability leading to low oral bioavailability. To improve these limitations, this study investigated the potential of AmB-loaded polymeric micelles (AmB-PM) to increase intestinal absorption. AmB-PM were prepared with polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol copolymer (Soluplus^®) as a polymeric carrier and used a modified solvent diffusion and microfluidics (NanoAssemblr^®) method. AmB-PM have a mean particle size of ~80 nm and are mono-disperse with a polydispersity index <0.2. The entrapment efficiency of AmB was up to 95% and achieved with a high drug loading up to ~20% (w/w) with a total amount of incorporated drug of 1.08 ± 0.01 mg/mL. Importantly, compared to free drug, AmB-PM protected AmB from degradation in an acidic (simulated gastric) environment. Viability studies in Caco-2 cells confirmed the safety/low toxicity of AmB-PM. In vitro cellular absorption studies confirmed that AmB-PM increased AmB uptake in Caco-2 cells 6-fold more than free AmB (i.e., 25% compared with 4% within 30 min). Furthermore, the permeability of AmB across Caco-2 monolayers was significantly faster (2-fold) and more pronounced for AmB-PM in comparison to free drug (3.5-fold increase). Thus, the developed AmB-PM show promise as a novel oral delivery system for AmB and justifies further investigation. Full article

(This article belongs to the Section Pharmaceutical Technology)

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10 pages, 999 KiB

Open AccessCommunication

Assessment of the Potential Skin Application of Plectranthus ecklonii Benth.

by Marisa Nicolai, Joana Mota, Ana S. Fernandes, Filipe Pereira, Paula Pereira, Catarina P. Reis, Maria Valéria Robles Velasco, André Rolim Baby, Catarina Rosado and Patrícia Rijo

Pharmaceuticals 2020, 13(6), 120; https://doi.org/10.3390/ph13060120 - 10 Jun 2020

Cited by 17 | Viewed by 3485

Abstract

Plectranthus ecklonii Benth. has widespread ethnobotanical use in African folk medicine for its medicinal properties in skin conditions. In this study, two different basic formulations containing P. ecklonii extracts were prepared, one in an organic solvent and the other using water. The aqueous [...] Read more.

Plectranthus ecklonii Benth. has widespread ethnobotanical use in African folk medicine for its medicinal properties in skin conditions. In this study, two different basic formulations containing P. ecklonii extracts were prepared, one in an organic solvent and the other using water. The aqueous extract only contained rosmarinic acid (RA) at 2.02 mM, and the organic extract contained RA and parvifloron D at 0.29 and 3.13 mM, respectively. RA in aqueous solution permeated skin; however, in P. ecklonii organic extract, this was not detected. Thus, P. ecklonii aqueous extract was further studied and combined with benzophenone-4, which elevated the sun protection factor (SPF) by 19.49%. No significant cytotoxic effects were observed from the aqueous extract. The Staphylococcus epidermidis strain was used to determine a minimum inhibitory concentration (MIC) value of 10 µg·mL⁻¹. The aqueous extract inhibited the activity of acetylcholinesterase by 59.14 ± 4.97%, and the IC₅₀ value was 12.9 µg·mL⁻¹. The association of the P. ecklonii extract with a UV filter substantially elevated its SPF efficacy. Following the multiple bioactivities of the extract and its active substances, a finished product could be claimed as a multifunctional cosmeceutical with broad skin valuable effects, from UV protection to antiaging action. Full article

(This article belongs to the Special Issue Medicinal Plants 2020)

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10 pages, 1682 KiB

Open AccessArticle

Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model

by Istvan Merchenthaler, Malcolm Lane, Christina Stennett, Min Zhan, Vien Nguyen, Katalin Prokai-Tatrai and Laszlo Prokai

Pharmaceuticals 2020, 13(6), 119; https://doi.org/10.3390/ph13060119 - 10 Jun 2020

Cited by 5 | Viewed by 3309

Abstract

Hot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17β-estradiol, E₂ [...] Read more.

Hot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17β-estradiol, E₂) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E₂. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E₂ in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E₂ induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED. Full article

(This article belongs to the Section Pharmacology)

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22 pages, 12198 KiB

Open AccessArticle

Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1

by Sonam Roy, Amarjyoti Das Mahapatra, Taj Mohammad, Preeti Gupta, Mohamed F. Alajmi, Afzal Hussain, Md. Tabish Rehman, Bhaskar Datta and Md. Imtaiyaz Hassan

Pharmaceuticals 2020, 13(6), 118; https://doi.org/10.3390/ph13060118 - 9 Jun 2020

Cited by 15 | Viewed by 4751

Abstract

Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 [...] Read more.

Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC₅₀ values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)

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22 pages, 3957 KiB

Open AccessArticle

Effects of Carbamazepine, Lacosamide and Zonisamide on Gliotransmitter Release Associated with Activated Astroglial Hemichannels

by Kouji Fukuyama, Yuto Ueda and Motohiro Okada

Pharmaceuticals 2020, 13(6), 117; https://doi.org/10.3390/ph13060117 - 5 Jun 2020

Cited by 29 | Viewed by 3491

Abstract

Recent studies using the genetic partial epilepsy model have demonstrated that hyperfunction of astroglial hemichannels contributes to pathomechanism of epileptic seizure. Therefore, to explore the novel anticonvulsive mechanisms, the present study determined the effects of voltage-dependent Na⁺ channel (VDSC)-inhibiting anticonvulsants, carbamazepine (CBZ), [...] Read more.

Recent studies using the genetic partial epilepsy model have demonstrated that hyperfunction of astroglial hemichannels contributes to pathomechanism of epileptic seizure. Therefore, to explore the novel anticonvulsive mechanisms, the present study determined the effects of voltage-dependent Na⁺ channel (VDSC)-inhibiting anticonvulsants, carbamazepine (CBZ), lacosamide (LCM), and zonisamide (ZNS) on the astroglial release of l-glutamate and adenosine triphosphate (ATP). The effects of subchronic administration of therapeutic-relevant dose of three anticonvulsants on the release of l-glutamate and ATP in the orbitofrontal cortex (OFC) were determined using microdialysis. The concentration-dependent effects of acute and subchronic administrations of anticonvulsants on astroglial gliotransmitter release were determined using primary cultured astrocytes. The concentration-dependent effects of subchronic administrations of anticonvulsants on connexin43 (Cx43) expression in the plasma membrane of primary cultured astrocytes were determined using the Simple Western system. An increase in the levels of extracellular K⁺ resulted in a concentration-dependent increase in the astroglial release of l-glutamate and ATP. The depleted levels of extracellular Ca²⁺ alone did not affect astroglial gliotransmitter release but did accelerate K⁺-evoked gliotransmitter release via activation of astroglial hemichannels. Both non-selective hemichannel inhibitor carbenoxolone (CBX) and selective Cx43 inhibitor GAP19 prevented both gliotransmitter release through activated astroglial hemichannels and the hemichannel-activating process induced by elevation of the levels of extracellular K⁺ with depletion of the levels of extracellular Ca²⁺. ZNS subchronically decreased Cx43 expression and acutely/subchronically inhibited Cx43 hemichannel activity. LCM acutely inhibited hemichannel activity but did not subchronically affect Cx43 expression. Therapeutic-relevant concentration of CBZ did not affect hemichannel activity or Cx43 expression, but supratherapeutic concentration of CBZ decreased Cx43 expression and hemichannel activity. Therefore, the present study demonstrated the distinct effects of CBZ, LCM, and ZNS on gliotransmitter release via modulation of astroglial hemichannel function. The different features of the effects of three VDSC-inhibiting anticonvulsants on astroglial transmission associated with hemichannels, at least partially, possibly contributing to the formation of the properties of these three anticonvulsants, including the antiepileptic spectrum and adverse effects regarding mood and cognitive disturbance. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders)

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23 pages, 596 KiB

Open AccessReview

Pharmacological Treatments for Patients with Treatment-Resistant Depression

by Valerie L. Ruberto, Manish K. Jha and James W. Murrough

Pharmaceuticals 2020, 13(6), 116; https://doi.org/10.3390/ph13060116 - 4 Jun 2020

Cited by 92 | Viewed by 18399

Abstract

Over a third of patients with major depressive disorder (MDD) do not have an adequate response to first-line antidepressant treatments, i.e., they have treatment-resistant depression (TRD). These patients tend to have a more severe course of illness and are at an increased risk [...] Read more.

Over a third of patients with major depressive disorder (MDD) do not have an adequate response to first-line antidepressant treatments, i.e., they have treatment-resistant depression (TRD). These patients tend to have a more severe course of illness and are at an increased risk of suicide. Next step treatment options for patients with TRD, include switching to a different antidepressant, combining more than one antidepressant, or augmenting an antidepressant with another (non-antidepressant) medication. It is unclear which of these treatment approaches should be applied to a given patient, and in what order. Due to this ambiguity, comparing antidepressants and augmentation agents on the basis of their efficacy, tolerability, and speed of symptom relief would be beneficial for clinicians. To accomplish this, a systematic search was conducted following PRISMA guidelines. Only randomized controlled trials were included in this qualitative synthesis, resulting in 66 articles. This review identified several effective pharmaco-therapeutic strategies that are currently available for patients with TRD. Ketamine and esketamine appear to be effective for the treatment of TRD. Augmentation with certain second generation antipsychotics, such as quetiapine or aripiprazole is likewise effective, and may be preferred over switching to antidepressant monotherapy. While the combination of olanzapine and fluoxetine was one of the first pharmacotherapy approved for TRD, and its use may be limited by metabolic side-effects. Other effective strategies include augmentation with lithium, liothyronine (T3), lamotrigine, or combination of antidepressants including bupropion, tricyclics, or mirtazapine. There is insufficient research to demonstrate the efficacy of ziprasidone or levothyroxine (T4). A shared decision-making approach is recommended to guide treatment selection to address each patient’s individual needs. Full article

(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)

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11 pages, 2599 KiB

Open AccessArticle

Micromeria fruticosa Induces Cell Cycle Arrest and Apoptosis in Breast and Colorectal Cancer Cells

by Waseem El-Huneidi, Naglaa G. Shehab, Khuloud Bajbouj, Arya Vinod, Ahmed El-Serafi, Jasmin Shafarin, Lara J. Bou Malhab, Wael M. Abdel-Rahman and Eman Abu-Gharbieh

Pharmaceuticals 2020, 13(6), 115; https://doi.org/10.3390/ph13060115 - 3 Jun 2020

Cited by 14 | Viewed by 4431

Abstract

Micromeria fruticosa (L.) Druce subsp. serpyllifolia (Lamiaceae) has been used widely in folk medicine to alleviate various ailments such as abdominal pains, diarrhea, colds, eye infections, heart disorders and wounds. A few reports have confirmed different therapeutic potentialities of its extracts, including the [...] Read more.

Micromeria fruticosa (L.) Druce subsp. serpyllifolia (Lamiaceae) has been used widely in folk medicine to alleviate various ailments such as abdominal pains, diarrhea, colds, eye infections, heart disorders and wounds. A few reports have confirmed different therapeutic potentialities of its extracts, including the anti-inflammatory, gastroprotective, analgesic, antiobesity and antidiabetic activities. This study aimed to investigate the mechanistic pathway of the antiproliferative activity of the ethanolic extract of M. fruticosa on two different cancer cell lines, namely human breast (mammary carcinoma F7 (MCF-7)) and human colorectal (human colon tumor cells (HCT-116)) cell lines. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) assay, Annexin V-FITC/PI, caspases 8/9 and cell cycle analyses, qRT-PCR and Western blot were used to assess the effect of M. fruticosa on cytotoxicity, apoptosis, cell cycle, cell cycle-related genes and protein expression profiles in MCF-7 and HCT-116. The extract inhibits cell proliferation in a time- and dose-dependent manner. The half-maximal inhibitory concentration (IC₅₀) for both cell lines was found to be 100 μg/mL. Apoptosis induction was confirmed by Annexin V-FITC/PI, that was related to caspases 8 and 9 activities induction. Furthermore, the cell cycle analysis revealed arrest at G2/M phase. The underlying mechanism involved in the G2/M arrest was found to be associated with the downregulation of CDK1, cyclin B1 and survivin that was confirmed by qRT-PCR and Western blotting. Full article

(This article belongs to the Special Issue Medicinal Plants 2020)

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14 pages, 4169 KiB

Open AccessArticle

Effect of Chicken Bone Extracts on Metabolic and Mitochondrial Functions of K562 Cell Line

by Consiglia Pacelli, Alessandro Di Cerbo, Lucia Lecce, Claudia Piccoli, Sergio Canello, Gianandrea Guidetti and Nazzareno Capitanio

Pharmaceuticals 2020, 13(6), 114; https://doi.org/10.3390/ph13060114 - 2 Jun 2020

Cited by 13 | Viewed by 3849

Abstract

Background: Tetracyclines’ use in intensive animal farming has raised some concerns regarding the biosafety for humans. Increasing evidences have revealed the presence of these drugs in processed animal by-products, such as bone, throughout the food chain. A potential off-target of tetracyclines is the [...] Read more.

Background: Tetracyclines’ use in intensive animal farming has raised some concerns regarding the biosafety for humans. Increasing evidences have revealed the presence of these drugs in processed animal by-products, such as bone, throughout the food chain. A potential off-target of tetracyclines is the bacterial-like mitochondrial translational machinery, thereby causing proteostatic alterations in mitochondrial DNA-encoded components of the oxidative phosphorylation system. Methods: The Seahorse methodology, confocal microscopy imaging of mitochondrial potential and reactive oxygen species, and q-RT-PCR analysis of the expression of genes involved in mitochondrial biogenesis and mitophagy were carried out on human lymphoblast derived K562 cell line challenged with bone powder derived from chicken treated with or without oxytetracycline and pure oxytetracycline. Results: A complex dose-dependent profile was attained with a low dosage of bone powder extracts causing a metabolic adaptation hallmarked by stimulation of the mitochondrial respiration and enhanced expression of mitochondriogenic factors in particular in cells challenged with oxytetracycline-free bone extract. Conversely, a higher dosage of bone powder extracts, regardless of their source, caused a progressive inhibition of mitochondrial respiration and glycolysis, ultimately leading to cell death. No significant effects of the pure oxytetracycline were observed. Conclusion: Bone powder, regardless of chicken treatment, contains and releases factors/chemicals responsible for the observed effects on energy metabolism. Quantitative differential effects appear to depend on biochemical alterations in the bone matrix caused by antibiotics rather than antibiotics themselves. Full article

(This article belongs to the Section Medicinal Chemistry)

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16 pages, 2423 KiB

Open AccessArticle

Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy

by Antonio Laghezza, Luca Piemontese, Leonardo Brunetti, Alessia Caradonna, Mariangela Agamennone, Antonella Di Pizio, Giorgio Pochetti, Roberta Montanari, Davide Capelli, Marilena Tauro, Fulvio Loiodice and Paolo Tortorella

Pharmaceuticals 2020, 13(6), 113; https://doi.org/10.3390/ph13060113 - 1 Jun 2020

Cited by 3 | Viewed by 3430

Abstract

Matrix metalloproteinases (MMPs) are a family of enzymes involved at different stages of cancer progression and metastasis. We previously identified a novel class of bisphosphonic inhibitors, selective for MMPs crucial for bone remodeling, such as MMP-2. Due to the increasing relevance of specific [...] Read more.

Matrix metalloproteinases (MMPs) are a family of enzymes involved at different stages of cancer progression and metastasis. We previously identified a novel class of bisphosphonic inhibitors, selective for MMPs crucial for bone remodeling, such as MMP-2. Due to the increasing relevance of specific MMPs at various stages of tumor malignancy, we focused on improving potency towards certain isoforms. Here, we tackled MMP-9 because of its confirmed role in tumor invasion, metastasis, angiogenesis, and immuno-response, making it an ideal target for cancer therapy. Using a computational analysis, we designed and characterized potent MMP-2/MMP-9 inhibitors. This is a promising approach to develop and clinically translate inhibitors that could be used in combination with standard care therapy for the treatment of skeletal malignancies. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 860 KiB

Open AccessReview

Harnessing the Power of Eph/ephrin Biosemiotics for Theranostic Applications

by Robert M. Hughes and Jitka A.I. Virag

Pharmaceuticals 2020, 13(6), 112; https://doi.org/10.3390/ph13060112 - 1 Jun 2020

Cited by 6 | Viewed by 5027

Abstract

Comprehensive basic biological knowledge of the Eph/ephrin system in the physiologic setting is needed to facilitate an understanding of its role and the effects of pathological processes on its activity, thereby paving the way for development of prospective therapeutic targets. To this end, [...] Read more.

Comprehensive basic biological knowledge of the Eph/ephrin system in the physiologic setting is needed to facilitate an understanding of its role and the effects of pathological processes on its activity, thereby paving the way for development of prospective therapeutic targets. To this end, this review briefly addresses what is currently known and being investigated in order to highlight the gaps and possible avenues for further investigation to capitalize on their diverse potential. Full article

(This article belongs to the Special Issue Targeting the Eph–ephrin System)

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45 pages, 2197 KiB

Open AccessReview

Novel 1,2,4-Oxadiazole Derivatives in Drug Discovery

by Karol Biernacki, Mateusz Daśko, Olga Ciupak, Konrad Kubiński, Janusz Rachon and Sebastian Demkowicz

Pharmaceuticals 2020, 13(6), 111; https://doi.org/10.3390/ph13060111 - 29 May 2020

Cited by 113 | Viewed by 10787

Abstract

Five-membered 1,2,4-oxadiazole heterocyclic ring has received considerable attention because of its unique bioisosteric properties and an unusually wide spectrum of biological activities. Thus, it is a perfect framework for the novel drug development. After a century since the 1,2,4-oxadiazole have been discovered, the [...] Read more.

Five-membered 1,2,4-oxadiazole heterocyclic ring has received considerable attention because of its unique bioisosteric properties and an unusually wide spectrum of biological activities. Thus, it is a perfect framework for the novel drug development. After a century since the 1,2,4-oxadiazole have been discovered, the uncommon potential attracted medicinal chemists’ attention, leading to the discovery of a few presently accessible drugs containing 1,2,4-oxadiazole unit. It is worth noting that the interest in a 1,2,4-oxadiazoles’ biological application has been doubled in the last fifteen years. Herein, after a concise historical introduction, we present a comprehensive overview of the recent achievements in the synthesis of 1,2,4-oxadiazole-based compounds and the major advances in their biological applications in the period of the last five years as well as brief remarks on prospects for further development. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)

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14 pages, 1932 KiB

Open AccessArticle

Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci

by Eric Mühlberg, Florian Umstätter, Cornelius Domhan, Tobias Hertlein, Knut Ohlsen, Andreas Krause, Christian Kleist, Barbro Beijer, Stefan Zimmermann, Uwe Haberkorn, Walter Mier and Philipp Uhl

Pharmaceuticals 2020, 13(6), 110; https://doi.org/10.3390/ph13060110 - 29 May 2020

Cited by 17 | Viewed by 10123

Abstract

Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria [...] Read more.

Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure–activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria. Full article

(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)

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17 pages, 3300 KiB

Open AccessArticle

Generation of Stable cisPt Resistant Lung Adenocarcinoma Cells

by Nico Ruprecht, Lukas Hofmann, Martin Nils Hungerbühler, Christoph Kempf, Johannes Thomas Heverhagen and Hendrik von Tengg-Kobligk

Pharmaceuticals 2020, 13(6), 109; https://doi.org/10.3390/ph13060109 - 29 May 2020

Cited by 8 | Viewed by 4251

Abstract

Platinum compounds represent the backbone of combined chemotherapy protocols for advanced lung cancer. The mechanisms responsible for its frequent primary or acquired resistance to cisplatin (cisPt)-based chemotherapy remains enigmatic. The availability of two cell lines of the same origin, one resistant and the [...] Read more.

Platinum compounds represent the backbone of combined chemotherapy protocols for advanced lung cancer. The mechanisms responsible for its frequent primary or acquired resistance to cisplatin (cisPt)-based chemotherapy remains enigmatic. The availability of two cell lines of the same origin, one resistant and the other sensitive, will facilitate research to reveal the mechanism of resistance formation. Lung adenocarcinoma cells, A240286S (A24), were cultivated in increasing cisPt concentrations over a prolonged time. After a significant increase in IC₅₀ was measured, cultivation of the cells was continued in absence of cisPt and IC₅₀s determined over a long period (>7 months). As a result, a cell line with lasting, high-level cisPt resistance, designated (D-)A24cisPt8.0, was obtained. The cells were cross-resistant to oxaliplatin and to pemetrexed at a low level. Previous publications have claimed that Leucine-rich repeat-containing protein 8 (LRRC8A and LRRC8D) of the volume-regulated anion channels (VRACs) affect cellular resistance to cisPt. Even though cisPt decreased LRRC8D expression levels, we showed by knockdown and overexpression experiments with LRRC8A and D that these proteins do not govern the observed cisPt resistance. The tumor cell sublines described here provide a powerful model to study the mechanisms of resistance to cisPt in lung cancer cells and beyond. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 3270 KiB

Open AccessCommunication

Physicochemical Investigation of Psoralen Binding to Double Stranded DNA through Electroanalytical and Cheminformatic Approaches

by Douglas Vieira Thomaz, Matheus Gabriel de Oliveira, Edson Silvio Batista Rodrigues, Vinicius Barreto da Silva and Pierre Alexandre dos Santos

Pharmaceuticals 2020, 13(6), 108; https://doi.org/10.3390/ph13060108 - 28 May 2020

Cited by 7 | Viewed by 3472

Abstract

This work showcased the first physicochemical investigation of psoralen (PSO) binding to double stranded DNA (dsDNA) through electroanalytical methods. Results evidenced that PSO presents one non-reversible anodic peak at electric potential (E_pa) ≈ 1.42 V, which is associated with its [...] Read more.

This work showcased the first physicochemical investigation of psoralen (PSO) binding to double stranded DNA (dsDNA) through electroanalytical methods. Results evidenced that PSO presents one non-reversible anodic peak at electric potential (E_pa) ≈ 1.42 V, which is associated with its oxidation and the formation of an epoxide derivative. Moreover, PSO analytical signal (i.e., faradaic current) decreases linearly with the addition of dsDNA, while the electric potential associated to PSO oxidation shifts towards more positive values, indicating thence that dsDNA addition hinders PSO oxidation. These findings were corroborated by the chemoinformatic study, which evidenced that PSO intercalated noncovalently at first between base-pairs of the DNA duplex, and then irreversibly formed adducts with both DNA strands, leading up to the formation of a cross-link which bridges the DNA helix, which explains the linear dependence between the faradaic current generated by PSO oxidation and the concentration of DNA in the test-solution, as well as the dependence between E_p and the addition of dsDNA solution. Therefore, the findings herein reported evidence of the applicability of electroanalytical approaches, such as voltammetry in the study of DNA intercalating agents. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Electronic Conference on Medicinal Chemistry)

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10 pages, 2523 KiB

Open AccessArticle

Excess Ascorbate is a Chemical Stress Agent against Proteins and Cells

by Maria Lehene, Eva Fischer-Fodor, Florina Scurtu, Niculina D. Hădade, Emese Gal, Augustin C. Mot, Alina Matei and Radu Silaghi-Dumitrescu

Pharmaceuticals 2020, 13(6), 107; https://doi.org/10.3390/ph13060107 - 27 May 2020

Cited by 7 | Viewed by 5067

Abstract

Excess ascorbate (as expected in intravenous treatment proposed for COVID-19 management, for example) oxidizes and/or degrades hemoglobin and albumin, as evidenced by UV-vis spectroscopy, gel electrophoresis, and mass spectrometry. It also degrades hemoglobin in intact blood or in isolated erythrocytes. The survival rates [...] Read more.

Excess ascorbate (as expected in intravenous treatment proposed for COVID-19 management, for example) oxidizes and/or degrades hemoglobin and albumin, as evidenced by UV-vis spectroscopy, gel electrophoresis, and mass spectrometry. It also degrades hemoglobin in intact blood or in isolated erythrocytes. The survival rates and metabolic activities of several leukocyte subsets implicated in the antiviral cellular immune response are also affected. Excess ascorbate is thus an unselective biological stress agent. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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35 pages, 4273 KiB

Open AccessReview

Animal Models of Metabolic Epilepsy and Epilepsy Associated Metabolic Dysfunction: A Systematic Review

by Uday Praful Kundap, Yam Nath Paudel and Mohd. Farooq Shaikh

Pharmaceuticals 2020, 13(6), 106; https://doi.org/10.3390/ph13060106 - 26 May 2020

Cited by 13 | Viewed by 5735

Abstract

Epilepsy is a serious neurological disorder affecting around 70 million people globally and is characterized by spontaneous recurrent seizures. Recent evidence indicates that dysfunction in metabolic processes can lead to the alteration of neuronal and network excitability, thereby contributing to epileptogenesis. Developing a [...] Read more.

Epilepsy is a serious neurological disorder affecting around 70 million people globally and is characterized by spontaneous recurrent seizures. Recent evidence indicates that dysfunction in metabolic processes can lead to the alteration of neuronal and network excitability, thereby contributing to epileptogenesis. Developing a suitable animal model that can recapitulate all the clinical phenotypes of human metabolic epilepsy (ME) is crucial yet challenging. The specific environment of many symptoms as well as the primary state of the applicable neurobiology, genetics, and lack of valid biomarkers/diagnostic tests are the key factors that hinder the process of developing a suitable animal model. The present systematic review summarizes the current state of available animal models of metabolic dysfunction associated with epileptic disorders. A systematic search was performed by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model. A range of electronic databases, including google scholar, Springer, PubMed, ScienceDirect, and Scopus, were scanned between January 2000 and April 2020. Based on the selection criteria, 23 eligible articles were chosen and are discussed in the current review. Critical analysis of the selected literature delineated several available approaches that have been modeled into metabolic epilepsy and pointed out several drawbacks associated with the currently available models. The result describes available models of metabolic dysfunction associated with epileptic disorder, such as mitochondrial respiration deficits, Lafora disease (LD) model-altered glycogen metabolism, causing epilepsy, glucose transporter 1 (GLUT1) deficiency, adiponectin responsive seizures, phospholipid dysfunction, glutaric aciduria, mitochondrial disorders, pyruvate dehydrogenase (PDH) α-subunit gene (PDHA1), pyridoxine dependent epilepsy (PDE), BCL2-associated agonist of cell death (BAD), Kcna1 knock out (KO), and long noncoding RNAs (lncRNA) cancer susceptibility candidate 2 (lncRNA CASC2). Finally, the review highlights certain focus areas that may increase the possibilities of developing more suitable animal models and underscores the importance of the rationalization of animal models and evaluation methods for studying ME. The review also suggests the pressing need of developing precise robust animal models and evaluation methods for investigating ME. Full article

(This article belongs to the Section Pharmacology)

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