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Journal Cover Pharmaceuticals
  [SJR: 1.245]   [H-I: 26]   [5 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Print) 1424-8247
   Published by MDPI Homepage  [148 journals]
  • Pharmaceuticals, Vol. 10, Pages 5: D11-Mediated Inhibition of Protein

    • Authors: Susanne Schaefer, Tina Svenstrup, Mette Fischer, Barbara Guerra
      First page: 5
      Abstract: Compelling evidence indicates that protein kinase CK2 plays an important role in many steps of cancer initiation and progression, therefore, the development of effective and cell-permeable inhibitors targeting this kinase has become an important objective for the treatment of a variety of cancer types including glioblastoma. We have recently identified 1,3-dichloro-6-[(E)-((4-methoxyphenyl)imino)methyl]dibenzo(b,d)furan-2,7-diol (D11) as a potent and selective inhibitor of protein kinase CK2. In this study, we have further characterized this compound and demonstrated that it suppresses CK2 kinase activity by mixed type inhibition (KI 7.7 nM, KI′ 42 nM). Incubation of glioblastoma cells with D11 induces cell death and upon hypoxia the compound leads to HIF-1α destabilization. The analysis of differential mRNA expression related to human hypoxia signaling pathway revealed that D11-mediated inhibition of CK2 caused strong down-regulation of genes associated with the hypoxia response including ANGPTL4, CA9, IGFBP3, MMP9, SLC2A1 and VEGFA. Taken together, the results reported here support the notion that including D11 in future treatment regimens might turn out to be a promising strategy to target tumor hypoxia to overcome resistance to radio- and chemotherapy.
      PubDate: 2017-01-01
      DOI: 10.3390/ph10010005
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 6: Identification of a Potent Allosteric
           Inhibitor of Human Protein Kinase CK2 by Bacterial Surface Display Library

    • Authors: Christian Nienberg, Claudia Garmann, Andreas Gratz, Andre Bollacke, Claudia Götz, Joachim Jose
      First page: 6
      Abstract: Human protein kinase CK2 has emerged as promising target for the treatment of neoplastic diseases. The vast majority of kinase inhibitors known today target the ATP binding site, which is highly conserved among kinases and hence leads to limited selectivity. In order to identify non-ATP competitive inhibitors, a 12-mer peptide library of 6 × 105 variants was displayed on the surface of E. coli by autodisplay. Screening of this peptide library on variants with affinity to CK2 was performed by fluorophore-conjugated CK2 and subsequent flow cytometry. Single cell sorting of CK2-bound E. coli yielded new peptide variants, which were tested on inhibition of CK2 by a CE-based assay. Peptide B2 (DCRGLIVMIKLH) was the most potent inhibitor of both, CK2 holoenzyme and the catalytic CK2α subunit (IC50 = 0.8 µM). Using different ATP concentrations and different substrate concentrations for IC50 determination, B2 was shown to be neither ATP- nor substrate competitive. By microscale thermophoresis (MST) the KD value of B2 with CK2α was determined to be 2.16 µM, whereas no binding of B2 to CK2β-subunit was detectable. To our surprise, besides inhibition of enzymatic activity, B2 also disturbed the interaction of CK2α with CK2β at higher concentrations (≥25 µM).
      PubDate: 2017-01-05
      DOI: 10.3390/ph10010006
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 7: CK2—An Emerging Target for
           Neurological and Psychiatric Disorders

    • Authors: Julia Castello, Andre Ragnauth, Eitan Friedman, Heike Rebholz
      First page: 7
      Abstract: Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell survival pathways. CK2 is also upregulated in the most prevalent and aggressive cancer of brain tissue, glioblastoma multiforme, and in preclinical models, pharmacological inhibition of the kinase has proven successful in reducing tumor size and animal mortality. CK2 is highly expressed in the mammalian brain and has many bona fide substrates that are crucial in neuronal or glial homeostasis and signaling processes across synapses. Full and conditional CK2 knockout mice have further elucidated the importance of CK2 in brain development, neuronal activity, and behavior. This review will discuss recent advances in the field that point to CK2 as a regulator of neuronal functions and as a potential novel target to treat neurological and psychiatric disorders.
      PubDate: 2017-01-05
      DOI: 10.3390/ph10010007
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 8: Development of Pharmacophore Model for
           Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database

    • Authors: Samer Haidar, Zouhair Bouaziz, Christelle Marminon, Tuomo Laitinen, Antti Poso, Marc Le Borgne, Joachim Jose
      First page: 8
      Abstract: Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones. Beside others, structures with an indeno[1,2-b]indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors of human protein kinase CK2, we report here on the generation of common feature pharmacophore model to further explain the binding requirements for human CK2 inhibitors. Nine common chemical features of indeno[1,2-b]indole-type CK2 inhibitors were determined using MOE software (Chemical Computing Group, Montreal, Canada). This pharmacophore model was used for database mining with the aim to identify novel scaffolds for developing new potent and selective CK2 inhibitors. Using this strategy several structures were selected by searching inside the ZINC compound database. One of the selected compounds was bikaverin (6,11-dihydroxy-3,8-dimethoxy-1-methylbenzo[b]xanthene-7,10,12-trione), a natural compound which is produced by several kinds of fungi. This compound was tested on human recombinant CK2 and turned out to be an active inhibitor with an IC50 value of 1.24 µM.
      PubDate: 2017-01-09
      DOI: 10.3390/ph10010008
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 9: Structural Hypervariability of the Two
           Human Protein Kinase CK2 Catalytic Subunit Paralogs Revealed by Complex

    • Authors: Karsten Niefind, Nils Bischoff, Andriy Golub, Volodymyr Bdzhola, Anatoliy Balanda, Andriy Prykhod’ko, Sergiy Yarmoluk
      First page: 9
      Abstract: Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2α, the catalytic subunit of human protein kinase CK2, or its paralog CK2α′ in complex with two ATP-competitive inhibitors—based on either a flavonol or a thieno[2,3-d]pyrimidine framework—are presented. The structures show examples for extreme structural deformations of the ATP-binding loop and its neighbourhood and of the hinge/helix αD region, i.e., of two zones of the broader ATP site environment. Thus, they supplement our picture of the conformational space available for CK2α and CK2α′. Further, they document the potential of synthetic ligands to trap unusual conformations of the enzymes and allow to envision a new generation of inhibitors that stabilize such conformations.
      PubDate: 2017-01-11
      DOI: 10.3390/ph10010009
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 10: Acknowledgement to Reviewers of
           Pharmaceuticals in 2016

    • Authors: Pharmaceuticals Editorial Office
      First page: 10
      Abstract: The editors of Pharmaceuticals would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.
      PubDate: 2017-01-10
      DOI: 10.3390/ph10010010
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 11: Exploring the CK2 Paradox: Restless,
           Dangerous, Dispensable

    • Authors: Cinzia Franchin, Christian Borgo, Silvia Zaramella, Luca Cesaro, Giorgio Arrigoni, Mauro Salvi, Lorenzo Pinna
      First page: 11
      Abstract: The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein) that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but it later came to be one of the most pleiotropic protein kinases. Being active in the absence of phosphorylation and/or specific stimuli, it looks unsuitable to participate in signaling cascades, but its “lateral” implication in a variety of signaling pathways is now soundly documented. At variance with many “onco-kinases”, CK2 is constitutively active, and no oncogenic CK2 mutant is known; still high CK2 activity correlates to neoplasia. Its pleiotropy and essential role may cast doubts on the actual “druggability” of CK2; however, a CK2 inhibitor is now in Phase II clinical trials for the treatment of cancer, and cell clones viable in the absence of CK2 are providing information about the mechanism by which cancer becomes addicted to high CK2 levels. A phosphoproteomics analysis of these CK2 null cells suggests that CK2 pleiotropy may be less pronounced than expected and supports the idea that the phosphoproteome generated by this kinase is flexible and not rigidly pre-determined.
      PubDate: 2017-01-20
      DOI: 10.3390/ph10010011
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 12: 188Re(V) Nitrido Radiopharmaceuticals
           for Radionuclide Therapy

    • Authors: Alessandra Boschi, Petra Martini, Licia Uccelli
      First page: 12
      Abstract: The favorable nuclear properties of rhenium-188 for therapeutic application are described, together with new methods for the preparation of high yield and stable 188Re radiopharmaceuticals characterized by the presence of the nitride rhenium core in their final chemical structure. 188Re is readily available from an 188W/188Re generator system and a parallelism between the general synthetic procedures applied for the preparation of nitride technetium-99m and rhenium-188 theranostics radiopharmaceuticals is reported. Although some differences between the chemical characteristics of the two metallic nitrido fragments are highlighted, it is apparent that the same general procedures developed for the labelling of biologically active molecules with technetium-99m can be applied to rhenium-188 with minor modification. The availability of these chemical strategies, that allow the obtainment, in very high yield and in physiological condition, of 188Re radiopharmaceuticals, gives a new attractive prospective to employ this radionuclide for therapeutic applications.
      PubDate: 2017-01-19
      DOI: 10.3390/ph10010012
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 13: Ablation of Protein Kinase CK2β in
           Skeletal Muscle Fibers Interferes with Their Oxidative Capacity

    • Authors: Nane Eiber, Luca Simeone, Said Hashemolhosseini
      First page: 13
      Abstract: The tetrameric protein kinase CK2 was identified playing a role at neuromuscular junctions by studying CK2β-deficient muscle fibers in mice, and in cultured immortalized C2C12 muscle cells after individual knockdown of CK2α and CK2β subunits. In muscle cells, CK2 activity appeared to be at least required for regular aggregation of nicotinic acetylcholine receptors, which serves as a hallmark for the presence of a postsynaptic apparatus. Here, we set out to determine whether any other feature accompanies CK2β-deficient muscle fibers. Hind limb muscles gastrocnemius, plantaris, and soleus of adult wildtype and CK2β-deficient mice were dissected, cross-sectioned, and stained histochemically by Gomori trichrome and for nicotinamide adenine dinucleotide (NADH) dehydrogenase and succinate dehydrogenase (SDH) enzymatic activities. A reduction of oxidative enzymatic activity was determined for CK2β-deficient muscle fibers in comparison with wildtype controls. Importantly, the CK2β-deficient fibers, muscle fibers that typically exhibit high NADH dehydrogenase and SDH activities, like slow-type fibers, showed a marked reduction in these activities. Altogether, our data indicate additional impairments in the absence of CK2β in skeletal muscle fibers, pointing to an eventual mitochondrial myopathy.
      PubDate: 2017-01-19
      DOI: 10.3390/ph10010013
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 14: Aptamers in Bordeaux, 24–25 June

    • Authors: Jean-Jacques Toulmé, Paloma Giangrande, Günter Mayer, Beatrix Suess, Frédéric Ducongé, Bruce Sullenger, Vittorio de Franciscis, Fabien Darfeuille, Eric Peyrin
      First page: 14
      Abstract: The symposium covered the many different aspects of the selection and the characterization of aptamers as well as their application in analytical, diagnostic and therapeutic areas. Natural and artificial riboswitches were discussed. Recent advances for the design of mutated polymerases and of chemically modified nucleic acid bases that provide aptamers with new properties were presented. The power of aptamer platforms for multiplex analysis of biomarkers of major human diseases was described. The potential of aptamers for the treatment of cancer or cardiovascular diseases was also presented. Brief summaries of the lectures presented during the symposium are given in this report. A second edition of “Aptamers in Bordeaux” will take place on September 2017 (
      PubDate: 2017-01-20
      DOI: 10.3390/ph10010014
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 15: Relationship between Surface
           Properties and In Vitro Drug Release from Compressed Matrix Containing
           Polymeric Materials with Different Hydrophobicity Degrees

    • Authors: Cristhian Yarce, Juan Echeverri, Mario Palacio, Carlos Rivera, Constain Salamanca
      First page: 15
      Abstract: This work is the continuation of a study focused on establishing relations between surface thermodynamic properties and in vitro release mechanisms using a model drug (ampicillin trihydrate), besides analyzing the granulometric properties of new polymeric materials and thus establishing the potential to be used in the pharmaceutical field as modified delivery excipients. To do this, we used copolymeric materials derived from maleic anhydride with decreasing polarity corresponding to poly(isobutylene-alt-maleic acid) (hydrophilic), sodium salt of poly(maleic acid-alt-octadecene) (amphiphilic), poly(maleic anhydride-alt-octadecene) (hydrophobic) and the reference polymer hydroxyl-propyl-methyl-cellulose (HPMC). Each material alone and in blends underwent spectroscopic characterization by FTIR, thermal characterization by DSC and granulometric characterization using flow and compaction tests. Each tablet was prepared at different polymer ratios of 0%, 10%, 20%, 30% and 40%, and the surface properties were determined, including the roughness by micro-visualization, contact angle and water absorption rate by the sessile drop method and obtaining Wadh and surface free energy (SFE) using the semi-empirical models of Young–Dupré and  Owens-Wendt-Rabel-Käelbe (OWRK), respectively. Dissolution profiles were determined simulating physiological conditions in vitro, where the kinetic models of order-zero, order-one, Higuchi and Korsmeyer–Peppas were evaluated. The results showed a strong relationship between the proportion and nature of the polymer to the surface thermodynamic properties and kinetic release mechanism.
      PubDate: 2017-01-24
      DOI: 10.3390/ph10010015
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 16: In Search of Small Molecule Inhibitors
           Targeting the Flexible CK2 Subunit Interface

    • Authors: Benoît Bestgen, Zakia Belaid-Choucair, Thierry Lomberget, Marc Le Borgne, Odile Filhol, Claude Cochet
      First page: 16
      Abstract: Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way.
      PubDate: 2017-02-03
      DOI: 10.3390/ph10010016
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 17: “The 24th Conference” of the
           Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A)

    • Authors: Jean-Jacques Hélesbeux, Olivier Duval
      First page: 17
      Abstract: The GP2A European Conference is a two-day meeting focused on medicinal chemistry and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, MS studies, in vitro in vivo assays, and structure activity relationships. s of keynote lectures, plenary lectures, junior lectures, flash presentations, and posters presented during the meeting are collated in this report.
      PubDate: 2017-01-28
      DOI: 10.3390/ph10010017
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 18: CK2 in Cancer: Cellular and
           Biochemical Mechanisms and Potential Therapeutic Target

    • Authors: Melissa Chua, Charina Ortega, Ayesha Sheikh, Migi Lee, Hussein Abdul-Rassoul, Kevan Hartshorn, Isabel Dominguez
      First page: 18
      Abstract: CK2 genes are overexpressed in many human cancers, and most often overexpression is associated with worse prognosis. Site-specific expression in mice leads to cancer development (e.g., breast, lymphoma) indicating the oncogenic nature of CK2. CK2 is involved in many key aspects of cancer including inhibition of apoptosis, modulation of signaling pathways, DNA damage response, and cell cycle regulation. A number of CK2 inhibitors are now available and have been shown to have activity against various cancers in vitro and in pre-clinical models. Some of these inhibitors are now undergoing exploration in clinical trials as well. In this review, we will examine some of the major cancers in which CK2 inhibition has promise based on in vitro and pre-clinical studies, the proposed cellular and signaling mechanisms of anti-cancer activity by CK2 inhibitors, and the current or recent clinical trials using CK2 inhibitors.
      PubDate: 2017-01-28
      DOI: 10.3390/ph10010018
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 19: Barriers to the Access of Bevacizumab
           in Patients with Solid Tumors and the Potential Impact of Biosimilars: A
           Physician Survey

    • Authors: Bradley Monk, Philip Lammers, Thomas Cartwright, Ira Jacobs
      First page: 19
      Abstract: Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US (n = 150), Europe (n = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; n = 130) examined use of and barriers to accessing bevacizumab as treatment of advanced solid tumors. We also assessed the likelihood that physicians would prescribe a bevacizumab biosimilar, if available. Bevacizumab was frequently used as early-line therapy in metastatic colorectal cancer, metastatic non-squamous non–small-cell lung cancer, and metastatic ovarian cancer (all markets), and as a second-line therapy in glioblastoma multiforme (US, EM). A greater percentage of EM-based physicians cited access-related issues as a barrier to prescribing bevacizumab versus US and EU physicians. Lack of reimbursement and high out-of-pocket costs were cited as predominant barriers to prescribing and common reasons for reducing the number of planned cycles. Overall, ~50% of physicians reported they “definitely” or “probably” would prescribe a bevacizumab biosimilar, if available. Efficacy and safety data in specific tumor types and lower cost were factors cited that would increase likelihood to prescribe a bevacizumab biosimilar. A lower cost bevacizumab biosimilar could address the unmet needs of patients and physicians worldwide, and may have the greatest impact on patient outcomes in EM.
      PubDate: 2017-01-28
      DOI: 10.3390/ph10010019
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 20: Second International Electronic
           Conference on Medicinal Chemistry (ECMC-2)

    • Authors: Annie Mayence, Jean Eynde
      First page: 20
      Abstract: The second International Electronic Conference on Medicinal Chemistry, organized and sponsored by the publisher MDPI AG and the Journal Pharmaceuticals, took place in November 2016 on the SciForum website ( More than 150 authors from 22 countries participated in the event. Selected works presented during the scientific meeting are disclosed in this report.
      PubDate: 2017-01-31
      DOI: 10.3390/ph10010020
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 21: The Link between Protein Kinase CK2
           and Atypical Kinase Rio1

    • Authors: Konrad Kubiński, Maciej Masłyk
      First page: 21
      Abstract: The atypical kinase Rio1 is widespread in many organisms, ranging from Archaebacteria to humans, and is an essential factor in ribosome biogenesis. Little is known about the protein substrates of the enzyme and small-molecule inhibitors of the kinase. Protein kinase CK2 was the first interaction partner of Rio1, identified in yeast cells. The enzyme from various sources undergoes CK2-mediated phosphorylation at several sites and this modification regulates the activity of Rio1. The aim of this review is to present studies of the relationship between the two different kinases, with respect to CK2-mediated phosphorylation of Rio1, regulation of Rio1 activity, and similar susceptibility of the kinases to benzimidazole inhibitors.
      PubDate: 2017-02-07
      DOI: 10.3390/ph10010021
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 22: Inhibition of Protein Kinase CK2
           Prevents Adipogenic Differentiation of Mesenchymal Stem Cells Like
           C3H/10T1/2 Cells

    • Authors: Lisa Schwind, Sarah Schetting, Mathias Montenarh
      First page: 22
      Abstract: Protein kinase CK2 as a holoenzyme is composed of two catalytic α- or α’-subunits and two non-catalytic β-subunits. Knock-out experiments revealed that CK2α and CK2β are required for embryonic development. Little is known about the role of CK2 during differentiation of stem cells. Mesenchymal stem cells (MSCs) are multipotent cells which can be differentiated into adipocytes in vitro. Thus, MSCs and in particular C3H/10T1/2 cells are excellent tools to study a possible role of CK2 in adipogenesis. We found downregulation of the CK2 catalytic subunits as well as a decrease in CK2 kinase activity with progression of differentiation. Inhibition of CK2 using the potent inhibitor CX-4945 impeded differentiation of C3H/10T1/2 cells into adipocytes. The inhibited cells lacked the observed decrease in CK2 expression, but showed a constant expression of all three CK2 subunits. Furthermore, inhibition of CK2 resulted in decreased cell proliferation in the early differentiation phase. Analysis of the main signaling cascade revealed an elevated expression of C/EBPβ and C/EBPδ and reduced expression of the adipogenic master regulators C/EBPα and PPARγ2. Thus, CK2 seems to be implicated in the regulation of different steps early in the adipogenic differentiation of MSC.
      PubDate: 2017-02-09
      DOI: 10.3390/ph10010022
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 23: RNA-Eluting Surfaces for the
           Modulation of Gene Expression as A Novel Stent Concept

    • Authors: Olivia Koenig, Diane Zengerle, Nadja Perle, Susanne Hossfeld, Bernd Neumann, Andreas Behring, Meltem Avci-Adali, Tobias Walker, Christian Schlensak, Hans Wendel, Andrea Nolte
      First page: 23
      Abstract: Presently, a new era of drug-eluting stents is continuing to improve late adverse effects such as thrombosis after coronary stent implantation in atherosclerotic vessels. The application of gene expression–modulating stents releasing specific small interfering RNAs (siRNAs) or messenger RNAs (mRNAs) to the vascular wall might have the potential to improve the regeneration of the vessel wall and to inhibit adverse effects as a new promising therapeutic strategy. Different poly (lactic-co-glycolic acid) (PLGA) resomers for their ability as an siRNA delivery carrier against intercellular adhesion molecule (ICAM)-1 with a depot effect were tested. Biodegradability, hemocompatibility, and high cell viability were found in all PLGAs. We generated PLGA coatings with incorporated siRNA that were able to transfect EA.hy926 and human vascular endothelial cells. Transfected EA.hy926 showed significant siICAM-1 knockdown. Furthermore, co-transfection of siRNA and enhanced green fluorescent protein (eGFP) mRNA led to the expression of eGFP as well as to the siRNA transfection. Using our PLGA and siRNA multilayers, we reached high transfection efficiencies in EA.hy926 cells until day six and long-lasting transfection until day 20. Our results indicate that siRNA and mRNA nanoparticles incorporated in PLGA films have the potential for the modulation of gene expression after stent implantation to achieve accelerated regeneration of endothelial cells and to reduce the risk of restenosis.
      PubDate: 2017-02-10
      DOI: 10.3390/ph10010023
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 24: Targeting Protein Kinase CK2:
           Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in
           Immunocompetent Mice

    • Authors: Laura Ferrer-Font, Lucia Villamañan, Nuria Arias-Ramos, Jordi Vilardell, Maria Plana, Maria Ruzzene, Lorenzo Pinna, Emilio Itarte, Carles Arús, Ana Candiota
      First page: 24
      Abstract: Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response.
      PubDate: 2017-02-12
      DOI: 10.3390/ph10010024
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 25: CK2 Molecular Targeting—Tumor
           Cell-Specific Delivery of RNAi in Various Models of Cancer

    • Authors: Janeen Trembley, Betsy Kren, Md. Abedin, Rachel Vogel, Claire Cannon, Gretchen Unger, Khalil Ahmed
      First page: 25
      Abstract: Protein kinase CK2 demonstrates increased protein expression relative to non-transformed cells in the majority of cancers that have been examined. The elevated levels of CK2 are involved in promoting not only continued proliferation of cancer cells but also their resistance to cell death; thus, CK2 has emerged as a plausible target for cancer therapy. Our focus has been to target CK2 catalytic subunits at the molecular level using RNA interference (RNAi) strategies to achieve their downregulation. The delivery of oligonucleotide therapeutic agents warrants that they are protected and are delivered specifically to cancer cells. The latter is particularly important since CK2 is a ubiquitous signal that is essential for survival. To achieve these goals, we have developed a nanocapsule that has the properties of delivering an anti-CK2 RNAi therapeutic cargo, in a protected manner, specifically to cancer cells. Tenfibgen (TBG) is used as the ligand to target tenascin-C receptors, which are elevated in cancer cells. This strategy is effective for inhibiting growth and inducing death in several types of xenograft tumors, and the nanocapsule elicits no safety concerns in animals. Further investigation of this therapeutic approach for its translation is warranted.
      PubDate: 2017-02-21
      DOI: 10.3390/ph10010025
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 26: The Development of CK2 Inhibitors:
           From Traditional Pharmacology to in Silico Rational Drug Design

    • Authors: Giorgio Cozza
      First page: 26
      Abstract: Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by “trial and error testing”. In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range. The screening of big chemical libraries and the optimization of hit compounds by Structure Based Drug Design (SBDD) provide telling examples of a fruitful application of rational drug design to the development of CK2 inhibitors. Ligand Based Drug Design (LBDD) models have been also applied to CK2 drug discovery, however they were mainly focused on methodology improvements rather than being critical for de novo design and optimization. This manuscript provides detailed description of in silico methodologies whose applications to the design and development of CK2 inhibitors proved successful and promising.
      PubDate: 2017-02-20
      DOI: 10.3390/ph10010026
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 27: Protein Kinase CK2: Intricate
           Relationships within Regulatory Cellular Networks

    • Authors: Teresa Nuñez de Villavicencio-Diaz, Adam Rabalski, David Litchfield
      First page: 27
      Abstract: Protein kinase CK2 is a small family of protein kinases that has been implicated in an expanding array of biological processes. While it is widely accepted that CK2 is a regulatory participant in a multitude of fundamental cellular processes, CK2 is often considered to be a constitutively active enzyme which raises questions about how it can be a regulatory participant in intricately controlled cellular processes. To resolve this apparent paradox, we have performed a systematic analysis of the published literature using text mining as well as mining of proteomic databases together with computational assembly of networks that involve CK2. These analyses reinforce the notion that CK2 is involved in a broad variety of biological processes and also reveal an extensive interplay between CK2 phosphorylation and other post-translational modifications. The interplay between CK2 and other post-translational modifications suggests that CK2 does have intricate roles in orchestrating cellular events. In this respect, phosphorylation of specific substrates by CK2 could be regulated by other post-translational modifications and CK2 could also have roles in modulating other post-translational modifications. Collectively, these observations suggest that the actions of CK2 are precisely coordinated with other constituents of regulatory cellular networks.
      PubDate: 2017-03-05
      DOI: 10.3390/ph10010027
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 28: Targeted Drugs as Maintenance Therapy
           after Autologous Stem Cell Transplantation in Patients with Mantle Cell

    • Authors: Fengting Yan, Ajay Gopal, Solomon Graf
      First page: 28
      Abstract: The treatment landscape for mantle cell lymphoma (MCL) is rapidly evolving toward the incorporation of novel and biologically targeted pharmaceuticals with improved disease activity and gentler toxicity profiles compared with conventional chemotherapeutics. Upfront intensive treatment of MCL includes autologous stem cell transplantation (SCT) consolidation aimed at deepening and lengthening disease remission, but subsequent relapse occurs. Maintenance therapy after autologous SCT in patients with MCL in remission features lower-intensity treatments given over extended periods to improve disease outcomes. Targeted drugs are a natural fit for this space, and are the focus of considerable clinical investigation. This review summarizes recent advances in the field and their potential impact on treatment practices for MCL.
      PubDate: 2017-03-10
      DOI: 10.3390/ph10010028
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 29: Theranostic Value of Multimers:
           Lessons Learned from Trimerization of Neurotensin Receptor Ligands and
           Other Targeting Vectors

    • Authors: Simone Maschauer, Jürgen Einsiedel, Dominik Reich, Harald Hübner, Peter Gmeiner, Hans-Jürgen Wester, Olaf Prante, Johannes Notni
      First page: 29
      Abstract: Neurotensin receptor 1 (NTS1) is overexpressed on a variety of cancer entities; for example, prostate cancer, ductal pancreatic adenocarcinoma, and breast cancer. Therefore, it represents an interesting target for the diagnosis of these cancers types by positron emission tomography (PET) [...]
      PubDate: 2017-03-10
      DOI: 10.3390/ph10010029
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 30: Current Status of Radiopharmaceuticals
           for the Theranostics of Neuroendocrine Neoplasms

    • Authors: Melpomeni Fani, Petra Peitl, Irina Velikyan
      First page: 30
      Abstract: : Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors.
      PubDate: 2017-03-15
      DOI: 10.3390/ph10010030
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 31: Anacardic Acid Constituents from
           Cashew Nut Shell Liquid: NMR Characterization and the Effect of
           Unsaturation on Its Biological Activities

    • Authors: Selene Morais, Katherine Silva, Halisson Araujo, Icaro Vieira, Daniela Alves, Raquel Fontenelle, Artur Silva
      First page: 31
      Abstract: Anacardic acids are the main constituents of natural cashew nut shell liquid (CNSL), obtained via the extraction of cashew shells with hexane at room temperature. This raw material presents high technological potential due to its various biological properties. The main components of CNSL are the anacardic acids, salicylic acid derivatives presenting a side chain of fifteen carbon atoms with different degrees of unsaturation (monoene–15:1, diene–15:2, and triene–15:3). Each constituent was isolated by column chromatography using silica gel impregnated with silver nitrate. The structures of the compounds were characterized by nuclear magnetic resonance through complete and unequivocal proton and carbon assignments. The effect of the side chain unsaturation was also evaluated in relation to antioxidant, antifungal and anticholinesterase activities, and toxicity against Artemia salina. The triene anacardic acid provided better results in antioxidant activity assessed by the inhibition of the free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH), higher cytotoxicity against A. salina, and acetylcholinesterase (AChE) inhibition. Thus, increasing the unsaturation of the side chain of anacardic acid increases its action against free radicals, AChE enzyme, and A. salina nauplii. In relation to antifungal activity, an inverse result was obtained, and the linearity of the molecule plays an important role, with monoene being the most active. In conclusion, the changes in structure of anacardic acids, which cause differences in polarity, contribute to the increase or decrease in the biological activity assessed.
      PubDate: 2017-03-16
      DOI: 10.3390/ph10010031
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 32: Aptamers: Biomedical Interest and

    • Authors: Cristina Romero-López, Alfredo Berzal-Herranz
      First page: 32
      Abstract: Aptamers are short DNA or RNA oligonucleotides specialized in the specific and efficient binding to a target molecule. They are obtained by in vitro selection or evolution processes. It was in 1990 that two independent research groups described the bases of a new in vitro technology for the identification of RNA molecules able to specifically bind to a target [1,2]. Tuerk and Gold established the principals of the in vitro selection process that was named SELEX (Systematic Evolution of Ligands by Exponential enrichment), which is based on iterative cycles of binding, partitioning, and amplification of oligonucleotides from a pool of variant sequences [2]. Ellington and Szostak coined the term aptamer to define the selected molecules by the application of this method [1]. To date, numerous reports have described the isolation of aptamers directed against a great variety of targets covering a wide diversity of molecules varying in nature, size, and complexity ranging from ions to whole cells, including small molecules (e.g., aminoacids, nucleotides, antibiotics), peptides, proteins, nucleic acids, and viruses, among others (for example, see [3–6]). Modifications and optimization of the SELEX procedure aimed to get newly modified aptamers has also attracted much interest (examples can be found in [7,8]). These advances along with the parallel progresses in the nucleic acids chemistry and cellular delivery fields have allowed for the rise of a new hope in developing aptamers as efficient molecular tools for diagnostics and therapeutics (for recent comprehensive reviews, see [9–11]).
      PubDate: 2017-03-16
      DOI: 10.3390/ph10010032
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 9, Pages 60: pMPES: A Modular Peptide Expression
           System for the Delivery of Antimicrobial Peptides to the Site of
           Gastrointestinal Infections Using Probiotics

    • Authors: Kathryn Geldart, Brittany Forkus, Evelyn McChesney, Madeline McCue, Yiannis Kaznessis
      First page: 60
      Abstract: Antimicrobial peptides are a promising alternative to traditional antibiotics, but their utility is limited by high production costs and poor bioavailability profiles. Bacterial production and delivery of antimicrobial peptides (AMPs) directly at the site of infection may offer a path for effective therapeutic application. In this study, we have developed a vector that can be used for the production and secretion of seven antimicrobial peptides from both Escherichia coli MC1061 F’ and probiotic E.coli Nissle 1917. The vector pMPES (Modular Peptide Expression System) employs the Microcin V (MccV) secretion system and a powerful synthetic promoter to drive AMP production. Herein, we demonstrate the capacity of pMPES to produce inhibitory levels of MccV, Microcin L (MccL), Microcin N (McnN), Enterocin A (EntA), Enterocin P (EntP), Hiracin JM79 (HirJM79) and Enterocin B (EntB). To our knowledge, this is the first demonstration of such a broadly-applicable secretion system for AMP production. This type of modular expression system could expedite the development of sorely needed antimicrobial technologies
      PubDate: 2016-10-05
      DOI: 10.3390/ph9040060
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 61: Lactoferrin from Milk: Nutraceutical
           and Pharmacological Properties

    • Authors: Francesco Giansanti, Gloria Panella, Loris Leboffe, Giovanni Antonini
      First page: 61
      Abstract: Lactoferrin is an iron-binding protein present in large quantities in colostrum and in breast milk, in external secretions and in polymorphonuclear leukocytes. Lactoferrin’s main function is non-immune protection. Among several protective activities shown by lactoferrin, those displayed by orally administered lactoferrin are: (i) antimicrobial activity, which has been presumed due to iron deprivation, but more recently attributed also to a specific interaction with the bacterial cell wall and extended to viruses and parasites; (ii) immunomodulatory activity, with a direct effect on the development of the immune system in the newborn, together with a specific antinflammatory effects; (iii) a more recently discovered anticancer activity. It is worth noting that most of the protective activities of lactoferrin have been found, sometimes to a greater extent, also in peptides derived from limited proteolysis of lactoferrin that could be generated after lactoferrin ingestion. Lactoferrin could therefore be considered an ideal nutraceutic product because of its relatively cheap production from bovine milk and of its widely recognized tolerance after ingestion, along with its well demonstrated protective activities. The most important protective activities shown by orally administered bovine lactoferrin are reviewed in this article.
      PubDate: 2016-09-27
      DOI: 10.3390/ph9040061
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 62: Nanosized Drug Delivery Systems in
           Gastrointestinal Targeting: Interactions with Microbiota

    • Authors: Michail Karavolos, Alina Holban
      First page: 62
      Abstract: The new age of nanotechnology has signaled a stream of entrepreneurial possibilities in various areas, form industry to medicine. Drug delivery has benefited the most by introducing nanostructured systems in the transport and controlled release of therapeutic molecules at targeted sites associated with a particular disease. As many nanosized particles reach the gastrointestinal tract by various means, their interactions with the molecular components of this highly active niche are intensively investigated. The well-characterized antimicrobial activities of numerous nanoparticles are currently being considered as a reliable and efficient alternative to the eminent world crisis in antimicrobial drug discovery. The interactions of nanosystems present in the gastrointestinal route with host microbiota is unavoidable; hence, a major research initiative is needed to explore the mechanisms and effects of these nanomaterials on microbiota and the impact that microbiota may have in the outcome of therapies entailing drug delivery nanosystems through the gastrointestinal route. These coordinated studies will provide novel techniques to replace or act synergistically with current technologies and help develop new treatments for major diseases via the discovery of unique antimicrobial molecules.
      PubDate: 2016-09-29
      DOI: 10.3390/ph9040062
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 63: Green Extraction from Pomegranate Marcs
           for the Production of Functional Foods and Cosmetics

    • Authors: Raffaella Boggia, Federica Turrini, Carla Villa, Chiara Lacapra, Paola Zunin, Brunella Parodi
      First page: 63
      Abstract: The aim of this study was to investigate the potential of retrieving polyphenolic antioxidants directly from wet pomegranate marcs: the fresh by-products obtained after pomegranate juice processing. These by-products mainly consist of internal membranes (endocarp) and aril residues. Even if they are still edible, they are usually discharged during juice production and, thus, they represent a great challenge in an eco-sustainable industrial context. Green technologies, such as ultrasound assisted extraction (UAE) and microwave assisted extraction (MAE), have been employed to convert these organic residues into recycled products with high added value. UAE and MAE were used both in parallel and in series in order to make a comparison and to ensure exhaustive extractions, respectively. Water, as an environmentally friendly extraction solvent, has been employed. The results were compared with those ones coming from a conventional extraction. The most promising extract, in terms of total polyphenol yield and radical scavenging activity, has been tested both as a potential natural additive and as a functional ingredient after its incorporation in a real food model and in a real cosmetic matrix, respectively. This study represents a proposal to the agro-alimentary sector given the general need of environmental “responsible care”.
      PubDate: 2016-10-18
      DOI: 10.3390/ph9040063
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 64: Aptamers: A New Technological Platform
           in Cancer Immunotherapy

    • Authors: Fernando Pastor
      First page: 64
      Abstract: The renaissance of cancer immunotherapy is, nowadays, a reality. In the near future, it will be very likely among the first-line treatments for cancer patients. There are several different approaches to modulate the immune system to fight against tumor maladies but, so far, monoclonal antibodies may currently be the most successful immuno-tools used to that end. The number of ongoing clinical trials with monoclonal antibodies has been increasing exponentially over the last few years upon the Food and Drug Administration (FDA) approval of the first immune-checkpoint blockade antibodies. In spite of the proved antitumor effect of these reagents, the unleashing of the immune system to fight cancer cells has a cost, namely auto-inflammatory toxicity. Additionally, only a small fraction of all patients treated with immune-checkpoint antibodies have a clinical benefit. Taking into account all this, it is urgent new therapeutic reagents are developed with a contained toxicity that could facilitate the combination of different immune-modulating pathways to broaden the antitumor effect in most cancer patients. Based on preclinical data, oligonucleotide aptamers could fulfill this need. Aptamers have not only been successfully used as antagonists of immune-checkpoint receptors, but also as agonists of immunostimulatory receptors in cancer immunotherapy. The simplicity of aptamers to be engineered for the specific delivery of different types of cargos to tumor cells and immune cells so as to harvest an efficient antitumor immune response gives aptamers a significant advantage over antibodies. In this review all of the recent applications of aptamers in cancer immunotherapy will be described.
      PubDate: 2016-10-24
      DOI: 10.3390/ph9040064
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 65: Herbal Products in Italy: The Thin Line
           between Phytotherapy, Nutrition and Parapharmaceuticals; A Normative
           Overview of the Fastest Growing Market in Europe

    • Authors: Marco Biagi, Rita Pecorari, Giovanni Appendino, Elisabetta Miraldi, Anna Magnano, Paolo Governa, Giulia Cettolin, Daniela Giachetti
      First page: 65
      Abstract: The Italian herbal products market is the most prosperous in Europe. The proof is represented by the use of these products in several marketing categories, ranging from medicine to nutrition and cosmetics. Market and legislation in Italy are at the same time cause and consequence of this peculiar situation. In fact, the legislation on botanical food supplements in Italy is very permissive and at the same time the market shows an overall satisfaction of users and strong feedback in terms of consumption, which brings a widening use of medicinal plants, formerly the prerogative of pharmaceuticals, to other fields such as nutrition. This review summarizes the market and normative panorama of herbal products in Italy, highlighting the blurred boundaries of health indications, marketing authorizations and quality controls between herbal medicines and non pharmaceutical products, such as food supplements, cosmetics and other herbal-based “parapharmaceuticals”.
      PubDate: 2016-10-29
      DOI: 10.3390/ph9040065
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 66: Use of Capsaicin to Treat Pain:
           Mechanistic and Therapeutic Considerations

    • Authors: Man-Kyo Chung, James Campbell
      First page: 66
      Abstract: Capsaicin is the pungent ingredient of chili peppers and is approved as a topical treatment of neuropathic pain. The analgesia lasts for several months after a single treatment. Capsaicin selectively activates TRPV1, a Ca2+-permeable cationic ion channel that is enriched in the terminals of certain nociceptors. Activation is followed by a prolonged decreased response to noxious stimuli. Interest also exists in the use of injectable capsaicin as a treatment for focal pain conditions, such as arthritis and other musculoskeletal conditions. Recently injection of capsaicin showed therapeutic efficacy in patients with Morton’s neuroma, a painful foot condition associated with compression of one of the digital nerves. The relief of pain was associated with no change in tactile sensibility. Though injection evokes short term pain, the brief systemic exposure and potential to establish long term analgesia without other sensory changes creates an attractive clinical profile. Short-term and long-term effects arise from both functional and structural changes in nociceptive terminals. In this review, we discuss how local administration of capsaicin may induce ablation of nociceptive terminals and the clinical implications.
      PubDate: 2016-11-01
      DOI: 10.3390/ph9040066
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 67: pH Dependent Antimicrobial Peptides and
           Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

    • Authors: Erum Malik, Sarah Dennison, Frederick Harris, David Phoenix
      First page: 67
      Abstract: Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel delivery systems. Nonetheless, many pH dependent AMPs and antimicrobial proteins have yet to be fully characterized and these molecules, as a whole, represent an untapped source of novel biologically active agents that could aid fulfillment of the urgent need for alternatives to conventional antibiotics, helping to avert a return to the pre-antibiotic era.
      PubDate: 2016-11-01
      DOI: 10.3390/ph9040067
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 68: The Development of a Parenteral
           Pharmaceutical Formulation of a New Class of Compounds of Nitrosourea

    • Authors: Ludmila Nikolaeva, Natalia Oborotova, Natalia Bunyatyan, Xi Zhang, Ekaterina Sanarova, Anna Lantsova, Olga Orlova, Alevtina Polozkova
      First page: 68
      Abstract: Despite the rapid development of medical technologies, chemotherapy treatment still occupies an important place in clinical oncology. In this regard, the current research in this area focuses on the synthesis of new highly effective antitumor substances that have minimal side effects and the development of stable pharmaceutical formulations (PF) on their basis. In order to solve this problem, the I. Ya. Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences actively sought for original substances, namely, nitrosourea (NU) derivatives, one of the most promising classes of anticancer drugs. As a result of this research, a novel NU derivative was synthesized, namely ormustine, which showed high antitumor activity in preliminary preclinical trials. It is now crucial to develop an ormustine pharmaceutical formulation. Conducted technological studies showed that the most suitable solvent for the drug substance is 0.1 M hydrochloric acid, which ensures its rapid dissolution by ultrasonic treatment. A significant reduction in the concentration of the active ingredient during the storage of the solution required the development of a technique of its lyophilization and the selection of a shaper such as a Kollidon 17 PF. Upon completion of the development of a pharmaceutical formulation of ormustine, its stability after lyophilization was demonstrated, and a sufficient amount of the drug has been acquired for preclinical research.
      PubDate: 2016-11-01
      DOI: 10.3390/ph9040068
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 69: Aptamer-Mediated Targeted Delivery of
           Therapeutics: An Update

    • Authors: Silvia Catuogno, Carla Esposito, Vittorio de Franciscis
      First page: 69
      Abstract: The selective delivery of drugs in a cell- or tissue-specific manner represents the main challenge for medical research; in order to reduce the occurrence of unwanted off-target effects. In this regard, nucleic acid aptamers have emerged as an attractive class of carrier molecules due to their ability to bind with high affinity to specific ligands; their high chemical flexibility; as well as tissue penetration capability. To date, different aptamer-drug systems and aptamer–nanoparticles systems, in which nanoparticles function together with aptamers for the targeted delivery, have been successfully developed for a wide range of therapeutics, including toxins; peptides; chemotherapeutics and oligonucleotides. Therefore, aptamer-mediated drug delivery represents a powerful tool for the safe and effective treatment of different human pathologies, including cancer; neurological diseases; immunological diseases and so on. In this review, we will summarize recent progress in the field of aptamer-mediated drug delivery and we will discuss the advantages, the achieved objectives and the challenges to be still addressed in the near future, in order to improve the effectiveness of therapies.
      PubDate: 2016-11-03
      DOI: 10.3390/ph9040069
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 70: Blocking TRPA1 in Respiratory
           Disorders: Does It Hold a Promise?

    • Authors: Indranil Mukhopadhyay, Abhay Kulkarni, Neelima Khairatkar-Joshi
      First page: 70
      Abstract: Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel is expressed abundantly on the C fibers that innervate almost entire respiratory tract starting from oral cavity and oropharynx, conducting airways in the trachea, bronchi, terminal bronchioles, respiratory bronchioles and upto alveolar ducts and alveoli. Functional presence of TRPA1 on non-neuronal cells got recognized recently. TRPA1 plays a well-recognized role of “chemosensor”, detecting presence of exogenous irritants and endogenous pro-inflammatory mediators that are implicated in airway inflammation and sensory symptoms like chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cystic fibrosis. TRPA1 can remain activated chronically due to elevated levels and continued presence of such endogenous ligands and pro-inflammatory mediators. Several selective TRPA1 antagonists have been tested in animal models of respiratory disease and their performance is very promising. Although there is no TRPA1 antagonist in advanced clinical trials or approved on market yet to treat respiratory diseases, however, limited but promising evidences available so far indicate likelihood that targeting TRPA1 may present a new therapy in treatment of respiratory diseases in near future. This review will focus on in vitro, animal and human evidences that strengthen the proposed role of TRPA1 in modulation of specific airway sensory responses and also on preclinical and clinical progress of selected TRPA1 antagonists.
      PubDate: 2016-11-05
      DOI: 10.3390/ph9040070
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 71: Curcumin as a Modulator of
           P-Glycoprotein in Cancer: Challenges and Perspectives

    • Authors: Vanessa Lopes-Rodrigues, Emília Sousa, M. Vasconcelos
      First page: 71
      Abstract: Multidrug resistance (MDR) presents a serious challenge to the efficiency of cancer treatment, and may be associated with the overexpression of drug efflux pumps. P-glycoprotein (P-gp) is a drug efflux pump often found overexpressed in cases of acquired MDR. Nevertheless, there are no P-gp inhibitors being used in the current clinical practice, due to toxicity problems, drug interactions, or pharmacokinetic issues. Therefore, it is important to identify novel inhibitors of P-gp activity or expression. Curcumin is a secondary metabolite isolated from the turmeric of Curcuma longa L. which has been associated with several biological activities, particularly P-gp modulatory activity (by inhibiting both P-gp function and expression). However, curcumin shows extensive metabolism and instability, which has justified the recent and intensive search for analogs of curcumin that maintain the P-gp modulatory activity but have enhanced stability. This review summarizes and compares the effects of curcumin and several curcumin analogs on P-glycoprotein function and expression, emphasizing the potential of these molecules for the possible development of safe and effective inhibitors of P-gp to overcome MDR in human cancer.
      PubDate: 2016-11-10
      DOI: 10.3390/ph9040071
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 72: Nociceptive TRP Channels: Sensory
           Detectors and Transducers in Multiple Pain Pathologies

    • Authors: Aaron Mickle, Andrew Shepherd, Durga Mohapatra
      First page: 72
      Abstract: Specialized receptors belonging to the transient receptor potential (TRP) family of ligand-gated ion channels constitute the critical detectors and transducers of pain-causing stimuli. Nociceptive TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system. Several of these TRP channels are also expressed in neurons of the central nervous system, and in non-neuronal cells that communicate with sensory nerves. Nociceptive TRPs are activated by specific physico-chemical stimuli to provide the excitatory trigger in neurons. In addition, decades of research has identified a large number of immune and neuromodulators as mediators of nociceptive TRP channel activation during injury, inflammatory and other pathological conditions. These findings have led to aggressive targeting of TRP channels for the development of new-generation analgesics. This review summarizes the complex activation and/or modulation of nociceptive TRP channels under pathophysiological conditions, and how these changes underlie acute and chronic pain conditions. Furthermore, development of small-molecule antagonists for several TRP channels as analgesics, and the positive and negative outcomes of these drugs in clinical trials are discussed. Understanding the diverse functional and modulatory properties of nociceptive TRP channels is critical to function-based drug targeting for the development of evidence-based and efficacious new generation analgesics.
      PubDate: 2016-11-14
      DOI: 10.3390/ph9040072
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 73: 30ièmes Journées
           Franco-Belges de Pharmacochimie

    • Authors: Samia Aci-Sèche, Frédéric Buron, Karen Plé, Laurent Robin, Franck Suzenet, Sylvain Routier
      First page: 73
      Abstract: The “Journées Franco-Belges de Pharmacochimie” is a recognized annual meeting in organic and medicinal chemistry known for the quality of scientific exchange and conviviality. Young researchers were encouraged to present their work and share ideas with senior scientists. s of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.
      PubDate: 2016-11-18
      DOI: 10.3390/ph9040073
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 74: Assessment of the Activity of
           Tigecycline against Gram-Positive and Gram-Negative Organisms Collected
           from Italy between 2012 and 2014, as Part of the Tigecycline Evaluation
           and Surveillance Trial (T.E.S.T.)

    • Authors: Stefania Stefani, Michael Dowzicky
      First page: 74
      Abstract: As part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T) we report the in vitro activity of tigecycline and its comparators against Gram-negative and Gram-positive organisms collected from Italian centers between 2012 and 2014. Minimum inhibitory concentrations were determined according to the broth microdilution methodology of the Clinical and Laboratory Standards Institute, and antimicrobial resistance was determined using the European Committee on Antimicrobial Susceptibility Testing interpretive criteria. Among the Enterobacteriaceae, 31% of Escherichia coli isolates, 22% of Klebsiella pneumoniae, and 1% of Klebsiella oxytoca were extended-spectrum β-lactamase producers (ESBLs). Resistance rates among ESBL-K. pneumoniae and ESBL-E. coli to meropenem were 24% and <1%, respectively. Thirty-seven percent of K. pneumoniae were multidrug resistant (MDR) strains. Resistance rates among isolates of Acinetobacter baumannii to amikacin, levofloxacin and meropenem were between 84% and 94%. Eighty percent of A. baumannii isolates were MDR strains. Methicillin-resistant Staphylococcus aureus (MRSA) accounted for 38% of S. aureus isolates. No isolates of MRSA were resistant to linezolid, tigecycline or vancomycin. Antimicrobial resistance remains a problem in Italy with increasing numbers of MDR organisms. Despite high levels, MRSA rates appear to be stabilising. Tigecycline retains its in vitro activity against the majority of organisms, including those with multidrug resistance.
      PubDate: 2016-11-26
      DOI: 10.3390/ph9040074
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 75: Methods of Synthesis, Properties and
           Biomedical Applications of CuO Nanoparticles

    • Authors: Madalina Grigore, Elena Biscu, Alina Holban, Monica Gestal, Alexandru Grumezescu
      First page: 75
      Abstract: This study aims to provide an updated survey of the main synthesis methods of copper oxide (CuO) nanoparticles in order to obtain tailored nanosystems for various biomedical applications. The synthesis approach significantly impacts the properties of such nanoparticles and these properties in turn have a significant impact on their biomedical applications. Although not widely investigated as an efficient drug delivery system, CuO nanoparticles have great biological properties including effective antimicrobial action against a wide range of pathogens and also drug resistant bacteria. These properties have led to the development of various approaches with direct applications to the biomedical field, such as tailored surfaces with antimicrobial effect, wound dressings and modified textiles. It is also believed that these nanosystems could represent efficient alternatives in the development of smart systems utilized both for the detection of pathogens and for the treatment of infections.
      PubDate: 2016-11-30
      DOI: 10.3390/ph9040075
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 76: Applications of High-Throughput
           Sequencing for In Vitro Selection and Characterization of Aptamers

    • Authors: Nam Nguyen Quang, Gérald Perret, Frédéric Ducongé
      First page: 76
      Abstract: Aptamers are identified through an iterative process of evolutionary selection starting from a random pool containing billions of sequences. Simultaneously to the amplification of high-affinity candidates, the diversity in the pool is exponentially reduced after several rounds of in vitro selection. Until now, cloning and Sanger sequencing of about 100 sequences was usually used to identify the enriched candidates. However, High-Throughput Sequencing (HTS) is now extensively used to replace such low throughput sequencing approaches. Providing a deeper analysis of the library, HTS is expected to accelerate the identification of aptamers as well as to identify aptamers with higher affinity. It is also expected that it can provide important information on the binding site of the aptamers. Nevertheless, HTS requires handling a large amount of data that is only possible through the development of new in silico methods. Here, this review presents these different strategies that have been recently developed to improve the identification and characterization of aptamers using HTS.
      PubDate: 2016-12-10
      DOI: 10.3390/ph9040076
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 77: TRP Channels in Skin Biology and

    • Authors: Michael Caterina, Zixuan Pang
      First page: 77
      Abstract: Ion channels of the Transient Receptor Potential (TRP) family mediate the influx of monovalent and/or divalent cations into cells in response to a host of chemical or physical stimuli. In the skin, TRP channels are expressed in many cell types, including keratinocytes, sensory neurons, melanocytes, and immune/inflammatory cells. Within these diverse cell types, TRP channels participate in physiological processes ranging from sensation to skin homeostasis. In addition, there is a growing body of evidence implicating abnormal TRP channel function, as a product of excessive or deficient channel activity, in pathological skin conditions such as chronic pain and itch, dermatitis, vitiligo, alopecia, wound healing, skin carcinogenesis, and skin barrier compromise. These diverse functions, coupled with the fact that many TRP channels possess pharmacologically accessible sites, make this family of proteins appealing therapeutic targets for skin disorders.
      PubDate: 2016-12-14
      DOI: 10.3390/ph9040077
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 78: Use of Aptamers as Diagnostics Tools
           and Antiviral Agents for Human Viruses

    • Authors: Víctor González, M. Martín, Gerónimo Fernández, Ana García-Sacristán
      First page: 78
      Abstract: Appropriate diagnosis is the key factor for treatment of viral diseases. Time is the most important factor in rapidly developing and epidemiologically dangerous diseases, such as influenza, Ebola and SARS. Chronic viral diseases such as HIV-1 or HCV are asymptomatic or oligosymptomatic and the therapeutic success mainly depends on early detection of the infective agent. Over the last years, aptamer technology has been used in a wide range of diagnostic and therapeutic applications and, concretely, several strategies are currently being explored using aptamers against virus proteins. From a diagnostics point of view, aptamers are being designed as a bio-recognition element in diagnostic systems to detect viral proteins either in the blood (serum or plasma) or into infected cells. Another potential use of aptamers is for therapeutics of viral infections, interfering in the interaction between the virus and the host using aptamers targeting host-cell matrix receptors, or attacking the virus intracellularly, targeting proteins implicated in the viral replication cycle. In this paper, we review how aptamers working against viral proteins are discovered, with a focus on recent advances that improve the aptamers’ properties as a real tool for viral infection detection and treatment.
      PubDate: 2016-12-16
      DOI: 10.3390/ph9040078
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 80: The New Role for an Old Kinase: Protein
           Kinase CK2 Regulates Metal Ion Transport

    • Authors: Adam Johnson, Ming Wu
      First page: 80
      Abstract: The pleiotropic serine/threonine protein kinase CK2 was the first kinase discovered. It is renowned for its role in cell proliferation and anti-apoptosis. The complexity of this kinase is well reflected by the findings of past decades in terms of its heterotetrameric structure, subcellular location, constitutive activity and the extensive catalogue of substrates. With the advent of non-biased high-throughput functional genomics such as genome-wide deletion mutant screening, novel aspects of CK2 functionality have been revealed. Our recent discoveries using the model organism Saccharomyces cerevisiae and mammalian cells demonstrate that CK2 regulates metal toxicity. Extensive literature search reveals that there are few but elegant works on the role of CK2 in regulating the sodium and zinc channels. As both CK2 and metal ions are key players in cell biology and oncogenesis, understanding the details of CK2’s regulation of metal ion homeostasis has a direct bearing on cancer research. In this review, we aim to garner the recent data and gain insights into the role of CK2 in metal ion transport.
      PubDate: 2016-12-21
      DOI: 10.3390/ph9040080
      Issue No: Vol. 9, No. 4 (2016)
  • Pharmaceuticals, Vol. 9, Pages 34: Relationship between Surface Properties
           and In Vitro Drug Release from a Compressed Matrix Containing an
           Amphiphilic Polymer Material

    • Authors: Cristhian Yarce, Diego Pineda, Clara Correa, Constain Salamanca
      First page: 34
      Abstract: The performance of compressed tablet drug delivery systems made using polymeric materials depend on multiple factors, such as surface properties like contact angle, surface free energy and water absorption rate, besides the release mechanisms driven by the kind of polymer used. Hence, it should be possible to establish a relationship between the surface properties and the drug release kinetics. Compressed tablets with different proportions of poly(maleic acid-alt-octadecene) potassium salt (0%, 10%, 20%, 30% and 40%) were prepared. Blends of a model drug (ampicillin trihydrate) and the polymer material were analyzed by DSC. The surface properties of the tablets were determined by the sessile drop method, while the surface energy was determined using the semi-empirical Young-Dupre, Neumann and OWRK models. The release profiles were determined simulating in vitro conditions (buffer solutions pH 1.2 and pH 7.4 with ionic strength of 1.5 M at 37 °C (310.15 K)). A kinetic analysis of the dissolution profiles using different models (zero order, first order, Higuchi and Korsmeyer-Peppas) was realized. The results showed a significant effect of the proportion of polymer in both the surface properties of the tablets and the dissolution release, indicating a relationship between the kinetic and thermodynamic properties.
      PubDate: 2016-06-24
      DOI: 10.3390/ph9030034
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 35: Announcing the 2016 Pharmaceuticals
           Travel Award for Young Investigators

    • Authors: Jean Vanden Eynde
      First page: 35
      Abstract: For the first time in its short history, our journal is able, this year, to support a young researcher in the field of medicinal chemistry by offering a travel grant of 800 CHF.[...]
      PubDate: 2016-06-27
      DOI: 10.3390/ph9030035
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 36: Site-Specific Labeling of Protein
           Kinase CK2: Combining Surface Display and Click Chemistry for Drug
           Discovery Applications

    • Authors: Christian Nienberg, Anika Retterath, Kira-Sophie Becher, Thorsten Saenger, Henning Mootz, Joachim Jose
      First page: 36
      Abstract: Human CK2 is a heterotetrameric constitutively active serine/threonine protein kinase and is an emerging target in current anti-cancer drug discovery. The kinase is composed of two catalytic CK2α subunits and two regulatory CK2β subunits. In order to establish an assay to identify protein-protein-interaction inhibitors (PPI) of the CK2α/CK2β interface, a bioorthogonal click reaction was used to modify the protein kinase α-subunit with a fluorophore. By expanding the genetic code, the unnatural amino acid para azidophenylalanine (pAzF) could be incorporated into CK2α. Performing the SPAAC click reaction (Strain-Promoted Azide-Alkyne Cycloaddition) by the use of a dibenzylcyclooctyne-fluorophore (DBCO-fluorophore) led to a specifically labeled human protein kinase CK2α. This site-specific labeling does not impair the phosphorylation activity of CK2, which was evaluated by capillary electrophoresis. Furthermore a dissociation constant (KD) of 631 ± 86.2 nM was determined for the substrate αS1-casein towards CK2α. This labeling strategy was also applied to CK2β subunit on Escherichia coli, indicating the site-specific modifications of proteins on the bacterial cell surface when displayed by Autodisplay.
      PubDate: 2016-06-27
      DOI: 10.3390/ph9030036
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 37: Strategies to Overcome Heparins’
           Low Oral Bioavailability

    • Authors: Ana Neves, Marta Correia-da-Silva, Emília Sousa, Madalena Pinto
      First page: 37
      Abstract: Even after a century, heparin is still the most effective anticoagulant available with few side effects. The poor oral absorption of heparins triggered the search for strategies to achieve oral bioavailability since this route has evident advantages over parenteral administration. Several approaches emerged, such as conjugation of heparins with bile acids and lipids, formulation with penetration enhancers, and encapsulation of heparins in micro and nanoparticles. Some of these strategies appear to have potential as good delivery systems to overcome heparin’s low oral bioavailability. Nevertheless, none have reached the market yet. Overall, this review aims to provide insights regarding the oral bioavailability of heparin.
      PubDate: 2016-06-29
      DOI: 10.3390/ph9030037
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 38: Heparin: Past, Present, and Future

    • Authors: Eziafa Oduah, Robert Linhardt, Susan Sharfstein
      First page: 38
      Abstract: Heparin, the most widely used anticoagulant drug in the world today, remains an animal-derived product with the attendant risks of adulteration and contamination. A contamination crisis in 2007–2008 increased the impetus to provide non-animal-derived sources of heparin, produced under cGMP conditions. In addition, recent studies suggest that heparin may have significant antineoplastic activity, separate and distinct from its anticoagulant activity, while other studies indicate a role for heparin in treating inflammation, infertility, and infectious disease. A variety of strategies have been proposed to produce a bioengineered heparin. In this review, we discuss several of these strategies including microbial production, mammalian cell production, and chemoenzymatic modification. We also propose strategies for creating “designer” heparins and heparan-sulfates with various biochemical and physiological properties.
      PubDate: 2016-07-04
      DOI: 10.3390/ph9030038
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 39: Odanacatib, a Cathepsin K Cysteine
           Protease Inhibitor, Kills Hookworm In Vivo

    • Authors: Jon Vermeire, Brian Suzuki, Conor Caffrey
      First page: 39
      Abstract: Hookworm infection is chief among soil-transmitted helminthiases (STHs) for the chronic morbidly inflicted. Deworming via mass drug administration (MDA) programs most often employs single doses of benzimidazole drugs to which resistance is a constant threat. To discover new drugs, we employ a hamster model of hookworm infection with Ancylostoma ceylanicum and use albendazole (ABZ; 10 mg/kg orally) as the gold standard therapy. We previously showed that a single oral 100 mg/kg dose of the cathepsin cysteine protease (CP) inhibitor, K11777, offers near cure of infection that is associated with a 95% reduction in the parasite’s resident CP activity. We confirm these findings here and demonstrate that odanacatib (ODN), Merck’s cathepsin K inhibitor and post-clinical Phase III drug candidate for treatment of osteoporosis, decreases worm burden by 73% at the same dose with a 51% reduction in the parasite’s CP activity. Unlike K11777, ODN is a modest inhibitor of both mammalian cathepsin B and the predominant cathepsin B-like activity measureable in hookworm extracts. ODN’s somewhat unexpected efficacy, therefore, may be due to its excellent pharmacokinetic (PK) profile which allows for sustained plasma exposure and, possibly, sufficient perturbation of hookworm cathepsin B activity to be detrimental to survival. Accordingly, identifying a CP inhibitor(s) that combines the inhibition potency of K11777 and the PK attributes of ODN could lead to a drug that is effective at a lower dose. Achieving this would potentially provide an alternative or back-up to the current anti-hookworm drug, albendazole.
      PubDate: 2016-07-04
      DOI: 10.3390/ph9030039
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 40: Functions of Cationic Host Defense
           Peptides in Immunity

    • Authors: Mahadevappa Hemshekhar, Vidyanand Anaparti, Neeloffer Mookherjee
      First page: 40
      Abstract: Cationic host defense peptides are a widely distributed family of immunomodulatory molecules with antimicrobial properties. The biological functions of these peptides include the ability to influence innate and adaptive immunity for efficient resolution of infections and simultaneous modulation of inflammatory responses. This unique dual bioactivity of controlling infections and inflammation has gained substantial attention in the last three decades and consequent interest in the development of these peptide mimics as immunomodulatory therapeutic candidates. In this review, we summarize the current literature on the wide range of functions of cationic host defense peptides in the context of the mammalian immune system.
      PubDate: 2016-07-04
      DOI: 10.3390/ph9030040
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 41: Multiple Functions of the New
           Cytokine-Based Antimicrobial Peptide Thymic Stromal Lymphopoietin (TSLP)

    • Authors: Louise Bjerkan, Andreas Sonesson, Karl Schenck
      First page: 41
      Abstract: Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine, hitherto mostly known to be involved in inflammatory responses and immunoregulation. The human tslp gene gives rise to two transcription and translation variants: a long form (lfTSLP) that is induced by inflammation, and a short, constitutively-expressed form (sfTSLP), that appears to be downregulated by inflammation. The TSLP forms can be produced by a number of cell types, including epithelial and dendritic cells (DCs). lfTSLP can activate mast cells, DCs, and T cells through binding to the lfTSLP receptor (TSLPR) and has a pro-inflammatory function. In contrast, sfTSLP inhibits cytokine secretion of DCs, but the receptor mediating this effect is unknown. Our recent studies have demonstrated that both forms of TSLP display potent antimicrobial activity, exceeding that of many other known antimicrobial peptides (AMPs), with sfTSLP having the strongest effect. The AMP activity is primarily mediated by the C-terminal region of the protein and is localized within a 34-mer peptide (MKK34) that spans the C-terminal α-helical region in TSLP. Fluorescent studies of peptide-treated bacteria, electron microscopy, and liposome leakage models showed that MKK34 exerted membrane-disrupting effects comparable to those of LL-37. Expression of TSLP in skin, oral mucosa, salivary glands, and intestine is part of the defense barrier that aids in the control of both commensal and pathogenic microbes.
      PubDate: 2016-07-05
      DOI: 10.3390/ph9030041
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 42: Polylactic Acid—Lemongrass Essential
           Oil Nanocapsules with Antimicrobial Properties

    • Authors: Ioannis Liakos, Alexandru Grumezescu, Alina Holban, Iordache Florin, Francesca D’Autilia, Riccardo Carzino, Paolo Bianchini, Athanassia Athanassiou
      First page: 42
      Abstract: Polylactic acid was combined with lemongrass essential oil (EO) to produce functional nanocapsules (NCs). The obtained polylactic acid nanoparticles showed antimicrobial activity both with and without the presence of lemongrass oil; however, the presence of EO improved the activity of the NCs. The presence of lemongrass assisted the formation of well-separated NCs and also provided enhanced antimicrobial properties, since lemongrass is known for its antimicrobial character. Fluorescence microscopy was used to optically observe the nanoparticles and NCs and revealed the attachment of lemongrass oil with the polylactic acid NCs. Dynamic light scattering was used to determine their size. UV absorption was used to determine the exact amount of lemongrass oil found in the polylactic acid—lemongrass oil NCs, which was important for understanding the minimum inhibitory concentration for the antimicrobial experiments. A series of clinically important microbial species were used in the study and the obtained NCs proved to have very good antimicrobial properties against all tested strains. Such NCs can be used for the design of ecological strategies, based on natural alternatives, which may be efficient against severe infections, including those that involve resistant pathogens and biofilms or those with difficult to reach localization.
      PubDate: 2016-07-07
      DOI: 10.3390/ph9030042
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 43: Convergent Synthesis of Two Fluorescent
           Ebselen-Coumarin Heterodimers

    • Authors: Jim Küppers, Anna Schulz-Fincke, Jerzy Palus, Mirosław Giurg, Jacek Skarżewski, Michael Gütschow
      First page: 43
      Abstract: The organo-seleniumdrug ebselen exhibits a wide range of pharmacological effects that are predominantly due to its interference with redox systems catalyzed by seleno enzymes, e.g., glutathione peroxidase and thioredoxin reductase. Moreover, ebselen can covalently interact with thiol groups of several enzymes. According to its pleiotropic mode of action, ebselen has been investigated in clinical trials for the prevention and treatment of different ailments. Fluorescence-labeled probes containing ebselen are expected to be suitable for further biological and medicinal studies. We therefore designed and synthesized two coumarin-tagged activity-based probes bearing the ebselen warhead. The heterodimers differ by the nature of the spacer structure, for which—in the second compound—a PEG/two-amide spacer was introduced. The interaction of this probe and of ebselen with two cysteine proteases was investigated.
      PubDate: 2016-07-08
      DOI: 10.3390/ph9030043
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 44: TRPM8 Puts the Chill on Prostate Cancer

    • Authors: Guillaume Grolez, Dimitra Gkika
      First page: 44
      Abstract: Prostate cancer (PCa) is one of the most frequently diagnosed cancers in developed countries. Several studies suggest that variations in calcium homeostasis are involved in carcinogenesis. Interestingly, (Transient Receptor Potential Melastatin member 8) TRPM8 calcium permeable channel expression is differentially regulated during prostate carcinogenesis, thereby suggesting a potential functional role for this channel in those cell processes, which are important for PCa evolution. Indeed, several studies have shown that TRPM8 plays a key role in processes such as the proliferation, viability and cell migration of PCa cells. Where cell migration is concerned, TRPM8 seems to have a protective anti-invasive effect and could be a particularly promising therapeutic target. The goal of this review is to inventory advances in understanding of the role of TRPM8 in the installation and progression of PCa.
      PubDate: 2016-07-09
      DOI: 10.3390/ph9030044
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 45: TRPV1 and TRPM8 in Treatment of Chronic

    • Authors: Eva Millqvist
      First page: 45
      Abstract: Chronic cough is common in the population, and among some there is no evident medical explanation for the symptoms. Such a refractory or idiopathic cough is now often regarded as a neuropathic disease due to dysfunctional airway ion channels, though the knowledge in this field is still limited. Persistent coughing and a cough reflex easily triggered by irritating stimuli, often in combination with perceived dyspnea, are characteristics of this disease. The patients have impaired quality of life and often reduced work capacity, followed by social and economic consequences. Despite the large number of individuals suffering from such a persisting cough, there is an unmet clinical need for effective cough medicines. The cough treatment available today often has little or no effect. Adverse effects mostly follow centrally acting cough drugs comprised of morphine and codeine, which demands the physician’s awareness. The possibilities of modulating airway transient receptor potential (TRP) ion channels may indicate new ways to treat the persistent cough “without a reason”. The TRP ion channel vanilloid 1 (TRPV1) and the TRP melastin 8 (TRPM8) appear as two candidates in the search for cough therapy, both as single targets and in reciprocal interaction.
      PubDate: 2016-07-28
      DOI: 10.3390/ph9030045
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 46: Differential Activation of TRP Channels
           in the Adult Rat Spinal Substantia Gelatinosa by Stereoisomers of
           Plant-Derived Chemicals

    • Authors: Eiichi Kumamoto, Tsugumi Fujita
      First page: 46
      Abstract: Activation of TRPV1, TRPA1 or TRPM8 channel expressed in the central terminal of dorsal root ganglion (DRG) neuron increases the spontaneous release of l-glutamate onto spinal dorsal horn lamina II (substantia gelatinosa; SG) neurons which play a pivotal role in regulating nociceptive transmission. The TRP channels are activated by various plant-derived chemicals. Although stereoisomers activate or modulate ion channels in a distinct manner, this phenomenon is not fully addressed for TRP channels. By applying the whole-cell patch-clamp technique to SG neurons of adult rat spinal cord slices, we found out that all of plant-derived chemicals, carvacrol, thymol, carvone and cineole, increase the frequency of spontaneous excitatory postsynaptic current, a measure of the spontaneous release of l-glutamate from nerve terminals, by activating TRP channels. The presynaptic activities were different between stereoisomers (carvacrol and thymol; (−)-carvone and (+)-carvone; 1,8-cineole and 1,4-cineole) in the extent or the types of TRP channels activated, indicating that TRP channels in the SG are activated by stereoisomers in a distinct manner. This result could serve to know the properties of the central terminal TRP channels that are targets of drugs for alleviating pain.
      PubDate: 2016-07-28
      DOI: 10.3390/ph9030046
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 47: Resiniferatoxin: The Evolution of the
           “Molecular Scalpel” for Chronic Pain Relief

    • Authors: Dorothy Brown
      First page: 47
      Abstract: Control of chronic pain is frequently inadequate or can be associated with debilitating side effects. Ablation of certain nociceptive neurons, while retaining all other sensory modalities and motor function, represents a new therapeutic approach to controlling severe pain while avoiding off-target side effects. transient receptor potential cation channel subfamily V member 1 (TRPV1) is a calcium permeable nonselective cation channel expressed on the peripheral and central terminals of small-diameter sensory neurons. Highly selective chemoablation of TRPV1-containing peripheral nerve endings, or the entire TRPV1-expressing neuron itself, can be used to control chronic pain. Administration of the potent TRPV1 agonist resiniferatoxin (RTX) to neuronal perikarya or nerve terminals induces calcium cytotoxicity and selective lesioning of the TRPV1-expressing nociceptive primary afferent population. This selective neuroablation has been coined “molecular neurosurgery” and has the advantage of sparing motor, proprioceptive, and other somatosensory functions that are so important for coordinated movement, performing activities of daily living, and maintaining quality of life. This review examines the mechanisms and preclinical data underlying the therapeutic use of RTX and examples of such use for the management of chronic pain in clinical veterinary and human pain states.
      PubDate: 2016-08-11
      DOI: 10.3390/ph9030047
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 48: Nutraceutical Improvement Increases the
           Protective Activity of Broccoli Sprout Juice in a Human Intestinal Cell
           Model of Gut Inflammation

    • Authors: Simonetta Ferruzza, Fausta Natella, Giulia Ranaldi, Chiara Murgia, Carlotta Rossi, Kajetan Trošt, Fulvio Mattivi, Mirella Nardini, Mariateresa Maldini, Anna Giusti, Elisabetta Moneta, Cristina Scaccini, Yula Sambuy, Giorgio Morelli, Simona Baima
      First page: 48
      Abstract: Benefits to health from a high consumption of fruits and vegetables are well established and have been attributed to bioactive secondary metabolites present in edible plants. However, the effects of specific health-related phytochemicals within a complex food matrix are difficult to assess. In an attempt to address this problem, we have used elicitation to improve the nutraceutical content of seedlings of Brassica oleracea grown under controlled conditions. Analysis, by LC-MS, of the glucosinolate, isothiocyanate and phenolic compound content of juices obtained from sprouts indicated that elicitation induces an enrichment of several phenolics, particularly of the anthocyanin fraction. To test the biological activity of basal and enriched juices we took advantage of a recently developed in vitro model of inflamed human intestinal epithelium. Both sprouts’ juices protected intestinal barrier integrity in Caco-2 cells exposed to tumor necrosis factor α under marginal zinc deprivation, with the enriched juice showing higher protection. Multivariate regression analysis indicated that the extent of rescue from stress-induced epithelial dysfunction correlated with the composition in bioactive molecules of the juices and, in particular, with a group of phenolic compounds, including several anthocyanins, quercetin-3-Glc, cryptochlorogenic, neochlorogenic and cinnamic acids.
      PubDate: 2016-08-12
      DOI: 10.3390/ph9030048
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 49: Acceptability, Safety, and Efficacy of
           Oral Administration of Extracts of Black or Red Maca (Lepidium meyenii) in
           Adult Human Subjects: A Randomized, Double-Blind, Placebo-Controlled Study

    • Authors: Carla Gonzales-Arimborgo, Irma Yupanqui, Elsa Montero, Dulce Alarcón-Yaquetto, Alisson Zevallos-Concha, Lidia Caballero, Manuel Gasco, Jianping Zhao, Ikhlas Khan, Gustavo Gonzales
      First page: 49
      Abstract: The plant maca, grown at 4000 m altitude in the Peruvian Central Andes, contains hypocotyls that have been used as food and in traditional medicine for centuries. The aim of this research was to provide results on some health effects of oral administration of spray-dried extracts of black or red maca (Lepidium meyenii) in adult human subjects living at low (LA) and high altitude (HA). A total of 175 participants were given 3 g of either placebo, black, or red maca extract daily for 12 weeks. Primary outcomes were changes in sexual desire, mood, energy, health-related quality of life score (HRQL), and chronic mountain sickness (CMS) score, or in glycaemia, blood pressure, and hemoglobin levels. Secondary outcomes were acceptability and safety, assessed using the Likert test and side effect self-recording, respectively, and the effect of altitude. At low altitude, 32, 30, and 32 participants started the study receiving placebo, red maca, or black maca, respectively. At high altitudes, 33, 35, and 31 participants started the study receiving placebo, red maca, and black maca, respectively. Consumption of spray-dried extracts of red and black maca resulted in improvement in mood, energy, and health status, and reduced CMS score. Fatty acids and macamides were higher in spray-dried extracts of black maca than in red maca. GABA predominated in spray-dried extracts of red maca. Effects on mood, energy, and CMS score were better with red maca. Black maca and, in smaller proportions, red maca reduced hemoglobin levels only in highlanders with abnormally high hemoglobin levels; neither variety of maca reduced hemoglobin levels in lowlanders. Black maca reduced blood glucose levels. Both varieties produced similar responses in mood, and HRQL score. Maca extracts consumed at LA or HA had good acceptability and did not show serious adverse effects. In conclusion, maca extract consumption relative to the placebo improved quality of life parameters. Differences in the level of improvement between red and black maca are probably due to differences in the composition of these two plant varieties. Both maca extracts were well tolerated and safe.
      PubDate: 2016-08-18
      DOI: 10.3390/ph9030049
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 50: TRP Channels as Therapeutic Targets in
           Diabetes and Obesity

    • Authors: Andrea Zsombok, Andrei Derbenev
      First page: 50
      Abstract: During the last three to four decades the prevalence of obesity and diabetes mellitus has greatly increased worldwide, including in the United States. Both the short- and long-term forecasts predict serious consequences for the near future, and encourage the development of solutions for the prevention and management of obesity and diabetes mellitus. Transient receptor potential (TRP) channels were identified in tissues and organs important for the control of whole body metabolism. A variety of TRP channels has been shown to play a role in the regulation of hormone release, energy expenditure, pancreatic function, and neurotransmitter release in control, obese and/or diabetic conditions. Moreover, dietary supplementation of natural ligands of TRP channels has been shown to have potential beneficial effects in obese and diabetic conditions. These findings raised the interest and likelihood for potential drug development. In this mini-review, we discuss possibilities for better management of obesity and diabetes mellitus based on TRP-dependent mechanisms.
      PubDate: 2016-08-17
      DOI: 10.3390/ph9030050
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 51: Design and Prototype of an Automated
           Column-Switching HPLC System for Radiometabolite Analysis

    • Authors: Neil Vasdev, Thomas Collier
      First page: 51
      Abstract: Column-switching high performance liquid chromatography (HPLC) is extensively used for the critical analysis of radiolabeled ligands and their metabolites in plasma. However, the lack of streamlined apparatus and consequently varying protocols remain as a challenge among positron emission tomography laboratories. We report here the prototype apparatus and implementation of a fully automated and simplified column-switching procedure to allow for the easy and automated determination of radioligands and their metabolites in up to 5 mL of plasma. The system has been used with conventional UV and coincidence radiation detectors, as well as with a single quadrupole mass spectrometer.
      PubDate: 2016-08-17
      DOI: 10.3390/ph9030051
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 52: TRPV1: A Target for Rational Drug

    • Authors: Vincenzo Carnevale, Tibor Rohacs
      First page: 52
      Abstract: Transient Receptor Potential Vanilloid 1 (TRPV1) is a non-selective, Ca2+ permeable cation channel activated by noxious heat, and chemical ligands, such as capsaicin and resiniferatoxin (RTX). Many compounds have been developed that either activate or inhibit TRPV1, but none of them are in routine clinical practice. This review will discuss the rationale for antagonists and agonists of TRPV1 for pain relief and other conditions, and strategies to develop new, better drugs to target this ion channel, using the newly available high-resolution structures.
      PubDate: 2016-08-23
      DOI: 10.3390/ph9030052
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 53: The Role of Antimicrobial Peptides in
           Influenza Virus Infection and Their Potential as Antiviral and
           Immunomodulatory Therapy

    • Authors: I-Ni Hsieh, Kevan Hartshorn
      First page: 53
      Abstract: Influenza A virus (IAV) remains a major threat that can cause severe morbidity and mortality due to rapid genomic variation. Resistance of IAVs to current anti-IAV drugs has been emerging, and antimicrobial peptides (AMPs) have been considered to be potential candidates for novel treatment against IAV infection. AMPs are endogenous proteins playing important roles in host defense through direct antimicrobial and antiviral activities and through immunomodulatory effects. In this review, we will discuss the anti-IAV and immunomodulatory effects of classical AMPs (defensins and cathelicidins), and proteins more recently discovered to have AMP-like activity (histones and Alzheimer’s associated β-amyloid). We will discuss the interactions between AMPs and other host defense proteins. Major emphasis will be placed on novel synthetic AMPs derived from modification of natural proteins, and on potential methods of increasing expression of endogenous AMPs, since these approaches may lead to novel antiviral therapeutics.
      PubDate: 2016-09-06
      DOI: 10.3390/ph9030053
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 54: Preparation of Temozolomide-Loaded
           Nanoparticles for Glioblastoma Multiforme Targeting—Ideal Versus Reality

    • Authors: Chooi Lee, Ing Ooi
      First page: 54
      Abstract: Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ’s efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach.
      PubDate: 2016-09-08
      DOI: 10.3390/ph9030054
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 55: TRPV3 in Drug Development

    • Authors: Lisa Broad, Adrian Mogg, Elizabeth Eberle, Marcia Tolley, Dominic Li, Kelly Knopp
      First page: 55
      Abstract: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist.
      PubDate: 2016-09-09
      DOI: 10.3390/ph9030055
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 56: Therapeutic Potential of Gramicidin S
           in the Treatment of Root Canal Infections

    • Authors: Marina Berditsch, Hannah Lux, Oleg Babii, Sergii Afonin, Anne Ulrich
      First page: 56
      Abstract: An intrinsic clindamycin-resistant Enterococcus faecalis, the most common single species present in teeth after failed root canal therapy, often possesses acquired tetracycline resistance. In these cases, root canal infections are commonly treated with Ledermix® paste, which contains demeclocycline, or the new alternative endodontic paste Odontopaste, which contains clindamycin; however, these treatments are often ineffective. We studied the killing activity of the cyclic antimicrobial peptide gramicidin S (GS) against planktonic and biofilm cells of tetracycline-resistant clinical isolates of E. faecalis. The high therapeutic potential of GS for the topical treatment of problematic teeth is based on the rapid bactericidal effect toward the biofilm-forming, tetracycline-resistant E. faecalis. GS reduces the cell number of planktonic cells within 20–40 min at a concentration of 40–80 μg/mL. It kills the cells of pre-grown biofilms at concentrations of 100–200 μg/mL, such that no re-growth is possible. The translocation of the peptide into the cell interior and its complexation with intracellular nucleotides, including the alarmon ppGpp, can explain its anti-biofilm effect. The successful treatment of persistently infected root canals of two volunteers confirms the high effectiveness of GS. The broad GS activity towards resistant, biofilm-forming E. faecalis suggests its applications for approval in root canal medication.
      PubDate: 2016-09-07
      DOI: 10.3390/ph9030056
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 57: Targeting TRPM2 in ROS-Coupled Diseases

    • Authors: Shinichiro Yamamoto, Shunichi Shimizu
      First page: 57
      Abstract: Under pathological conditions such as inflammation and ischemia-reperfusion injury large amounts of reactive oxygen species (ROS) are generated which, in return, contribute to the development and exacerbation of disease. The second member of the transient receptor potential (TRP) melastatin subfamily, TRPM2, is a Ca2+-permeable non-selective cation channel, activated by ROS in an ADP-ribose mediated fashion. In other words, TRPM2 functions as a transducer that converts oxidative stress into Ca2+ signaling. There is good evidence that TRPM2 plays an important role in ROS-coupled diseases. For example, in monocytes the influx of Ca2+ through TRPM2 activated by ROS contributes to the aggravation of inflammation via chemokine production. In this review, the focus is on TRPM2 as a molecular linker between ROS and Ca2+ signaling in ROS-coupled diseases.
      PubDate: 2016-09-07
      DOI: 10.3390/ph9030057
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 58: 1H and 15N NMR Analyses on Heparin,
           Heparan Sulfates and Related Monosaccharides Concerning the Chemical
           Exchange Regime of the N-Sulfo-Glucosamine Sulfamate Proton

    • Authors: Vitor Pomin
      First page: 58
      Abstract: Heparin and heparan sulfate are structurally related glycosaminoglycans (GAGs). Both GAGs present, although in different concentrations, N-sulfo-glucosamine (GlcNS) as one of their various composing units. The conditional fast exchange property of the GlcNS sulfamate proton in these GAGs has been pointed as the main barrier to its signal detection via NMR experiments, especially 1H-15N HSQC. Here, a series of NMR spectra is collected on heparin, heparan sulfate and related monosaccharides. The N-acetyl glucosamine-linked uronic acid types of these GAGs were properly assigned in the 1H-15N HSQC spectra. Dynamic nuclear polarization (DNP) was employed in order to facilitate 1D spectral acquisition of the sulfamate 15N signal of free GlcNS. Analyses on the multiplet pattern of scalar couplings of GlcNS 15N has helped to understand the chemical properties of the sulfamate proton in solution. The singlet peak observed for GlcNS happens due to fast chemical exchange of the GlcNS sulfamate proton in solution. Analyses on kinetics of alpha-beta anomeric mutarotation via 1H NMR spectra have been performed in GlcNS as well as other glucose-based monosaccharides. 1D 1H and 2D 1H-15N HSQC spectra recorded at low temperature for free GlcNS dissolved in a proton-rich solution showed signals from all exchangeable protons, including those belonging to the sulfamate group. This work suits well to the current grand celebration of one-century-anniversary of the discovery of heparin.
      PubDate: 2016-09-07
      DOI: 10.3390/ph9030058
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 59: Antimicrobial Peptides Targeting
           Gram-Positive Bacteria

    • Authors: Nermina Malanovic, Karl Lohner
      First page: 59
      Abstract: Antimicrobial peptides (AMPs) have remarkably different structures as well as biological activity profiles, whereupon most of these peptides are supposed to kill bacteria via membrane damage. In order to understand their molecular mechanism and target cell specificity for Gram-positive bacteria, it is essential to consider the architecture of their cell envelopes. Before AMPs can interact with the cytoplasmic membrane of Gram-positive bacteria, they have to traverse the cell wall composed of wall- and lipoteichoic acids and peptidoglycan. While interaction of AMPs with peptidoglycan might rather facilitate penetration, interaction with anionic teichoic acids may act as either a trap for AMPs or a ladder for a route to the cytoplasmic membrane. Interaction with the cytoplasmic membrane frequently leads to lipid segregation affecting membrane domain organization, which affects membrane permeability, inhibits cell division processes or leads to delocalization of essential peripheral membrane proteins. Further, precursors of cell wall components, especially the highly conserved lipid II, are directly targeted by AMPs. Thereby, the peptides do not inhibit peptidoglycan synthesis via binding to proteins like common antibiotics, but form a complex with the precursor molecule, which in addition can promote pore formation and membrane disruption. Thus, the multifaceted mode of actions will make AMPs superior to antibiotics that act only on one specific target.
      PubDate: 2016-09-20
      DOI: 10.3390/ph9030059
      Issue No: Vol. 9, No. 3 (2016)
  • Pharmaceuticals, Vol. 9, Pages 17: Non-Steroidal Anti-Inflammatory Drugs
           and Aspirin Therapy for the Treatment of Acute and Recurrent Idiopathic

    • Authors: Nicholas Schwier, Nicole Tran
      First page: 17
      Abstract: Aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay of therapy for the treatment of idiopathic pericarditis (IP). A comprehensive review consisting of pertinent clinical literature, pharmacokinetic, and pharmacodynamic considerations, has not been released in recent years. This review will facilitate the clinician’s understanding of pharmacotherapeutic considerations for using ASA/NSAIDs to treat IP. Data were compiled using clinical literature consisting of case reports, cohort data, retrospective and prospective studies, and manufacturer package inserts. ASA, ibuprofen, indometacin, and ketorolac relatively have the most evidence in the treatment of IP, provide symptomatic relief of IP, and should be tapered accordingly. ASA is the drug of choice in patients with coronary artery disease (CAD), heart failure (HF), or renal disease, but should be avoided in patients with asthma and nasal polyps, who are naïve to ASA therapy. Ibuprofen is an inexpensive and relatively accessible option in patients who do not have concomitant CAD, HF, or renal disease. Indometacin is not available over-the-counter in the USA, and has a relatively higher incidence of central nervous system (CNS) adverse effects. Ketorolac is an intravenous option; however, clinicians must be mindful of the maximum dose that can be administered. While ASA/NSAIDs do not ameliorate the disease process of IP, they are part of first-line therapy (along with colchicine), for preventing recurrence of IP. ASA/NSAID choice should be dictated by comorbid conditions, tolerability, and adverse effects. Additionally, the clinician should be mindful of considerations such as tapering, high-sensitivity CRP monitoring, bleeding risk, and contraindications to ASA/NSAID therapy.
      PubDate: 2016-03-23
      DOI: 10.3390/ph9020017
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 18: A Selenium Containing Inhibitor for the
           Treatment of Hepatocellular Cancer

    • Authors: Hephzibah Tagaram, Dhimant Desai, Guangfu Li, Dai Liu, C. Rountree, Kavitha Gowda, Arthur Berg, Shantu Amin, Kevin Staveley-O’Carroll, Eric Kimchi
      First page: 18
      Abstract: Hepatocellular carcinoma (HCC) is the third most deadly cancer in the world. New treatment strategies are desperately needed due to limited standard therapies. Activation of the Erk, Akt, and STAT3pathways is implicated in the prognosis of HCC. The Se,Se′-1,4-phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe), is a selenium-containing MAPK and PI3 kinase inhibitor, effectively inhibit tumorigenesis in a variety of experimental models. The aim of our study is to demonstrate the potential role of PBISe in the treatment of HCC. The anti-proliferative and pro-apoptotic ability of PBISe is studied in vitro in four human HCC cell lines and in vivo in a spontaneous murine HCC model. Inhibition of cancer growth was performed by cell viability assay and apoptosis by caspase 3/7, PARP cleavage, annexin-V, and TUNEL assays. Role of PBISe on PI3 kinase, MAPK and STAT3 signaling is determined by Western blotting. In vivo effects of PBISe on tumor sizes were monitored using MRI in a spontaneous murine HCC. Liver tissues from the PBISe-treated mice are analyzed for angiogenesis, proliferation, and signaling pathway markers. Overall, PBISe activated caspase-3/7 and increased DNA fragmentation, which is positively correlated with the increased PARP cleavage. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling with significant reduction in the tumor sizes (p < 0.007). PBISe-treated tumors reduced survival marker PCNA, and angiogenesis markers Vegf-A, Vegf-R3 and CD34. These results demonstrate the chemotherapeutic effects of PBISe, by inhibiting tumor growth and facilitating tumor apoptosis for HCC treatment.
      PubDate: 2016-03-24
      DOI: 10.3390/ph9020018
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 19: Search for Potent and Selective Aurora
           A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model

    • Authors: Natalya Vasilevich, Victor Tatarskiy, Elena Aksenova, Denis Kazyulkin, Ilya Afanasyev
      First page: 19
      Abstract: Based on the data for compounds known from the literature to be active against various types of Ser/Thr kinases, a general pharmachophore model for these types of kinases was developed. The search for the molecules fitting to this pharmacophore among the ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against Ser/Thr kinases such as Aurora A, Aurora B and Haspin. Our work on the optimization of these molecules against Aurora A kinase allowed us to achieve several hits in a 3–5 nM range of activity with rather good selectivity and Absorption, Distribution, Metabolism, and Excretion (ADME) properties, and cytotoxicity against 16 cancer cell lines. Thus, we showed the possibility to fine-tune the general Ser/Thr pharmacophore to design active and selective compounds against desired types of kinases.
      PubDate: 2016-04-13
      DOI: 10.3390/ph9020019
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 20: Alkanediamide-Linked Bisbenzamidines
           Are Promising Antiparasitic Agents

    • Authors: Jean Vanden Eynde, Annie Mayence, Madhusoodanan Mottamal, Cyrus Bacchi, Nigel Yarlett, Marcel Kaiser, Reto Brun, Tien Huang
      First page: 20
      Abstract: A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b.) subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive strain (NF54) and a chloroquine-resistant strain (K1). The in vitro cytotoxicity was determined against rat myoblast cells (L6). Seven compounds (5, 6, 10, 11, 12, 14, 15) showed high potency against both strains of T. brucei and P. falciparum with the inhibitory concentrations for 50% (IC50) in the nanomolar range (IC50 = 1–96 nM). None of the tested derivatives was significantly active against T. cruzi or L. donovani. Three of the more potent compounds (5, 6, 11) were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002) or drug-resistant (KETRI 2538 and KETRI 1992) clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences as possible binding sites for these compounds. Several of the tested compounds are suitable leads for the development of improved antiparasitic agents.
      PubDate: 2016-04-19
      DOI: 10.3390/ph9020020
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 21: The Post-Ovariectomy Interval Affects
           the Antidepressant-Like Action of Citalopram Combined with
           Ethynyl-Estradiol in the Forced Swim Test in Middle Aged Rats

    • Authors: Nelly Vega Rivera, Alfredo Gallardo Tenorio, Alonso Fernández-Guasti, Erika Estrada Camarena
      First page: 21
      Abstract: The use of a combined therapy with low doses of estrogens plus antidepressants to treat depression associated to perimenopause could be advantageous. However the use of these combinations is controversial due to several factors, including the time of intervention in relation to menopause onset. This paper analyzes whether time post-OVX influences the antidepressant-like action of a combination of ethynyl-estradiol (EE2) and citalopram (CIT) in the forced swim test (FST). Middle-aged (15 months old) female Wistar rats were ovariectomized and after one or three weeks treated with EE2 (1.25, 2.5 or 5.0 µg/rat, s.c.; −48 h) or CIT (1.25, 2.5, 5.0 or 10 mg/kg, i.p./3 injections in 24 h) and tested in the FST. In a second experiment, after one or three weeks of OVX, rats received a combination of an ineffective dose of EE2 (1.25 µg/rat, s.c., −48 h) plus CIT (2.5 mg/kg, i.p./3 injections in 24 h) and subjected to the FST. Finally, the uteri were removed and weighted to obtain an index of the peripheral effects of EE2 administration. EE2 (2.5 or 5.0 µg/rat) reduced immobility after one but not three weeks of OVX. In contrast, no CIT dose reduced immobility at one or three weeks after OVX. When EE2 (1.25 µg/rat) was combined with CIT (2.5 mg/kg) an antidepressant-like effect was observed at one but not three weeks post-OVX. The weight of the uteri augmented when EE2 was administrated three weeks after OVX. The data suggest that the time post-OVX is a crucial factor that contributes to observe the antidepressant-like effect of EE2 alone or in combination with CIT.
      PubDate: 2016-05-03
      DOI: 10.3390/ph9020021
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 22: Development of a New Radiofluorinated
           Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

    • Authors: Jianrong Liu, Barbara Wenzel, Sladjana Dukic-Stefanovic, Rodrigo Teodoro, Friedrich-Alexander Ludwig, Winnie Deuther-Conrad, Susann Schröder, Jean-Michel Chezal, Emmanuel Moreau, Peter Brust, Aurélie Maisonial-Besset
      First page: 22
      Abstract: Phosphodiesterases (PDEs) are enzymes that play a major role in cell signalling by hydrolysing the secondary messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) throughout the body and brain. Altered cyclic nucleotide-mediated signalling has been associated with a wide array of disorders, including neurodegenerative disorders. Recently, PDE5 has been shown to be involved in neurodegenerative disorders such as Alzheimer’s disease, but its precise role has not been elucidated yet. To visualize and quantify the expression of this enzyme in brain, we developed a radiotracer for specific PET imaging of PDE5. A quinoline-based lead compound has been structurally modified resulting in the fluoroethoxymethyl derivative ICF24027 with high inhibitory activity towards PDE5 (IC50 = 1.86 nM). Radiolabelling with fluorine-18 was performed by a one-step nucleophilic substitution reaction using a tosylate precursor (RCY(EOB) = 12.9% ± 1.8%; RCP > 99%; SA(EOS) = 70–126 GBq/μmol). In vitro autoradiographic studies of [18F]ICF24027 on different mouse tissue as well as on porcine brain slices demonstrated a moderate specific binding to PDE5. In vivo studies in mice revealed that [18F]ICF24027 was metabolized under formation of brain penetrable radiometabolites making the radiotracer unsuitable for PET imaging of PDE5 in brain.
      PubDate: 2016-04-21
      DOI: 10.3390/ph9020022
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 23: Evaluating the Role of p38 MAPK in the
           Accelerated Cell Senescence of Werner Syndrome Fibroblasts

    • Authors: Terence Davis, Amy Brook, Michal Rokicki, Mark Bagley, David Kipling
      First page: 23
      Abstract: Progeroid syndromes show features of accelerated ageing and are used as models for human ageing, of which Werner syndrome (WS) is one of the most widely studied. WS fibroblasts show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo use. In this work we used a panel of different p38 inhibitors selected for: (1) having been used successfully in vivo in either animal models or human clinical trials; (2) different modes of binding to p38; and (3) different off-target kinase specificity profiles, in order to critically address the role of p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796 the most effective.
      PubDate: 2016-04-28
      DOI: 10.3390/ph9020023
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 24: Unexploited Antineoplastic Effects of
           Commercially Available Anti-Diabetic Drugs

    • Authors: Panagiota Papanagnou, Theodora Stivarou, Maria Tsironi
      First page: 24
      Abstract: The development of efficacious antitumor compounds with minimal toxicity is a hot research topic. Numerous cancer cell targeted agents are evaluated daily in laboratories for their antitumorigenicity at the pre-clinical level, but the process of their introduction into the market is costly and time-consuming. More importantly, even if these new antitumor agents manage to gain approval, clinicians have no former experience with them. Accruing evidence supports the idea that several medications already used to treat pathologies other than cancer display pleiotropic effects, exhibiting multi-level anti-cancer activity and chemosensitizing properties. This review aims to present the anticancer properties of marketed drugs (i.e., metformin and pioglitazone) used for the management of diabetes mellitus (DM) type II. Mode of action, pre-clinical in vitro and in vivo or clinical data as well as clinical applicability are discussed here. Given the precious multi-year clinical experience with these non-antineoplastic drugs their repurposing in oncology is a challenging alternative that would aid towards the development of therapeutic schemes with less toxicity than those of conventional chemotherapeutic agents. More importantly, harnessing the antitumor function of these agents would save precious time from bench to bedside to aid the fight in the arena of cancer.
      PubDate: 2016-05-06
      DOI: 10.3390/ph9020024
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 25: Chemical Variations on the p53
           Reactivation Theme

    • Authors: Carlos Ribeiro, Cecília Rodrigues, Rui Moreira, Maria Santos
      First page: 25
      Abstract: Among the tumor suppressor genes, p53 is one of the most studied. It is widely regarded as the “guardian of the genome”, playing a major role in carcinogenesis. In fact, direct inactivation of the TP53 gene occurs in more than 50% of malignancies, and in tumors that retain wild-type p53 status, its function is usually inactivated by overexpression of negative regulators (e.g., MDM2 and MDMX). Hence, restoring p53 function in cancer cells represents a valuable anticancer approach. In this review, we will present an updated overview of the most relevant small molecules developed to restore p53 function in cancer cells through inhibition of the p53-MDMs interaction, or direct targeting of wild-type p53 or mutated p53. In addition, optimization approaches used for the development of small molecules that have entered clinical trials will be presented.
      PubDate: 2016-05-13
      DOI: 10.3390/ph9020025
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 26: How Efficient Is My (Medicinal)

    • Authors: Jean Vanden Eynde
      First page: 26
      Abstract: “Greening” a chemical transformation is not about only changing the nature of a solvent or decreasing the reaction temperature. There are metrics enabling a critical quantification of the efficiency of an experimental protocol. Some of them are applied to different sequences for the preparation of paracetamol in order to understand their performance parameters and elucidate pathways for improvement.
      PubDate: 2016-05-16
      DOI: 10.3390/ph9020026
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 27: Pharmacologic Evaluation of
           Antidepressant Activity and Synthesis of
           2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine Hydrobromide

    • Authors: Alexey Sarapultsev, Oleg Chupakhin, Petr Sarapultsev, Larisa Sidorova, Tatiana Tseitler
      First page: 27
      Abstract: Substituted thiadiazines exert a reliable therapeutic effect in treating stress, and a schematic description of their ability to influence all aspects of a stress response has been depicted. This study was conducted to pharmacologically evaluate compound L-17, a substituted thiadiazine, (2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide) for possible anti-psychotic/antidepressant activity. Compound L-17 was synthesized by cyclocondensation of α-bromoacetophenone with the original morpholine-4-carbothionic acid hydrazide. Pharmacologic evaluations were conducted using methods described by E.F. Lavretskaya (1985), and in accordance with published guidelines for studying drugs for neuroleptic activity. Compound L-17 was evaluated for various possible mechanisms of action, including its effects on cholinergic system agonists/antagonists, dopaminergic neurotransmission, the adrenergic system, and 5-HT3 serotonin receptors. One or more of these mechanisms may be responsible for the beneficial effects shown by thiadiazine compounds in experiments conducted to evaluate their activity in models of acute stress and acute myocardial infarction.
      PubDate: 2016-05-19
      DOI: 10.3390/ph9020027
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 28: Targeted Therapies for the Treatment of
           Pediatric Non-Hodgkin Lymphomas: Present and Future

    • Authors: Caryn Sorge, Jenny McDaniel, Ana Xavier
      First page: 28
      Abstract: Pediatric Non-Hodgkin Lymphomas (NHL) are a diverse group of malignancies and as such treatment can vary based on the different biological characteristics of each malignancy. Significant advancements are being made in the treatment and outcomes of this group of malignancies. This is in large part due to novel targeted drug therapies that are being used in combination with traditional chemotherapy. Here, we discuss several new lines of therapy that are being developed or are in current use for pediatric patients with NHL.
      PubDate: 2016-05-19
      DOI: 10.3390/ph9020028
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 29: Improved Aptamers for the Diagnosis and
           Potential Treatment of HER2-Positive Cancer

    • Authors: Marlies Gijs, Gregory Penner, Garth Blackler, Nathalie Impens, Sarah Baatout, André Luxen, An Aerts
      First page: 29
      Abstract: Aptamers provide a potential source of alternative targeting molecules for existing antibody diagnostics and therapeutics. In this work, we selected novel DNA aptamers targeting the HER2 receptor by an adherent whole-cell SELEX approach. Individual aptamers were identified by next generation sequencing and bioinformatics analysis. Two aptamers, HeA2_1 and HeA2_3, were shown to bind the HER2 protein with affinities in the nanomolar range. In addition, both aptamers were able to bind with high specificity to HER2-overexpressing cells and HER2-positive tumor tissue samples. Furthermore, we demonstrated that aptamer HeA2_3 is being internalized into cancer cells and has an inhibitory effect on cancer cell growth and viability. In the end, we selected novel DNA aptamers with great potential for the diagnosis and possible treatment of HER2-positive cancer.
      PubDate: 2016-05-19
      DOI: 10.3390/ph9020029
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 30: The Antistaphylococcal Activity of
           Citropin 1.1 and Temporin A against Planktonic Cells and Biofilms Formed
           by Isolates from Patients with Atopic Dermatitis: An Assessment of Their
           Potential to Induce Microbial Resistance Compared to Conventional

    • Authors: Malgorzata Dawgul, Wioletta Baranska-Rybak, Lidia Piechowicz, Marta Bauer, Damian Neubauer, Roman Nowicki, Wojciech Kamysz
      First page: 30
      Abstract: Staphylococcus aureus (SA) colonizes the vast majority of patients with atopic dermatitis (AD). Its resistance to antibiotics and ability to form biofilms are the main origins of therapeutic complications. Endogenous antimicrobial peptides (AMPs) exhibit strong activity against SA, including antibiotic resistant strains as well as bacteria existing in biofilm form. The purpose of the present work was to determine the antistaphylococcal activity of two amphibian peptides against SA isolated from patients with AD. The AMPs demonstrated permanent activity towards strains exposed to sublethal concentrations of the compounds and significantly stronger antibiofilm activity in comparison to that of conventional antimicrobials. The results suggest the potential application of amphibian AMPs as promising antistaphylococcal agents for the management of skin infections.
      PubDate: 2016-05-25
      DOI: 10.3390/ph9020030
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 31: Feasibility of Multiple Examinations
           Using 68Ga-Labelled Collagelin Analogues: Organ Distribution in Rat for
           Extrapolation to Human Organ and Whole-Body Radiation Dosimetry

    • Authors: Irina Velikyan, Ulrika Rosenström, Thomas Bulenga, Olof Eriksson, Gunnar Antoni
      First page: 31
      Abstract: Objectives: Fibrosis is involved in many chronic diseases. It affects the functionality of vital organs, such as liver, lung, heart and kidney. Two novel imaging agents for positron emission tomography (PET) imaging of fibrosis have previously pre-clinically demonstrated promising target binding and organ distribution characteristics. However, the relevant disease monitoring in the clinical setup would require multiple repetitive examinations per year. Thus, it is of paramount importance to investigate the absorbed doses and total effective doses and thus, the potential maximum number of examinations per year. Methods: Two cyclic peptide (c[CPGRVMHGLHLGDDEGPC]) analogues coupled via an ethylene glycol linker (EG2) to either 2-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazonan-1-yl)acetic acid (NO2A-Col) or 4-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-5-(tert-butoxy)-5-oxopentanoic acid (NODAGA-Col) were labelled with 68Ga. The resulting agents, [68Ga]Ga-NO2A-Col and [68Ga]Ga-NODAGA-Col, were administered in the tail vein of male and female Sprague–Dawley rats (N = 24). An ex vivo organ distribution study was performed at the 5-, 10-, 20-, 40-, 60- and 120-min time points. The resulting data were extrapolated for the estimation of human organ and total body absorbed and total effective doses using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1) assuming a similar organ distribution pattern between the species. Time-integrated radioactivity in each organ was calculated by trapezoidal integration followed by a single-exponential fit to the data points extrapolated to infinity. The resulting values were used for the residence time calculation. Results: Ex vivo organ distribution data revealed fast blood clearance and washout from most of the organs. Although the highest organ absorbed dose was found for kidneys (0.1 mGy/MBq), this organ was not the dose-limiting one and would allow for the administration of over 1460 MBq per year for both [68Ga]Ga-NO2A-Col and [68Ga]Ga-NODAGA-Col. The total effective dose was the limiting parameter with 0.0155/0.0156 (female/male) mSv/MBq and 0.0164/0.0158 (female/male) mSv/MBq, respectively, for [68Ga]Ga-NO2A-Col and [68Ga]Ga-NODAGA-Col. This corresponded to the total amount of radioactivity that could be administered per year of 643 and 621 MBq before reaching the annual limit of 10 mSv. Thus, up to six examinations would be possible. The residence time and organ absorbed doses in liver and spleen were higher for [68Ga]Ga-NODAGA-Col as compared to [68Ga]Ga-NO2A-Col. Conclusion: The limiting parameter for the administered dose was the total effective dose that would allow for at least six examinations per year that might be sufficient for adequate disease monitoring in longitudinal studies and a routine clinical setup.
      PubDate: 2016-06-06
      DOI: 10.3390/ph9020031
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 32: Synthesis and Pharmacological
           Properties of Novel Esters Based on Monocyclic Terpenes and GABA

    • Authors: Mariia Nesterkina, Iryna Kravchenko
      First page: 32
      Abstract: Novel esters of γ-aminobutyric acid (GABA) with monocyclic terpenes were synthesized via Steglich esterification and characterized by 1H-NMR, IR and mass spectral studies. Their anticonvulsant, analgesic and anti-inflammatory activities were evaluated by a PTZ-induced convulsion model, AITC-induced hyperalgesia and AITC-induced paw edema, respectively. All studied esters, as well as their parent terpenes, were found to produce antinociceptive effects in the AITC-induced model and attenuate acute pain more than the reference drug benzocaine after their topical application. GABA esters of l-menthol and thymol were also shown to exceed the reference drug ibuprofen in their ability to decrease the inflammatory state induced by intraplantar injection of the TRPA1 activator AITC. The present findings indicate that GABA esters of carvacrol and guaiacol are not a classical prodrug and possess their own pharmacological activity. Prolonged antiseizure action of the ester based on the amino acid and guaiacol (200 mg/kg) was revealed at 24 h after oral administration. Furthermore, orally co-administered gidazepam (1 mg/kg) and GABA esters of l-menthol, thymol and carvacrol produce synergistic seizure prevention effects.
      PubDate: 2016-06-13
      DOI: 10.3390/ph9020032
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 33: Tumor Heterogeneity, Single-Cell
           Sequencing, and Drug Resistance

    • Authors: Felix Schmidt, Thomas Efferth
      First page: 33
      Abstract: Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1) single cell isolation (e.g., by laser-capture microdissection), fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase), and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems). Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients.
      PubDate: 2016-06-16
      DOI: 10.3390/ph9020033
      Issue No: Vol. 9, No. 2 (2016)
  • Pharmaceuticals, Vol. 9, Pages 12: Minimally-Myelosuppressive
           Asparaginase-Containing Induction Regimen for Treatment of a Jehovah’s
           Witness with mutant IDH1/NPM1/NRAS Acute Myeloid Leukemia

    • Authors: Ashkan Emadi, Najeebah Bade, Brandi Stevenson, Zeba Singh
      First page: 12
      Abstract: Treatment of patients with acute myeloid leukemia (AML) who do not wish to accept blood product transfusion, including Jehovah’s Witnesses, is extremely challenging. The use of conventional chemotherapy for induction of complete remission (CR) results in profound anemia and thrombocytopenia requiring frequent transfusions of blood products, without which such treatment will be life-threatening. Finding a well tolerable, minimally myelosuppressive induction regimen for such patients with AML is a clear example of area of unmet medical need. Here, we report a successful treatment of a 52-year-old Jehovah’s Witness with newly diagnosed AML with peg-asparaginase, vincristine and methylprednisolone. The AML was characterized with normal karyotype, and mutations in isocitrate dehydrogenase 1 (IDH1-Arg132Ser), nucleophosmin 1 (NPM1-Trp289Cysfs*12) and neuroblastoma RAS viral oncogene homolog (NRAS-G1y12Va1). After one 28-day cycle of treatment, the patient achieved complete remission with incomplete count recovery (CRi) and after the second cycle, he achieved CR with full blood count recovery. The patient has never received any blood products. Notwithstanding that myeloperoxidase-induced oxidative degradation of vincristine results in its lack of activity as monotherapy in AML, its combination with corticosteroid and asparaginase has resulted in a robust remission in this patient. Diminished steroid clearance by asparaginase activity as well as reduction in serum glutamine level induced by glutaminase enzymatic activity of asparaginase may have contributed to effective killing of the myeloblasts that carry IDH1/NPM1/NRAS mutations. In conclusion, asparaginase-containing regimens, which are approved for treatment of acute lymphoblastic leukemia (ALL) but not AML, can be used to treat patients with AML who do not accept blood transfusion.
      PubDate: 2016-03-10
      DOI: 10.3390/ph9010012
      Issue No: Vol. 9, No. 1 (2016)
  • Pharmaceuticals, Vol. 9, Pages 13: Potential Use of Antimicrobial Peptides
           as Vaginal Spermicides/Microbicides

    • Authors: Nongnuj Tanphaichitr, Nopparat Srakaew, Rhea Alonzi, Wongsakorn Kiattiburut, Kessiri Kongmanas, Ruina Zhi, Weihua Li, Mark Baker, Guanshun Wang, Duane Hickling
      First page: 13
      Abstract: The concurrent increases in global population and sexually transmitted infection (STI) demand a search for agents with dual spermicidal and microbicidal properties for topical vaginal application. Previous attempts to develop the surfactant spermicide, nonoxynol-9 (N-9), into a vaginal microbicide were unsuccessful largely due to its inefficiency to kill microbes. Furthermore, N-9 causes damage to the vaginal epithelium, thus accelerating microbes to enter the women’s body. For this reason, antimicrobial peptides (AMPs), naturally secreted by all forms of life as part of innate immunity, deserve evaluation for their potential spermicidal effects. To date, twelve spermicidal AMPs have been described including LL-37, magainin 2 and nisin A. Human cathelicidin LL-37 is the most promising spermicidal AMP to be further developed for vaginal use for the following reasons. First, it is a human AMP naturally produced in the vagina after intercourse. Second, LL-37 exerts microbicidal effects to numerous microbes including those that cause STI. Third, its cytotoxicity is selective to sperm and not to the female reproductive tract. Furthermore, the spermicidal effects of LL-37 have been demonstrated in vivo in mice. Therefore, the availability of LL-37 as a vaginal spermicide/microbicide will empower women for self-protection against unwanted pregnancies and STI.
      PubDate: 2016-03-11
      DOI: 10.3390/ph9010013
      Issue No: Vol. 9, No. 1 (2016)
  • Pharmaceuticals, Vol. 9, Pages 14: First International Electronic
           Conference on Medicinal Chemistry (ECMC-1)

    • Authors: Annie Mayence, Jean Vanden Eynde
      First page: 14
      Abstract: The first International Electronic Conference on Medicinal Chemistry, organized and sponsored by MDPI AG, publisher, and the Journal Pharmaceuticals, took place in November 2015 on the SciForum website. More than 200 authors from 18 countries participated in the event and was attended by 25,000 visitors who had the opportunity to browse among 55 presentations, keynotes, and videos. A short description of some works presented during that scientific meeting is disclosed in this report.
      PubDate: 2016-03-11
      DOI: 10.3390/ph9010014
      Issue No: Vol. 9, No. 1 (2016)
  • Pharmaceuticals, Vol. 9, Pages 15: 11th National Meeting of Organic
           Chemistry and 4th Meeting of Therapeutic Chemistry

    • Authors: Maria Sousa, Maria Araújo, Maria do Vale, Paula Andrade, Paula Branco, Paula Gomes, Rui Moreira, Teresa Pinho e Melo, Victor Freitas
      First page: 15
      Abstract: For the first time under the auspices of Sociedade Portuguesa de Química, the competences of two important fields of Chemistry are brought together into a single event, the 11st National Organic Chemistry Meeting and the the 4th National Medicinal Chemistry Meeting, to highlight complementarities and to promote new synergies. s of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.
      PubDate: 2016-03-17
      DOI: 10.3390/ph9010015
      Issue No: Vol. 9, No. 1 (2016)
  • Pharmaceuticals, Vol. 9, Pages 16: Activity of Gallium Meso- and
           Protoporphyrin IX against Biofilms of Multidrug-Resistant Acinetobacter
           baumannii Isolates

    • Authors: David Chang, Rebecca Garcia, Kevin Akers, Katrin Mende, Clinton Murray, Joseph Wenke, Carlos Sanchez
      First page: 16
      Abstract: Acinetobacter baumannii is a challenging pathogen due to antimicrobial resistance and biofilm development. The role of iron in bacterial physiology has prompted the evaluation of iron-modulation as an antimicrobial strategy. The non-reducible iron analog gallium(III) nitrate, Ga(NO3)3, has been shown to inhibit A. baumannii planktonic growth; however, utilization of heme-iron by clinical isolates has been associated with development of tolerance. These observations prompted the evaluation of iron-heme sources on planktonic and biofilm growth, as well as antimicrobial activities of gallium meso- and protoporphyrin IX (Ga-MPIX and Ga-PPIX), metal heme derivatives against planktonic and biofilm bacteria of multidrug-resistant (MDR) clinical isolates of A. baumannii in vitro. Ga(NO3)3 was moderately effective at reducing planktonic bacteria (64 to 128 µM) with little activity against biofilms (≥512 µM). In contrast, Ga-MPIX and Ga-PPIX were highly active against planktonic bacteria (0.25 to 8 µM). Cytotoxic effects in human fibroblasts were observed following exposure to concentrations exceeding 128 µM of Ga-MPIX and Ga-PPIX. We observed that the gallium metal heme conjugates were more active against planktonic and biofilm bacteria, possibly due to utilization of heme-iron as demonstrated by the enhanced effects on bacterial growth and biofilm formation.
      PubDate: 2016-03-17
      DOI: 10.3390/ph9010016
      Issue No: Vol. 9, No. 1 (2016)
  • Pharmaceuticals, Vol. 10, Pages 1: Progress Confirmed for Pharmaceuticals
           in 2016

    • Authors: Jean Vanden Eynde
      First page: 1
      Abstract: n/a
      PubDate: 2016-12-26
      DOI: 10.3390/ph10010001
      Issue No: Vol. 10, No. 1 (2016)
  • Pharmaceuticals, Vol. 10, Pages 2: The Phosphorylation of PDX-1 by Protein
           Kinase CK2 Is Crucial for Its Stability

    • Authors: Sabrina Klein, Rui Meng, Mathias Montenarh, Claudia Götz
      First page: 2
      Abstract: The homeodomain protein PDX-1 is a critical regulator of pancreatic development and insulin production in pancreatic β-cells. We have recently shown that PDX-1 is a substrate of protein kinase CK2; a multifunctional protein kinase which is implicated in the regulation of various cellular aspects, such as differentiation, proliferation, and survival. The CK2 phosphorylation site of PDX-1 is located within the binding region of the E3 ubiquitin ligase adaptor protein PCIF1. To study the interaction between PDX-1 and PCIF1 we used immunofluorescence analysis, co-immunoprecipitation, GST-pull-down studies, and proximity ligation assay (PLA). For the analysis of the stability of PDX-1 we performed a cycloheximide chase. We used PDX-1 in its wild-type form as well as phosphomutants of the CK2 phosphorylation site. In pancreatic β-cells PDX-1 binds to PCIF1. The phosphorylation of PDX-1 by CK2 increases the ratio of PCIF1 bound to PDX-1. The stability of PDX-1 is extended in the absence of CK2 phosphorylation. Our results identified protein kinase CK2 as new important modulator of the stability of PDX-1.
      PubDate: 2016-12-28
      DOI: 10.3390/ph10010002
      Issue No: Vol. 10, No. 1 (2016)
  • Pharmaceuticals, Vol. 10, Pages 3: Germinated Thai Black Rice Extract
           Protects Experimental Diabetic Rats from Oxidative Stress and Other
           Diabetes-Related Consequences

    • Authors: Chaiyavat Chaiyasut, Bhagavathi Sivamaruthi, Noppawat Pengkumsri, Waranya Keapai, Periyanaina Kesika, Manee Saelee, Parichart Tojing, Sasithorn Sirilun, Khontaros Chaiyasut, Sartjin Peerajan, Narissara Lailerd
      First page: 3
      Abstract: Background: Diabetes mellitus (DM), particularly type 2 DM (T2DM), is one of the most common metabolic disorder worldwide. The prevention measures and treatment strategies for DM are improving steadily. The current study explains the impact of germination on phytochemical content of Thai black rice (BR), and the influence of germinated BR extract (GBRE) supplementation on diabetic conditions in rats. Methods: BR was germinated and the phenolic, anthocyanin, and γ-aminobutyric acid (GABA) content of the extract were analyzed using HPLC and spectrophotometric methods. Streptozotocin-induced diabetic rats were supplemented with high and low doses of GBRE. The plasma glucose, insulin, cholesterol, triglyceride levels, antioxidant status, and antioxidant enzyme levels of treated animals were assessed using ELISA and spectrophotometric methods. Results: Germination enhanced the GABA content of BR, and GBRE intervention improved the total antioxidant capacity and antioxidant enzymes levels in diabetic rats. The plasma glucose, cholesterol, triglyceride levels, insulin resistance and glucose tolerance were reduced, and the degree of insulin secretion in rat plasma was significantly increased upon GBRE treatment. Both pre and post-treatment approaches showed the anti-diabetic ability of GBRE. In most of the analyzed parameters, GBRE was quite equal to the performance of drug-metformin. Conclusions: GBRE supplementation helps prevent and manage the consequences of DM.
      PubDate: 2016-12-28
      DOI: 10.3390/ph10010003
      Issue No: Vol. 10, No. 1 (2016)
  • Pharmaceuticals, Vol. 10, Pages 4: Drosophila Protein Kinase CK2:
           Genetics, Regulatory Complexity and Emerging Roles during Development

    • Authors: Mohna Bandyopadhyay, Scott Arbet, Clifton Bishop, Ashok Bidwai
      First page: 4
      Abstract: CK2 is a Ser/Thr protein kinase that is highly conserved amongst all eukaryotes. It is a well-known oncogenic kinase that regulates vital cell autonomous functions and animal development. Genetic studies in the fruit fly Drosophila are providing unique insights into the roles of CK2 in cell signaling, embryogenesis, organogenesis, neurogenesis, and the circadian clock, and are revealing hitherto unknown complexities in CK2 functions and regulation. Here, we review Drosophila CK2 with respect to its structure, subunit diversity, potential mechanisms of regulation, developmental abnormalities linked to mutations in the gene encoding CK2 subunits, and emerging roles in multiple aspects of eye development. We examine the Drosophila CK2 “interaction map” and the eye-specific “transcriptome” databases, which raise the prospect that this protein kinase has many additional targets in the developing eye. We discuss the possibility that CK2 functions during early retinal neurogenesis in Drosophila and mammals bear greater similarity than has been recognized, and that this conservation may extend to other developmental programs. Together, these studies underscore the immense power of the Drosophila model organism to provide new insights and avenues to further investigate developmentally relevant targets of this protein kinase.
      PubDate: 2016-12-29
      DOI: 10.3390/ph10010004
      Issue No: Vol. 10, No. 1 (2016)
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