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  Subjects -> CHEMISTRY (Total: 762 journals)
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CHEMISTRY (527 journals)            First | 1 2 3 4 5 6 | Last

Journal of Inclusion Phenomena and Macrocyclic Chemistry     Hybrid Journal   (2 followers)
Journal of Inorganic Biochemistry     Hybrid Journal   (3 followers)
Journal of Labelled Compounds and Radiopharmaceuticals     Hybrid Journal  
Journal of Macromolecular Science, Part A: Pure and Applied Chemistry     Hybrid Journal   (4 followers)
Journal of Mass Spectrometry     Hybrid Journal   (19 followers)
Journal of Materials Chemistry A     Full-text available via subscription   (22 followers)
Journal of Materials Chemistry B     Full-text available via subscription   (5 followers)
Journal of Materials Chemistry C     Full-text available via subscription   (6 followers)
Journal of Materials Research     Full-text available via subscription   (8 followers)
Journal of Mathematical Chemistry     Hybrid Journal   (4 followers)
Journal of Medicinal Chemistry     Full-text available via subscription   (96 followers)
Journal of Membrane Science     Hybrid Journal   (8 followers)
Journal of Modern Chemistry & Chemical Technology     Full-text available via subscription   (1 follower)
Journal of Molecular Catalysis A: Chemical     Hybrid Journal   (2 followers)
Journal of Molecular Graphics and Modelling     Hybrid Journal   (3 followers)
Journal of Molecular Liquids     Hybrid Journal   (3 followers)
Journal of Molecular Modeling     Hybrid Journal   (3 followers)
Journal of Molecular Recognition     Hybrid Journal  
Journal of Molecular Spectroscopy     Hybrid Journal   (6 followers)
Journal of Molecular Structure     Hybrid Journal   (3 followers)
Journal of Nanostructure in Chemistry     Open Access   (5 followers)
Journal of Natural Gas Chemistry     Full-text available via subscription   (2 followers)
Journal of Nepal Chemical Society     Open Access  
Journal of Nucleic Acids Investigation     Open Access   (2 followers)
Journal of Ocean University of China (English Edition)     Hybrid Journal   (2 followers)
Journal of Organometallic Chemistry     Hybrid Journal   (12 followers)
Journal of Photochemistry and Photobiology A: Chemistry     Hybrid Journal   (3 followers)
Journal of Photochemistry and Photobiology C: Photochemistry Reviews     Full-text available via subscription   (4 followers)
Journal of Polymer Science Part A: Polymer Chemistry     Hybrid Journal   (115 followers)
Journal of Polymers     Open Access  
Journal of Porphyrins and Phthalocyanines     Hybrid Journal   (2 followers)
Journal of Pure and Applied Chemistry Research     Open Access  
Journal of Raman Spectroscopy     Hybrid Journal   (9 followers)
Journal of Saudi Chemical Society     Open Access  
Journal of Solid State Chemistry     Hybrid Journal   (12 followers)
Journal of Solution Chemistry     Hybrid Journal  
Journal of Structural Chemistry     Hybrid Journal  
Journal of Sulfur Chemistry     Hybrid Journal   (2 followers)
Journal of Superhard Materials     Hybrid Journal   (1 follower)
Journal of Surfactants and Detergents     Hybrid Journal   (5 followers)
Journal of Systems Chemistry     Open Access   (1 follower)
Journal of Taibah University for Science     Open Access  
Journal of the American Chemical Society     Full-text available via subscription   (178 followers)
Journal of the American Society for Mass Spectrometry     Hybrid Journal   (15 followers)
Journal of the American Society of Brewing Chemists     Full-text available via subscription   (1 follower)
Journal of the Bangladesh Chemical Society     Open Access  
Journal of the Chilean Chemical Society     Open Access   (2 followers)
Journal of the Iranian Chemical Society     Hybrid Journal   (1 follower)
Journal of the Korean Society for Applied Biological Chemistry     Hybrid Journal   (1 follower)
Journal of the Mexican Chemical Society     Open Access   (1 follower)
Journal of Theoretical and Computational Chemistry     Hybrid Journal   (6 followers)
Journal of Theoretical Chemistry     Open Access  
Journal of Wood Chemistry and Technology     Hybrid Journal   (7 followers)
JPC - Journal of Planar Chromatography - Modern TLC     Full-text available via subscription   (5 followers)
Jurnal Penelitian Sains (JPS)     Open Access  
Jurnal Teknologi Informasi     Open Access   (3 followers)
Kinetics and Catalysis     Hybrid Journal   (3 followers)
Korea-Australia Rheology Journal     Hybrid Journal  
Langmuir     Full-text available via subscription   (35 followers)
Latvian Journal of Chemistry     Open Access   (1 follower)
Lebensmittelchemie     Hybrid Journal   (1 follower)
Lipid Insights     Open Access   (1 follower)
Luminescence     Hybrid Journal   (1 follower)
Macromolecular Materials & Engineering     Hybrid Journal   (2 followers)
Macromolecular Rapid Communications     Hybrid Journal   (4 followers)
Macromolecular Research     Hybrid Journal  
Macromolecular Symposia     Hybrid Journal  
Macromolecular Theory and Simulations     Hybrid Journal  
Macromolecules     Full-text available via subscription   (31 followers)
Magnetic Resonance in Chemistry     Hybrid Journal   (4 followers)
Main Group Chemistry     Hybrid Journal  
Marine Chemistry     Hybrid Journal   (4 followers)
Marine Drugs     Open Access   (4 followers)
MATEC Web of Conferences     Open Access  
Materials Characterization     Hybrid Journal   (21 followers)
Materials Horizons     Full-text available via subscription  
Materials Research Bulletin     Hybrid Journal   (14 followers)
Materials Science Monographs     Full-text available via subscription   (1 follower)
Materials Science-Poland     Hybrid Journal  
Materials Sciences and Applications     Open Access   (3 followers)
MedChemComm     Full-text available via subscription   (3 followers)
Medicinal Chemistry Research     Hybrid Journal   (8 followers)
Metallography, Microstructure, and Analysis     Hybrid Journal   (1 follower)
Metallomics     Full-text available via subscription  
Micro and Nano Systems Letters     Open Access   (1 follower)
Microchimica Acta     Hybrid Journal   (1 follower)
Microporous and Mesoporous Materials     Hybrid Journal   (3 followers)
Modern Research in Catalysis     Open Access   (1 follower)
Molbank     Open Access  
Molecules     Open Access   (2 followers)
Molecules and Cells     Hybrid Journal   (1 follower)
Monatshefte für Chemie - Chemical Monthly     Hybrid Journal   (3 followers)
Moscow University Chemistry Bulletin     Hybrid Journal   (2 followers)
MRS Bulletin     Full-text available via subscription   (4 followers)
MRS Online Proceedings     Full-text available via subscription   (1 follower)
Nachrichten aus der Chemie     Full-text available via subscription   (1 follower)
Nano Reviews     Open Access   (15 followers)
Nanomaterials and the Environment     Open Access  
Nanoscale     Full-text available via subscription   (11 followers)
Nanoscale Research Letters     Open Access   (4 followers)

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Pharmaceuticals    [7 followers]  Follow    
  This is an Open Access Journal Open Access journal
     ISSN (Print) 1424-8247
     Published by MDPI Homepage  [119 journals]   [SJR: 0.46]   [H-I: 13]
  • Pharmaceuticals, Vol. 7, Pages 366-391: “Specificity
           Determinants” Improve Therapeutic Indices of Two Antimicrobial
           Peptides Piscidin 1 and Dermaseptin S4 Against the Gram-negative Pathogens
           Acinetobacter baumannii and Pseudomonas aeruginosa
    • Authors: Ziqing Jiang, Adriana Vasil, Michael Vasil, Robert Hodges
      Pages: 366 - 391
      Abstract: A new class of antimicrobial agents with lower rates of resistance and different targets is urgently needed because of the rapidly increasing resistance to classical antibiotics. Amphipathic cationic α-helical antimicrobial peptides (AMPs) represent such a class of compounds. In our previous studies, using a 26-residue de novo designed antimicrobial peptide, we proposed the concept of “specificity determinant(s)”: positively charged residue(s) in the center of the non-polar face of AMPs that could decrease hemolytic activity/toxicity but increase or maintain the same level of antimicrobial activity to increase dramatically the therapeutic index. In the current study, we used d-enantiomers of two AMPs, Piscidin 1 isolated from fish and dermaseptin S4 isolated from frog. We substituted different positions in the center of the hydrophobic face with one or two lysine residue(s) (one or two “specificity determinant(s)”). This simple modification not only maintained or improved antimicrobial activity against Gram-negative pathogens Acinetobacter baumannii (11 strains) and Pseudomonas aeruginosa (6 strains), but also dramatically decreased hemolytic activity of human red blood cells, as predicted. Therapeutic indices improved by 55-fold and 730-fold for piscidin 1 (I9K) and dermaseptin S4 (L7K, A14K), respectively, against A. baumannii. Similarly, the therapeutic indices improved 32-fold and 980-fold for piscidin 1 (I9K) and dermaseptin S4 (L7K, A14K), respectively, against P. aeruginosa.
      PubDate: 2014-03-25
      DOI: 10.3390/ph7040366
      Issue No: Vol. 7, No. 4 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 392-418: Radiolabeling of Nanoparticles and
           Polymers for PET Imaging
    • Authors: Katharina Stockhofe, Johannes Postema, Hanno Schieferstein, Tobias Ross
      Pages: 392 - 418
      Abstract: Nanomedicine has become an emerging field in imaging and therapy of malignancies. Nanodimensional drug delivery systems have already been used in the clinic, as carriers for sensitive chemotherapeutics or highly toxic substances. In addition, those nanodimensional structures are further able to carry and deliver radionuclides. In the development process, non-invasive imaging by means of positron emission tomography (PET) represents an ideal tool for investigations of pharmacological profiles and to find the optimal nanodimensional architecture of the aimed-at drug delivery system. Furthermore, in a personalized therapy approach, molecular imaging modalities are essential for patient screening/selection and monitoring. Hence, labeling methods for potential drug delivery systems are an indispensable need to provide the radiolabeled analog. In this review, we describe and discuss various approaches and methods for the labeling of potential drug delivery systems using positron emitters.
      PubDate: 2014-04-02
      DOI: 10.3390/ph7040392
      Issue No: Vol. 7, No. 4 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 419-432: The Impact of Lipoproteins on
           Wound Healing: Topical HDL Therapy Corrects Delayed Wound Healing in
           Apolipoprotein E Deficient Mice
    • Authors: Stephanie Gordts, Ilayaraja Muthuramu, Ruhul Amin, Frank Jacobs, Bart De Geest
      Pages: 419 - 432
      Abstract: Chronic non-healing wounds lead to considerable morbidity and mortality. Pleiotropic effects of high density lipoproteins (HDL) may beneficially affect wound healing. The objectives of this murine study were: (1) to investigate the hypothesis that hypercholesterolemia induces impaired wound healing and (2) to study the effect of topical HDL administration in a model of delayed wound healing. A circular full thickness wound was created on the back of each mouse. A silicone splint was used to counteract wound contraction. Coverage of the wound by granulation tissue and by epithelium was quantified every 2 days. Re-epithelialization from day 0 till day 10 was unexpectedly increased by 21.3% (p < 0.05) in C57BL/6 low density lipoprotein (LDLr) deficient mice with severe hypercholesterolemia (489 ± 14 mg/dL) compared to C57BL/6 mice and this effect was entirely abrogated following cholesterol lowering adenoviral LDLr gene transfer. In contrast, re-epithelialization in hypercholesterolemic (434 ± 16 mg/dL) C57BL/6 apolipoprotein (apo) E−/− mice was 22.6% (p < 0.0001) lower than in C57BL/6 mice. Topical HDL gel administered every 2 days increased re-epithelialization by 25.7% (p < 0.01) in apo E−/− mice. In conclusion, topical HDL application is an innovative therapeutic strategy that corrects impaired wound healing in apo E−/− mice.
      PubDate: 2014-04-03
      DOI: 10.3390/ph7040419
      Issue No: Vol. 7, No. 4 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 433-452: Amino Acid Prodrugs: An Approach
           to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir
    • Authors: Mitesh Patel, Nanda Mandava, Mitan Gokulgandhi, Dhananjay Pal, Ashim Mitra
      Pages: 433 - 452
      Abstract: Poor systemic concentrations of lopinavir (LPV) following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their potential to circumvent efflux processes and first pass effects. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to LPV. Prodrug formation was confirmed by the LCMS/MS and NMR technique. Interaction of LPV prodrugs with efflux proteins were carried out in P-gp (MDCK-MDR1) and MRP2 (MDCK-MRP2) transfected cells. Aqueous solubility studies demonstrated that prodrugs generate higher solubility relative to LPV. Prodrugs displayed higher stability under acidic conditions and degraded significantly with rise in pH. Uptake and transport data suggested that prodrugs carry significantly lower affinity towards P-gp and MRP2 relative to LPV. Moreover, prodrugs exhibited higher liver microsomal stability relative to LPV. Hence, amino acid prodrug modification might be a viable approach for enhancing LPV absorption across intestinal epithelial and brain endothelial cells which expresses high levels of P-gp and MRP2.
      PubDate: 2014-04-10
      DOI: 10.3390/ph7040433
      Issue No: Vol. 7, No. 4 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 220-247: Avian Antimicrobial Host Defense
           Peptides: From Biology to Therapeutic Applications
    • Authors: Guolong Zhang, Lakshmi Sunkara
      Pages: 220 - 247
      Abstract: Host defense peptides (HDPs) are an important first line of defense with antimicrobial and immunomoduatory properties. Because they act on the microbial membranes or host immune cells, HDPs pose a low risk of triggering microbial resistance and therefore, are being actively investigated as a novel class of antimicrobials and vaccine adjuvants. Cathelicidins and β-defensins are two major families of HDPs in avian species. More than a dozen HDPs exist in birds, with the genes in each HDP family clustered in a single chromosomal segment, apparently as a result of gene duplication and diversification. In contrast to their mammalian counterparts that adopt various spatial conformations, mature avian cathelicidins are mostly α-helical. Avian β-defensins, on the other hand, adopt triple-stranded β-sheet structures similar to their mammalian relatives. Besides classical β-defensins, a group of avian-specific β-defensin-related peptides, namely ovodefensins, exist with a different six-cysteine motif. Like their mammalian counterparts, avian cathelicidins and defensins are derived from either myeloid or epithelial origin expressed in a majority of tissues with broad-spectrum antibacterial and immune regulatory activities. Structure-function relationship studies with several avian HDPs have led to identification of the peptide analogs with potential for use as antimicrobials and vaccine adjuvants. Dietary modulation of endogenous HDP synthesis has also emerged as a promising alternative approach to disease control and prevention in chickens.
      PubDate: 2014-02-27
      DOI: 10.3390/ph7030220
      Issue No: Vol. 7, No. 3 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 248-250: Acknowledgement to Reviewers of
           Pharmaceuticals in 2013
    • Authors: Pharmaceuticals Editorial Office
      Pages: 248 - 250
      Abstract: The editors of Pharmaceuticals would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2013.
      PubDate: 2014-02-27
      DOI: 10.3390/ph7030248
      Issue No: Vol. 7, No. 3 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 251-264: Lucifensins, the Insect Defensins
           of Biomedical Importance: The Story behind Maggot Therapy
    • Authors: Václav Čeřovský, Robert Bém
      Pages: 251 - 264
      Abstract: Defensins are the most widespread antimicrobial peptides characterised in insects. These cyclic peptides, 4–6 kDa in size, are folded into α-helical/β-sheet mixed structures and have a common conserved motif of three intramolecular disulfide bridges with a Cys1-Cys4, Cys2-Cys5 and Cys3-Cys6 connectivity. They have the ability to kill especially Gram-positive bacteria and some fungi, but Gram-negative bacteria are more resistant against them. Among them are the medicinally important compounds lucifensin and lucifensin II, which have recently been identified in the medicinal larvae of the blowflies Lucilia sericata and Lucilia cuprina, respectively. These defensins contribute to wound healing during a procedure known as maggot debridement therapy (MDT) which is routinely used at hospitals worldwide. Here we discuss the decades-long story of the effort to isolate and characterise these two defensins from the bodies of medicinal larvae or from their secretions/excretions. Furthermore, our previous studies showed that the free-range larvae of L. sericata acutely eliminated most of the Gram-positive strains of bacteria and some Gram-negative strains in patients with infected diabetic foot ulcers, but MDT was ineffective during the healing of wounds infected with Pseudomonas sp. and Acinetobacter sp. The bactericidal role of lucifensins secreted into the infected wound by larvae during MDT and its ability to enhance host immunity by functioning as immunomodulator is also discussed.
      PubDate: 2014-02-27
      DOI: 10.3390/ph7030251
      Issue No: Vol. 7, No. 3 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 265-310: Antimicrobial Peptides from Fish
    • Authors: Jorge Masso-Silva, Gill Diamond
      Pages: 265 - 310
      Abstract: Antimicrobial peptides (AMPs) are found widely distributed through Nature, and participate in the innate host defense of each species. Fish are a great source of these peptides, as they express all of the major classes of AMPs, including defensins, cathelicidins, hepcidins, histone-derived peptides, and a fish-specific class of the cecropin family, called piscidins. As with other species, the fish peptides exhibit broad-spectrum antimicrobial activity, killing both fish and human pathogens. They are also immunomodulatory, and their genes are highly responsive to microbes and innate immuno-stimulatory molecules. Recent research has demonstrated that some of the unique properties of fish peptides, including their ability to act even in very high salt concentrations, make them good potential targets for development as therapeutic antimicrobials. Further, the stimulation of their gene expression by exogenous factors could be useful in preventing pathogenic microbes in aquaculture.
      PubDate: 2014-03-03
      DOI: 10.3390/ph7030265
      Issue No: Vol. 7, No. 3 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 311-338: Radiolabeled Cetuximab Conjugates
           for EGFR Targeted Cancer Diagnostics and Therapy
    • Authors: Wiebke Sihver, Jens Pietzsch, Mechthild Krause, Michael Baumann, Jörg Steinbach, Hans-Jürgen Pietzsch
      Pages: 311 - 338
      Abstract: The epidermal growth factor receptor (EGFR) has evolved over years into a main molecular target for the treatment of different cancer entities. In this regard, the anti-EGFR antibody cetuximab has been approved alone or in combination with: (a) chemotherapy for treatment of colorectal and head and neck squamous cell carcinoma and (b) with external radiotherapy for treatment of head and neck squamous cell carcinoma. The conjugation of radionuclides to cetuximab in combination with the specific targeting properties of this antibody might increase its therapeutic efficiency. This review article gives an overview of the preclinical studies that have been performed with radiolabeled cetuximab for imaging and/or treatment of different tumor models. A particularly promising approach seems to be the treatment with therapeutic radionuclide-labeled cetuximab in combination with external radiotherapy. Present data support an important impact of the tumor micromilieu on treatment response that needs to be further validated in patients. Another important challenge is the reduction of nonspecific uptake of the radioactive substance in metabolic organs like liver and radiosensitive organs like bone marrow and kidneys. Overall, the integration of diagnosis, treatment and monitoring as a theranostic approach appears to be a promising strategy for improvement of individualized cancer treatment.
      PubDate: 2014-03-05
      DOI: 10.3390/ph7030311
      Issue No: Vol. 7, No. 3 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 339-352: Synthesis and Preliminary
           Evaluation of a 2-Oxoquinoline Carboxylic Acid Derivative for PET Imaging
           the Cannabinoid Type 2 Receptor
    • Authors: Linjing Mu, Roger Slavik, Adrienne Müller, Kasim Popaj, Stjepko Čermak, Markus Weber, Roger Schibli, Stefanie Krämer, Simon Ametamey
      Pages: 339 - 352
      Abstract: Cannabinoid receptor subtype 2 (CB2) has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer’s disease. The CB2 receptor is therefore considered as a very promising target for therapeutic approaches as well as for imaging. A promising 2-oxoquinoline derivative designated KP23 was synthesized and radiolabeled and its potential as a ligand for PET imaging the CB2 receptor was evaluated. [11C]KP23 was obtained in 10%–25% radiochemical yield (decay corrected) and 99% radiochemical purity. It showed high stability in phosphate buffer, rat and mouse plasma. In vitro autoradiography of rat and mouse spleen slices, as spleen expresses a high physiological expression of CB2 receptors, demonstrated that [11C]KP23 exhibits specific binding towards CB2. High spleen uptake of [11C]KP23 was observed in dynamic in vivo PET studies with Wistar rats. In conclusion, [11C]KP23 showed promising in vitro and in vivo characteristics. Further evaluation with diseased animal model which has higher CB2 expression levels in the brain is warranted.
      PubDate: 2014-03-06
      DOI: 10.3390/ph7030339
      Issue No: Vol. 7, No. 3 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 353-365: Folate Receptor Targeted
           Alpha-Therapy Using Terbium-149
    • Authors: Cristina Müller, Josefine Reber, Stephanie Haller, Holger Dorrer, Ulli Köster, Karl Johnston, Konstantin Zhernosekov, Andreas Türler, Roger Schibli
      Pages: 353 - 365
      Abstract: Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice.
      PubDate: 2014-03-13
      DOI: 10.3390/ph7030353
      Issue No: Vol. 7, No. 3 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 113-135: From Single Target to
           Multitarget/Network Therapeutics in Alzheimer’s Therapy
    • Authors: Hailin Zheng, Mati Fridkin, Moussa Youdim
      Pages: 113 - 135
      Abstract: Brain network dysfunction in Alzheimer’s disease (AD) involves many proteins (enzymes), processes and pathways, which overlap and influence one another in AD pathogenesis. This complexity challenges the dominant paradigm in drug discovery or a single-target drug for a single mechanism. Although this paradigm has achieved considerable success in some particular diseases, it has failed to provide effective approaches to AD therapy. Network medicines may offer alternative hope for effective treatment of AD and other complex diseases. In contrast to the single-target drug approach, network medicines employ a holistic approach to restore network dysfunction by simultaneously targeting key components in disease networks. In this paper, we explore several drugs either in the clinic or under development for AD therapy in term of their design strategies, diverse mechanisms of action and disease-modifying potential. These drugs act as multi-target ligands and may serve as leads for further development as network medicines.
      PubDate: 2014-01-23
      DOI: 10.3390/ph7020113
      Issue No: Vol. 7, No. 2 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 136-168: Mercury-Supported Biomimetic
           Membranes for the Investigation of Antimicrobial Peptides
    • Authors: Lucia Becucci, Rolando Guidelli
      Pages: 136 - 168
      Abstract: Tethered bilayer lipid membranes (tBLMs) consist of a lipid bilayer interposed between an aqueous solution and a hydrophilic “spacer” anchored to a gold or mercury electrode. There is great potential for application of these biomimetic membranes for the elucidation of structure-function relationships of membrane peptides and proteins. A drawback in the use of mercury-supported tBLMs with respect to gold-supported ones is represented by the difficulty in applying surface sensitive, spectroscopic and scanning probe microscopic techniques to gather information on the architecture of these biomimetic membranes. Nonetheless, mercury-supported tBLMs are definitely superior to gold-supported biomimetic membranes for the investigation of the function of membrane peptides and proteins, thanks to a fluidity and lipid lateral mobility comparable with those of bilayer lipid membranes interposed between two aqueous phases (BLMs), but with a much higher robustness and resistance to electric fields. The different features of mercury-supported tBLMs reconstituted with functionally active membrane proteins and peptides of bacteriological or pharmacological interest may be disclosed by a judicious choice of the most appropriate electrochemical techniques. We will describe the way in which electrochemical impedance spectroscopy, potential-step chronocoulometry, cyclic voltammetry and phase-sensitive AC voltammetry are conveniently employed to investigate the structure of mercury-supported tBLMs and the mode of interaction of antimicrobial peptides reconstituted into them.
      PubDate: 2014-01-23
      DOI: 10.3390/ph7020136
      Issue No: Vol. 7, No. 2 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 169-191: The Dipeptide Monoester Prodrugs
           of Floxuridine and Gemcitabine—Feasibility of Orally Administrable
           Nucleoside Analogs
    • Authors: Yasuhiro Tsume, Blanca Bermejo, Gordon Amidon
      Pages: 169 - 191
      Abstract: Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.
      PubDate: 2014-01-27
      DOI: 10.3390/ph7020169
      Issue No: Vol. 7, No. 2 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 192-206: Mitochondrial FAD-linked
           Glycerol-3-phosphate Dehydrogenase: A Target for Cancer Therapeutics
    • Authors: Gurmit Singh
      Pages: 192 - 206
      Abstract: Imbalances in cellular redox state are frequently observed in cancer cells, and contribute significantly to cancer progression and apoptotic resistance. Hydrogen peroxide (H2O2) is one reactive oxygen species (ROS) that is produced in excess within cancer cells. In this study, we investigated the mitochondrial glycerol-3-phosphate-dependent (GPD2) ROS production in PC-3 cells and demonstrated the importance of excessive H2O2 production on their survival. By exploiting the abnormal H2O2 production of PC-3 cells, we initiated a high-throughput screening of the Canadian Compound Collection, composed of 29,586 small molecules, targeting the glycerophosphate-dependent H2O2 formation in PC-3 cells. Eighteen compounds were identified to have significant inhibitory activity. These compounds have not been previously characterized as inhibitors of the enzyme. Six of these compounds were further analyzed in PC-3 cells and dose response studies displayed an inhibitory and anti-oxidative potency that ranged from 1 µM to 30 µM. The results presented here demonstrate that inhibitors of mitochondrial GPD2 activity elicit anti-proliferative effects on cancer cells.
      PubDate: 2014-02-11
      DOI: 10.3390/ph7020192
      Issue No: Vol. 7, No. 2 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 207-219: Design of Prodrugs to Enhance
           Colonic Absorption by Increasing Lipophilicity and Blocking Ionization
    • Authors: Rebecca Nofsinger, Sophie-Dorothee Clas, Rosa Sanchez, Abbas Walji, Kimberly Manser, Becky Nissley, Jaume Balsells, Amrithraj Nair, Qun Dang, David Bennett, Michael Hafey, Junying Wang, John Higgins, Allen Templeton, Paul Coleman, Jay Grobler, Ronald Smith, Yunhui Wu
      Pages: 207 - 219
      Abstract: Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to enhance the colonic absorption of a drug molecule with a short half-life via a prodrug approach to deliver sustained plasma exposure and enable once daily (QD) dosing. The compound has poor absorption in the colon and by the addition of a promoiety to block the ionization of the molecule as well as increase lipophilicity, the relative colonic absorption increased from 9% to 40% in the retrograde dog colonic model. A combination of acceptable solubility and stability in the gastrointestinal tract (GI) as well as permeability was used to select suitable prodrugs to optimize colonic absorption.
      PubDate: 2014-02-24
      DOI: 10.3390/ph7020207
      Issue No: Vol. 7, No. 2 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 46-57: Ritonavir-Mediated Induction of
           Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways
    • Authors: Ramesh Batchu, Oksana Gruzdyn, Christopher Bryant, Aamer Qazi, Sanjeev Kumar, Sreedhar Chamala, Shu Kung, Ramana Sanka, Udaya Puttagunta, Donald Weaver, Scott Gruber
      Pages: 46 - 57
      Abstract: Recent observations suggest a lower incidence of malignancies in patients infected with HIV during treatment with Highly Active Anti-Retroviral Therapy (HAART) utilizing protease inhibitors. We investigated the effects of ritonavir, a FDA approved HIV protease inhibitor, on proliferation of pancreatic ductal adeno-carcinoma (PDAC) cell lines. Human PDAC cell lines BxPC-3, MIA PaCa-2, and PANC-1 were propagated under standard conditions and treated with serial dilutions of ritonavir. Ritonavir inhibited cell growth in a dose-dependent manner as well as activated the intrinsic apoptotic pathway in human pancreatic ductal adenocarcinoma (PDAC) cell lines. We observed down-modulation of cell-cycle promoting and up-regulation of cell-cycle inhibitory genes; enhanced interaction of retinoblastoma protein (RB) with E2F-1 transcription factor; inhibition of phosphorylation of RB, resulting in sequestration of E2F-1 and subsequent down-regulation of S phase genes; decreased interaction of E2F-1 with its consensus binding sites; inhibition of cell motility and invasiveness; and inhibition of the AKT pathway. Our results demonstrate a potential use of ritonavir as part of combination chemotherapy for PDAC. Since ritonavir is FDA approved for HIV, drug repositioning for PDAC would limit the costs and reduce risks.
      PubDate: 2014-01-09
      DOI: 10.3390/ph7010046
      Issue No: Vol. 7, No. 1 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 58-77: Host-Defense Peptides with
           Therapeutic Potential from Skin Secretions of Frogs from the Family
           Pipidae
    • Authors: J. Michael Conlon, Milena Mechkarska
      Pages: 58 - 77
      Abstract: Skin secretions from frogs belonging to the genera Xenopus, Silurana, Hymenochirus, and Pseudhymenochirus in the family Pipidae are a rich source of host-defense peptides with varying degrees of antimicrobial activities and cytotoxicities to mammalian cells. Magainin, peptide glycine-leucine-amide (PGLa), caerulein-precursor fragment (CPF), and xenopsin-precursor fragment (XPF) peptides have been isolated from norepinephrine-stimulated skin secretions from several species of Xenopus and Silurana. Hymenochirins and pseudhymenochirins have been isolated from Hymenochirus boettgeri and Pseudhymenochirus merlini. A major obstacle to the development of these peptides as anti-infective agents is their hemolytic activities against human erythrocytes. Analogs of the magainins, CPF peptides and hymenochirin-1B with increased antimicrobial potencies and low cytotoxicities have been developed that are active (MIC < 5 μM) against multidrug-resistant clinical isolates of Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, Stenotrophomonas maltophilia and Klebsiella pneumoniae. Despite this, the therapeutic potential of frog skin peptides as anti-infective agents has not been realized so that alternative clinical applications as anti-cancer, anti-viral, anti-diabetic, or immunomodulatory drugs are being explored.
      PubDate: 2014-01-15
      DOI: 10.3390/ph7010058
      Issue No: Vol. 7, No. 1 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 78-112: Asymmetric Synthesis of Spirocyclic
           2-Benzopyrans for Positron Emission Tomography of σ1 Receptors in the
           Brain
    • Authors: Katharina Holl, Dirk Schepmann, Steffen Fischer, Friedrich-Alexander Ludwig, Achim Hiller, Cornelius Donat, Winnie Deuther-Conrad, Peter Brust, Bernhard Wünsch
      Pages: 78 - 112
      Abstract: Sharpless asymmetric dihydroxylation of styrene derivative 6 afforded chiral triols (R)-7 and (S)-7, which were cyclized with tosyl chloride in the presence of Bu2SnO to provide 2-benzopyrans (R)-4 and (S)-4 with high regioselectivity. The additional hydroxy moiety in the 4-position was exploited for the introduction of various substituents. Williamson ether synthesis and replacement of the Boc protective group with a benzyl moiety led to potent σ1 ligands with high σ1/σ2-selectivity. With exception of the ethoxy derivative 16, the (R)-configured enantiomers represent eutomers with eudismic ratios of up to 29 for the ester (R)-18. The methyl ether (R)-15 represents the most potent σ1 ligand of this series of compounds, with a Ki value of 1.2 nM and an eudismic ratio of 7. Tosylate (R)-21 was used as precursor for the radiosynthesis of [18F]-(R)-20, which was available by nucleophilic substitution with K[18F]F K222 carbonate complex. The radiochemical yield of [18F]-(R)-20 was 18%–20%, the radiochemical purity greater than 97% and the specific radioactivity 175–300 GBq/µmol. Although radiometabolites were detected in plasma, urine and liver samples, radiometabolites were not found in brain samples. After 30 min, the uptake of the radiotracer in the brain was 3.4% of injected dose per gram of tissue and could be reduced by coadministration of the σ1 antagonist haloperidol. [18F]-(R)-20 was able to label those regions of the brain, which were reported to have high density of σ1 receptors.
      PubDate: 2014-01-22
      DOI: 10.3390/ph7010078
      Issue No: Vol. 7, No. 1 (2014)
       
  • Pharmaceuticals, Vol. 7, Pages 1-17: A New Phenylpyrazoleanilide, Y-320,
           Inhibits Interleukin 17 Production and Ameliorates Collagen-Induced
           Arthritis in Mice and Cynomolgus Monkeys
    • Authors: Hiroyuki Ushio, Seigo Ishibuchi, Koichi Oshita, Noriyasu Seki, Hirotoshi Kataoka, Kunio Sugahara, Kunitomo Adachi, Kenji Chiba
      Pages: 1 - 17
      Abstract: Interleukin (IL)-15 and IL-17 are thought to play an important role in the pathogenesis of rheumatoid arthritis (RA) because both pro-inflammatory cytokines are found in synovial fluid of RA patients. In this study, we examined the pharmacological profiles of Y-320, a new phenylpyrazoleanilide immunomodulator. Y-320 inhibited IL-17 production by CD4 T cells stimulated with IL-15 with IC50 values of 20 to 60 nM. Oral administration of Y-320 (0.3 to 3 mg/kg) significantly inhibited the development and progression of arthritis and joint destruction with reduction of IL-17 mRNA expression in arthritic joints of type II collagen-induced arthritis (CIA) in DBA/1J mice. Y-320 in combination with anti-murine tumor necrosis factor-α monoclonal antibody showed a synergistic effect on mouse CIA. Moreover, therapeutic treatment with Y-320 (0.3 and 1 mg/kg orally) ameliorated CIA in cynomolgus monkeys. Our results suggest that Y-320, an orally active inhibitor for IL-17 production, provides a useful therapy for RA.
      PubDate: 2013-12-23
      DOI: 10.3390/ph7010001
      Issue No: Vol. 7, No. 1 (2013)
       
  • Pharmaceuticals, Vol. 7, Pages 18-28: Immunosuppressive Therapy in
           Immune-Mediated Liver Disease in the Non-Transplanted Patient
    • Authors: Anita Abhyankar, Elliot Tapper, Alan Bonder
      Pages: 18 - 28
      Abstract: Autoimmune liver disease management goals are primarily slowing disease progression and symptomatic treatment. There are few options for curative medical management other than transplant for a spectrum of autoimmune liver disease that encompasses autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis as well as their overlap syndromes. These diseases are managed primarily with immunosuppressive therapy. Herein, we review the current literature, detailing the promise and pitfalls of the recommended immunosuppressive therapy for these challenging diseases.
      PubDate: 2013-12-30
      DOI: 10.3390/ph7010018
      Issue No: Vol. 7, No. 1 (2013)
       
  • Pharmaceuticals, Vol. 7, Pages 29-45: Are AMPA Receptor Positive
           Allosteric Modulators Potential Pharmacotherapeutics for Addiction'
    • Authors: Lucas Watterson, M. Olive
      Pages: 29 - 45
      Abstract: Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications.
      PubDate: 2013-12-30
      DOI: 10.3390/ph7010029
      Issue No: Vol. 7, No. 1 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1082-1093: Structural and Affinity Analyses
           of G-Quadruplex DNA Aptamers for Camptothecin Derivatives
    • Authors: Hiroto Fujita, Yuri Imaizumi, Yuuya Kasahara, Shunsuke Kitadume, Hiroaki Ozaki, Masayasu Kuwahara, Naoki Sugimoto
      Pages: 1082 - 1093
      Abstract: We recently selected DNA aptamers that bind to camptothecin (CPT) and CPT derivatives from a 70-mer oligodeoxyribonucleotide (ODN) library using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) method. The target-binding activity of the obtained 70-mer CPT-binding DNA aptamer, termed CA-70, which contains a 16-mer guanine (G)-core motif (G3TG3TG3T2G3) that forms a three-tiered G-quadruplex, was determined using fluorescence titration. In this study, truncated fragments of CA-70 that all have the G-core motif, CA-40, -20, -19, -18A, -18B, -17, and -16, were carefully analyzed. We found that CA-40 retained the target-binding activity, whereas CA-20, -19, and -18B exhibited little or no binding activities. Further, not only CA-18A but also the shorter length fragments CA-17 and -16 clearly retained the binding activity, indicating that tail strands of the G-quadruplex structure can significantly affect the target binding of G-quadruplex DNA aptamers. Further analyses using circular dichroism (CD) spectroscopy and fluorescence polarization (FP) assay were conducted to investigate the structure and affinity of G-quadruplex DNA aptamers.
      PubDate: 2013-08-29
      DOI: 10.3390/ph6091082
      Issue No: Vol. 6, No. 9 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1094-1129: Clinical Pharmacology of
           Furosemide in Neonates: A Review
    • Authors: Gian Pacifici
      Pages: 1094 - 1129
      Abstract: Furosemide is the diuretic most used in newborn infants. It blocks the Na+-K+-2Cl− symporter in the thick ascending limb of the loop of Henle increasing urinary excretion of Na+ and Cl−. This article aimed to review the published data on the clinical pharmacology of furosemide in neonates to provide a critical, comprehensive, authoritative and, updated survey on the metabolism, pharmacokinetics, pharmacodynamics and side-effects of furosemide in neonates. The bibliographic search was performed using PubMed and EMBASE databases as search engines; January 2013 was the cutoff point. Furosemide half-life (t1/2) is 6 to 20-fold longer, clearance (Cl) is 1.2 to 14-fold smaller and volume of distribution (Vd) is 1.3 to 6-fold larger than the adult values. t1/2 shortens and Cl increases as the neonatal maturation proceeds. Continuous intravenous infusion of furosemide yields more controlled diuresis than the intermittent intravenous infusion. Furosemide may be administered by inhalation to infants with chronic lung disease to improve pulmonary mechanics. Furosemide stimulates prostaglandin E2 synthesis, a potent dilator of the patent ductus arteriosus, and the administration of furosemide to any preterm infants should be carefully weighed against the risk of precipitation of a symptomatic patent ductus arteriosus. Infants with low birthweight treated with chronic furosemide are at risk for the development of intra-renal calcifications.
      PubDate: 2013-09-05
      DOI: 10.3390/ph6091094
      Issue No: Vol. 6, No. 9 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1130-1144: What Goes around Comes around-A
           Comparative Study of the Influence of Chemical Modifications on the
           Antimicrobial Properties of Small Cyclic Peptides
    • Authors: Kathi Scheinpflug, Heike Nikolenko, Igor Komarov, Marina Rautenbach, Margitta Dathe
      Pages: 1130 - 1144
      Abstract: Tryptophan and arginine-rich cyclic hexapeptides of the type cyclo-RRRWFW combine high antibacterial activity with rapid cell killing kinetics, but show low toxicity in human cell lines. The peptides fulfil the structural requirements for membrane interaction such as high amphipathicity and cationic charge, but membrane permeabilisation, which is the most common mode of action of antimicrobial peptides (AMPs), could not be observed. Our current studies focus on elucidating a putative membrane translocation mechanism whereupon the peptides might interfere with intracellular processes. These investigations require particular analytical tools: fluorescent analogues and peptides bearing appropriate reactive groups were synthesized and characterized in order to be used in confocal laser scanning microscopy and HPLC analysis. We found that minimal changes in both the cationic and hydrophobic domain of the peptides in most cases led to significant reduction of antimicrobial activity and/or changes in the mode of action. However, we were able to identify two modified peptides which exhibited properties similar to those of the cyclic parent hexapeptide and are suitable for subsequent studies on membrane translocation and uptake into bacterial cells.
      PubDate: 2013-09-06
      DOI: 10.3390/ph6091130
      Issue No: Vol. 6, No. 9 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1145-1169: Dynamic Cross Talk between S1P
           and CXCL12 Regulates Hematopoietic Stem Cells Migration, Development and
           Bone Remodeling
    • Authors: Karin Golan, Orit Kollet, Tsvee Lapidot
      Pages: 1145 - 1169
      Abstract: Hematopoietic stem cells (HSCs) are mostly retained in a quiescent non-motile mode in their bone marrow (BM) niches, shifting to a migratory cycling and differentiating state to replenish the blood with mature leukocytes on demand. The balance between the major chemo-attractants CXCL12, predominantly in the BM, and S1P, mainly in the blood, dynamically regulates HSC recruitment to the circulation versus their retention in the BM. During alarm situations, stress-signals induce a decrease in CXCL12 levels in the BM, while S1P levels are rapidly and transiently increased in the circulation, thus favoring mobilization of stem cells as part of host defense and repair mechanisms. Myeloid cytokines, including G-CSF, up-regulate S1P signaling in the BM via the PI3K pathway. Induced CXCL12 secretion from stromal cells via reactive oxygen species (ROS) generation and increased S1P1 expression and ROS signaling in HSCs, all facilitate mobilization. Bone turnover is also modulated by both CXCL12 and S1P, regulating the dynamic BM stromal microenvironment, osteoclasts and stem cell niches which all functionally express CXCL12 and S1P receptors. Overall, CXCL12 and S1P levels in the BM and circulation are synchronized to mutually control HSC motility, leukocyte production and osteoclast/osteoblast bone turnover during homeostasis and stress situations.
      PubDate: 2013-09-23
      DOI: 10.3390/ph6091145
      Issue No: Vol. 6, No. 9 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 915-928: Targeting Platelet Thrombin
           Receptor Signaling to Prevent Thrombosis
    • Authors: Eric Wallace, Susan Smyth
      Pages: 915 - 928
      Abstract: Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more comprehensive antithrombotic effects. We review the pathophysiology of atherothrombosis, platelet activation by thrombin, the role of platelet protease activated receptors (PAR), and the clinical data supporting their use.
      PubDate: 2013-08-02
      DOI: 10.3390/ph6080915
      Issue No: Vol. 6, No. 8 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 929-959: Rationale and Means to Target
           Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer
    • Authors: Laura Campbell, Pamela Maxwell, David Waugh
      Pages: 929 - 959
      Abstract: It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through two G protein-coupled receptors, CXCR1 and CXCR2. Elevated CXCL8-CXCR1/2 signaling within the tumor microenvironment of numerous cancers is known to enhance tumor progression via activation of signaling pathways promoting proliferation, angiogenesis, migration, invasion and cell survival. This review provides an overview of established roles of CXCL8-CXCR1/2 signaling in cancer and subsequently, discusses the possible strategies of targeting CXCL8-CXCR1/2 signaling in cancer, covering indirect strategies (e.g., anti-inflammatories, NFκB inhibitors) and direct CXCL8 or CXCR1/2 inhibition (e.g., neutralizing antibodies, small molecule receptor antagonists, pepducin inhibitors and siRNA strategies). Reports of pre-clinical cancer studies and clinical trials using CXCL8-CXCR1/2-targeting strategies for the treatment of inflammatory diseases will be discussed. The future translational opportunities for use of such agents in oncology will be discussed, with emphasis on exploitation in stratified populations.
      PubDate: 2013-08-06
      DOI: 10.3390/ph6080929
      Issue No: Vol. 6, No. 8 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 960-987: The Inhibition of Stat5 by a
           Peptide Aptamer Ligand Specific for the DNA Binding Domain Prevents Target
           Gene Transactivation and the Growth of Breast and Prostate Tumor Cells
    • Authors: Axel Weber, Corina Borghouts, Christian Brendel, Richard Moriggl, Natalia Delis, Boris Brill, Vida Vafaizadeh, Bernd Groner
      Pages: 960 - 987
      Abstract: The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment.
      PubDate: 2013-08-20
      DOI: 10.3390/ph6080960
      Issue No: Vol. 6, No. 8 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 988-1038: Personalizing Colon Cancer
           Therapeutics: Targeting Old and New Mechanisms of Action
    • Authors: Christina Kline, Wafik El-Deiry
      Pages: 988 - 1038
      Abstract: The use of pharmaceuticals for colon cancer treatment has been increasingly personalized, in part due to the development of new molecular tools. In this review, we discuss the old and new colon cancer chemotherapeutics, and the parameters that have been shown to be predictive of efficacy and safety of these chemotherapeutics. In addition, we discuss how alternate pharmaceuticals have been developed in light of a potential lack of response or resistance to a particular chemotherapeutic.
      PubDate: 2013-08-21
      DOI: 10.3390/ph6080988
      Issue No: Vol. 6, No. 8 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1039-1054: Current Evidence of Chinese
           Herbal Constituents with Effects on NMDA Receptor Blockade
    • Authors: Willmann Liang, Wai Lam, Hong Tang, Ping Leung, David Yew
      Pages: 1039 - 1054
      Abstract: NMDA receptor (NMDA-R) is an important molecular entity governing a wide range of functions in the central nervous system. For example, the NMDA-R is involved in memory and cognition, and impairment of both (as in Alzheimer’s Disease) is attributed to NMDA-mediated neurotoxicity. With greater understanding of the NMDA-R structure, antagonists with varying degrees of binding-site and subtype selectivity have been developed and put into clinical use. Discovery of target-specific Chinese herbs have also been made in parallel. This article provides an overview of the known active sites on the NMDA-R, followed by a discussion of the relevant herbs and their constituents. Experimental evidence supporting the inhibitory role of the herbal compounds on the NMDA-R is highlighted. For some of the compounds, potential research directions are also proposed to further elucidate the underlying mechanisms of the herbs. It is envisaged that future investigations based on the present data will allow more clinically relevant herbs to be identified.
      PubDate: 2013-08-21
      DOI: 10.3390/ph6081039
      Issue No: Vol. 6, No. 8 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1055-1081: Characterization of
           Antimicrobial Peptides toward the Development of Novel Antibiotics
    • Authors: Wataru Aoki, Mitsuyoshi Ueda
      Pages: 1055 - 1081
      Abstract: Antimicrobial agents have eradicated many infectious diseases and significantly improved our living environment. However, abuse of antimicrobial agents has accelerated the emergence of multidrug-resistant microorganisms, and there is an urgent need for novel antibiotics. Antimicrobial peptides (AMPs) have attracted attention as a novel class of antimicrobial agents because AMPs efficiently kill a wide range of species, including bacteria, fungi, and viruses, via a novel mechanism of action. In addition, they are effective against pathogens that are resistant to almost all conventional antibiotics. AMPs have promising properties; they directly disrupt the functions of cellular membranes and nucleic acids, and the rate of appearance of AMP-resistant strains is very low. However, as pharmaceuticals, AMPs exhibit unfavorable properties, such as instability, hemolytic activity, high cost of production, salt sensitivity, and a broad spectrum of activity. Therefore, it is vital to improve these properties to develop novel AMP treatments. Here, we have reviewed the basic biochemical properties of AMPs and the recent strategies used to modulate these properties of AMPs to enhance their safety.
      PubDate: 2013-08-21
      DOI: 10.3390/ph6081055
      Issue No: Vol. 6, No. 8 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 788-812: Voltage-Gated Calcium Channel
           Antagonists and Traumatic Brain Injury
    • Authors: Gene Gurkoff, Kiarash Shahlaie, Bruce Lyeth, Robert Berman
      Pages: 788 - 812
      Abstract: Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC) antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i). These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.
      PubDate: 2013-06-26
      DOI: 10.3390/ph6070788
      Issue No: Vol. 6, No. 7 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 813-836: Current Challenges and Future
           Directions in Recombinant AAV-Mediated Gene Therapy of Duchenne Muscular
           Dystrophy
    • Authors: Takashi Okada, Shin'ichi Takeda
      Pages: 813 - 836
      Abstract: Various characteristics of adeno-associated virus (AAV)-based vectors with long-term safe expression have made it an exciting transduction tool for clinical gene therapy of Duchenne muscular dystrophy (DMD). Although host immune reactions against the vector as well as transgene products were detected in some instances of the clinical studies, there have been promising observations. Methods of producing AAV vectors for considerable in vivo experimentation and clinical investigations have been developed and a number of studies with AAV vector-mediated muscle transduction were attempted. Notably, an intravenous limb perfusion transduction technique enables extensive transgene expression in the skeletal muscles without noticeable adverse events. Furthermore, cardiac transduction by the rAAV9-microdystrophin would be promising to prevent development of cardiac dysfunction. Recent achievements in transduction technology suggest that long-term transgene expression with therapeutic benefits in DMD treatment would be achieved by the rAAV-mediated transduction strategy with an adequate regimen to regulate host immune response.
      PubDate: 2013-06-27
      DOI: 10.3390/ph6070813
      Issue No: Vol. 6, No. 7 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 837-850: Diamidines versus Monoamidines as
           Anti-Pneumocystis Agents: An in Vivo Study
    • Authors: Dimitri Stanicki, Muriel Pottier, Nausicaa Gantois, Claire Pinçon, Delphine Forge, Isabelle Mahieu, Sébastien Boutry, Jean Eynde, Anna Martinez, Eduardo Dei-Cas, El-Moukhtar Aliouat
      Pages: 837 - 850
      Abstract: Some compounds articulated around a piperazine or an ethylenediamine linker have been evaluated in vitro to determine their activity in the presence of a 3T6 fibroblast cell line and an axenic culture of Pneumocystis carinii, respectively. The most efficient antifungal derivatives, namely N,N′-bis(benzamidine-4-yl)ethane-1,2-diamine (compound 6, a diamidine) and N-(benzamidine-4-yl)-N′-phenylethane-1,2-diamine (compound 7, a monoamidine), exhibited no cytotoxicity and were evaluated in vivo in a rat model. Only the diamidine 6 emerged as a promising hit for further studies.
      PubDate: 2013-07-01
      DOI: 10.3390/ph6070837
      Issue No: Vol. 6, No. 7 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 851-866: Role of Diuretics and
           Ultrafiltration in Congestive Heart Failure
    • Authors: Dmitry Shchekochikhin, Fawaz Al Ammary, Jo Ann Lindenfeld, Robert Schrier
      Pages: 851 - 866
      Abstract: Volume overload in heart failure (HF) results from neurohumoral activation causing renal sodium and water retention secondary to arterial underfilling. Volume overload not only causes signs and symptoms of congestion, but can impact myocardial remodeling and HF progression. Thus, treating congestion is a cornerstone of HF management. Loop diuretics are the most commonly used drugs in this setting. However, up to 30% of the patients with decompensated HF present with loop-diuretic resistance. A universally accepted definition of loop diuretic resistance, however, is lacking. Several approaches to treat diuretic-resistant HF are available, including addition of distal acting thiazide diuretics, natriuretic doses of mineralocorticoid receptor antagonists (MRAs), or vasoactive drugs. Slow continuous veno-venous ultrafiltration is another option. Ultrafiltration, if it is started early in the course of HF decompensation, may result in prominent decongestion and a reduction in re-hospitalization. On the other hand, ultrafiltration in HF patients with worsening renal function and volume overload after aggressive treatment with loop diuretics, failed to show benefit compared to a stepwise pharmacological approach, including diuretics and vasoactive drugs. Early detection of congested HF patients for ultrafiltration treatment might improve decongestion and reduce readmission. However, the best patient characteristics and best timing of ultrafiltration requires further evaluation in randomized controlled studies.
      PubDate: 2013-07-04
      DOI: 10.3390/ph6070851
      Issue No: Vol. 6, No. 7 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 867-880: Protein-Based Blood Substitutes:
           Recent Attempts at Controlling Pro-Oxidant Reactivity with and Beyond
           Hemoglobin
    • Authors: Violeta-Florina Scurtu, Augustin Moţ, Radu Silaghi-Dumitrescu
      Pages: 867 - 880
      Abstract: Reviewed here are recent attempts to produce protein-based artificial oxygen carriers (“blood substitutes”). Most of these involve chemical or physical modifications on hemoglobin, although a recent line of research using hemerythrin instead of hemoglobin is also described. The focus is set on the extent to which these modifications alter the redox reactivity of the proteins, and on ways in which this can be done systematically and purposefully, within the framework of a working hypothesis where redox side-reactions hold an important role in the physiological outcome of experimental transfusions with artificial oxygen carriers.
      PubDate: 2013-07-04
      DOI: 10.3390/ph6070867
      Issue No: Vol. 6, No. 7 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 881-914: New Aspects of Gene-Silencing for
           the Treatment of Cardiovascular Diseases
    • Authors: Olivia Koenig, Tobias Walker, Nadja Perle, Almuth Zech, Bernd Neumann, Christian Schlensak, Hans-Peter Wendel, Andrea Nolte
      Pages: 881 - 914
      Abstract: Coronary heart disease (CHD), mainly caused by atherosclerosis, represents the single leading cause of death in industrialized countries. Besides the classical interventional therapies new applications for treatment of vascular wall pathologies are appearing on the horizon. RNA interference (RNAi) represents a novel therapeutic strategy due to sequence-specific gene-silencing through the use of small interfering RNA (siRNA). The modulation of gene expression by short RNAs provides a powerful tool to theoretically silence any disease-related or disease-promoting gene of interest. In this review we outline the RNAi mechanisms, the currently used delivery systems and their possible applications to the cardiovascular system. Especially, the optimization of the targeting and transfection procedures could enhance the efficiency of siRNA delivery drastically and might open the way to clinical applicability. The new findings of the last years may show the techniques to new innovative therapies and could probably play an important role in treating CHD in the future.
      PubDate: 2013-07-19
      DOI: 10.3390/ph6070881
      Issue No: Vol. 6, No. 7 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 689-699: Calcium Channel Blockers as
           Tocolytics: Principles of Their Actions, Adverse Effects and Therapeutic
           Combinations
    • Authors: Róbert Gáspár, Judit Hajagos-Tóth
      Pages: 689 - 699
      Abstract: Dihydropyridine Ca2+ channel blockers (CCBs) are widely accepted in the treatment of premature labour. Their mechanism of action in tocolysis involves the blockade of L-type Ca2+ channels, influenced by the Ca2+-activated K+ channels, beta-adrenergic receptors (β-ARs) and sexual hormones. In clinical practice, most experience has been gained with the use of nifedipine, whose efficacy is superior or comparable to those of β-agonists and oxytocin antagonists. Additionally, it has a favourable adverse effect profile as compared with the majority of other tocolytics. The most frequent and well-tolerated side-effects of CCBs are tachycardia, headache and hypotension. In tocolytic therapy efforts are currently being made to find combinations of tocolytic agents that yield better therapeutic action. The available human and animal studies suggest that the combination of CCBs with β-AR agonists is beneficial, although such combinations can pose risk of pulmonary oedema in multiple pregnancies and maternal cardiovascular diseases. Preclinical data indicate the potential benefit of combinations of CCBs and oxytocin antagonists. However, the combinations of CCBs with progesterone or cyclooxygenase inhibitors may decrease their efficacy. The CCBs are likely to remain one of the most important groups of drugs for the rapid inhibition of premature uterine contractions. Their significance may be magnified by further clinical studies on their combined use for tocolysis.
      PubDate: 2013-05-23
      DOI: 10.3390/ph6060689
      Issue No: Vol. 6, No. 6 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 700-715: Virtual Lead Identification of
           Farnesyltransferase Inhibitors Based on Ligand and Structure-Based
           Pharmacophore Techniques
    • Authors: Qosay Al-Balas, Haneen Amawi, Mohammad Hassan, Amjad Qandil, Ammar Almaaytah, Nizar Mhaidat
      Pages: 700 - 715
      Abstract: Farnesyltransferase enzyme (FTase) is considered an essential enzyme in the Ras signaling pathway associated with cancer. Thus, designing inhibitors for this enzyme might lead to the discovery of compounds with effective anticancer activity. In an attempt to obtain effective FTase inhibitors, pharmacophore hypotheses were generated using structure-based and ligand-based approaches built in Discovery Studio v3.1. Knowing the presence of the zinc feature is essential for inhibitor’s binding to the active site of FTase enzyme; further customization was applied to include this feature in the generated pharmacophore hypotheses. These pharmacophore hypotheses were thoroughly validated using various procedures such as ROC analysis and ligand pharmacophore mapping. The validated pharmacophore hypotheses were used to screen 3D databases to identify possible hits. Those which were both high ranked and showed sufficient ability to bind the zinc feature in active site, were further refined by applying drug-like criteria such as Lipiniski’s “rule of five” and ADMET filters. Finally, the two candidate compounds (ZINC39323901 and ZINC01034774) were allowed to dock using CDOCKER and GOLD in the active site of FTase enzyme to optimize hit selection.
      PubDate: 2013-05-27
      DOI: 10.3390/ph6060700
      Issue No: Vol. 6, No. 6 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 716-727: Dysregulation of the Mammalian
           Target of Rapamycin and p27Kip1 Promotes Intimal Hyperplasia in Diabetes
           Mellitus
    • Authors: Thomas Woods
      Pages: 716 - 727
      Abstract: The proliferation and migration of vascular smooth muscle cells (VSMCs) in the intima of an artery, known as intimal hyperplasia, is an important component of cardiovascular diseases. This is seen most clearly in the case of in-stent restenosis, where drug eluting stents are used to deliver agents that prevent VSMC proliferation and migration. One class of agents that are highly effective in the prevention of in-stent restenosis is the mammalian Target of Rapamycin (mTOR) inhibitors. Inhibition of mTOR blocks protein synthesis, cell cycle progression, and cell migration. Key to the effects on cell cycle progression and cell migration is the inhibition of mTOR-mediated degradation of p27Kip1 protein. p27Kip1 is a cyclin dependent kinase inhibitor that is elevated in quiescent VSMCs and inhibits the G1 to S phase transition and cell migration. Under normal conditions, vascular injury promotes degradation of p27Kip1 protein in an mTOR dependent manner. Recent reports from our lab suggest that in the presence of diabetes mellitus, elevation of extracellular signal response kinase activity may promote decreased p27Kip1 mRNA and produce a relative resistance to mTOR inhibition. Here we review these findings and their relevance to designing treatments for cardiovascular disease in the presence of diabetes mellitus.
      PubDate: 2013-05-27
      DOI: 10.3390/ph6060716
      Issue No: Vol. 6, No. 6 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 728-758: Database-Guided Discovery of
           Potent Peptides to Combat HIV-1 or Superbugs
    • Authors: Guangshun Wang
      Pages: 728 - 758
      Abstract: Antimicrobial peptides (AMPs), small host defense proteins, are indispensable for the protection of multicellular organisms such as plants and animals from infection. The number of AMPs discovered per year increased steadily since the 1980s. Over 2,000 natural AMPs from bacteria, protozoa, fungi, plants, and animals have been registered into the antimicrobial peptide database (APD). The majority of these AMPs (>86%) possess 11–50 amino acids with a net charge from 0 to +7 and hydrophobic percentages between 31–70%. This article summarizes peptide discovery on the basis of the APD. The major methods are the linguistic model, database screening, de novo design, and template-based design. Using these methods, we identified various potent peptides against human immunodeficiency virus type 1 (HIV-1) or methicillin-resistant Staphylococcus aureus (MRSA). While the stepwise designed anti-HIV peptide is disulfide-linked and rich in arginines, the ab initio designed anti-MRSA peptide is linear and rich in leucines. Thus, there are different requirements for antiviral and antibacterial peptides, which could kill pathogens via different molecular targets. The biased amino acid composition in the database-designed peptides, or natural peptides such as θ-defensins, requires the use of the improved two-dimensional NMR method for structural determination to avoid the publication of misleading structure and dynamics. In the case of human cathelicidin LL-37, structural determination requires 3D NMR techniques. The high-quality structure of LL-37 provides a solid basis for understanding its interactions with membranes of bacteria and other pathogens. In conclusion, the APD database is a comprehensive platform for storing, classifying, searching, predicting, and designing potent peptides against pathogenic bacteria, viruses, fungi, parasites, and cancer cells.
      PubDate: 2013-05-27
      DOI: 10.3390/ph6060728
      Issue No: Vol. 6, No. 6 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 759-776: How
           “Pharmacoresistant” is Cav2.3, the Major Component of
           Voltage-Gated R-type Ca2+ Channels'
    • Authors: Toni Schneider, Maxine Dibué, Jürgen Hescheler
      Pages: 759 - 776
      Abstract: Membrane-bound voltage-gated Ca2+ channels (VGCCs) are targets for specific signaling complexes, which regulate important processes like gene expression, neurotransmitter release and neuronal excitability. It is becoming increasingly evident that the so called “resistant” (R-type) VGCC Cav2.3 is critical in several physiologic and pathophysiologic processes in the central nervous system, vascular system and in endocrine systems. However its eponymous attribute of pharmacologic inertness initially made in depth investigation of the channel difficult. Although the identification of SNX-482 as a fairly specific inhibitor of Cav2.3 in the nanomolar range has enabled insights into the channels properties, availability of other pharmacologic modulators of Cav2.3 with different chemical, physical and biological properties are of great importance for future investigations. Therefore the literature was screened systematically for molecules that modulate Cav2.3 VGCCs.
      PubDate: 2013-05-27
      DOI: 10.3390/ph6060759
      Issue No: Vol. 6, No. 6 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 777-787: Phorbol Ester Modulation of Ca2+
           Channels Mediates Nociceptive Transmission in Dorsal Horn Neurones
    • Authors: Li Yang, Iqbal Topia, Toni Schneider, Gary Stephens
      Pages: 777 - 787
      Abstract: Phorbol esters are analogues of diacylglycerol which activate C1 domain proteins, such as protein kinase C (PKC). Phorbol ester/PKC pathways have been proposed as potential therapeutic targets for chronic pain states, potentially by phosphorylating proteins involved in nociception, such as voltage-dependent Ca2+ channels (VDCCs). In this brief report, we investigate the potential involvement of CaV2 VDCC subtypes in functional effects of the phorbol ester, phorbol 12-myristate 13-acetate (PMA) on nociceptive transmission in the spinal cord. Effects of PMA and of selective pharmacological blockers of CaV2 VDCC subtypes on nociceptive transmission at laminae II dorsal horn neurones were examined in mouse spinal cord slices. Experiments were extended to CaV2.3(−/−) mice to complement pharmacological studies. PMA increased the mean frequency of spontaneous postsynaptic currents (sPSCs) in dorsal horn neurones, without an effect on event amplitude or half-width. sPSC frequency was reduced by selective VDCC blockers, w-agatoxin-IVA (AgTX; CaV2.1), w-conotoxin-GVIA (CTX; CaV2.2) or SNX-482 (CaV2.3). PMA effects were attenuated in the presence of each VDCC blocker and, also, in CaV2.3(−/−) mice. These initial data demonstrate that PMA increases nociceptive transmission at dorsal horn neurones via actions on different CaV2 subtypes suggesting potential anti-nociceptive targets in this system.
      PubDate: 2013-05-29
      DOI: 10.3390/ph6060777
      Issue No: Vol. 6, No. 6 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 579-603: Advances in Mammalian Cell Line
           Development Technologies for Recombinant Protein Production
    • Authors: Tingfeng Lai, Yuansheng Yang, Say Ng
      Pages: 579 - 603
      Abstract: From 2006 to 2011, an average of 15 novel recombinant protein therapeutics have been approved by US Food and Drug Administration (FDA) annually. In addition, the expiration of blockbuster biologics has also spurred the emergence of biosimilars. The increasing numbers of innovator biologic products and biosimilars have thus fuelled the demand of production cell lines with high productivity. Currently, mammalian cell line development technologies used by most biopharmaceutical companies are based on either the methotrexate (MTX) amplification technology or the glutamine synthetase (GS) system. With both systems, the cell clones obtained are highly heterogeneous, as a result of random genome integration by the gene of interest and the gene amplification process. Consequently, large numbers of cell clones have to be screened to identify rare stable high producer cell clones. As such, the cell line development process typically requires 6 to 12 months and is a time, capital and labour intensive process. This article reviews established advances in protein expression and clone screening which are the core technologies in mammalian cell line development. Advancements in these component technologies are vital to improve the speed and efficiency of generating robust and highly productive cell line for large scale production of protein therapeutics.
      PubDate: 2013-04-26
      DOI: 10.3390/ph6050579
      Issue No: Vol. 6, No. 5 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 604-622: Improved Estimation of
           Protein-Ligand Binding Free Energy by Using the Ligand-Entropy and
           Mobility of Water Molecules
    • Authors: Yoshifumi Fukunishi, Haruki Nakamura
      Pages: 604 - 622
      Abstract: We previously developed the direct interaction approximation (DIA) method to estimate the protein-ligand binding free energy (DG). The DIA method estimates the DG value based on the direct van der Waals and electrostatic interaction energies between the protein and the ligand. In the current study, the effect of the entropy of the ligand was introduced with protein dynamic properties by molecular dynamics simulations, and the interaction between each residue of the protein and the ligand was also weighted considering the hydration of each residue. The molecular dynamics simulation of the apo target protein gave the hydration effect of each residue, under the assumption that the residues, which strongly bind the water molecules, are important in the protein-ligand binding. These two effects improved the reliability of the DIA method. In fact, the parameters used in the DIA became independent of the target protein. The averaged error of DG estimation was 1.3 kcal/mol and the correlation coefficient between the experimental DG value and the calculated DG value was 0.75.
      PubDate: 2013-04-26
      DOI: 10.3390/ph6050604
      Issue No: Vol. 6, No. 5 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 623-633: In Vitro Assessment of Clevidipine
           Using the Profilin1 Hypertensive Mouse Model
    • Authors: Hamdy Hassanain, Mohamed Hassona, Erika Puente, Chengwen Sun, Zeinb Abouelnaga, David Tulman, Sergio Bergese
      Pages: 623 - 633
      Abstract: Hypertension represents a major risk factor for cardiovascular events, associating with vascular hypertrophy and dysfunction in resistance vessels. Clevidipine is a novel antihypertensive drug working as a selective calcium channel antagonist with an ultra-short half-life that lowers arterial blood pressure by reducing systemic arterial resistance. The aim was to assess the effect of clevidipine on the hypertrophic vessels of profilin1 hypertensive transgenic mice compared to sodium nitroprusside (SNP) and labetalol using wire myograph techniques. The effects of clevidipine, SNP and labetalol on the hypertrophic vessels were studied on mesenteric arterial function from 8 profilin1 hypertrophic mice and eight non-transgenic controls. Our results showed a significant difference between the effects of the three drugs on the hypertrophic mesenteric arteries of transgenic profilin1 mice compared to the non-transgenic controls. The half maximal effective concentration (EC50) of clevidipine, SNP and labetalol in profilin1 mice (1.90 ± 0.05, 0.97 ± 0.07, 2.80 ± 0.05 nM, respectively) were significantly higher than the EC50 in non-transgenic controls (0.91 ± 0.06, 0.32 ± 0.06, 0.80 ± 0.09 nM, respectively). Moreover, the increase in the EC50 for clevidipine (2-fold) to produce the same effect on both normal and hypertrophic arteries was less than that of SNP (3-fold) and labetalol (3.5-fold). Therefore, we concluded clevidipine exhibited the lowest dose shift to relax the hypertrophic vessels compared to SNP and labetalol in the profilin1 hypertrophic animal mouse model.
      PubDate: 2013-04-29
      DOI: 10.3390/ph6050623
      Issue No: Vol. 6, No. 5 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 634-649: In Vivo Anti-Leukemia, Quantum
           Chemical Calculations and ADMET Investigations of Some Quaternary and
           Isothiouronium Surfactants
    • Authors: Ahmed El-Henawy, Manal Khowdiary, Abdelfattah Badawi, Hussein Soliman
      Pages: 634 - 649
      Abstract: Anti-leukemia screening of previously prepared isothiouronium and quaternary salts was performed, and some salts exhibited promising activity as anticancer agents. Quantum chemical calculations were utilized to explore the electronic structure and stability of these compounds. Computational studies have been carried out at the PM3 semiempirical molecular orbitals level, to establish the HOMO-LUMO, IP and ESP mapping of these compounds. The ADMET properties were also studied to gain a clear view of the potential oral bioavailability of these compounds. The surface properties calculated included critical micelle concentration (CMC), maximum surface excess (Γmax), minimum surface area (Amin), free energy of micellization (ΔGomic) and adsorption (ΔGoads).
      PubDate: 2013-04-29
      DOI: 10.3390/ph6050634
      Issue No: Vol. 6, No. 5 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 650-658: Natural Products as a Source for
           New Anti-Inflammatory and Analgesic Compounds through the Inhibition of
           Purinergic P2X Receptors
    • Authors: Rômulo Soares-Bezerra, Andrea Calheiros, Natiele da Silva Ferreira, Valber da Silva Frutuoso, Luiz Alves
      Pages: 650 - 658
      Abstract: Natural products have reemerged in traditional medicine as a potential source of new molecules or phytomedicines to help with health disorders. It has been established that members of the P2X subfamily, ATP-gated ion channels, are crucial to the inflammatory process and pain signalization. As such, several preclinical studies have demonstrated that P2X2R, P2X3R, P2X4R and P2X7R are promising pharmacological targets to control inflammatory and pain disorders. Several studies have indicated that natural products could be a good source of the new specific molecules needed for the treatment of diseases linked to inflammation and pain disorders through the regulation of these receptors. Herein, we discuss and give an overview of the applicability of natural products as a source to obtain P2X receptors (P2XR) selective antagonists for use in clinical treatment, which require further investigation.
      PubDate: 2013-04-29
      DOI: 10.3390/ph6050650
      Issue No: Vol. 6, No. 5 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 659-680: FedExosomes: Engineering
           Therapeutic Biological Nanoparticles that Truly Deliver
    • Authors: Michelle Marcus, Joshua Leonard
      Pages: 659 - 680
      Abstract: Many aspects of intercellular communication are mediated through “sending” and “receiving” packets of information via the secretion and subsequent receptor-mediated detection of biomolecular species including cytokines, chemokines, and even metabolites. Recent evidence has now established a new modality of intercellular communication through which biomolecular species are exchanged between cells via extracellular lipid vesicles. A particularly important class of extracellular vesicles is exosomes, which is a term generally applied to biological nanovesicles ~30–200 nm in diameter. Exosomes form through invagination of endosomes to encapsulate cytoplasmic contents, and upon fusion of these multivesicular endosomes to the cell surface, exosomes are released to the extracellular space and transport mRNA, microRNA (miRNA) and proteins between cells. Importantly, exosome-mediated delivery of such cargo molecules results in functional modulation of the recipient cell, and such modulation is sufficiently potent to modulate disease processes in vivo. It is possible that such functional delivery of biomolecules indicates that exosomes utilize native mechanisms (e.g., for internalization and trafficking) that may be harnessed by using exosomes to deliver exogenous RNA for therapeutic applications. A complementary perspective is that understanding the mechanisms of exosome-mediated transport may provide opportunities for “reverse engineering” such mechanisms to improve the performance of synthetic delivery vehicles. In this review, we summarize recent progress in harnessing exosomes for therapeutic RNA delivery, discuss the potential for engineering exosomes to overcome delivery challenges and establish robust technology platforms, and describe both potential challenges and advantages of utilizing exosomes as RNA delivery vehicles.
      PubDate: 2013-04-29
      DOI: 10.3390/ph6050659
      Issue No: Vol. 6, No. 5 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 681-688: Evolution of Biologics Screening
           Technologies
    • Authors: Peter Cariuk, Matthew Gardener, Tristan Vaughan
      Pages: 681 - 688
      Abstract: Screening for biologics, in particular antibody drugs, has evolved significantly over the last 20 years. Initially, the screening processes and technologies from many years experience with small molecules were adopted and modified to suit the needs of biologics discovery. Since then, antibody drug discovery has matured significantly and is today investing earlier in new technologies that commercial suppliers are now developing specifically to meet the growing needs of large molecule screening. Here, we review the evolution of screening and automation technologies employed in antibody discovery and highlight the benefits that these changes have brought.
      PubDate: 2013-05-14
      DOI: 10.3390/ph6050681
      Issue No: Vol. 6, No. 5 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 440-468: Design of siRNA Therapeutics from
           the Molecular Scale
    • Authors: Phillip Angart, Daniel Vocelle, Christina Chan, S. Walton
      Pages: 440 - 468
      Abstract: While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics.
      PubDate: 2013-03-25
      DOI: 10.3390/ph6040440
      Issue No: Vol. 6, No. 4 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 469-479: Interactions of a Dopamine D1
           Receptor Agonist with Glutamate NMDA Receptor Antagonists on the
           Volitional Consumption of Ethanol by the mHEP Rat
    • Authors: Brian McMillen, Courtney Lommatzsch, Michael Sayonh, Helen Williams
      Pages: 469 - 479
      Abstract: Stimulation of the dopamine D1 receptor is reported to cause the phosphorylation of DARPP-32 at the thre34 position and activates the protein. If intracellular Ca2+ is increased, such as after activation of the glutamate NMDA receptor, calcineurin activity increases and the phosphates will be removed. This balance of phosphorylation control suggests that a D1 receptor agonist and a NMDA glutamate receptor antagonist should have additive or synergistic actions to increase activated DARPP-32 and consequent behavioral effects. This hypothesis was tested in a volitional consumption of ethanol model: the selectively bred Myers’ high ethanol preferring (mHEP) rat. A 3-day baseline period was followed by 3-days of twice daily injections of drug(s) or vehicle(s) and then a 3-day post-treatment period. Vehicle, the D1 agonist SKF 38393, the non-competitive NMDA receptor antagonist memantine, or their combination were injected 2 h before and after lights out. The combination of 5.0 mg/kg SKF 38393 with either 3.0 or 10 mg/kg memantine did not produce an additive or synergistic effect. For example, 5.0 mg/kg SKF reduced consumption of ethanol by 27.3% and 10 mg/kg memantine by 39.8%. When combined, consumption declined by 48.2% and the proportion of ethanol solution to total fluids consumed declined by 17%. However, the consumption of food also declined by 36.6%. The latter result indicates that this dose combination had a non-specific effect. The combination of SKF 38393 with (+)-MK-801, another NMDA receptor antagonist, also failed to show an additive effect. The lack of additivity and specificity suggests that the hypothesis may not be correct for this in vivo model.  The interaction of these different receptor systems with intraneuronal signaling and behaviors needs to be studied further.
      PubDate: 2013-03-26
      DOI: 10.3390/ph6040469
      Issue No: Vol. 6, No. 4 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 480-499: NMDA Receptor Antagonists for
           Treatment of Depression
    • Authors: Zeynep Ates-Alagoz, Adeboye Adejare
      Pages: 480 - 499
      Abstract: Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery.
      PubDate: 2013-04-03
      DOI: 10.3390/ph6040480
      Issue No: Vol. 6, No. 4 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 500-509: The Three Catecholics Benserazide,
           Catechol and Pyrogallol are GPR35 Agonists
    • Authors: Huayun Deng, Ye Fang
      Pages: 500 - 509
      Abstract: Nearly 1% of all clinically used drugs are catecholics, a family of catechol-containing compounds. Using label-free dynamic mass redistribution and Tango β-arrestin translocation assays, we show that several catecholics, including benserazide, catechol, 3-methoxycatechol, pyrogallol, (+)-taxifolin and fenoldopam, display agonistic activity against GPR35.
      PubDate: 2013-04-08
      DOI: 10.3390/ph6040500
      Issue No: Vol. 6, No. 4 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 510-521: Delivery of RNAi-Based
           Oligonucleotides by Electropermeabilization
    • Authors: Sophie Chabot, Sandrine Pelofy, Justin Teissié, Muriel Golzio
      Pages: 510 - 521
      Abstract: For more than a decade, understanding of RNA interference (RNAi) has been a growing field of interest. The potent gene silencing ability that small oligonucleotides have offers new perspectives for cancer therapeutics. One of the present limits is that many biological barriers exist for their efficient delivery into target cells or tissues. Electropermeabilization (EP) is one of the physical methods successfully used to transfer small oligonucleotides into cells or tissues. EP consists in the direct application of calibrated electric pulses to cells or tissues that transiently permeabilize the plasma membranes, allowing efficient in vitro and in vivo. cytoplasmic delivery of exogenous molecules. The present review reports on the type of therapeutic RNAi-based oligonucleotides that can be electrotransferred, the mechanism(s) of their electrotransfer and the technical settings for pre-clinical purposes.
      PubDate: 2013-04-10
      DOI: 10.3390/ph6040510
      Issue No: Vol. 6, No. 4 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 522-535: Disease-Causing Allele-Specific
           Silencing by RNA Interference
    • Authors: Hirohiko Hohjoh
      Pages: 522 - 535
      Abstract: Small double-stranded RNAs (dsRNAs) of approximately 21-nucleotides in size, referred to as small interfering RNA (siRNA) duplexes, can induce sequence-specific posttranscriptional gene silencing, or RNA interference (RNAi). Since chemically synthesized siRNA duplexes were found to induce RNAi in mammalian cells, RNAi has become a powerful reverse genetic tool for suppressing the expression of a gene of interest in mammals, including human, and its application has been expanding to various fields. Recent studies further suggest that synthetic siRNA duplexes have the potential for specifically inhibiting the expression of an allele of interest without suppressing the expression of other alleles, i.e., siRNA duplexes likely confer allele-specific silencing. Such gene silencing by RNAi is an advanced technique with very promising applications. In this review, I would like to discuss the potential utility of allele-specific silencing by RNAi as a therapeutic method for dominantly inherited diseases, and describe possible improvements in siRNA duplexes for enhancing their efficacy.
      PubDate: 2013-04-11
      DOI: 10.3390/ph6040522
      Issue No: Vol. 6, No. 4 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 536-545: Toxicity Studies on Novel
           N-Substituted Bicyclo-Heptan-2-Amines at NMDA Receptors
    • Authors: Natalia Coleman, Zeynep Ates-Alagoz, Boyenoh Gaye, Michelle Farbaniec, Shengguo Sun, Adeboye Adejare
      Pages: 536 - 545
      Abstract: Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the toxic effects of the compounds as compared with memantine, an NMDA receptor antagonist that is FDA approved for treatment of Alzheimer’s disease, by testing these compounds on two cell lines: MDCK (to mimic blood brain barrier) and N2a (a neuronal cell line). The compounds showed toxicity profiles similar to those of memantine i.e., dose dependence above 100 μM and IC50 values above 150 μM for each cell line. It is known that the serum level of memantine under therapeutic conditions in patients is about 1 µM, indicting these compounds could have acceptable therapeutic indexes. 2-Phenyl-N-(2-(piperidin-1-yl) ethyl)bicyclo[2.2.1]heptan-2-amine (5a) was found to possess acceptable toxicity profiles in both cell lines. Interestingly, this was the compound identified as a good lead in our previous studies based on binding and anticonvulsant (MES) activity studies. It has thus emerged as an excellent lead compound for further studies.
      PubDate: 2013-04-12
      DOI: 10.3390/ph6040536
      Issue No: Vol. 6, No. 4 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 546-556: An Allosteric Modulator of the
           Adenosine A1 Receptor Improves Cardiac Function Following Ischaemia in
           Murine Isolated Hearts
    • Authors: Anna Butcher, Peter Scammells, Paul White, Shane Devine, Roselyn Rose'Meyer
      Pages: 546 - 556
      Abstract: The effect of an allosteric modulator of the adenosine A1 receptors was investigated using an ischaemia-reperfusion protocol in murine isolated hearts. Isolated hearts were perfused with Kreb-Henseleit solution gassed with carbogen gas (95% O2 and 5% CO2) in Langendorff mode and electrically paced at 480 bpm. Following 20 min equilibration and 20 min global normothermic ischaemia, the allosteric modulator VCP333 (1 μM) or the adenosine A1 receptor partial agonist VCP102 (10 μM) were infused after 5 min of reperfusion for 15 min. Upon termination of the drug treatment, reperfusion continued for a further 40 min. At the end of 60 min reperfusion, treatment with VCP333 or VCP102 improved the recovery of the left ventricular developed pressure when compared to control group responses (p < 0.05). Neither compound affected end diastolic pressure, coronary flow rates or dP/dtmax values when compared to control tissues during reperfusion (p > 0.05). The infusion of VCP102 or VCP333 during reperfusion reduced cardiac troponin I efflux to 6.7% and 25% respectively of control heart efflux (p < 0.05). This data indicates that the allosteric modulator of the adenosine A1 receptor (VCP333) has similar characteristics to the adenosine receptor partial agonist VCP102 as it improves cardiac function and reduces myocardial cell death following an ischaemic episode.
      PubDate: 2013-04-12
      DOI: 10.3390/ph6040546
      Issue No: Vol. 6, No. 4 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 557-578: Biologics in Dermatology
    • Authors: David Chandler, Anthony Bewley
      Pages: 557 - 578
      Abstract: Skin and subcutaneous diseases affect millions of people worldwide, causing significant morbidity. Biologics are becoming increasingly useful for the treatment of many skin diseases, particularly as alternatives for patients who have failed to tolerate or respond to conventional systemic therapies. Biological therapies provide a targeted approach to treatment through interaction with specific components of the underlying immune and inflammatory disease processes. This review article examines the increasing evidence base for biologics in dermatology, including well-established treatments and novel agents.
      PubDate: 2013-04-17
      DOI: 10.3390/ph6040557
      Issue No: Vol. 6, No. 4 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 287-294: RNAi Therapeutics in Autoimmune
           Disease
    • Authors: Kaleb Pauley, Seunghee Cha
      Pages: 287 - 294
      Abstract: Since the discovery of RNA interference (RNAi), excitement has grown over its potential therapeutic uses. Targeting RNAi pathways provides a powerful tool to change biological processes post-transcriptionally in various health conditions such as cancer or autoimmune diseases. Optimum design of shRNA, siRNA, and miRNA enhances stability and specificity of RNAi-based approaches whereas it has to reduce or prevent undesirable immune responses or off-target effects. Recent advances in understanding pathogenesis of autoimmune diseases have allowed application of these tools in vitro as well as in vivo with some degree of success. Further research on the design and delivery of effectors of RNAi pathway and underlying molecular basis of RNAi would warrant practical use of RNAi-based therapeutics in human applications. This review will focus on the approaches used for current therapeutics and their applications in autoimmune diseases, including rheumatoid arthritis and Sjögren’s syndrome.
      PubDate: 2013-03-05
      DOI: 10.3390/ph6030287
      Issue No: Vol. 6, No. 3 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 295-319: Methods for Evaluating
           Cell-Specific, Cell-Internalizing RNA Aptamers
    • Authors: Luiza Hernandez, Katie Flenker, Frank Hernandez, Aloysius Klingelhutz, James McNamara, Paloma Giangrande
      Pages: 295 - 319
      Abstract: Recent clinical trials of small interfering RNAs (siRNAs) highlight the need for robust delivery technologies that will facilitate the successful application of these therapeutics to humans. Arguably, cell targeting by conjugation to cell-specific ligands provides a viable solution to this problem. Synthetic RNA ligands (aptamers) represent an emerging class of pharmaceuticals with great potential for targeted therapeutic applications. For targeted delivery of siRNAs with aptamers, the aptamer-siRNA conjugate must be taken up by cells and reach the cytoplasm. To this end, we have developed cell-based selection approaches to isolate aptamers that internalize upon binding to their cognate receptor on the cell surface. Here we describe methods to monitor for cellular uptake of aptamers. These include: (1) antibody amplification microscopy, (2) microplate-based fluorescence assay, (3) a quantitative and ultrasensitive internalization method (“QUSIM”) and (4) a way to monitor for cytoplasmic delivery using the ribosome inactivating protein-based (RNA-RIP) assay. Collectively, these methods provide a toolset that can expedite the development of aptamer ligands to target and deliver therapeutic siRNAs in vivo.
      PubDate: 2013-03-14
      DOI: 10.3390/ph6030295
      Issue No: Vol. 6, No. 3 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 320-339: Cell Penetration Properties of a
           Highly Efficient Mini Maurocalcine Peptide
    • Authors: Céline Tisseyre, Eloi Bahembera, Lucie Dardevet, Jean-Marc Sabatier, Michel Ronjat, Michel De Waard
      Pages: 320 - 339
      Abstract: Maurocalcine is a highly potent cell-penetrating peptide isolated from the Tunisian scorpion Maurus palmatus. Many cell-penetrating peptide analogues have been derived from the full-length maurocalcine by internal cysteine substitutions and sequence truncation. Herein we have further characterized the cell-penetrating properties of one such peptide, MCaUF1-9, whose sequence matches that of the hydrophobic face of maurocalcine. This peptide shows very favorable cell-penetration efficacy compared to Tat, penetratin or polyarginine. The peptide appears so specialized in cell penetration that it seems hard to improve by site directed mutagenesis. A comparative analysis of the efficacies of similar peptides isolated from other toxin members of the same family leads to the identification of hadrucalcin’s hydrophobic face as an even better CPP. Protonation of the histidine residue at position 6 renders the cell penetration of MCaUF1-9 pH-sensitive. Greater cell penetration at acidic pH suggests that MCaUF1-9 can be used to specifically target cancer cells in vivo where tumor masses grow in more acidic environments.
      PubDate: 2013-03-18
      DOI: 10.3390/ph6030320
      Issue No: Vol. 6, No. 3 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 340-357: A Review of Therapeutic Aptamer
           Conjugates with Emphasis on New Approaches
    • Authors: John Bruno
      Pages: 340 - 357
      Abstract: The potential to emulate or enhance antibodies with nucleic acid aptamers while lowering costs has prompted development of new aptamer-protein, siRNA, drug, and nanoparticle conjugates. Specific focal points of this review discuss DNA aptamers covalently bound at their 3' ends to various proteins for enhanced stability and greater pharmacokinetic lifetimes in vivo. The proteins can include Fc tails of IgG for opsonization, and the first component of complement (C1q) to trigger complement-mediated lysis of antibiotic-resistant Gram negative bacteria, cancer cells and possibly some parasites during vulnerable stages. In addition, the 3' protein adduct may be a biotoxin, enzyme, or may simply be human serum albumin (HSA) or a drug known to bind HSA, thereby retarding kidney and other organ clearance and inhibiting serum exonucleases. In this review, the author summarizes existing therapeutic aptamer conjugate categories and describes his patented concept for PCR-based amplification of double-stranded aptamers followed by covalent attachment of proteins or other agents to the chemically vulnerable overhanging 3' adenine added by Taq polymerase. PCR amplification of aptamers could dramatically lower the current $2,000/gram cost of parallel chemical oligonucleotide synthesis, thereby enabling mass production of aptamer-3'-protein or drug conjugates to better compete against expensive humanized monoclonal antibodies.
      PubDate: 2013-03-19
      DOI: 10.3390/ph6030340
      Issue No: Vol. 6, No. 3 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 358-392: Inactivation of Caliciviruses
    • Authors: Raymond Nims, Mark Plavsic
      Pages: 358 - 392
      Abstract: The Caliciviridae family of viruses contains clinically important human and animal pathogens, as well as vesivirus 2117, a known contaminant of biopharmaceutical manufacturing processes employing Chinese hamster cells. An extensive literature exists for inactivation of various animal caliciviruses, especially feline calicivirus and murine norovirus. The caliciviruses are susceptible to wet heat inactivation at temperatures in excess of 60 °C with contact times of 30 min or greater, to UV-C inactivation at fluence ≥30 mJ/cm2, to high pressure processing >200 MPa for >5 min at 4 °C, and to certain photodynamic inactivation approaches. The enteric caliciviruses (e.g.; noroviruses) display resistance to inactivation by low pH, while the non-enteric species (e.g.; feline calicivirus) are much more susceptible. The caliciviruses are inactivated by a variety of chemicals, including alcohols, oxidizing agents, aldehydes, and β-propiolactone. As with inactivation of viruses in general, inactivation of caliciviruses by the various approaches may be matrix-, temperature-, and/or contact time-dependent. The susceptibilities of the caliciviruses to the various physical and chemical inactivation approaches are generally similar to those displayed by other small, non-enveloped viruses, with the exception that the parvoviruses and circoviruses may require higher temperatures for inactivation, while these families appear to be more susceptible to UV-C inactivation than are the caliciviruses.
      PubDate: 2013-03-21
      DOI: 10.3390/ph6030358
      Issue No: Vol. 6, No. 3 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 393-406: Characterization of N-Linked
           Glycosylation in a Monoclonal Antibody Produced in NS0 Cells Using
           Capillary Electrophoresis with Laser-Induced Fluorescence Detection
    • Authors: Melissa Hamm, Yang Wang, Richard Rustandi
      Pages: 393 - 406
      Abstract: The N-linked glycosylation in recombinant monoclonal antibodies (mAb) occurs at Asn297 on the Fc region in the CH2 domain. Glycosylation heterogeneities have been well documented to affect biological activities such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through their interaction with Fc-receptors. Hence, it is critical to monitor and characterize the N-linked glycosylation profile in a therapeutic protein such as a mAb for product consistency. In one approach, the glycans are first released from the mAb using an enzyme specific digestion, such as Protein N-Glycosidase F (PNGase) and subsequently they are labeled using a fluorophore, for example, 8-aminopyrene-1,3,6-trisulfonic acid (APTS) . Here we have applied this approach and used Capillary Electrophoresis with Laser-Induced Fluorescence detection (CE-LIF) to analyze a recombinant mAb produced in murine myeloma (NS0) cells. The technique provides short analysis times, efficient separations, and high sensitivity. CE-LIF peak identification was done by a combination of glycan standards and treatment with various exoglycosidases. Furthermore, the APTS-labeled glycans were also analyzed using hydrophilic interaction chromatography (HILIC) high performance liquid chromatography (HPLC) to aid identification of minor peaks by sample collection and off-line mass spectrometry (MS) analysis.
      PubDate: 2013-03-21
      DOI: 10.3390/ph6030393
      Issue No: Vol. 6, No. 3 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 407-439: Protein Kinase C Inhibitors as
           
    • Authors: Raouf Khalil
      Pages: 407 - 439
      Abstract: Blood pressure (BP) is regulated by multiple neuronal, hormonal, renal and vascular control mechanisms. Changes in signaling mechanisms in the endothelium, vascular smooth muscle (VSM) and extracellular matrix cause alterations in vascular tone and blood vessel remodeling and may lead to persistent increases in vascular resistance and hypertension (HTN). In VSM, activation of surface receptors by vasoconstrictor stimuli causes an increase in intracellular free Ca2+ concentration ([Ca2+]i), which forms a complex with calmodulin, activates myosin light chain (MLC) kinase and leads to MLC phosphorylation, actin-myosin interaction and VSM contraction. Vasoconstrictor agonists could also increase the production of diacylglycerol which activates protein kinase C (PKC). PKC is a family of Ca2+-dependent and Ca2+-independent isozymes that have different distributions in various blood vessels, and undergo translocation from the cytosol to the plasma membrane, cytoskeleton or the nucleus during cell activation. In VSM, PKC translocation to the cell surface may trigger a cascade of biochemical events leading to activation of mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK), a pathway that ultimately increases the myofilament force sensitivity to [Ca2+]i, and enhances actin-myosin interaction and VSM contraction. PKC translocation to the nucleus may induce transactivation of various genes and promote VSM growth and proliferation. PKC could also affect endothelium-derived relaxing and contracting factors as well as matrix metalloproteinases (MMPs) in the extracellular matrix further affecting vascular reactivity and remodeling. In addition to vasoactive factors, reactive oxygen species, inflammatory cytokines and other metabolic factors could affect PKC activity. Increased PKC expression and activity have been observed in vascular disease and in certain forms of experimental and human HTN. Targeting of vascular PKC using PKC inhibitors may function in concert with antioxidants, MMP inhibitors and cytokine antagonists to reduce VSM hyperactivity in certain forms of HTN that do not respond to Ca2+ channel blockers.
      PubDate: 2013-03-21
      DOI: 10.3390/ph6030407
      Issue No: Vol. 6, No. 3 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 124-160: siRNA Genome Screening Approaches
           to Therapeutic Drug Repositioning
    • Authors: Olivia Perwitasari, Abhijeet Bakre, S. Tompkins, Ralph Tripp
      Pages: 124 - 160
      Abstract: Bridging high-throughput screening (HTS) with RNA interference (RNAi) has allowed for rapid discovery of the molecular basis of many diseases, and identification of potential pathways for developing safe and effective treatments. These features have identified new host gene targets for existing drugs paving the pathway for therapeutic drug repositioning. Using RNAi to discover and help validate new drug targets has also provided a means to filter and prioritize promising therapeutics. This review summarizes these approaches across a spectrum of methods and targets in the host response to pathogens. Particular attention is given to the utility of drug repurposing utilizing the promiscuous nature of some drugs that affect multiple molecules or pathways, and how these biological pathways can be targeted to regulate disease outcome.
      PubDate: 2013-01-28
      DOI: 10.3390/ph6020124
      Issue No: Vol. 6, No. 2 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 161-183: Dendrimers for siRNA Delivery
    • Authors: Swati Biswas, Vladimir Torchilin
      Pages: 161 - 183
      Abstract: Since the discovery of the “starburst polymer”, later renamed as dendrimer, this class of polymers has gained considerable attention for numerous biomedical applications, due mainly to the unique characteristics of this macromolecule, including its monodispersity, uniformity, and the presence of numerous functionalizable terminal groups. In recent years, dendrimers have been studied extensively for their potential application as carriers for nucleic acid therapeutics, which utilize the cationic charge of the dendrimers for effective dendrimer-nucleic acid condensation. siRNA is considered a promising, versatile tool among various RNAi-based therapeutics, which can effectively regulate gene expression if delivered successfully inside the cells. This review reports on the advancements in the development of dendrimers as siRNA carriers.
      PubDate: 2013-02-04
      DOI: 10.3390/ph6020161
      Issue No: Vol. 6, No. 2 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 184-203: Relationships between Cargo, Cell
           Penetrating Peptides and Cell Type for Uptake of Non-Covalent Complexes
           into Live Cells
    • Authors: Andrea-Anneliese Keller, Franziska Mussbach, Reinhard Breitling, Peter Hemmerich, Buerk Schaefer, Stefan Lorkowski, Siegmund Reissmann
      Pages: 184 - 203
      Abstract: Modulating signaling pathways for research and therapy requires either suppression or expression of selected genes or internalization of proteins such as enzymes, antibodies, nucleotide binding proteins or substrates including nucleoside phosphates and enzyme inhibitors. Peptides, proteins and nucleotides are transported by fusing or conjugating them to cell penetrating peptides or by formation of non-covalent complexes. The latter is often preferred because of easy handling, uptake efficiency and auto-release of cargo into the live cell. In our studies complexes are formed with labeled or readily detectable cargoes for qualitative and quantitative estimation of their internalization. Properties and behavior of adhesion and suspension vertebrate cells as well as the protozoa Leishmania tarentolae are investigated with respect to proteolytic activity, uptake efficiency, intracellular localization and cytotoxicity. Our results show that peptide stability to membrane-bound, secreted or intracellular proteases varies between different CPPs and that the suitability of individual CPPs for a particular cargo in complex formation by non-covalent interactions requires detailed studies. Cells vary in their sensitivity to increasing concentrations of CPPs. Thus, most cells can be efficiently transduced with peptides, proteins and nucleotides with intracellular concentrations in the low micromole range. For each cargo, cell type and CPP the optimal conditions must be determined separately.
      PubDate: 2013-02-06
      DOI: 10.3390/ph6020184
      Issue No: Vol. 6, No. 2 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 204-222: Elucidating the Function of
           Penetratin and a Static Magnetic Field in Cellular Uptake of Magnetic
           Nanoparticles
    • Authors: Suman Chaudhary, Carol Smith, Pablo del Pino, Jesus de la Fuente, Margaret Mullin, Andrew Hursthouse, David Stirling, Catherine Berry
      Pages: 204 - 222
      Abstract: Nanotechnology plays an increasingly important role in the biomedical arena. In particular, magnetic nanoparticles (mNPs) have become important tools in molecular diagnostics, in vivo imaging and improved treatment of disease, with the ultimate aim of producing a more theranostic approach. Due to their small sizes, the nanoparticles can cross most of the biological barriers such as the blood vessels and the blood brain barrier, thus providing ubiquitous access to most tissues. In all biomedical applications maximum nanoparticle uptake into cells is required. Two promising methods employed to this end include functionalization of mNPs with cell-penetrating peptides to promote efficient translocation of cargo into the cell and the use of external magnetic fields for enhanced delivery. This study aimed to compare the effect of both penetratin and a static magnetic field with regards to the cellular uptake of 200 nm magnetic NPs and determine the route of uptake by both methods. Results demonstrated that both techniques increased particle uptake, with penetratin proving more cell specific. Clathrin- medicated endocytosis appeared to be responsible for uptake as shown via PCR and western blot, with Pitstop 2 (known to selectively block clathrin formation) blocking particle uptake. Interestingly, it was further shown that a magnetic field was able to reverse or overcome the blocking, suggesting an alternative route of uptake.
      PubDate: 2013-02-06
      DOI: 10.3390/ph6020204
      Issue No: Vol. 6, No. 2 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 223-250: RNAi Therapeutic Platforms for
           Lung Diseases
    • Authors: Yu Fujita, Fumitaka Takeshita, Kazuyoshi Kuwano, Takahiro Ochiya
      Pages: 223 - 250
      Abstract: RNA interference (RNAi) is rapidly becoming an important method for analyzing gene functions in many eukaryotes and holds promise for the development of therapeutic gene silencing. The induction of RNAi relies on small silencing RNAs, which affect specific messenger RNA (mRNA) degradation. Two types of small RNA molecules, i.e. small interfering RNAs (siRNAs) and microRNAs (miRNAs), are central to RNAi. Drug discovery studies and novel treatments of siRNAs are currently targeting a wide range of diseases, including various viral infections and cancers. Lung diseases in general are attractive targets for siRNA therapeutics because of their lethality and prevalence. In addition, the lung is anatomically accessible to therapeutic agents via the intrapulmonary route. Recently, increasing evidence indicates that miRNAs play an important role in lung abnormalities, such as inflammation and oncogenesis. Therefore, miRNAs are being targeted for therapeutic purposes. In this review, we present strategies for RNAi delivery and discuss the current state-of-the-art RNAi-based therapeutics for various lung diseases.
      PubDate: 2013-02-06
      DOI: 10.3390/ph6020223
      Issue No: Vol. 6, No. 2 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 251-268: NMDA Receptor Modulators in the
           Treatment of Drug Addiction
    • Authors: Seven Tomek, Amber Lacrosse, Natali Nemirovsky, M. Olive
      Pages: 251 - 268
      Abstract: Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.
      PubDate: 2013-02-06
      DOI: 10.3390/ph6020251
      Issue No: Vol. 6, No. 2 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 269-286: cGMP-Dependent Protein Kinase
           Inhibitors in Health and Disease
    • Authors: Stefanie Wolfertstetter, Johannes Huettner, Jens Schlossmann
      Pages: 269 - 286
      Abstract: cGMP-dependent protein kinases (PKG) exhibit diverse physiological functions in the mammalian system e.g., in vascular and gastrointestinal smooth muscles, in platelets, in kidney, in bone growth, nociception and in the central nervous system. Furthermore, PKG were found in insects and in the malaria parasite Plasmodium falciparum. Two different genes of PKG exist: a) the PKG-I gene that is expressed as cytosolic PKG-Iα or PKG-Iβ isoform, and b) the PKG-II gene, which expresses the membrane associated PKG-II protein. The enzyme kinetics, the localization and the substrates of these PKG enzymes differ utilizing different physiological functions. Various inhibitors of PKG were developed directed against diverse functional regions of the kinase. These inhibitors of PKG have been used to analyse the specific functions of these enzymes. The review article will summarize these different inhibitors regarding their specificity and their present applications in vitro and in vivo. Furthermore, it will be discussed that the distinct inhibition of the PKG enzymes could be used as a valuable pharmacological target e.g., in the treatment of cardiovascular diseases, diarrhea, cancer or malaria.
      PubDate: 2013-02-07
      DOI: 10.3390/ph6020269
      Issue No: Vol. 6, No. 2 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1451-1474: Effect of Essential Oils on
           Pathogenic Bacteria
    • Authors: Filomena Nazzaro, Florinda Fratianni, Laura De Martino, Raffaele Coppola, Vincenzo De Feo
      Pages: 1451 - 1474
      Abstract: The increasing resistance of microorganisms to conventional chemicals and drugs is a serious and evident worldwide problem that has prompted research into the identification of new biocides with broad activity. Plants and their derivatives, such as essential oils, are often used in folk medicine. In nature, essential oils play an important role in the protection of plants. Essential oils contain a wide variety of secondary metabolites that are capable of inhibiting or slowing the growth of bacteria, yeasts and moulds. Essential oils and their components have activity against a variety of targets, particularly the membrane and cytoplasm, and in some cases, they completely change the morphology of the cells. This brief review describes the activity of essential oils against pathogenic bacteria.
      PubDate: 2013-11-25
      DOI: 10.3390/ph6121451
      Issue No: Vol. 6, No. 12 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1475-1506: Glioblastoma Multiforme Therapy
           and Mechanisms of Resistance
    • Authors: Yulian Ramirez, Jessica Weatherbee, Richard Wheelhouse, Alonzo Ross
      Pages: 1475 - 1506
      Abstract: Glioblastoma multiforme (GBM) is a grade IV brain tumor characterized by a heterogeneous population of cells that are highly infiltrative, angiogenic and resistant to chemotherapy. The current standard of care, comprised of surgical resection followed by radiation and the chemotherapeutic agent temozolomide, only provides patients with a 12–14 month survival period post-diagnosis. Long-term survival for GBM patients remains uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. In this review we will describe the mechanisms of resistance, and how they may be overcome to improve the survival of GBM patients by implementing novel chemotherapy drugs, new drug combinations and new approaches relating to DNA damage, angiogenesis and autophagy.
      PubDate: 2013-11-25
      DOI: 10.3390/ph6121475
      Issue No: Vol. 6, No. 12 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1507-1542: Aptamer-Based Therapeutics: New
           Approaches to Combat Human Viral Diseases
    • Authors: Ka-To Shum, Jiehua Zhou, John Rossi
      Pages: 1507 - 1542
      Abstract: Viruses replicate inside the cells of an organism and continuously evolve to contend with an ever-changing environment. Many life-threatening diseases, such as AIDS, SARS, hepatitis and some cancers, are caused by viruses. Because viruses have small genome sizes and high mutability, there is currently a lack of and an urgent need for effective treatment for many viral pathogens. One approach that has recently received much attention is aptamer-based therapeutics. Aptamer technology has high target specificity and versatility, i.e., any viral proteins could potentially be targeted. Consequently, new aptamer-based therapeutics have the potential to lead a revolution in the development of anti-infective drugs. Additionally, aptamers can potentially bind any targets and any pathogen that is theoretically amenable to rapid targeting, making aptamers invaluable tools for treating a wide range of diseases. This review will provide a broad, comprehensive overview of viral therapies that use aptamers. The aptamer selection process will be described, followed by an explanation of the potential for treating virus infection by aptamers. Recent progress and prospective use of aptamers against a large variety of human viruses, such as HIV-1, HCV, HBV, SCoV, Rabies virus, HPV, HSV and influenza virus, with particular focus on clinical development of aptamers will also be described. Finally, we will discuss the challenges of advancing antiviral aptamer therapeutics and prospects for future success.
      PubDate: 2013-11-25
      DOI: 10.3390/ph6121507
      Issue No: Vol. 6, No. 12 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1543-1575: Antimicrobial Peptides
    • Authors: Ali Bahar, Dacheng Ren
      Pages: 1543 - 1575
      Abstract: The rapid increase in drug-resistant infections has presented a serious challenge to antimicrobial therapies. The failure of the most potent antibiotics to kill “superbugs” emphasizes the urgent need to develop other control agents. Here we review the history and new development of antimicrobial peptides (AMPs), a growing class of natural and synthetic peptides with a wide spectrum of targets including viruses, bacteria, fungi, and parasites. We summarize the major types of AMPs, their modes of action, and the common mechanisms of AMP resistance. In addition, we discuss the principles for designing effective AMPs and the potential of using AMPs to control biofilms (multicellular structures of bacteria embedded in extracellular matrixes) and persister cells (dormant phenotypic variants of bacterial cells that are highly tolerant to antibiotics).
      PubDate: 2013-11-28
      DOI: 10.3390/ph6121543
      Issue No: Vol. 6, No. 12 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1335-1346: A Review of Ten Years of the
           Study for Monitoring Antimicrobial Resistance Trends (SMART) from 2002 to
           2011
    • Authors: Ian Morrissey, Meredith Hackel, Robert Badal, Sam Bouchillon, Stephen Hawser, Douglas Biedenbach
      Pages: 1335 - 1346
      Abstract: Surveillance of antimicrobial agent resistance provides important information to guide microbiologists and infectious disease specialists understanding of the control and the spread of resistance mechanisms within the local environment. Continued monitoring of antimicrobial resistance patterns in the community and in local hospital environments is essential to guide effective empiric therapy. The Study for Monitoring Antimicrobial Resistance Trends (SMART) has monitored the in vitro susceptibility patterns of clinical Gram-negative bacilli to antimicrobial agents collected worldwide from intra-abdominal infections since 2002 and urinary tract infections since 2009. Resistance trends, with a particular focus on carbapenem resistance and the rate of extended-spectrum β-lactamases (ESBLs), were analyzed. Isolates from intra-abdominal infections (n = 92,086) and urinary-tract infections (n = 24,705) were collected and tested using Clinical and Laboratory Standards Institute methods. This review presents carbapenem susceptibility and ESBL rates over ten years of SMART study analysis, including key publications during this period. The SMART study has proved to be a valuable resource in determining pathogen prevalence and antibiotic susceptibility over the last ten years and continues to provide evidence for regulatory susceptibility breakpoints and clinical decision making.
      PubDate: 2013-11-01
      DOI: 10.3390/ph6111335
      Issue No: Vol. 6, No. 11 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1347-1360: Metabolic Interactions of Purine
           Derivatives with Human ABC Transporter ABCG2: Genetic Testing to Assess
           Gout Risk
    • Authors: Toshihisa Ishikawa, Wanping Aw, Kiyoko Kaneko
      Pages: 1347 - 1360
      Abstract: In mammals, excess purine nucleosides are removed from the body by breakdown in the liver and excretion from the kidneys. Uric acid is the end product of purine metabolism in humans. Two-thirds of uric acid in the human body is normally excreted through the kidney, whereas one-third undergoes uricolysis (decomposition of uric acid) in the gut. Elevated serum uric acid levels result in gout and could be a risk factor for cardiovascular disease and diabetes. Recent studies have shown that human ATP-binding cassette transporter ABCG2 plays a role of renal excretion of uric acid. Two non-synonymous single nucleotide polymorphisms (SNPs), i.e., 421C>A (major) and 376C>T (minor), in the ABCG2 gene result in impaired transport activity, owing to ubiquitination-mediated proteosomal degradation and truncation of ABCG2, respectively. These genetic polymorphisms are associated with hyperuricemia and gout. Allele frequencies of those SNPs are significantly higher in Asian populations than they are in African and Caucasian populations. A rapid and isothermal genotyping method has been developed to detect the SNP 421C>A, where one drop of peripheral blood is sufficient for the detection. Development of simple genotyping methods would serve to improve prevention and early therapeutic intervention for high-risk individuals in personalized healthcare.
      PubDate: 2013-11-04
      DOI: 10.3390/ph6111347
      Issue No: Vol. 6, No. 11 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1361-1380: Nanoparticles as Drug Delivery
           Systems in Cancer Medicine: Emphasis on RNAi-Containing Nanoliposomes
    • Authors: Mónica Díaz, Pablo Vivas-Mejia
      Pages: 1361 - 1380
      Abstract: Nanomedicine is a growing research field dealing with the creation and manipulation of materials at a nanometer scale for the better treatment, diagnosis and imaging of diseases. In cancer medicine, the use of nanoparticles as drug delivery systems has advanced the bioavailability, in vivo stability, intestinal absorption, solubility, sustained and targeted delivery, and therapeutic effectiveness of several anticancer agents. The expansion of novel nanoparticles for drug delivery is an exciting and challenging research filed, in particular for the delivery of emerging cancer therapies, including small interference RNA (siRNA) and microRNA (miRNAs)-based molecules. In this review, we focus on the currently available drug delivery systems for anticancer agents. In addition, we will discuss the promising use of nanoparticles for novel cancer treatment strategies.
      PubDate: 2013-11-04
      DOI: 10.3390/ph6111361
      Issue No: Vol. 6, No. 11 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1381-1406: Longitudinal Assessment of
           Antimicrobial Susceptibility among Gram-Negative and Gram-Positive
           Organisms Collected from Italy as Part of the Tigecycline Evaluation and
           Surveillance Trial between 2004 and 2011
    • Authors: Stefania Stefani, Michael Dowzicky
      Pages: 1381 - 1406
      Abstract: The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) was initiated in 2004 to longitudinally monitor the activity of the broad-spectrum glycylcycline antimicrobial tigecycline, and a suite of comparator agents, against an array of clinically important bacterial pathogens worldwide. In this report, we examine the activity of tigecycline and comparators against a collection of 13,245 clinical isolates, both Gram-positive (n = 4,078 and Gram-negative (n = 9,167), collected from 27 centres in Italy between 2004 and 2011. Susceptibility was established according to Clinical Laboratory Standards Institute guidelines. Tigecycline and linezolid exhibited very good activity against Gram-positive pathogens, with MIC90s ranging from 0.06 to 0.25 mg/L and 1–4 mg/L, respectively; vancomycin and the carbapenems also showed good activity against select Gram-positive pathogens. Tigecycline was the most active agent against Gram-negative pathogens (except P. aeruginosa), with MIC90s ranging from 0.25–2 mg/L (16 mg/L for P. aeruginosa). Amikacin and the carbapenems also possessed good activity against many Gram-negative pathogens here. ESBL-positive E. coli increased in prevalence from 2004 to 2011, while ESBL-positive Klebsiella spp., vancomycin-resistant enterococci and MRSA decreased in prevalence. Linezolid, tigecycline and vancomycin susceptibility were very stable over the course of this study, while susceptibility to ampicillin, piperacillin-tazobactam, ceftriaxone and levofloxacin varied over time according to pathogen; minocycline and cefepime susceptibility among several pathogens decreased during this study.
      PubDate: 2013-11-07
      DOI: 10.3390/ph6111381
      Issue No: Vol. 6, No. 11 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1407-1428: Structural Bioinformatics and
           Protein Docking Analysis of the Molecular Chaperone-Kinase Interactions:
           Towards Allosteric Inhibition of Protein Kinases by Targeting the
           Hsp90-Cdc37 Chaperone Machinery
    • Authors: Nathan Lawless, Kristin Blacklock, Elizabeth Berrigan, Gennady Verkhivker
      Pages: 1407 - 1428
      Abstract: A fundamental role of the Hsp90-Cdc37 chaperone system in mediating maturation of protein kinase clients and supporting kinase functional activity is essential for the integrity and viability of signaling pathways involved in cell cycle control and organism development. Despite significant advances in understanding structure and function of molecular chaperones, the molecular mechanisms and guiding principles of kinase recruitment to the chaperone system are lacking quantitative characterization. Structural and thermodynamic characterization of Hsp90-Cdc37 binding with protein kinase clients by modern experimental techniques is highly challenging, owing to a transient nature of chaperone-mediated interactions. In this work, we used experimentally-guided protein docking to probe the allosteric nature of the Hsp90-Cdc37 binding with the cyclin-dependent kinase 4 (Cdk4) kinase clients. The results of docking simulations suggest that the kinase recognition and recruitment to the chaperone system may be primarily determined by Cdc37 targeting of the N-terminal kinase lobe. The interactions of Hsp90 with the C-terminal kinase lobe may provide additional “molecular brakes” that can lock (or unlock) kinase from the system during client loading (release) stages. The results of this study support a central role of the Cdc37 chaperone in recognition and recruitment of the kinase clients. Structural analysis may have useful implications in developing strategies for allosteric inhibition of protein kinases by targeting the Hsp90-Cdc37 chaperone machinery.
      PubDate: 2013-11-11
      DOI: 10.3390/ph6111407
      Issue No: Vol. 6, No. 11 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1429-1450: Hedgehog Pathway Blockade
           Inhibits Melanoma Cell Growth in Vitro and in Vivo
    • Authors: Kathryn O'Reilly, Eleazar de Miera, Miguel Segura, Erica Friedman, Laura Poliseno, Sung Han, Judy Zhong, Jiri Zavadil, Anna Pavlick, Eva Hernando, Iman Osman
      Pages: 1429 - 1450
      Abstract: Previous reports have demonstrated a role for hedgehog signaling in melanoma progression, prompting us to explore the therapeutic benefit of targeting this pathway in melanoma. We profiled a panel of human melanoma cell lines and control melanocytes for altered expression of hedgehog pathway members and determined the consequences of both genetic and pharmacological inhibition of the hedgehog pathway activator Smoothened (SMO) in melanoma, both in vitro and in vivo. We also examined the relationship between altered expression of hedgehog pathway mediators and survival in a well-characterized cohort of metastatic melanoma patients with prospectively collected follow up information. Studies revealed that over 40% of the melanoma cell lines examined harbored significantly elevated levels of the hedgehog pathway mediators SMO, GLI2, and PTCH1 compared to melanocytes (p < 0.05). SMO inhibition using siRNA and the small molecule inhibitor, NVP-LDE-225, suppressed melanoma growth in vitro, particularly in those cell lines with moderate SMO and GLI2 expression. NVP-LDE-225 also induced apoptosis in vitro and inhibited melanoma growth in a xenograft model. Gene expression data also revealed evidence of compensatory up-regulation of two other developmental pathways, Notch and WNT, in response to hedgehog pathway inhibition. Pharmacological and genetic SMO inhibition also downregulated genes involved in human embryonic stem cell pluripotency. Finally, increased SMO expression and decreased expression of the hedgehog pathway repressor GLI3 correlated with shorter post recurrence survival in metastatic melanoma patients. Our data demonstrate that hedgehog pathway inhibition might be a promising targeted therapy in appropriately selected metastatic melanoma patients.
      PubDate: 2013-11-11
      DOI: 10.3390/ph6111429
      Issue No: Vol. 6, No. 11 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1170-1194: Safety of Immunosuppressive
           Drugs Used as Maintenance Therapy in Kidney Transplantation: A Systematic
           Review and Meta-Analysis
    • Authors: Celline Almeida, Micheline Silveira, Vânia de Araújo, Livia de Lemos, Juliana de Oliveira Costa, Carlos Reis, Francisco de Assis Acurcio, Maria das Gracas Braga Ceccato
      Pages: 1170 - 1194
      Abstract: To evaluate the safety of regimens containing calcineurin inhibitors (CNI), proliferation signal inhibitors (TOR-I) and antimetabolites, we conducted a meta-analysis of randomized clinical trials (RCTs) and observational studies. A total of 4,960 citations were identified in our electronic search and 14 additional articles were identified through hand searching. Forty-eight articles (11,432 participants) from 42 studies (38 RCTs and four cohorts) met the inclusion criteria. Meta-analysis results revealed the following: (i) tacrolimus was associated with an increased risk for diabetes and lower risk of dyslipidemia, compared to cyclosporine; (ii) mycophenolate mofetil (MMF) was associated with increased risk for total infections, abdominal pain, diarrhea and vomiting, compared with azathioprine; (iii) sirolimus was associated with higher risk of anemia, diabetes, dyslipidemia, lymphoceles and withdrawal compared to tacrolimus or cyclosporine, and cyclosporine was associated with an increased risk of CMV infection; (iv) the combination of CNI with antimetabolites was associated with more adverse events than CNI alone; (v) TOR-I was related to more adverse events than MMF. The data observed in this meta-analysis are similar to those describe by others authors; thus, the choice of treatment must be made by the clinical staff based on specific patient characteristics.
      PubDate: 2013-09-30
      DOI: 10.3390/ph6101170
      Issue No: Vol. 6, No. 10 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1195-1220: MicroRNAs as Molecular Targets
           for Cancer Therapy: On the Modulation of MicroRNA Expression
    • Authors: Pedro Costa, Maria Pedroso de Lima
      Pages: 1195 - 1220
      Abstract: The discovery of small RNA molecules with the capacity to regulate messenger RNA (mRNA) stability and translation (and consequently protein synthesis) has revealed an additional level of post-transcriptional gene control. MicroRNAs (miRNAs), an evolutionarily conserved class of small noncoding RNAs that regulate gene expression post-transcriptionally by base pairing to complementary sequences in the 3' untranslated regions of target mRNAs, are part of this modulatory RNA network playing a pivotal role in cell fate. Functional studies indicate that miRNAs are involved in the regulation of almost every biological pathway, while changes in miRNA expression are associated with several human pathologies, including cancer. By targeting oncogenes and tumor suppressors, miRNAs have the ability to modulate key cellular processes that define the cell phenotype, making them highly promising therapeutic targets. Over the last few years, miRNA-based anti-cancer therapeutic approaches have been exploited, either alone or in combination with standard targeted therapies, aiming at enhancing tumor cell killing and, ideally, promoting tumor regression and disease remission. Here we provide an overview on the involvement of miRNAs in cancer pathology, emphasizing the mechanisms of miRNA regulation. Strategies for modulating miRNA expression are presented and illustrated with representative examples of their application in a therapeutic context.
      PubDate: 2013-09-30
      DOI: 10.3390/ph6101195
      Issue No: Vol. 6, No. 10 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1221-1286: The Use of Central Nervous
           System Active Drugs During Pregnancy
    • Authors: Bengt Källén, Natalia Borg, Margareta Reis
      Pages: 1221 - 1286
      Abstract: CNS-active drugs are used relatively often during pregnancy. Use during early pregnancy may increase the risk of a congenital malformation; use during the later part of pregnancy may be associated with preterm birth, intrauterine growth disturbances and neonatal morbidity. There is also a possibility that drug exposure can affect brain development with long-term neuropsychological harm as a result. This paper summarizes the literature on such drugs used during pregnancy: opioids, anticonvulsants, drugs used for Parkinson’s disease, neuroleptics, sedatives and hypnotics, antidepressants, psychostimulants, and some other CNS-active drugs. In addition to an overview of the literature, data from the Swedish Medical Birth Register (1996–2011) are presented. The exposure data are either based on midwife interviews towards the end of the first trimester or on linkage with a prescribed drug register. An association between malformations and maternal use of anticonvulsants and notably valproic acid is well known from the literature and also demonstrated in the present study. Some other associations between drug exposure and outcome were found.
      PubDate: 2013-10-10
      DOI: 10.3390/ph6101221
      Issue No: Vol. 6, No. 10 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1287-1303: Glibenclamide for the Treatment
           of Acute CNS Injury
    • Authors: David Kurland, Cigdem Tosun, Adam Pampori, Jason Karimy, Nicholas Caffes, Volodymyr Gerzanich, J. Simard
      Pages: 1287 - 1303
      Abstract: First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis—all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.
      PubDate: 2013-10-11
      DOI: 10.3390/ph6101287
      Issue No: Vol. 6, No. 10 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1304-1321: Drug Repositioning: An
           Opportunity to Develop Novel Treatments for Alzheimer’s Disease
    • Authors: Anne Corbett, Gareth Williams, Clive Ballard
      Pages: 1304 - 1321
      Abstract: Alzheimer’s Disease (AD) is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery.
      PubDate: 2013-10-11
      DOI: 10.3390/ph6101304
      Issue No: Vol. 6, No. 10 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1322-1334: Loss of Response to Long-Term
           Infliximab Therapy in Children with Crohn’s Disease
    • Authors: Oliver Gouldthorpe, Anthony Catto-Smith, George Alex, Di Simpson
      Pages: 1322 - 1334
      Abstract: Secondary loss of response (LoR) often precludes further use of infliximab in children with Crohn’s disease. Immunomodulators may reduce the incidence of LoR but their combination with infliximab presents safety concerns. We aimed to determine the long-term durability of infliximab response in paediatric Crohn’s, effect of immunomodulators on LoR, and secondarily the effect of infliximab on growth. We retrospectively audited patients on maintenance infliximab at a single centre. Data included height and weight, Paediatric Crohn’s Disease Activity Index (PCDAI), and immunomodulator use. 71 children (32% female, mean age 14.4 years) had been commenced on maintenance infliximab before July 2011. 89% had been on immunomodulators concurrently with infliximab. LoR occurred in 20 (28%), with a median time to LoR of 4.31 years. LoR was significantly increased in children who did not enter remission (PCDAI ≤ 10) after induction (p < 0.05). LoR occurred more frequently in the 72% who ceased immunomodulators, but this failed to reach statistical significance (p = 0.300). Height and weight SDS improved significantly on infliximab. Infliximab is a durable long-term therapy for paediatric Crohn’s refractory to conventional therapy. A large-magnitude increase in the rate of loss of response after immunomodulator cessation was not observed.
      PubDate: 2013-10-16
      DOI: 10.3390/ph6101322
      Issue No: Vol. 6, No. 10 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 25-31: Stability of Recombinant Tissue
           Plasminogen Activator at −30 °C over One Year
    • Authors: Abdulmalik Alkatheri
      Pages: 25 - 31
      Abstract: Recombinant tissue plasminogen activator (rt-PA) is used to restore patency and avoid inadvertent removal of peripheral and central venous catheters. rt-PA was reconstituted (1 mg/mL) then cryopreserved at −30 °C for 1, 2, 3, 6, 8, and 12 months and, then its stability was determined. After cryopreservation for one and two months, rt-PA kept more than 95% of its activity compared to standard samples, while cryopreservation for three months caused 8% loss of activity. However, after cryopreservation for six months or more, rt-PA retained only 87.5% or less activity compared to standard samples. Therefore, it is recommended that reconstituted rt-PA be cryopreserved at −30 °C for a maximum period of three months.
      PubDate: 2013-01-02
      DOI: 10.3390/ph6010025
      Issue No: Vol. 6, No. 1 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 32-53: The Potential Role of Cell
           Penetrating Peptides in the Intracellular Delivery of Proteins for Therapy
           of Erythroid Related Disorders
    • Authors: Lefkothea Papadopoulou, Asterios Tsiftsoglou
      Pages: 32 - 53
      Abstract: The erythroid related disorders (ERDs) represent a large group of hematological diseases, which in most cases are attributed either to the deficiency or malfunction of biosynthetic enzymes or oxygen transport proteins. Current treatments for these disorders include histo-compatible erythrocyte transfusions or allogeneic hematopoietic stem cell (HSC) transplantation. Gene therapy delivered via suitable viral vectors or genetically modified HSCs have been under way. Protein Transduction Domain (PTD) technology has allowed the production and intracellular delivery of recombinant therapeutic proteins, bearing Cell Penetrating Peptides (CPPs), into a variety of mammalian cells. Remarkable progress in the field of protein transduction leads to the development of novel protein therapeutics (CPP-mediated PTs) for the treatment of monogenetic and/or metabolic disorders. The “concept” developed in this paper is the intracellular protein delivery made possible via the PTD technology as a novel therapeutic intervention for treatment of ERDs. This can be achieved via four stages including: (i) the production of genetically engineered human CPP-mediated PT of interest, since the corresponding native protein either is missing or is mutated in the erythroid progenitor cell (ErPCs) or mature erythrocytes of patients; (ii) isolation of target cells from the peripheral blood of the selected patients; (iii) ex vivo transduction of cells with the CPP-mediated PT of interest; and (iv) re-administration of the successfully transduced cells back into the same patients.
      PubDate: 2013-01-07
      DOI: 10.3390/ph6010032
      Issue No: Vol. 6, No. 1 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 54-69: A Potent (R)-alpha-bis-lipoyl
           Derivative Containing 8-Hydroxyquinoline Scaffold: Synthesis and
           Biological Evaluation of Its Neuroprotective Capabilities in SH-SY5Y Human
           Neuroblastoma Cells
    • Authors: Ivana Cacciatore, Erika Fornasari, Leonardo Baldassarre, Catia Cornacchia, Stefania Fulle, Ester Di Filippo, Tiziana Pietrangelo, Francesco Pinnen
      Pages: 54 - 69
      Abstract: A novel bis-lipoyl derivative containing 8-hydroxyquinoline scaffold (LA-HQ-LA, 5) was synthesized as a new multifunctional drug candidate with antioxidant, chelant, and neuroprotective properties for the treatment of neurodegenerative diseases. We have investigated the potential effectiveness of LA-HQ-LA against the cytotoxicity induced by 6-OHDA and H2O2 on human neuroblastoma SH-SY5Y cell line. Our outcomes showed that LA-HQ-LA resulted in significant neuroprotective and antioxidant effects against H2O2- and 6-OHDA-induced neurotoxicity in human neuroblastoma SH-SY5Y cells, as assessed by MTT assay. In particular, it showed potent neuroprotective effects against 6-OHDA in RA/PMA differentiated cells at all the tested concentrations.
      PubDate: 2013-01-07
      DOI: 10.3390/ph6010054
      Issue No: Vol. 6, No. 1 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 70-84: Clevidipine for Perioperative Blood
           Pressure Control in Infants and Children
    • Authors: Joseph Tobias, David Tulman, Sergio Bergese
      Pages: 70 - 84
      Abstract: Various pharmacologic agents have been used for perioperative BP control in pediatric patients, including sodium nitroprusside, nitroglycerin, β-adrenergic antagonists, fenoldopam, and calcium channel antagonists. Of the calcium antagonists, the majority of the clinical experience remains with the dihydropyridine nicardipine. Clevidipine is a short-acting, intravenous calcium channel antagonist of the dihydropyridine class. It undergoes rapid metabolism by non-specific blood and tissue esterases with a half-life of less than 1 minute. As a dihydropyridine, its cellular and end-organ effects parallel those of nicardipine. The clevidipine trials in the adult population have demonstrated efficacy in rapidly controlling BP in various clinical scenarios with a favorable adverse effect profile similar to nicardipine. Data from large clinical trials regarding the safety and efficacy of clevidipine in children is lacking. This manuscript aims to review the commonly used pharmacologic agents for perioperative BP control in children, discuss the role of calcium channel antagonists such as nicardipine, and outline the preliminary data regarding clevidipine in the pediatric population.
      PubDate: 2013-01-15
      DOI: 10.3390/ph6010070
      Issue No: Vol. 6, No. 1 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 85-107: Nanoparticle-Based Delivery of RNAi
           Therapeutics: Progress and Challenges
    • Authors: Jiehua Zhou, Ka-To Shum, John Burnett, John Rossi
      Pages: 85 - 107
      Abstract: RNA interference (RNAi) is an evolutionarily conserved, endogenous process for post-transcriptional regulation of gene expression. Although RNAi therapeutics have recently progressed through the pipeline toward clinical trials, the application of these as ideal, clinical therapeutics requires the development of safe and effective delivery systems. Inspired by the immense progress with nanotechnology in drug delivery, efforts have been dedicated to the development of nanoparticle-based RNAi delivery systems. For example, a precisely engineered, multifunctional nanocarrier with combined passive and active targeting capabilities may address the delivery challenges for the widespread use of RNAi as a therapy. Therefore, in this review, we introduce the major hurdles in achieving efficient RNAi delivery and discuss the current advances in applying nanotechnology-based delivery systems to overcome the delivery hurdles of RNAi therapeutics. In particular, some representative examples of nanoparticle-based delivery formulations for targeted RNAi therapeutics are highlighted.
      PubDate: 2013-01-16
      DOI: 10.3390/ph6010085
      Issue No: Vol. 6, No. 1 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 108-123: Neurotransmitter CART as a New
           Therapeutic Candidate for Parkinson’s Disease
    • Authors: Peizhong Mao, Charles Meshul, Philippe Thuillier, P. Reddy
      Pages: 108 - 123
      Abstract: Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. To date, there is no effective treatment that halts its progression. Increasing evidence indicates that mitochondria play an important role in the development of PD. Hence mitochondria-targeted approaches or agents may have therapeutic promise for treatment of the disease. Neuropeptide CART (cocaine-amphetamine-regulated transcript), a hypothalamus and midbrain enriched neurotransmitter with an antioxidant property, can be found in mitochondria, which is the main source of reactive oxygen species. Systemic administration of CART has been found to ameliorate dopaminergic neuronal loss and improve motor functions in a mouse model of PD. In this article, we summarize recent progress in studies investigating the relationship between CART, dopamine, and the pathophysiology of PD, with a focus on mitochondria-related topics.
      PubDate: 2013-01-18
      DOI: 10.3390/ph6010108
      Issue No: Vol. 6, No. 1 (2013)
       
  • Pharmaceuticals, Vol. 6, Pages 1-24: Strategies To Modulate Heritable
           Epigenetic Defects in Cellular Machinery: Lessons from Nature
    • Authors: Ganesh Pandian, Hiroshi Sugiyama
      Pages: 1 - 24
      Abstract: Natural epigenetic processes precisely orchestrate the intricate gene network by expressing and suppressing genes at the right place and time, thereby playing an essential role in maintaining the cellular homeostasis. Environment-mediated alteration of this natural epigenomic pattern causes abnormal cell behavior and shifts the cell from the normal to a diseased state, leading to certain cancers and neurodegenerative disorders. Unlike heritable diseases that are caused by the irreversible mutations in DNA, epigenetic errors can be reversed. Inheritance of epigenetic memory is also a major concern in the clinical translation of the Nobel Prize-winning discovery of induced pluripotent stem cell technology. Consequently, there is an increasing interest in the development of novel epigenetic switch-based therapeutic strategies that could potentially restore the heritable changes in epigenetically inherited disorders. Here we give a comprehensive overview of epigenetic inheritance and suggest the prospects of therapeutic gene modulation using epigenetic-based drugs, in particular histone deacetylase inhibitors. This review suggests that there is a need to develop therapeutic strategies that effectively mimic the natural environment and include the ways to modulate the gene expression at both the genetic and epigenetic levels. The development of tailor-made small molecules that could epigenetically alter DNA in a sequence-specific manner is a promising approach for restoring defects in an altered epigenome and may offer a sustainable solution to some unresolved clinical issues.
      PubDate: 2012-12-27
      DOI: 10.3390/ph6010001
      Issue No: Vol. 6, No. 1 (2012)
       
  • Pharmaceuticals, Vol. 5, Pages 1346-1371: Mechanistic and Pharmacological
           Issues of Aspirin as an Anticancer Agent
    • Authors: Melania Dovizio, Stefania Tacconelli, Carlos Sostres, Emanuela Ricciotti, Paola Patrignani
      Pages: 1346 - 1371
      Abstract: Recent findings have shown that aspirin, taken for several years, reduces the long-term risk of some cancers, particularly colorectal cancer. The result that aspirin benefit is detectable at daily low-doses (at least 75mg), the same used for the prevention of cardiovascular disease, positions the antiplatelet action of aspirin at the center of its antitumor efficacy. At low-doses given every 24 h, aspirin is acting by a complete and persistent inhibition of cyclooxygenase (COX)-1 in platelets (in the pre-systemic circulation) while causing a limited and rapidly reversible inhibitory effect on COX-2 and/or COX-1 expressed in nucleated cells. Aspirin has a short half-life in human circulation (approximately 20 min); nucleated cells have the ability to resynthesize the acetylated COX-isozymes within a few hours, while platelets do not. COX-independent mechanisms of aspirin, such as the inhibition of Wnt/ b-catenin and NF-kB signaling and the acetylation of extra-COX proteins, have been suggested to play a role in its chemo-preventive effects, but their relevance remains to be demonstrated in vivo at clinical doses. In conclusion, the results of clinical pharmacology and the analysis of randomized and epidemiological studies suggest that colorectal cancer and atherothrombosis share a common mechanism of disease, i.e. enhanced platelet activation in response to injury at distinct sites.
      PubDate: 2012-12-05
      DOI: 10.3390/ph5121346
      Issue No: Vol. 5, No. 12 (2012)
       
  • Pharmaceuticals, Vol. 5, Pages 1372-1392: The Liver as a Target Organ for
           Gene Therapy: State of the Art, Challenges, and Future Perspectives
    • Authors: Frank Jacobs, Stephanie Gordts, Ilayaraja Muthuramu, Bart De Geest
      Pages: 1372 - 1392
      Abstract: The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene transfer strategy should deliver the transgene DNA to parenchymal liver cells with accuracy and precision in the absence of side effects. Liver sinusoids are highly specialized capillaries with a particular endothelial lining: the endothelium contains open fenestrae, whereas a basal lamina is lacking. Fenestrae provide a direct access of gene transfer vectors to the space of Disse, in which numerous microvilli from parenchymal liver cells protrude. The small diameter of fenestrae in humans constitutes an anatomical barrier for most gene transfer vectors with the exception of adeno-associated viral (AAV) vectors. Recent studies have demonstrated the superiority of novel AAV serotypes for hepatocyte-directed gene transfer applications based on enhanced transduction, reduced prevalence of neutralizing antibodies, and diminished capsid immune responses. In a landmark clinical trial, hemophilia B was successfully treated with an AAV8 human factor IX expressing vector. Notwithstanding significant progress, clinical experience with these technologies remains very limited and many unanswered questions warrant further study. Therefore, the field should continue to progress as it has over the past decade, cautiously and diligently.
      PubDate: 2012-12-10
      DOI: 10.3390/ph5121372
      Issue No: Vol. 5, No. 12 (2012)
       
  • Pharmaceuticals, Vol. 5, Pages 1393-1408: Biosimilars: Company Strategies
           to Capture Value from the Biologics Market
    • Authors: Bruno Calo-Fernández, Juan Martínez-Hurtado
      Pages: 1393 - 1408
      Abstract: Patents for several biologic blockbusters will expire in the next few years. The arrival of biosimilars, the biologic equivalent of chemical generics, will have an impact on the current biopharmaceuticals market. Five core capabilities have been identified as paramount for those companies aiming to enter the biosimilars market: research and development, manufacturing, supporting activities, marketing, and lobbying. Understanding the importance of each of these capabilities will be key to maximising the value generated from the biologics patent cliff.
      PubDate: 2012-12-12
      DOI: 10.3390/ph5121393
      Issue No: Vol. 5, No. 12 (2012)
       
 
 
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