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CHEMISTRY (554 journals)            First | 1 2 3 4 5 6 | Last

Journal of Chromatography A     Hybrid Journal   (Followers: 45)
Journal of Chromatography Library     Full-text available via subscription   (Followers: 5)
Journal of Colloid and Interface Science     Hybrid Journal   (Followers: 12)
Journal of Computational Chemistry     Hybrid Journal   (Followers: 13)
Journal of Coordination Chemistry     Hybrid Journal   (Followers: 1)
Journal of Dispersion Science and Technology     Hybrid Journal  
Journal of Encapsulation and Adsorption Sciences     Open Access   (Followers: 5)
Journal of Environmental Chemistry and Ecotoxicology     Open Access   (Followers: 2)
Journal of Flow Chemistry     Full-text available via subscription   (Followers: 1)
Journal of Fluorescence     Hybrid Journal   (Followers: 3)
Journal of Fluorine Chemistry     Hybrid Journal   (Followers: 6)
Journal of Fuel Chemistry and Technology     Full-text available via subscription   (Followers: 5)
Journal of Great Lakes Research     Hybrid Journal   (Followers: 7)
Journal of Heterocyclic Chemistry     Hybrid Journal   (Followers: 5)
Journal of Immunoassay and Immunochemistry     Hybrid Journal   (Followers: 3)
Journal of Inclusion Phenomena and Macrocyclic Chemistry     Hybrid Journal   (Followers: 1)
Journal of Inorganic Biochemistry     Hybrid Journal   (Followers: 2)
Journal of Labelled Compounds and Radiopharmaceuticals     Hybrid Journal   (Followers: 1)
Journal of Macromolecular Science, Part A: Pure and Applied Chemistry     Hybrid Journal   (Followers: 4)
Journal of Mass Spectrometry     Hybrid Journal   (Followers: 20)
Journal of Materials Chemistry A : Materials for Energy and Sustainability     Full-text available via subscription   (Followers: 23)
Journal of Materials Chemistry B : Materials for Biology and Medicine     Full-text available via subscription   (Followers: 5)
Journal of Materials Chemistry C : Materials for Optical, Magnetic and Electronic Devices     Full-text available via subscription   (Followers: 6)
Journal of Materials Physics and Chemistry     Open Access  
Journal of Materials Research     Full-text available via subscription   (Followers: 9)
Journal of Mathematical Chemistry     Hybrid Journal   (Followers: 4)
Journal of Medicinal Chemistry     Full-text available via subscription   (Followers: 206)
Journal of Membrane Science     Hybrid Journal   (Followers: 11)
Journal of Modern Chemistry & Chemical Technology     Full-text available via subscription   (Followers: 2)
Journal of Molecular Catalysis A: Chemical     Hybrid Journal   (Followers: 2)
Journal of Molecular Graphics and Modelling     Hybrid Journal   (Followers: 4)
Journal of Molecular Liquids     Hybrid Journal   (Followers: 3)
Journal of Molecular Modeling     Hybrid Journal   (Followers: 3)
Journal of Molecular Recognition     Hybrid Journal   (Followers: 2)
Journal of Molecular Spectroscopy     Hybrid Journal   (Followers: 6)
Journal of Molecular Structure     Hybrid Journal   (Followers: 3)
Journal of Nanoparticles     Open Access  
Journal of Nanostructure in Chemistry     Open Access   (Followers: 5)
Journal of Natural Gas Chemistry     Full-text available via subscription   (Followers: 2)
Journal of Nepal Chemical Society     Open Access  
Journal of Nucleic Acids Investigation     Open Access   (Followers: 2)
Journal of Ocean University of China (English Edition)     Hybrid Journal   (Followers: 2)
Journal of Organometallic Chemistry     Hybrid Journal   (Followers: 12)
Journal of Photochemistry and Photobiology A: Chemistry     Hybrid Journal   (Followers: 4)
Journal of Photochemistry and Photobiology C: Photochemistry Reviews     Full-text available via subscription   (Followers: 4)
Journal of Polymer & Composites     Full-text available via subscription  
Journal of Polymer and Biopolymer Physics Chemistry     Open Access  
Journal of Polymer Science Part A: Polymer Chemistry     Hybrid Journal   (Followers: 187)
Journal of Polymers     Open Access   (Followers: 1)
Journal of Porphyrins and Phthalocyanines     Hybrid Journal   (Followers: 2)
Journal of Pure and Applied Chemistry Research     Open Access   (Followers: 1)
Journal of Raman Spectroscopy     Hybrid Journal   (Followers: 10)
Journal of Saudi Chemical Society     Open Access  
Journal of Solid State Chemistry     Hybrid Journal   (Followers: 14)
Journal of Solution Chemistry     Hybrid Journal  
Journal of Structural Chemistry     Hybrid Journal  
Journal of Sulfur Chemistry     Hybrid Journal   (Followers: 2)
Journal of Superhard Materials     Hybrid Journal   (Followers: 1)
Journal of Surfactants and Detergents     Hybrid Journal   (Followers: 5)
Journal of Systems Chemistry     Open Access   (Followers: 1)
Journal of Taibah University for Science     Open Access  
Journal of the American Chemical Society     Full-text available via subscription   (Followers: 292)
Journal of the American Society for Mass Spectrometry     Hybrid Journal   (Followers: 18)
Journal of the American Society of Brewing Chemists     Full-text available via subscription   (Followers: 1)
Journal of the Bangladesh Chemical Society     Open Access  
Journal of the Chilean Chemical Society     Open Access   (Followers: 2)
Journal of the Iranian Chemical Society     Hybrid Journal   (Followers: 1)
Journal of the Korean Society for Applied Biological Chemistry     Hybrid Journal   (Followers: 1)
Journal of the Mexican Chemical Society     Open Access   (Followers: 1)
Journal of Theoretical and Computational Chemistry     Hybrid Journal   (Followers: 7)
Journal of Theoretical Chemistry     Open Access  
Journal of Wood Chemistry and Technology     Hybrid Journal   (Followers: 7)
JPC - Journal of Planar Chromatography - Modern TLC     Full-text available via subscription   (Followers: 6)
Jurnal Penelitian Sains (JPS)     Open Access  
Jurnal Teknologi Informasi     Open Access   (Followers: 3)
Kinetics and Catalysis     Hybrid Journal   (Followers: 3)
Korea-Australia Rheology Journal     Hybrid Journal  
Langmuir     Full-text available via subscription   (Followers: 36)
Latvian Journal of Chemistry     Open Access   (Followers: 1)
Lebensmittelchemie     Hybrid Journal   (Followers: 1)
Lipid Insights     Open Access   (Followers: 1)
Luminescence     Hybrid Journal   (Followers: 1)
Macromolecular Materials & Engineering     Hybrid Journal   (Followers: 4)
Macromolecular Rapid Communications     Hybrid Journal   (Followers: 4)
Macromolecular Research     Hybrid Journal  
Macromolecular Symposia     Hybrid Journal  
Macromolecular Theory and Simulations     Hybrid Journal  
Macromolecules     Full-text available via subscription   (Followers: 31)
Magnetic Resonance in Chemistry     Hybrid Journal   (Followers: 4)
Main Group Chemistry     Hybrid Journal  
Marine Chemistry     Hybrid Journal   (Followers: 4)
Marine Drugs     Open Access   (Followers: 4)
MATEC Web of Conferences     Open Access  
Materials Characterization     Hybrid Journal   (Followers: 25)
Materials Horizons     Full-text available via subscription  
Materials Research Bulletin     Hybrid Journal   (Followers: 18)
Materials Science Monographs     Full-text available via subscription   (Followers: 1)
Materials Science-Poland     Hybrid Journal  
Materials Sciences and Applications     Open Access   (Followers: 4)
MedChemComm     Full-text available via subscription   (Followers: 4)

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  This is an Open Access Journal Open Access journal
     ISSN (Print) 1424-8247
     Published by MDPI Homepage  [124 journals]   [SJR: 0.46]   [H-I: 13]
  • Pharmaceuticals, Vol. 7, Pages 913-942: Phytochemical Modulators of
           Mitochondria: The Search for Chemopreventive Agents and Supportive

    • Authors: Maja Grabacka, Malgorzata Gawin, Malgorzata Pierzchalska
      Pages: 913 - 942
      Abstract: Mitochondria are crucially important for maintaining not only the energy homeostasis, but the proper cellular functions in a general sense. Impairment of mitochondrial functions is observed in a broad variety of pathological states such as neoplastic transformations and cancer, neurodegenerative diseases, metabolic disorders and chronic inflammation. Currently, in parallel to the classical drug design approaches, there is an increasing interest in the screening for natural bioactive substances, mainly phytochemicals, in order to develop new therapeutic solutions for the mentioned pathologies. Dietary phytochemicals such as resveratrol, curcumin and sulforaphane are very well tolerated and can effectively complement classical pharmacological therapeutic regimens. In this paper we disscuss the effect of the chosen phytochemicals (e.g., resveratrol, curcumin, sulforaphane) on various aspects of mitochondrial biology, namely mitochondrial biogenesis, membrane potential and reactive oxygen species production, signaling to and from the nucleus and unfolded protein response.
      PubDate: 2014-09-04
      DOI: 10.3390/ph7090913
      Issue No: Vol. 7, No. 9 (2014)
  • Pharmaceuticals, Vol. 7, Pages 943-953: Barriers to the Use of Trastuzumab
           for HER2+ Breast Cancer and the Potential Impact of Biosimilars: A
           Physician Survey in the United States and Emerging Markets

    • Authors: Philip Lammers, Carmen Criscitiello, Giuseppe Curigliano, Ira Jacobs
      Pages: 943 - 953
      Abstract: Trastuzumab in combination with chemotherapy has become a standard of care for patients with HER2+ breast cancer. The cost of therapy, however, can limit patient access to trastuzumab in areas with limited financial resources for treatment reimbursement. This study examined access to trastuzumab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia and Brazil via physician survey. The study also investigated if the availability of a biosimilar to trastuzumab would improve access to and use of HER2 monoclonal antibody therapy. Across all countries, a subset of oncologists reported barriers to the use of trastuzumab in a neoadjuvant, adjuvant or metastatic setting. Common barriers to the use of trastuzumab included issues related to insurance coverage, drug availability and cost to the patient. Overall, nearly half of oncologists reported that they would increase the use of HER2 monoclonal antibody therapy across all treatment settings if a lower cost biosimilar to trastuzumab were available. We conclude that the introduction of a biosimilar to trastuzumab may alleviate cost-related barriers to treatment and could increase patient access to HER2-directed therapy in all countries examined.
      PubDate: 2014-09-17
      DOI: 10.3390/ph7090943
      Issue No: Vol. 7, No. 9 (2014)
  • Pharmaceuticals, Vol. 7, Pages 954-989: The Overarching Influence of the

    • Authors: Luis Vitetta, Rachel Manuel, Joyce Zhou, Anthony Linnane, Sean Hall, Samantha Coulson
      Pages: 954 - 989
      Abstract: At the time of birth, humans experience an induced pro-inflammatory beneficial event. The mediators of this encouraged activity, is a fleet of bacteria that assault all mucosal surfaces as well as the skin. Thus initiating effects that eventually provide the infant with immune tissue maturation. These effects occur beneath an emergent immune system surveillance and antigenic tolerance capability radar. Over time, continuous and regulated interactions with environmental as well as commensal microbial, viral, and other antigens lead to an adapted and maintained symbiotic state of tolerance, especially in the gastrointestinal tract (GIT) the organ site of the largest microbial biomass. However, the perplexing and much debated surprise has been that all microbes need not be targeted for destruction. The advent of sophisticated genomic techniques has led to microbiome studies that have begun to clarify the critical and important biochemical activities that commensal bacteria provide to ensure continued GIT homeostasis. Until recently, the GIT and its associated micro-biometabolome was a neglected factor in chronic disease development and end organ function. A systematic underestimation has been to undervalue the contribution of a persistent GIT dysbiotic (a gut barrier associated abnormality) state. Dysbiosis provides a plausible clue as to the origin of systemic metabolic disorders encountered in clinical practice that may explain the epidemic of chronic diseases. Here we further build a hypothesis that posits the role that subtle adverse responses by the GIT microbiome may have in chronic diseases. Environmentally/nutritionally/and gut derived triggers can maintain microbiome perturbations that drive an abnormal overload of dysbiosis. Live probiotic cultures with specific metabolic properties may assist the GIT microbiota and reduce the local metabolic dysfunctions. As such the effect may translate to a useful clinical treatment approach for patients diagnosed with a metabolic disease for end organs such as the kidney and liver. A profile emerges that shows that bacteria are diverse, abundant, and ubiquitous and have significantly influenced the evolution of the eukaryotic cell.
      PubDate: 2014-09-19
      DOI: 10.3390/ph7090954
      Issue No: Vol. 7, No. 9 (2014)
  • Pharmaceuticals, Vol. 7, Pages 850-865: Pain Management in Ambulatory
           Surgery—A Review

    • Authors: Jan Jakobsson
      Pages: 850 - 865
      Abstract: Day surgery, coming to and leaving the hospital on the same day as surgery as well as ambulatory surgery, leaving hospital within twenty-three hours is increasingly being adopted. There are several potential benefits associated with the avoidance of in-hospital care. Early discharge demands a rapid recovery and low incidence and intensity of surgery and anaesthesia related side-effects; such as pain, nausea and fatigue. Patients must be fit enough and symptom intensity so low that self-care is feasible in order to secure quality of care. Preventive multi-modal analgesia has become the gold standard. Administering paracetamol, NSIADs prior to start of surgery and decreasing the noxious influx by the use of local anaesthetics by peripheral block or infiltration in surgical field prior to incision and at wound closure in combination with intra-operative fast acting opioid analgesics, e.g., remifentanil, have become standard of care. Single preoperative 0.1 mg/kg dose dexamethasone has a combined action, anti-emetic and provides enhanced analgesia. Additional α-2-agonists and/or gabapentin or pregabalin may be used in addition to facilitate the pain management if patients are at risk for more pronounced pain. Paracetamol, NSAIDs and rescue oral opioid is the basic concept for self-care during the first 3–5 days after common day/ambulatory surgical procedures.
      PubDate: 2014-07-24
      DOI: 10.3390/ph7080850
      Issue No: Vol. 7, No. 8 (2014)
  • Pharmaceuticals, Vol. 7, Pages 866-880: The Fungal Defensin Family

    • Authors: Jiajia Wu, Bin Gao, Shunyi Zhu
      Pages: 866 - 880
      Abstract: Fungi are an emerging source of peptide antibiotics. With the availability of a large number of model fungal genome sequences, we can expect that more and more fungal defensin-like peptides (fDLPs) will be discovered by sequence similarity search. Here, we report a total of 69 new fDLPs encoded by 63 genes, in which a group of fDLPs derived from dermatophytes are defined as a new family (fDEF8) according to sequence and phylogenetic analyses. In the oleaginous fungus Mortierella alpine, fDLPs have undergone extensive gene expansion. Our work further enlarges the fungal defensin family and will help characterize new peptide antibiotics with therapeutic potential.
      PubDate: 2014-08-18
      DOI: 10.3390/ph7080866
      Issue No: Vol. 7, No. 8 (2014)
  • Pharmaceuticals, Vol. 7, Pages 881-893: Condensation of Plasmid DNA
           Enhances Mitochondrial Association in Skeletal Muscle Following
           Hydrodynamic Limb Vein Injection

    • Authors: Yukari Yasuzaki, Yuma Yamada, Yutaka Fukuda, Hideyoshi Harashima
      Pages: 881 - 893
      Abstract: Mitochondrial gene therapy and diagnosis have the potential to provide substantial medical benefits. However, the utility of this approach has not yet been realized because the technology available for mitochondrial gene delivery continues to be a bottleneck. We previously reported on mitochondrial gene delivery in skeletal muscle using hydrodynamic limb vein (HLV) injection. HLV injection, a useful method for nuclear transgene expression, involves the rapid injection of a large volume of naked plasmid DNA (pDNA). Moreover, the use of a condensed form of pDNA enhances the nuclear transgene expression by the HLV injection. The purpose of this study was to compare naked pDNA and condensed pDNA for mitochondrial association in skeletal muscle, when used in conjunction with HLV injection. PCR analysis showed that the use of condensed pDNA rather than naked pDNA resulted in a more effective mitochondrial association with pDNA, suggesting that the physicochemical state of pDNA plays a key role. Moreover, no mitochondrial toxicities in skeletal muscle following the HLV injection of condensed pDNA were confirmed, as evidenced by cytochrome c oxidase activity and mitochondrial membrane potential. These findings have the potential to contribute to the development for in vivo mitochondrial gene delivery system.
      PubDate: 2014-08-21
      DOI: 10.3390/ph7080881
      Issue No: Vol. 7, No. 8 (2014)
  • Pharmaceuticals, Vol. 7, Pages 894-912: Mitochondrial Targeted
           Endonuclease III DNA Repair Enzyme Protects against Ventilator Induced
           Lung Injury in Mice

    • Authors: Masahiro Hashizume, Marc Mouner, Joshua Chouteau, Olena Gorodnya, Mykhaylo Ruchko, Glenn Wilson, Mark Gillespie, James Parker
      Pages: 894 - 912
      Abstract: The mitochondrial targeted DNA repair enzyme, 8-oxoguanine DNA glycosylase 1, was previously reported to protect against mitochondrial DNA (mtDNA) damage and ventilator induced lung injury (VILI). In the present study we determined whether mitochondrial targeted endonuclease III (EndoIII) which cleaves oxidized pyrimidines rather than purines from damaged DNA would also protect the lung. Minimal injury from 1 h ventilation at 40 cmH2O peak inflation pressure (PIP) was reversed by EndoIII pretreatment. Moderate lung injury due to ventilation for 2 h at 40 cmH2O PIP produced a 25-fold increase in total extravascular albumin space, a 60% increase in W/D weight ratio, and marked increases in MIP-2 and IL-6. Oxidative mtDNA damage and decreases in the total tissue glutathione (GSH) and the GSH/GSSH ratio also occurred. All of these indices of injury were attenuated by mitochondrial targeted EndoIII. Massive lung injury caused by 2 h ventilation at 50 cmH2O PIP was not attenuated by EndoIII pretreatment, but all untreated mice died prior to completing the two hour ventilation protocol, whereas all EndoIII-treated mice lived for the duration of ventilation. Thus, mitochondrial targeted DNA repair enzymes were protective against mild and moderate lung damage and they enhanced survival in the most severely injured group.
      PubDate: 2014-08-22
      DOI: 10.3390/ph7080894
      Issue No: Vol. 7, No. 8 (2014)
  • Pharmaceuticals, Vol. 7, Pages 754-764: Correlation between the Serum
           Pepsinogen I Level and the Symptom Degree in Proton Pump Inhibitor-Users
           Administered with a Probiotic

    • Authors: Muneki Igarashi, Jun Nagano, Ayumi Tsuda, Takayoshi Suzuki, Jun Koike, Tetsufumi Uchida, Masashi Matsushima, Tetsuya Mine, Yasuhiro Koga
      Pages: 754 - 764
      Abstract: In patients with functional upper gastrointestinal disorders such as gastroesophageal reflux disease and functional dyspepsia, the presence of symptoms is thought to occur in the absence of any organic diseases and the mechanisms behind this remain unclear. We therefore examined the relationship between stomach-related biomarker levels and symptoms. Twenty-four outpatients who had taken proton-pump inhibitors every day were enrolled in this study. The subjects consumed yogurt containing 109 colony-forming units of Lactobacillus gasseri OLL2716 (LG21) every day for three months. They underwent four clinical examinations in total. Each examination consisted of answering a questionnaire with a frequency scale for the symptoms of GERD (FSSG), and included measurements of the serum gastrin, ghrelin, and pepsinogens I and II levels. As a result, the FSSG score and the PGI value showed a decrease and an increase, respectively, after LG21 treatment when analyzed without age adjustment. A multiple regression analysis with additional adjustments for gender and age revealed a strong association between the PGI value and the FSSG symptom scores. Therefore either the PGI level itself or the factors regulating the PGI level might be involved in the etiology of these symptoms.
      PubDate: 2014-06-25
      DOI: 10.3390/ph7070754
      Issue No: Vol. 7, No. 7 (2014)
  • Pharmaceuticals, Vol. 7, Pages 765-778: Imaging Biomarkers or Biomarker

    • Authors: Markus Mitterhauser, Wolfgang Wadsak
      Pages: 765 - 778
      Abstract: Since biomarker imaging is traditionally understood as imaging of molecular probes, we highly recommend to avoid any confusion with the previously defined term “imaging biomarkers” and, therefore, only use “molecular probe imaging (MPI)” in that context. Molecular probes (MPs) comprise all kinds of molecules administered to an organism which inherently carry a signalling moiety. This review highlights the basic concepts and differences of molecular probe imaging using specific biomarkers. In particular, PET radiopharmaceuticals are discussed in more detail. Specific radiochemical and radiopharmacological aspects as well as some legal issues are presented.
      PubDate: 2014-06-25
      DOI: 10.3390/ph7070765
      Issue No: Vol. 7, No. 7 (2014)
  • Pharmaceuticals, Vol. 7, Pages 779-796: Novel Preclinical and
           Radiopharmaceutical Aspects of [68Ga]Ga-PSMA-HBED-CC: A New PET Tracer for
           Imaging of Prostate Cancer

    • Authors: Matthias Eder, Oliver Neels, Miriam Müller, Ulrike Bauder-Wüst, Yvonne Remde, Martin Schäfer, Ute Hennrich, Michael Eisenhut, Ali Afshar-Oromieh, Uwe Haberkorn, Klaus Kopka
      Pages: 779 - 796
      Abstract: The detection of prostate cancer lesions by PET imaging of the prostate-specific membrane antigen (PSMA) has gained highest clinical impact during the last years. 68Ga-labelled Glu-urea-Lys(Ahx)-HBED-CC ([68Ga]Ga-PSMA-HBED-CC) represents a successful novel PSMA inhibitor radiotracer which has recently demonstrated its suitability in individual first-in-man studies. The radiometal chelator HBED-CC used in this molecule represents a rather rarely used acyclic complexing agent with chemical characteristics favourably influencing the biological functionality of the PSMA inhibitor. The simple replacement of HBED-CC by the prominent radiometal chelator DOTA was shown to dramatically reduce the in vivo imaging quality of the respective 68Ga-labelled PSMA-targeted tracer proving that HBED-CC contributes intrinsically to the PSMA binding of the Glu-urea-Lys(Ahx) pharmacophore. Owing to the obvious growing clinical impact, this work aims to reflect the properties of HBED-CC as acyclic radiometal chelator and presents novel preclinical data and relevant aspects of the radiopharmaceutical production process of [68Ga]Ga-PSMA-HBED-CC.
      PubDate: 2014-06-30
      DOI: 10.3390/ph7070779
      Issue No: Vol. 7, No. 7 (2014)
  • Pharmaceuticals, Vol. 7, Pages 797-838: The Medicinal Chemistry of
           Imidazotetrazine Prodrugs

    • Authors: Catherine Moody, Richard Wheelhouse
      Pages: 797 - 838
      Abstract: Temozolomide (TMZ) is the standard first line treatment for malignant glioma, reaching “blockbuster” status in 2010, yet it remains the only drug in its class. The main constraints on the clinical effectiveness of TMZ therapy are its requirement for active DNA mismatch repair (MMR) proteins for activity, and inherent resistance through O6-methyl guanine-DNA methyl transferase (MGMT) activity. Moreover, acquired resistance, due to MMR mutation, results in aggressive TMZ-resistant tumour regrowth following good initial responses. Much of the attraction in TMZ as a drug lies in its PK/PD properties: it is acid stable and has 100% oral bioavailability; it also has excellent distribution properties, crosses the blood-brain barrier, and there is direct evidence of tumour localisation. This review seeks to unravel some of the mysteries of the imidazotetrazine class of compounds to which TMZ belongs. In addition to an overview of different synthetic strategies, we explore the somewhat unusual chemical reactivity of the imidazotetrazines, probing their mechanisms of reaction, examining which attributes are required for an active drug molecule and reviewing the use of this combined knowledge towards the development of new and improved anti-cancer agents.
      PubDate: 2014-07-10
      DOI: 10.3390/ph7070797
      Issue No: Vol. 7, No. 7 (2014)
  • Pharmaceuticals, Vol. 7, Pages 839-849: Pharmaceuticals—Special
           Issue on Radiopharmaceutical Chemistry between Imaging and

    • Authors: Klaus Kopka
      Pages: 839 - 849
      Abstract: The fields of molecular biology, immunology and genetics have generated many important developments that advance the understanding of the induction and progression of oncological, cardiological and neurological diseases as well as the identification of disease-associated molecules and drugs that specifically target diseased cells during therapy. These insights have triggered the development of targeted radiopharmaceuticals which open up a new dimension of radiopharmaceutical sciences in nuclear medicine. Radiopharmaceuticals, also called radiotracers, are radiolabelled molecules, bearing a “radioactive lantern”, and used as molecular probes to address clinically relevant biological targets such as receptors, enzymes, transport systems and others. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) realised in the en-vogue hybrid technologies PET/CT, SPECT/CT and PET/MRI represent the state-of-the-art diagnostic imaging technologies in nuclear medicine which are used to follow the trace of the administered radiopharmaceutical noninvasively thereby in vivo visualising and assessing biological processes at the subcellular and molecular level in a highly sensitive manner. In this connexion novel radiopharmaceuticals for the noninvasive molecular imaging of early disease states and monitoring of treatment responses in vivo by means of PET/CT, SPECT/CT and PET/MRI are indispensable prerequisites to further advance and strengthen the unique competence of radiopharmaceutical sciences. In the era of personalised medicine the diagnostic potential of radiopharmaceuticals is directly linked to a subsequent individual therapeutic approach called endoradiotherapy. Depending on the “radioactive lantern” (gamma or particle emitter) used for radiolabelling of the respective tracer molecule, the field of Radiopharmaceutical Chemistry can contribute to the set-up of an “in vivo theranostic” approach especially in tumour patients by offering tailor-made (radio)chemical entities labelled either with a diagnostic or a therapeutic radionuclide. [...]
      PubDate: 2014-07-16
      DOI: 10.3390/ph7070839
      Issue No: Vol. 7, No. 7 (2014)
  • Pharmaceuticals, Vol. 7, Pages 634-661: Involvement of HDAC1 and HDAC3 in
           the Pathology of Polyglutamine Disorders: Therapeutic Implications for
           Selective HDAC1/HDAC3 Inhibitors

    • Authors: Elizabeth Thomas
      Pages: 634 - 661
      Abstract: Histone deacetylases (HDACs) enzymes, which affect the acetylation status of histones and other important cellular proteins, have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Emerging studies have demonstrated that different types of HDAC inhibitors show beneficial effects in various experimental models of neurological disorders. HDAC enzymes comprise a large family of proteins, with18 HDAC enzymes currently identified in humans. Hence, an important question for HDAC inhibitor therapeutics is which HDAC enzyme(s) is/are important for the amelioration of disease phenotypes, as it has become clear that individual HDAC enzymes play different biological roles in the brain. This review will discuss evidence supporting the involvement of HDAC1 and HDAC3 in polyglutamine disorders, including Huntington’s disease, and the use of HDAC1- and HDAC3-selective HDAC inhibitors as therapeutic intervention for these disorders. Further, while HDAC inhibitors are known alter chromatin structure resulting in changes in gene transcription, understanding the exact mechanisms responsible for the preclinical efficacy of these compounds remains a challenge. The potential chromatin-related and non-chromatin-related mechanisms of action of selective HDAC inhibitors will also be discussed.
      PubDate: 2014-05-26
      DOI: 10.3390/ph7060634
      Issue No: Vol. 7, No. 6 (2014)
  • Pharmaceuticals, Vol. 7, Pages 662-675: A Bombesin-Shepherdin
           Radioconjugate Designed for Combined Extra- and Intracellular Targeting

    • Authors: Christiane Fischer, Sandra Vomstein, Thomas Mindt
      Pages: 662 - 675
      Abstract: Radiolabeled peptides which target tumor-specific membrane structures of cancer cells represent a promising class of targeted radiopharmaceuticals for the diagnosis and therapy of cancer. A potential drawback of a number of reported radiopeptides is the rapid washout of a substantial fraction of the initially delivered radioactivity from cancer cells and tumors. This renders the initial targeting effort in part futile and results in a lower imaging quality and efficacy of the radiotracer than achievable. We are investigating the combination of internalizing radiopeptides with molecular entities specific for an intracellular target. By enabling intracellular interactions of the radioconjugate, we aim at reducing/decelerating the externalization of radioactivity from cancer cells. Using the “click-to-chelate” approach, the 99mTc-tricarbonyl core as a reporter probe for single-photon emission computed tomography (SPECT) was combined with the binding sequence of bombesin for extracellular targeting of the gastrin-releasing peptide receptor (GRP-r) and peptidic inhibitors of the cytosolic heat shock 90 protein (Hsp90) for intracellular targeting. Receptor-specific uptake of the multifunctional radioconjugate could be confirmed, however, the cellular washout of radioactivity was not improved. We assume that either endosomal trapping or lysosomal degradation of the radioconjugate is accountable for these observations.
      PubDate: 2014-05-27
      DOI: 10.3390/ph7060662
      Issue No: Vol. 7, No. 6 (2014)
  • Pharmaceuticals, Vol. 7, Pages 676-694: Part Two: Evaluation of
           N-methylbupropion as a Potential Bupropion Prodrug

    • Authors: Paul O'Byrne, Robert williams, John walsh, John Gilmer
      Pages: 676 - 694
      Abstract: N-methylbupropion was selected as a potential prodrug from our in vitro screening of analogues of bupropion described in the preceding paper. This study describes in vivo pharmacokinetics of N-methylbupropion in the guinea-pig animal model, which is reported to best predict human metabolism of bupropion. The suitability of the guinea pig was established by studying N-demethylation of N-methylbupropion using S9 liver fractions. An LC-MS method was developed and validated to measure N-methylbupropion, bupropion and their metabolites in plasma and brain tissue. In separate studies, the prodrug was delivered by intraperitoneal injection (IP) to assess hepatic metabolism and then by oral gavage (PO) to assess the contribution from intestinal enzymes. Bupropion was administered in parallel. The pharmacokinetic profile of bupropion and N-methylbupropion were not comparable when dosed by intraperitoneal injection but when dosed orally, N-methylbupropion showed a comparable bupropion and metabolite PK plasma profile to bupropion. Plasma and brain levels of N-methylbupropion show that it is extensively metabolized to bupropion and its metabolites, and N-methyl-threo-hydrobupropion. This data coupled to the reduced DAT and NET system in vitro activity described in paper 1 would suggest that the N-methyl derivative of bupropion may have potential as an oral prodrug of bupropion in humans.
      PubDate: 2014-05-28
      DOI: 10.3390/ph7060676
      Issue No: Vol. 7, No. 6 (2014)
  • Pharmaceuticals, Vol. 7, Pages 695-722: Conformational Analysis, Molecular
           Structure and Solid State Simulation of the Antiviral Drug Acyclovir
           (Zovirax) Using Density Functional Theory Methods

    • Authors: Margarita Alvarez-Ros, Mauricio Palafox
      Pages: 695 - 722
      Abstract: The five tautomers of the drug acyclovir (ACV) were determined and optimised at the MP2 and B3LYP quantum chemical levels of theory. The stability of the tautomers was correlated with different parameters. On the most stable tautomer N1 was carried out a comprehensive conformational analysis, and the whole conformational parameters (R, β, Φ, φ1, φ2, φ3, φ4, φ5) were studied as well as the NBO Natural atomic charges. The calculations were carried out with full relaxation of all geometrical parameters. The search located at least 78 stable structures within 8.5 kcal/mol electronic energy range of the global minimum, and classified in two groups according to the positive or negative value of the torsional angle j1. In the nitrogen atoms and in the O2' and O5' oxygen atoms of the most stable conformer appear a higher reactivity than in the natural nucleoside deoxyguanosine. The solid state was simulated through a dimer and tetramer forms and the structural parameters were compared with the X-ray crystal data available. Several general conclusions were emphasized.
      PubDate: 2014-06-06
      DOI: 10.3390/ph7060695
      Issue No: Vol. 7, No. 6 (2014)
  • Pharmaceuticals, Vol. 7, Pages 723-753: Antimicrobial Peptides in Reptiles

    • Authors: Monique van Hoek
      Pages: 723 - 753
      Abstract: Reptiles are among the oldest known amniotes and are highly diverse in their morphology and ecological niches. These animals have an evolutionarily ancient innate-immune system that is of great interest to scientists trying to identify new and useful antimicrobial peptides. Significant work in the last decade in the fields of biochemistry, proteomics and genomics has begun to reveal the complexity of reptilian antimicrobial peptides. Here, the current knowledge about antimicrobial peptides in reptiles is reviewed, with specific examples in each of the four orders: Testudines (turtles and tortosises), Sphenodontia (tuataras), Squamata (snakes and lizards), and Crocodilia (crocodilans). Examples are presented of the major classes of antimicrobial peptides expressed by reptiles including defensins, cathelicidins, liver-expressed peptides (hepcidin and LEAP-2), lysozyme, crotamine, and others. Some of these peptides have been identified and tested for their antibacterial or antiviral activity; others are only predicted as possible genes from genomic sequencing. Bioinformatic analysis of the reptile genomes is presented, revealing many predicted candidate antimicrobial peptides genes across this diverse class. The study of how these ancient creatures use antimicrobial peptides within their innate immune systems may reveal new understandings of our mammalian innate immune system and may also provide new and powerful antimicrobial peptides as scaffolds for potential therapeutic development.
      PubDate: 2014-06-10
      DOI: 10.3390/ph7060723
      Issue No: Vol. 7, No. 6 (2014)
  • Pharmaceuticals, Vol. 7, Pages 502-516: Enhanced Antimicrobial Activity of
           AamAP1-Lysine, a Novel Synthetic Peptide Analog Derived from the Scorpion
           Venom Peptide AamAP1

    • Authors: Ammar Almaaytah, Shadi Tarazi, Ahmad Abu-Alhaijaa, Yara Altall, Nizar Alshar'i, Khaldon Bodoor, Qosay Al-Balas
      Pages: 502 - 516
      Abstract: There is great interest in the development of antimicrobial peptides as a potentially novel class of antimicrobial agents. Several structural determinants are responsible for the antimicrobial and cytolytic activity of antimicrobial peptides. In our study, a new synthetic peptide analog, AamAP1-Lysine from the naturally occurring scorpion venom antimicrobial peptide AamAP1, was designed by modifying the parent peptide in order to increase the positive charge and optimize other physico-chemical parameters involved in antimicrobial activity. AamAP1-Lysine displayed potent antibacterial activity against Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration was in the range of 5 to 15 µM with a 10 fold increase in potency over the parent peptide. The hemolytic and antiproliferative activity of AamAP1-Lysine against eukaryotic mammalian cells was minimal at the concentration range needed to inhibit bacterial growth. The antibacterial mechanism analysis indicated that AamAP1-Lysine is probably inducing bacterial cell death through membrane damage and permeabilization determined by the release of β-galactosidase enzyme from peptide treated E. coli cells. DNA binding studies revealed that AamAP1-Lysine caused complete retardation of DNA migration and could display intracellular activities in addition to the membrane permeabilization mode of action reported earlier. In conclusion, AamAP1-Lysine could prove to be a potential candidate for antimicrobial drug development in future studies.
      PubDate: 2014-04-25
      DOI: 10.3390/ph7050502
      Issue No: Vol. 7, No. 5 (2014)
  • Pharmaceuticals, Vol. 7, Pages 517-529: Synthesis, Radiolabelling and In
           Vitro Characterization of the Gallium-68-, Yttrium-90- and
           Lutetium-177-Labelled PSMA Ligand, CHX-A''-DTPA-DUPA-Pep

    • Authors: Benjamin Baur, Christoph Solbach, Elena Andreolli, Gordon Winter, Hans-Jürgen Machulla, Sven Reske
      Pages: 517 - 529
      Abstract: Since prostate-specific membrane antigen (PSMA) has been identified as a diagnostic target for prostate cancer, many urea-based small PSMA-targeting molecules were developed. First, the clinical application of these Ga-68 labelled compounds in positron emission tomography (PET) showed their diagnostic potential. Besides, the therapy of prostate cancer is a demanding field, and the use of radiometals with PSMA bearing ligands is a valid approach. In this work, we describe the synthesis of a new PSMA ligand, CHX-A''-DTPA-DUPA-Pep, the subsequent labelling with Ga-68, Lu-177 and Y-90 and the first in vitro characterization. In cell investigations with PSMA-positive LNCaP C4-2 cells, KD values of ≤14.67 ± 1.95 nM were determined, indicating high biological activities towards PSMA. Radiosyntheses with Ga-68, Lu-177 and Y-90 were developed under mild reaction conditions (room temperature, moderate pH of 5.5 and 7.4, respectively) and resulted in nearly quantitative radiochemical yields within 5 min.
      PubDate: 2014-04-29
      DOI: 10.3390/ph7050517
      Issue No: Vol. 7, No. 5 (2014)
  • Pharmaceuticals, Vol. 7, Pages 530-544: Barriers to the Access and Use of
           Rituximab in Patients with Non-Hodgkin’s Lymphoma and Chronic
           Lymphocytic Leukemia: A Physician Survey

    • Authors: William Baer II, Archana Maini, Ira Jacobs
      Pages: 530 - 544
      Abstract: Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia.
      PubDate: 2014-05-07
      DOI: 10.3390/ph7050530
      Issue No: Vol. 7, No. 5 (2014)
  • Pharmaceuticals, Vol. 7, Pages 545-594: Human Antimicrobial Peptides and

    • Authors: Guangshun Wang
      Pages: 545 - 594
      Abstract: As the key components of innate immunity, human host defense antimicrobial peptides and proteins (AMPs) play a critical role in warding off invading microbial pathogens. In addition, AMPs can possess other biological functions such as apoptosis, wound healing, and immune modulation. This article provides an overview on the identification, activity, 3D structure, and mechanism of action of human AMPs selected from the antimicrobial peptide database. Over 100 such peptides have been identified from a variety of tissues and epithelial surfaces, including skin, eyes, ears, mouths, gut, immune, nervous and urinary systems. These peptides vary from 10 to 150 amino acids with a net charge between −3 and +20 and a hydrophobic content below 60%. The sequence diversity enables human AMPs to adopt various 3D structures and to attack pathogens by different mechanisms. While α-defensin HD-6 can self-assemble on the bacterial surface into nanonets to entangle bacteria, both HNP-1 and β-defensin hBD-3 are able to block cell wall biosynthesis by binding to lipid II. Lysozyme is well-characterized to cleave bacterial cell wall polysaccharides but can also kill bacteria by a non-catalytic mechanism. The two hydrophobic domains in the long amphipathic α-helix of human cathelicidin LL-37 lays the basis for binding and disrupting the curved anionic bacterial membrane surfaces by forming pores or via the carpet model. Furthermore, dermcidin may serve as ion channel by forming a long helix-bundle structure. In addition, the C-type lectin RegIIIα can initially recognize bacterial peptidoglycans followed by pore formation in the membrane. Finally, histatin 5 and GAPDH(2-32) can enter microbial cells to exert their effects. It appears that granulysin enters cells and kills intracellular pathogens with the aid of pore-forming perforin. This arsenal of human defense proteins not only keeps us healthy but also inspires the development of a new generation of personalized medicine to combat drug-resistant superbugs, fungi, viruses, parasites, or cancer. Alternatively, multiple factors (e.g., albumin, arginine, butyrate, calcium, cyclic AMP, isoleucine, short-chain fatty acids, UV B light, vitamin D, and zinc) are able to induce the expression of antimicrobial peptides, opening new avenues to the development of anti-infectious drugs.
      PubDate: 2014-05-13
      DOI: 10.3390/ph7050545
      Issue No: Vol. 7, No. 5 (2014)
  • Pharmaceuticals, Vol. 7, Pages 595-620: Synthesis, Screening and
           Pharmacokinetic Evaluation of Potential Prodrugs of Bupropion. Part One:
           In Vitro Development

    • Authors: Paul O'Byrne, Robert Williams, John Walsh, John Gilmer
      Pages: 595 - 620
      Abstract: In general, prodrugs are developed to circumvent deficiencies associated with the absorption, distribution, metabolism, excretion or toxicological (ADMET) profile associated with the active drug. In our study, we select bupropion, a drug with broad pharmacology incorporating dopaminergic, noradrenergic, nicotinic and cytokine modulation properties, but which is rapidly metabolized in vivo. we exploited its carbonyl and secondary amine functionality to facilitate the synthesis of bioprecursor prodrug forms with the sole objective of identifying analogues with enhanced properties over bupropion. A range of analogues were synthesized, ranging from N-methyl, N-benzyl, oximes, enol acetate and ether forms to examples where both functional groups were utilized to form oxadiazine, oxadiazinone, oxazolone and acetylated derivatives. we then developed an in vitro metabolic screen to simulate the human oral delivery route for these analogues. The selection of media in the screens contained a variety of pH, enzymatic and co-factor systems which mimic metabolic in vivo environments that drugs encounter when delivered orally. By coupling our in vitro screening tool to a selective hyphenated technique such as LC-MS, we were able to quickly select potential prodrugs for further in vitro and in vivo development. From the data generated, the N-alkylated bupropion analogues were shown to have the highest potential to act as bioprecursor prodrugs of bupropion.
      PubDate: 2014-05-14
      DOI: 10.3390/ph7050595
      Issue No: Vol. 7, No. 5 (2014)
  • Pharmaceuticals, Vol. 7, Pages 621-633: Development and Successful
           Validation of Simple and Fast TLC Spot Tests for Determination of
           Kryptofix® 2.2.2 and Tetrabutylammonium in 18F-Labeled

    • Authors: Matthias Kuntzsch, Denis Lamparter, Nils Brüggener, Marco Müller, Gabriele Kienzle, Gerald Reischl
      Pages: 621 - 633
      Abstract: Kryptofix® 2.2.2 (Kry) or tetrabutylammonium (TBA) are commonly used as phase transfer catalysts in 18F-radiopharmaceutical productions for positron emission tomography (PET). Due to their toxicity, quality control has to be performed before administration of the tracer to assure that limit concentration of residual reagent is not reached. Here, we describe the successful development and pharmaceutical validation (for specificity, accuracy and detection limit) of a simplified color spot test on TLC plates. We were able to prove its applicability as a general, time and resources saving, easy to handle and reliable method in daily routine analyzing 18F-tracer formulations for Kry (in [18F]FDG or [18F]FECh) or TBA contaminations (in [18F]FLT) with special regard to complex matrix compositions.
      PubDate: 2014-05-14
      DOI: 10.3390/ph7050621
      Issue No: Vol. 7, No. 5 (2014)
  • 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 453-463: Synthesis, In Vitro and In Vivo
           Evaluation of the N-ethoxycarbonylmorpholine Ester of Diclofenac as a

    • Authors: Jamal Jilani, Nasir Idkaidek, Karem Alzoubi
      Pages: 453 - 463
      Abstract: The N-ethoxycarbonylmorpholine moiety was evaluated as a novel prodrug moiety for carboxylic acid containing drugs represented by diclofenac (1). Compound 2, the N-ethoxycarbonylmorpholine ester of diclofenac was synthesized and evaluated as a potential prodrug. The stability of the synthesized prodrug was evaluated in solutions of pH 1 and 7.4, and in plasma. The ester’s half lives were found to be 8 h, 47 h and 21 min in pH 1, pH 7.4 and plasma, respectively. Equimolar doses of diclofenac sodium and its synthesized prodrug were administered orally to a group of rabbits in a crossover study to evaluate their pharmacokinetic parameters. The prodrug 2 shows a similar rate and extent of absorption as the parent drug (1). The ulcerogenicity of the prepared prodrug was evaluated and compared with the parent drug. The prodrug showed less ulcerogenicity as detected by fewer number and smaller size of ulcers. In conclusion, the newly synthesized N-ethoxycarbonylmorpholine ester of diclofenac prodrug showed appropriate stability properties at different pHs, similar pharmacokinetic profile, and much less ulcerogenecity at the GIT compared to the parent drug diclofenac.
      PubDate: 2014-04-14
      DOI: 10.3390/ph7040453
      Issue No: Vol. 7, No. 4 (2014)
  • Pharmaceuticals, Vol. 7, Pages 464-481: In Vivo Monitoring of the
           Antiangiogenic Effect of Neurotensin Receptor-Mediated Radiotherapy by
           Small-Animal Positron Emission Tomography: A Pilot Study

    • Authors: Simone Maschauer, Tina Ruckdeschel, Philipp Tripal, Roland Haubner, Jürgen Einsiedel, Harald Hübner, Peter Gmeiner, Torsten Kuwert, Olaf Prante
      Pages: 464 - 481
      Abstract: The neurotensin receptor (NTS1) has emerged as an interesting target for molecular imaging and radiotherapy of NTS-positive tumors due to the overexpression in a range of tumors. The aim of this study was to develop a 177Lu-labeled NTS1 radioligand, its application for radiotherapy in a preclinical model and the imaging of therapy success by small-animal positron emission tomography (µPET) using [68Ga]DOTA-RGD as a specific tracer for imaging angiogenesis. The 177Lu-labeled peptide was subjected to studies on HT29-tumor-bearing nude mice in vivo, defining four groups of animals (single dose, two fractionated doses, four fractionated doses and sham-treated animals). Body weight and tumor diameters were determined three times per week. Up to day 28 after treatment, µPET studies were performed with [68Ga]DOTA-RGD. At days 7–10 after treatment with four fractionated doses of 11–14 MBq (each at days 0, 3, 6 and 10), the tumor growth was slightly decreased in comparison with untreated animals. Using a single high dose of 51 MBq, a significantly decreased tumor diameter of about 50% was observed with the beginning of treatment. Our preliminary PET imaging data suggested decreased tumor uptake values of [68Ga]DOTA-RGD in treated animals compared to controls at day 7 after treatment. This pilot study suggests that early PET imaging with [68Ga]DOTA-RGD in radiotherapy studies to monitor integrin expression could be a promising tool to predict therapy success in vivo. Further successive PET experiments are needed to confirm the significance and predictive value of RGD-PET for NTS-mediated radiotherapy.
      PubDate: 2014-04-16
      DOI: 10.3390/ph7040464
      Issue No: Vol. 7, No. 4 (2014)
  • Pharmaceuticals, Vol. 7, Pages 482-501: β-Boomerang Antimicrobial and
           Antiendotoxic Peptides: Lipidation and Disulfide Bond Effects on Activity
           and Structure

    • Authors: Harini Mohanram, Surajit Bhattacharjya
      Pages: 482 - 501
      Abstract: Drug-resistant Gram-negative bacterial pathogens and endotoxin- or lipopolysaccharide (LPS)-mediated inflammations are among some of the most  prominent health issues globally. Antimicrobial peptides (AMPs) are eminent molecules that can kill drug-resistant strains and neutralize LPS toxicity. LPS, the outer layer of the outer membrane of Gram-negative bacteria safeguards cell integrity against hydrophobic compounds, including antibiotics and AMPs. Apart from maintaining structural integrity, LPS, when released into the blood stream, also induces inflammatory pathways leading to septic shock. In previous works, we have reported the de novo design of a set of 12-amino acid long cationic/hydrophobic peptides for LPS binding and activity. These peptides adopt β-boomerang like conformations in complex with LPS. Structure-activity studies demonstrated some critical features of the β-boomerang scaffold that may be utilized for the further development of potent analogs. In this work, β-boomerang lipopeptides were designed and structure-activity correlation studies were carried out. These lipopeptides were homo-dimerized through a disulfide bridge to stabilize conformations and for improved activity. The designed peptides exhibited potent antibacterial activity and efficiently neutralized LPS toxicity under in vitro assays. NMR structure of C4YI13C in aqueous solution demonstrated the conserved folding of the lipopeptide with a boomerang aromatic lock stabilized with disulfide bond at the C-terminus and acylation at the N-terminus. These lipo-peptides displaying bacterial sterilization and low hemolytic activity may be useful for future applications as antimicrobial and antiendotoxin molecules.
      PubDate: 2014-04-21
      DOI: 10.3390/ph7040482
      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 1028-1048: Role of Microglial M1/M2
           Polarization in Relapse and Remission of Psychiatric Disorders and

    • Authors: Yutaka Nakagawa, Kenji Chiba
      Pages: 1028 - 1048
      Abstract: Psychiatric disorders such as schizophrenia and major depressive disorder were thought to be caused by neurotransmitter abnormalities. Patients with these disorders often experience relapse and remission; however the underlying molecular mechanisms of relapse and remission still remain unclear. Recent advanced immunological analyses have revealed that M1/M2 polarization of macrophages plays an important role in controlling the balance between promotion and suppression in inflammation. Microglial cells share certain characteristics with macrophages and contribute to immune-surveillance in the central nervous system (CNS). In this review, we summarize immunoregulatory functions of microglia and discuss a possible role of microglial M1/M2 polarization in relapse and remission of psychiatric disorders and diseases. M1 polarized microglia can produce pro-inflammatory cytokines, reactive oxygen species, and nitric oxide, suggesting that these molecules contribute to dysfunction of neural network in the CNS. Alternatively, M2 polarized microglia express cytokines and receptors that are implicated in inhibiting inflammation and restoring homeostasis. Based on these aspects, we propose a possibility that M1 and M2 microglia are related to relapse and remission, respectively in psychiatric disorders and diseases. Consequently, a target molecule skewing M2 polarization of microglia may provide beneficial therapies for these disorders and diseases in the CNS.
      PubDate: 2014-11-25
      DOI: 10.3390/ph7121028
      Issue No: Vol. 7, No. 12 (2014)
  • Pharmaceuticals, Vol. 7, Pages 1049-1068: Adoptive Immunotherapy for
           Hematological Malignancies Using T Cells Gene-Modified to Express Tumor
           Antigen-Specific Receptors

    • Authors: Hiroshi Fujiwara
      Pages: 1049 - 1068
      Abstract: Accumulating clinical evidence suggests that adoptive T-cell immunotherapy could be a promising option for control of cancer; evident examples include the graft-vs-leukemia effect mediated by donor lymphocyte infusion (DLI) and therapeutic infusion of ex vivo-expanded tumor-infiltrating lymphocytes (TIL) for melanoma. Currently, along with advances in synthetic immunology, gene-modified T cells retargeted to defined tumor antigens have been introduced as “cellular drugs”. As the functional properties of the adoptive immune response mediated by T lymphocytes are decisively regulated by their T-cell receptors (TCRs), transfer of genes encoding target antigen-specific receptors should enable polyclonal T cells to be uniformly redirected toward cancer cells. Clinically, anticancer adoptive immunotherapy using genetically engineered T cells has an impressive track record. Notable examples include the dramatic benefit of chimeric antigen receptor (CAR) gene-modified T cells redirected towards CD19 in patients with B-cell malignancy, and the encouraging results obtained with TCR gene-modified T cells redirected towards NY-ESO-1, a cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. This article overviews the current status of this treatment option, and discusses challenging issues that still restrain the full effectiveness of this strategy, especially in the context of hematological malignancy.
      PubDate: 2014-12-15
      DOI: 10.3390/ph7121049
      Issue No: Vol. 7, No. 12 (2014)
  • Pharmaceuticals, Vol. 7, Pages 1008-1027: Involvement of the Antioxidant
           Effect and Anti-inflammatory Response in Butyrate-Inhibited Vascular
           Smooth Muscle Cell Proliferation

    • Authors: Omana Mathew, Kasturi Ranganna, Shirlette Milton
      Pages: 1008 - 1027
      Abstract: Epigenetic mechanisms by altering the expression and, in turn, functions of target genes have potential to modify cellular processes that are characteristics of atherosclerosis, including inflammation, proliferation, migration and apoptosis/cell death. Butyrate, a natural epigenetic modifier and a histone deacetylase inhibitor (HDACi), is an inhibitor of vascular smooth muscle cell (VSMC) proliferation, a critical event in atherogenesis. Here, we examined whether glutathione peroxidases (GPxs), a family of antioxidant enzymes, are modulated by butyrate, contributing to its antiproliferation action on VSMC through the regulation of the inflammatory response by using western blotting, immunostaining methods and activity assay. Treatment of VSMC with butyrate not only upregulates glutathione peroxidase (GPx) 3 and GPx4, but also increases the overall catalytic activity of GPx supporting involvement of antioxidant effect in butyrate arrested VSMC proliferation. Moreover, analysis of the redox-sensitive NF-κB transcription factor system, the target of GPx, reveals that butyrate causes downregulation of IKKα, IKKβ, IkBα and NF-κBp65 expression and prevents NF-κBp65 phosphorylation at serine536 causing inhibition of the expression NF-κB target inflammatory genes, including inducible nitric oxide synthase, VCAM-1 and cyclooxygenase-2. Overall, these observations suggest a link between the antioxidant effect and anti-inflammatory response in butyrate-arrested VSMC proliferation, accentuating the atheroprotective and therapeutic potential of natural products, like butyrate, in vascular proliferative diseases.
      PubDate: 2014-11-10
      DOI: 10.3390/ph7111008
      Issue No: Vol. 7, No. 11 (2014)
  • Pharmaceuticals, Vol. 7, Pages 990-998: Ferric Citrate Hydrate as a
           Phosphate Binder and Risk of Aluminum Toxicity

    • Authors: Ajay Gupta
      Pages: 990 - 998
      Abstract: Ferric citrate hydrate was recently approved in Japan as an oral phosphate binder to be taken with food for the control of hyperphosphatemia in patients with chronic kidney disease (CKD). The daily therapeutic dose is about 3 to 6 g, which comprises about 2 to 4 g of citrate. Oral citrate solubilizes aluminum that is present in food and drinking water, and opens the tight junctions in the intestinal epithelium, thereby increasing aluminum absorption and urinary excretion. In healthy animals drinking tap water, oral citrate administration increased aluminum absorption and, over a 4-week period, increased aluminum deposition in brain and bone by about 2- and 20-fold, respectively. Renal excretion of aluminum is impaired in patients with chronic kidney disease, thereby increasing the risk of toxicity. Based on human and animal studies it can be surmised that patients with CKD who are treated with ferric citrate hydrate to control hyperphosphatemia are likely to experience enhanced absorption of aluminum from food and drinking water, thereby increasing the risk of aluminum overload and toxicity.
      PubDate: 2014-09-26
      DOI: 10.3390/ph7100990
      Issue No: Vol. 7, No. 10 (2014)
  • Pharmaceuticals, Vol. 7, Pages 999-1007: Recommendations for Probiotic Use
           in Humans—A 2014 Update

    • Authors: Martin Floch
      Pages: 999 - 1007
      Abstract: Probiotics have gained worldwide use during the last two decades. However, which probiotic to use in which clinical condition has remained confusing in some clinical conditions. We convened a workshop at Yale in conjunction with Harvard in 2005, inviting a spectrum of probiotic authorities to discuss and reach conclusions on recommendations for use in common clinical conditions; the workshop was reconvened again in 2008 and in 2011. Each time the group of authorities was enlarged and varied depending on research studies. This article lists the recommendations updated from 2011 and is amended to bring it up to date in childhood and adult diarrhea, antibiotic-associated diarrhea, necrotizing enterocolitis, inflammatory bowel disorders, irritable bowel syndrome, allergic disorders, and radiation enteritis pending our 4th Triennial Yale/Harvard workshop to be convened in 2015.
      PubDate: 2014-10-10
      DOI: 10.3390/ph7100999
      Issue No: Vol. 7, No. 10 (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

    • 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

    • 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

    • 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

    • 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

    • 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

    • 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

    • 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 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 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

    • 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)
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