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X-Ray Spectrometry     Hybrid Journal   (Followers: 9)
Zeitschrift für Naturforschung B : A Journal of Chemical Sciences     Open Access   (Followers: 1)

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Journal Cover Pharmaceuticals
  [SJR: 1.245]   [H-I: 26]   [5 followers]  Follow
    
  This is an Open Access Journal Open Access journal
   ISSN (Print) 1424-8247
   Published by MDPI Homepage  [146 journals]
  • Pharmaceuticals, Vol. 9, Pages 61: Lactoferrin from Milk: Nutraceutical
           and Pharmacological Properties

    • Authors: Francesco Giansanti, Gloria Panella, Loris Leboffe, Giovanni Antonini
      First page: 61
      Abstract: Lactoferrin is an iron-binding protein present in large quantities in colostrum and in breast milk, in external secretions and in polymorphonuclear leukocytes. Lactoferrin’s main function is non-immune protection. Among several protective activities shown by lactoferrin, those displayed by orally administered lactoferrin are: (i) antimicrobial activity, which has been presumed due to iron deprivation, but more recently attributed also to a specific interaction with the bacterial cell wall and extended to viruses and parasites; (ii) immunomodulatory activity, with a direct effect on the development of the immune system in the newborn, together with a specific antinflammatory effects; (iii) a more recently discovered anticancer activity. It is worth noting that most of the protective activities of lactoferrin have been found, sometimes to a greater extent, also in peptides derived from limited proteolysis of lactoferrin that could be generated after lactoferrin ingestion. Lactoferrin could therefore be considered an ideal nutraceutic product because of its relatively cheap production from bovine milk and of its widely recognized tolerance after ingestion, along with its well demonstrated protective activities. The most important protective activities shown by orally administered bovine lactoferrin are reviewed in this article.
      PubDate: 2016-09-27
      DOI: 10.3390/ph9040061
      Issue No: Vol. 9, No. 4 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 34: Relationship between Surface Properties
           and In Vitro Drug Release from a Compressed Matrix Containing an
           Amphiphilic Polymer Material

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    • Authors: Felix Schmidt, Thomas Efferth
      First page: 33
      Abstract: Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1) single cell isolation (e.g., by laser-capture microdissection), fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase), and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems). Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients.
      PubDate: 2016-06-16
      DOI: 10.3390/ph9020033
      Issue No: Vol. 9, No. 2 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 2: 3,1-Benzothiazines, 1,4-Benzodioxines
           and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused
           Screening Approach

    • First page: 2
      Abstract: The liver enzyme matriptase-2 is a multi-domain, transmembrane serine protease with an extracellular, C-terminal catalytic domain. Synthetic low-molecular weight inhibitors of matriptase-2 have potential as therapeutics to treat iron overload syndromes, in particular in patients with β-thalassemia. A sub-library of 64 compounds was screened for matriptase-2 inhibition and several active compounds were identified. (S)-Ethyl 2-(benzyl(3-((4-carbamidoylphenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-oxoacetate ((S)-12) showed an IC50 value of less than 10 µM. Structure-activity relationships were discussed and proposals to design new matriptase-2 inhibitors were made.
      PubDate: 2016-01-13
      DOI: 10.3390/ph9010002
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 3: The Role of Immunotherapy in Multiple
           Myeloma

    • Authors: Mehmet Kocoglu, Ashraf Badros
      First page: 3
      Abstract: Multiple myeloma is the second most common hematologic malignancy. The treatment of this disease has changed considerably over the last two decades with the introduction to the clinical practice of novel agents such as proteasome inhibitors and immunomodulatory drugs. Basic research efforts towards better understanding of normal and missing immune surveillence in myeloma have led to development of new strategies and therapies that require the engagement of the immune system. Many of these treatments are under clinical development and have already started providing encouraging results. We, for the second time in the last two decades, are about to witness another shift of the paradigm in the management of this ailment. This review will summarize the major approaches in myeloma immunotherapies.
      PubDate: 2016-01-14
      DOI: 10.3390/ph9010003
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 4: Hydroxylated Dimeric Naphthoquinones
           Increase the Generation of Reactive Oxygen Species, Induce Apoptosis of
           Acute Myeloid Leukemia Cells and Are Not Substrates of the Multidrug
           Resistance Proteins ABCB1 and ABCG2

    • Authors: Rena Lapidus, Brandon Carter-Cooper, Mariola Sadowska, Eun Choi, Omasiri Wonodi, Nidal Muvarak, Karthika Natarajan, Lakshmi Pidugu, Anil Jaiswal, Eric Toth, Feyruz Rassool, Arash Etemadi, Edward Sausville, Maria Baer, Ashkan Emadi
      First page: 4
      Abstract: Selective targeting of the oxidative state, which is a tightly balanced fundamental cellular property, is an attractive strategy for developing novel anti-leukemic chemotherapeutics with potential applications in the treatment of acute myeloid leukemia (AML), a molecularly heterogeneous disease. Dimeric naphthoquinones (BiQs) with the ability to undergo redox cycling and to generate reactive oxygen species (ROS) in cancer cells are a novel class of compounds with unique characteristics that make them excellent candidates to be tested against AML cells. We evaluated the effect of two BiQ analogues and one monomeric naphthoquinone in AML cell lines and primary cells from patients. All compounds possess one halogen and one hydroxyl group on the quinone cores. Dimeric, but not monomeric, naphthoquinones demonstrated significant anti-AML activity in the cell lines and primary cells from patients with favorable therapeutic index compared to normal hematopoietic cells. BiQ-1 effectively inhibited clonogenicity and induced apoptosis as measured by Western blotting and Annexin V staining and mitochondrial membrane depolarization by flow cytometry. BiQ-1 significantly enhances intracellular ROS levels in AML cells and upregulates expression of key anti-oxidant protein, Nrf2. Notably, systemic exposure to BiQ-1 was well tolerated in mice. In conclusion, we propose that BiQ-induced therapeutic augmentation of ROS in AML cells with dysregulation of antioxidants kill leukemic cells while normal cells remain relatively intact. Further studies are warranted to better understand this class of potential chemotherapeutics.
      PubDate: 2016-01-19
      DOI: 10.3390/ph9010004
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 5: Acknowledgement to Reviewers of
           Pharmaceuticals in 2015

    • Authors: Pharmaceuticals Editorial Office
      First page: 5
      Abstract: The editors of Pharmaceuticals would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. [...]
      PubDate: 2016-01-21
      DOI: 10.3390/ph9010005
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 6: 2015: A Transition Year for
           Pharmaceuticals?

    • Authors: Jean Vanden Eynde
      First page: 6
      Abstract: In this period, I could not start this editorial without wishing all of you a Happy New Year. This is also the opportunity for me to warmly thank, for their confidence, our authors, readers, reviewers, members of the editorial board, sponsors, as well as members of MDPI AG in Basel, Beijing, and Wuhan. [...]
      PubDate: 2016-01-27
      DOI: 10.3390/ph9010006
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 7: Biomolecules and Natural Medicine
           Preparations: Analysis of New Sources of Bioactive Compounds from Ribes
           and Rubus spp. Buds

    • Authors: Dario Donno, Maria Mellano, Alessandro Cerutti, Gabriele Beccaro
      First page: 7
      Abstract: It is well known that plants are important sources for the preparation of natural remedies as they contain many biologically active compounds. In particular, polyphenols, terpenic compounds, organic acids, and vitamins are the most widely occurring groups of phytochemicals. Some endemic species may be used for the production of herbal preparations containing phytochemicals with significant bioactivity, as antioxidant activity and anti-inflammatory capacities, and health benefits. Blackberry sprouts and blackcurrant buds are known to contain appreciable levels of bioactive compounds, including flavonols, phenolic acids, monoterpenes, vitamin C, and catechins, with several clinical effects. The aim of this research was to perform an analytical study of blackcurrant and blackberry bud-preparations, in order to identify and quantify the main biomarkers, obtaining a specific phytochemical fingerprint to evaluate the single botanical class contribution to total phytocomplex and relative bioactivity, using a High Performance Liquid Chromatograph−Diode Array Detector; the same analyses were performed both on the University laboratory and commercial preparations. Different chromatographic methods were used to determine concentrations of biomolecules in the preparations, allowing for quantification of statistically significant differences in their bioactive compound content both in the case of Ribes nigrum and Rubus cultivated varieties at different harvest stages. In blackcurrant bud-extracts the most important class was organic acids (50.98%) followed by monoterpenes (14.05%), while in blackberry preparations the main bioactive classes were catechins (50.06%) and organic acids (27.34%). Chemical, pharmaceutical and agronomic-environmental knowledge could be important for obtaining label certifications for the valorization of specific genotypes, with high clinical and pharmaceutical value: this study allowed to develop an effective tool for the natural preparation quality control and bioactivity evaluation through the chemical fingerprinting of bud preparations.
      PubDate: 2016-02-05
      DOI: 10.3390/ph9010007
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 8: Propofol and AZD3043 Inhibit Adult
           Muscle and Neuronal Nicotinic Acetylcholine Receptors Expressed in Xenopus
           Oocytes

    • Authors: Malin Jonsson Fagerlund, Johannes Krupp, Michael Dabrowski
      First page: 8
      Abstract: Propofol is a widely used general anaesthetic with muscle relaxant properties. Similarly as propofol, the new general anaesthetic AZD3043 targets the GABAA receptor for its anaesthetic effects, but the interaction with nicotinic acetylcholine receptors (nAChRs) has not been investigated. Notably, there is a gap of knowledge about the interaction between propofol and the nAChRs found in the adult neuromuscular junction. The objective was to evaluate whether propofol or AZD3043 interact with the α1β1δε, α3β2, or α7 nAChR subtypes that can be found in the neuromuscular junction and if there are any differences in affinity for those subtypes between propofol and AZD3043. Human nAChR subtypes α1β1δε, α3β2, and α7 were expressed into Xenopus oocytes and studied with an automated voltage-clamp. Propofol and AZD3043 inhibited ACh-induced currents in all of the nAChRs studied with inhibitory concentrations higher than those needed for general anaesthesia. AZD3043 was a more potent inhibitor at the adult muscle nAChR subtype compared to propofol. Propofol and AZD3043 inhibit nAChR subtypes that can be found in the adult NMJ in concentrations higher than needed for general anaesthesia. This finding needs to be evaluated in an in vitro nerve-muscle preparation and suggests one possible explanation for the muscle relaxant effect of propofol seen during higher doses.
      PubDate: 2016-02-06
      DOI: 10.3390/ph9010008
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 9: Cognitive Dysfunction in Major
           Depressive Disorder. A Translational Review in Animal Models of the
           Disease

    • Authors: Flavie Darcet, Alain Gardier, Raphael Gaillard, Denis David, Jean-Philippe Guilloux
      First page: 9
      Abstract: Major Depressive Disorder (MDD) is the most common psychiatric disease, affecting millions of people worldwide. In addition to the well-defined depressive symptoms, patients suffering from MDD consistently complain about cognitive disturbances, significantly exacerbating the burden of this illness. Among cognitive symptoms, impairments in attention, working memory, learning and memory or executive functions are often reported. However, available data about the heterogeneity of MDD patients and magnitude of cognitive symptoms through the different phases of MDD remain difficult to summarize. Thus, the first part of this review briefly overviewed clinical studies, focusing on the cognitive dysfunctions depending on the MDD type. As animal models are essential translational tools for underpinning the mechanisms of cognitive deficits in MDD, the second part of this review synthetized preclinical studies observing cognitive deficits in different rodent models of anxiety/depression. For each cognitive domain, we determined whether deficits could be shared across models. Particularly, we established whether specific stress-related procedures or unspecific criteria (such as species, sex or age) could segregate common cognitive alteration across models. Finally, the role of adult hippocampal neurogenesis in rodents in cognitive dysfunctions during MDD state was also discussed.
      PubDate: 2016-02-17
      DOI: 10.3390/ph9010009
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 10: Odontonutraceuticals: Pleiotropic
           Phytotherapeutic Agents for Oral Health

    • Authors: Elena Varoni, Marcello Iriti
      First page: 10
      Abstract: This brief commentary aims to focus on the urgency of further clinical research on phytotherapy in dentistry, and, noteworthy, to propose, for the first time, to the best of our knowledge, the term “odontonutraceuticals” to identify those phytochemicals relevant for the prevention and the treatment of oral diseases. A valuable impact is expected on nutritional, dental and biomedical sciences, suggesting the use of the suffix "odonto-" to define a specific field of nutraceutical research.
      PubDate: 2016-02-25
      DOI: 10.3390/ph9010010
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 11: Targeting Cell Survival Proteins for
           Cancer Cell Death

    • Authors: Manoj Pandey, Sahdeo Prasad, Amit Tyagi, Lokesh Deb, Jiamin Huang, Deepkamal Karelia, Shantu Amin, Bharat Aggarwal
      First page: 11
      Abstract: Escaping from cell death is one of the adaptations that enable cancer cells to stave off anticancer therapies. The key players in avoiding apoptosis are collectively known as survival proteins. Survival proteins comprise the Bcl-2, inhibitor of apoptosis (IAP), and heat shock protein (HSP) families. The aberrant expression of these proteins is associated with a range of biological activities that promote cancer cell survival, proliferation, and resistance to therapy. Several therapeutic strategies that target survival proteins are based on mimicking BH3 domains or the IAP-binding motif or competing with ATP for the Hsp90 ATP-binding pocket. Alternative strategies, including use of nutraceuticals, transcriptional repression, and antisense oligonucleotides, provide options to target survival proteins. This review focuses on the role of survival proteins in chemoresistance and current therapeutic strategies in preclinical or clinical trials that target survival protein signaling pathways. Recent approaches to target survival proteins-including nutraceuticals, small-molecule inhibitors, peptides, and Bcl-2-specific mimetic are explored. Therapeutic inventions targeting survival proteins are promising strategies to inhibit cancer cell survival and chemoresistance. However, complete eradication of resistance is a distant dream. For a successful clinical outcome, pretreatment with novel survival protein inhibitors alone or in combination with conventional therapies holds great promise.
      PubDate: 2016-02-25
      DOI: 10.3390/ph9010011
      Issue No: Vol. 9, No. 1 (2016)
       
  • Pharmaceuticals, Vol. 9, Pages 12: Minimally-Myelosuppressive
           Asparaginase-Containing Induction Regimen for Treatment of a Jehovah’s
           Witness with mutant IDH1/NPM1/NRAS Acute Myeloid Leukemia

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

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

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

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

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