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Journal of Applied Spectroscopy     Hybrid Journal   (Followers: 8)
Journal of Argentine Chemical Society     Open Access  
Journal of Biomaterials and Nanobiotechnology     Open Access   (Followers: 6)
Journal of Carbohydrate Chemistry     Hybrid Journal   (Followers: 5)
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Journal of Chromatography A     Hybrid Journal   (Followers: 57)
Journal of Clinical Toxicology     Open Access   (Followers: 1)
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Journal of Labelled Compounds and Radiopharmaceuticals     Hybrid Journal   (Followers: 1)
Journal of Macromolecular Science, Part A: Pure and Applied Chemistry     Hybrid Journal   (Followers: 3)
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Journal of Nepal Chemical Society     Open Access  
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Journal of Nucleic Acids Investigation     Open Access   (Followers: 2)
Journal of Ocean University of China (English Edition)     Hybrid Journal   (Followers: 1)
Journal of Organometallic Chemistry     Hybrid Journal   (Followers: 14)
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: 3)
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Journal of Polymer and Biopolymer Physics Chemistry     Open Access   (Followers: 3)
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Journal of Porphyrins and Phthalocyanines     Hybrid Journal   (Followers: 2)
Journal of Pure and Applied Chemistry Research     Open Access   (Followers: 1)
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Journal of Research Updates in Polymer Science     Hybrid Journal  
Journal of Saudi Chemical Society     Open Access  
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Journal of Superhard Materials     Hybrid Journal   (Followers: 1)
Journal of Surfactants and Detergents     Hybrid Journal   (Followers: 4)
Journal of Taibah University for Science     Open Access   (Followers: 1)
Journal of the American Chemical Society     Full-text available via subscription   (Followers: 257)
Journal of the American Society for Mass Spectrometry     Hybrid Journal   (Followers: 21)
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  
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: 8)
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: 5)
Jurnal Penelitian Sains (JPS)     Open Access  
Jurnal Teknologi Informasi     Open Access   (Followers: 3)
Karbala International Journal of Modern Science     Open Access  
Kinetics and Catalysis     Hybrid Journal   (Followers: 3)
Korea-Australia Rheology Journal     Hybrid Journal  
Langmuir     Full-text available via subscription   (Followers: 44)

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Journal Cover   Pharmaceuticals
  [SJR: 0.585]   [H-I: 16]   [5 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Print) 1424-8247
   Published by MDPI Homepage  [140 journals]
  • Pharmaceuticals, Vol. 8, Pages 664-674: Opioid Facilitation of
           β-Adrenergic Blockade: A New Pharmacological Condition'

    • Authors: Joseph Vamecq, Karine Mention-Mulliez, Francis Leclerc, Dries Dobbelaere
      Pages: 664 - 674
      Abstract: Recently, propranolol was suggested to prevent hyperlactatemia in a child with hypovolemic shock through β-adrenergic blockade. Though it is a known inhibitor of glycolysis, propranolol, outside this observation, has never been reported to fully protect against lactate overproduction. On the other hand, literature evidence exists for a cross-talk between β-adrenergic receptors (protein targets of propranolol) and δ-opioid receptor. In this literature context, it is hypothesized here that anti-diarrheic racecadotril (a pro-drug of thiorphan, an inhibitor of enkephalinases), which, in the cited observation, was co-administered with propranolol, might have facilitated the β-blocker-driven inhibition of glycolysis and resulting lactate production. The opioid-facilitated β-adrenergic blockade would be essentially additivity or even synergism putatively existing between antagonism of β-adrenergic receptors and agonism of δ-opioid receptor in lowering cellular cAMP and dependent functions.
      PubDate: 2015-09-25
      DOI: 10.3390/ph8040664
      Issue No: Vol. 8, No. 4 (2015)
  • Pharmaceuticals, Vol. 8, Pages 675-695: Mitochondrial Dysfunction and
           Disturbed Coherence: Gate to Cancer

    • Pages: 675 - 695
      Abstract: Continuous energy supply, a necessary condition for life, excites a state far from thermodynamic equilibrium, in particular coherent electric polar vibrations depending on water ordering in the cell. Disturbances in oxidative metabolism and coherence are a central issue in cancer development. Oxidative metabolism may be impaired by decreased pyruvate transfer to the mitochondrial matrix, either by parasitic consumption and/or mitochondrial dysfunction. This can in turn lead to disturbance in water molecules’ ordering, diminished power, and coherence of the electromagnetic field. In tumors with the Warburg (reverse Warburg) effect, mitochondrial dysfunction affects cancer cells (fibroblasts associated with cancer cells), and the electromagnetic field generated by microtubules in cancer cells has low power (high power due to transport of energy-rich metabolites from fibroblasts), disturbed coherence, and a shifted frequency spectrum according to changed power. Therapeutic strategies restoring mitochondrial function may trigger apoptosis in treated cells; yet, before this step is performed, induction (inhibition) of pyruvate dehydrogenase kinases (phosphatases) may restore the cancer state. In tumor tissues with the reverse Warburg effect, Caveolin-1 levels should be restored and the transport of energy-rich metabolites interrupted to cancer cells. In both cancer phenotypes, achieving permanently reversed mitochondrial dysfunction with metabolic-modulating drugs may be an effective, specific anti-cancer strategy.
      PubDate: 2015-09-30
      DOI: 10.3390/ph8040675
      Issue No: Vol. 8, No. 4 (2015)
  • Pharmaceuticals, Vol. 8, Pages 696-710: Controlling Persister and Biofilm
           Cells of Gram-Negative Bacteria with a New 1,3,5-Triazine Derivative

    • Authors: Ali Adem Bahar, Zhigang Liu, Meagan Garafalo, Neville Kallenbach, Dacheng Ren
      Pages: 696 - 710
      Abstract: Infections caused by multidrug-resistant bacteria have been on the rise. This important issue presents a great challenge to the healthcare system and creates an urgent need for alternative therapeutic agents. As a potential solution to this problem, antimicrobial peptides (AMPs) have attracted increasing attention due to their broad spectrum of targeted microbes. However, most AMPs are expensive to synthesize, have relatively high cytotoxicity to mammalian cells, and are susceptible to proteolytic degradation. In order to overcome these limitations, novel synthetic AMPs are desired. Using 1,3,5-triazine (TN) as a template, several combinatorial libraries with varying cationic charge and lipophilicity were designed and screened by the Kallenbach lab. From this screening, TN-5 was identified as a potent lead. In the present study, this compound was tested for its antimicrobial activities on Escherichia coli and Pseudomonas aeruginosa. In addition to regular planktonic cells, the effects on biofilms and persister cells (metabolically inactive and antibiotic tolerant subpopulation) were also investigated. TN-5 was found to have a minimum inhibitory concentration (MIC) of 12.8 μM for both species and kill regular planktonic cells of both species dose dependently. TN-5 is also effective against persister cells of both E. coli and P. aeruginosa. The killing of biofilm cells of the mucoid P. aeruginosa PDO300 was enhanced by alginate lyase.
      PubDate: 2015-10-10
      DOI: 10.3390/ph8040696
      Issue No: Vol. 8, No. 4 (2015)
  • Pharmaceuticals, Vol. 8, Pages 711-757: Antimicrobial Peptides from Plants

    • Authors: James Tam, Shujing Wang, Ka Wong, Wei Tan
      Pages: 711 - 757
      Abstract: Plant antimicrobial peptides (AMPs) have evolved differently from AMPs from other life forms. They are generally rich in cysteine residues which form multiple disulfides. In turn, the disulfides cross-braced plant AMPs as cystine-rich peptides to confer them with extraordinary high chemical, thermal and proteolytic stability. The cystine-rich or commonly known as cysteine-rich peptides (CRPs) of plant AMPs are classified into families based on their sequence similarity, cysteine motifs that determine their distinctive disulfide bond patterns and tertiary structure fold. Cystine-rich plant AMP families include thionins, defensins, hevein-like peptides, knottin-type peptides (linear and cyclic), lipid transfer proteins, α-hairpinin and snakins family. In addition, there are AMPs which are rich in other amino acids. The ability of plant AMPs to organize into specific families with conserved structural folds that enable sequence variation of non-Cys residues encased in the same scaffold within a particular family to play multiple functions. Furthermore, the ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues. These properties bode well for developing plant AMPs as potential therapeutics and for protection of crops through transgenic methods. This review provides an overview of the major families of plant AMPs, including their structures, functions, and putative mechanisms.
      PubDate: 2015-11-16
      DOI: 10.3390/ph8040711
      Issue No: Vol. 8, No. 4 (2015)
  • Pharmaceuticals, Vol. 8, Pages 758-777: 29ièmes Journées
           Franco-Belges de Pharmacochimie: Meeting Report

    • Authors: The Committee
      Pages: 758 - 777
      Abstract: The “Journées Franco-Belges de Pharmacochimie” is a recognized two-day annual meeting on Medicinal Chemistry that is renowned for the advanced science presented, conviviality, and outstanding opportunities for senior and young scientists to exchange knowledge. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.
      PubDate: 2015-11-17
      DOI: 10.3390/ph8040758
      Issue No: Vol. 8, No. 4 (2015)
  • Pharmaceuticals, Vol. 8, Pages 778-792: Non-Monotonic Survival of
           Staphylococcus aureus with Respect to Ciprofloxacin Concentration Arises
           from Prophage-Dependent Killing of Persisters

    • Authors: Elizabeth Sandvik, Christopher Fazen, Theresa Henry, Wendy Mok, Mark Brynildsen
      Pages: 778 - 792
      Abstract: Staphylococcus aureus is a notorious pathogen with a propensity to cause chronic, non-healing wounds. Bacterial persisters have been implicated in the recalcitrance of S. aureus infections, and this motivated us to examine the persistence of S. aureus to ciprofloxacin, a quinolone antibiotic. Upon treatment of exponential phase S. aureus with ciprofloxacin, we observed that survival was a non-monotonic function of ciprofloxacin concentration. Maximal killing occurred at 1 µg/mL ciprofloxacin, which corresponded to survival that was up to ~40-fold lower than that obtained with concentrations ≥ 5 µg/mL. Investigation of this phenomenon revealed that the non-monotonic response was associated with prophage induction, which facilitated killing of S. aureus persisters. Elimination of prophage induction with tetracycline was found to prevent cell lysis and persister killing. We anticipate that these findings may be useful for the design of quinolone treatments.
      PubDate: 2015-11-17
      DOI: 10.3390/ph8040778
      Issue No: Vol. 8, No. 4 (2015)
  • Pharmaceuticals, Vol. 8, Pages 366-415: Peptides and Peptidomimetics for
           Antimicrobial Drug Design

    • Pages: 366 - 415
      Abstract: The purpose of this paper is to introduce and highlight a few classes of traditional antimicrobial peptides with a focus on structure-activity relationship studies. After first dissecting the important physiochemical properties that influence the antimicrobial and toxic properties of antimicrobial peptides, the contributions of individual amino acids with respect to the peptides antibacterial properties are presented. A brief discussion of the mechanisms of action of different antimicrobials as well as the development of bacterial resistance towards antimicrobial peptides follows. Finally, current efforts on novel design strategies and peptidomimetics are introduced to illustrate the importance of antimicrobial peptide research in the development of future antibiotics.
      PubDate: 2015-07-13
      DOI: 10.3390/ph8030366
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 416-434: Toxicological Studies of 212Pb

    • Pages: 416 - 434
      Abstract: Faced with the novelty of a 212Pb-labeled monoclonal antibody (mAb) for clinical translation, concerns were expressed by the Food and Drug Administration (FDA) regarding 212Pb prematurely released from the mAb-chelate conjugate. The objective of this study was to simulate the worst case scenario of such a failure. Groups of Balb/c mice (n = 9–20) were administered 212Pb by intraperitoneal (0.0925–1.85 MBq) or intravenous (0.0925–1.11 MBq) injection and then euthanized at 7 or 90 days to assess acute or chronic effects. Weights were recorded prior to injection of the 212Pb and at the end of the observation periods. Blood samples were collected for clinical chemistry and blood cell analysis. Thirty tissues were harvested and formalin fixed for histopathological examination. Treatment related effects of the 212Pb were observed in the bone marrow, spleen, kidneys and the liver. Histological alterations in these organs were considered mild to moderate, indicating low grade toxicity, and not considered severe enough to affect function. This data was presented to the FDA and determined to be acceptable. The clinical trial with 212Pb-TCMC-trastuzumab was approved in January 2011 and the trial opened at the University of Alabama at Birmingham (UAB) in July.
      PubDate: 2015-07-24
      DOI: 10.3390/ph8030416
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 435-454: Bench to Bedside: Stability
           Studies of GMP Produced Trastuzumab-TCMC in Support of a Clinical Trial

    • Authors: Diane Milenic, Kwamena Baidoo, Martin Brechbiel
      Pages: 435 - 454
      Abstract: The first-in-human phase 1 clinical radioimmunotherapy (RIT) trial with 212Pb-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane-trastuzumab (212Pb-TCMC-trastuzumab) was completed in October 2014 as a joint effort at the University of Alabama (UAB) and the University of California San Diego Moores Cancer Center. The preliminary reports indicate that after five dose-levels of intraperitoneally administered 212Pb-TCMC-trastuzumab, patients with carcinomatosis experienced minimal agent-related toxicity. This report presents the data accumulated to date on the stability of the clinical grade, produced according to current good manufacturing practices (cGMP), TCMC-trastuzumab conducted in support of that clinical trial. Of the eleven tests performed with the cGMP TCMC-trastuzumab all but one remained within specifications throughout the 5 year testing period. The protein concentration varied by 0.01 mg/mL at 48 months. Two other assays, ion-exchange high performance liquid chromatography (IEX-HPLC) and a competitive radioimmunoassay (RIA) indicated that the cGMP TCMC-trastuzumab integrity may be changing, although the change thus far is within specifications. Subsequent stability testing will confirm if a trend has truly developed. The cGMP TCMC-trastuzumab was also evaluated for tolerance to higher temperatures and the potential of storage at −80 °C. The immunoconjugate proved stable when subjected to the lower temperatures and to multiple freeze-thaw cycles. The size exclusion (SE) HPLC analysis of the 203Pb-TCMC-trastuzumab was the only indicator that cGMP TCMC-trastuzumab may be sensitive to storage at 37 °C for 3 months.
      PubDate: 2015-07-29
      DOI: 10.3390/ph8030435
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 455-473: On the Quest of Cellular Functions
           of PEA-15 and the Therapeutic Opportunities

    • Authors: Yufeng Wei
      Pages: 455 - 473
      Abstract: Phosphoprotein enriched in astrocytes, 15 KDa (PEA-15), a ubiquitously expressed small protein in all mammals, is known for decades for its potent interactions with various protein partners along distinct biological pathways. Most notable interacting partners of PEA-15 include extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the mitogen activated protein kinase (MAPK) pathway, the Fas-associated death domain (FADD) protein involving in the formation of the death-inducing signaling complex (DISC), and the phospholipase D1 (PLD1) affecting the insulin sensitivity. However, the actual cellular functions of PEA-15 are still mysterious, and the question why this protein is expressed in almost all cell and tissue types remains unanswered. Here we synthesize the most recent structural, biological, and clinical studies on PEA-15 with emphases on its anti-apoptotic, anti-proliferative, and anti-inflammative properties, and propose a converged protective role of PEA-15 that maintains the balance of death and survival in different cell types. Under conditions that this delicate balance is unsustainable, PEA-15 may become pathological and lead to various diseases, including cancers and diabetes. Targeting PEA-15 interactions, or the use of PEA-15 protein as therapeutics, may provide a wider window of opportunities to treat these diseases.
      PubDate: 2015-07-31
      DOI: 10.3390/ph8030455
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 474-482: UCP2 Modulates Cardioprotective
           Effects of Ru360 in Isolated Cardiomyocytes during Ischemia

    • Authors: Lukas Motloch, Sara Reda, Martin Wolny, Uta Hoppe
      Pages: 474 - 482
      Abstract: Introduction: Ruthenium 360 (Ru360) has been shown to induce cardioprotective mechanisms in perfused hearts. The agent is a specific blocker of the main cardiac mitochondrial uptake mechanism, the mitochondrial calcium uniporter (MCU). UCP2, a mitochondrial membrane protein, which influences cardiac ROS formation was reported to interact with the MCU. Methods: To prove whether Ru360 affects ischemic cell injury on the singular cell level, cell viability (CV) in isolated cardiomyocytes from wild type mice (WT) was measured in a model of pelleting hypoxia (PH). To explore a possible influence of UCP2 on cellular survival, as well as on Ru360 function, cardiomyocytes from UCP2−/− mice were investigated. Results: During PH, Ru360 significantly improved CV in WT cardiomyocytes (Control 26.32% ± 1.58% vs. PH 13.60% ± 1.20% vs. PH+Ru360 19.98% ± 0.98%, n = 6; p < 0.05). No differences in the rate of apoptosis were observed in UCP2−/− vs. WT. In UCP2−/− cardiomyocytes, Ru360 reduced the rate of cell death. However, the effect was less pronounced compared to WT cardiomyocytes. Conclusion: Ru360 significantly reduces hypoxic cell injury by preventing single cell apoptosis in WT cardiomyoctes. UCP2 does not affect cell survival in hypoxic cardiomyocytes, but it might modulate cardioprotective effects of Ru360 during ischemia.
      PubDate: 2015-08-04
      DOI: 10.3390/ph8030474
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 483-503: Antifungal Activity of 14-Helical
           β-Peptides against Planktonic Cells and Biofilms of Candida Species

    • Authors: Namrata Raman, Myung-Ryul Lee, David Lynn, Sean Palecek
      Pages: 483 - 503
      Abstract: Candida albicans is the most prevalent cause of fungal infections and treatment is further complicated by the formation of drug resistant biofilms, often on the surfaces of implanted medical devices. In recent years, the incidence of fungal infections by other pathogenic Candida species such as C. glabrata, C. parapsilosis and C. tropicalis has increased. Amphiphilic, helical β-peptide structural mimetics of natural antimicrobial α-peptides have been shown to exhibit specific planktonic antifungal and anti-biofilm formation activity against C. albicans in vitro. Here, we demonstrate that β-peptides are also active against clinically isolated and drug resistant strains of C. albicans and against other opportunistic Candida spp. Different Candida species were susceptible to β-peptides to varying degrees, with C. tropicalis being the most and C. glabrata being the least susceptible. β-peptide hydrophobicity directly correlated with antifungal activity against all the Candida clinical strains and species tested. While β-peptides were largely ineffective at disrupting existing Candida biofilms, hydrophobic β-peptides were able to prevent the formation of C. albicans, C. glabrata, C. parapsilosis and C. tropicalis biofilms. The broad-spectrum antifungal activity of β-peptides against planktonic cells and in preventing biofilm formation suggests the promise of this class of molecules as therapeutics.
      PubDate: 2015-08-13
      DOI: 10.3390/ph8030483
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 504-511: Prospects for Anti-Biofilm

    • Authors: Philip Stewart
      Pages: 504 - 511
      Abstract: This commentary highlights several avenues currently being pursued in research labs to the development of new anti-biofilm pharmaceuticals. There is a real need for alternative therapeutic modalities for treating the persistent infections that sometimes form on implanted medical devices or compromised niches within the body. Strategies being researched include discovering new antimicrobial agents that kill microorganisms in biofilms more effectively than do existing antibiotics, designing drugs that block microbial adhesion or interfere with intercellular communication, developing chemistries to disperse biofilms, and combining agents with different mechanisms of action. Though the need is great, the pathway to commercialization of new drugs is steep. One possible streamlined approach to navigating the regulatory approval process is to repurpose old drugs, a strategy that a few groups have shown can yield agents with anti-biofilm properties.
      PubDate: 2015-08-27
      DOI: 10.3390/ph8030504
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 512-524: Use of Cyclo-Oxygenase Inhibitors
           Is Not Associated with Clinical Relapse in Inflammatory Bowel Disease: A
           Case-Control Study

    • Authors: Abigail Hensley, Ian Beales
      Pages: 512 - 524
      Abstract: Patients with inflammatory bowel disease (IBD) often have associated conditions, for which anti-inflammatory medication with cyclo-oxygenase (COX) inhibitors may be helpful. The current evidence is conflicting regarding the role of COX-inhibitors in causing relapse in IBD. This case-control study examined the association between the use of COX inhibitors and relapse of IBD. Logistic regression was used to analyse the relationship between COX-inhibitors and IBD relapse. Overall COX inhibitor use (combined non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 agents) had a negative association with relapse of IBD (adjusted OR 0.26, 95% CI 0.09–0.80). This negative association was confined to ulcerative colitis (UC) (adjusted OR = 0.06, 95% CI 0.01–0.50) and no association was found in Crohn’s disease (CD) patients (adjusted OR 1.25, 95% CI 0.18–7.46). The significant negative association between UC relapse and medication use was also seen with non-specific NSAIDs. Selective COX-2 inhibitor use was rare but non-significantly more common in stable patients. There was no association between low-dose aspirin or paracetamol use and relapse of CD or UC. We conclude that COX-inhibitor use was not associated with an increased risk of relapse in UC or CD, and may be protective in UC. Where indicated, NSAIDs should not be withheld from IBD patients.
      PubDate: 2015-09-07
      DOI: 10.3390/ph8030512
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 525-558: Ecology of Anti-Biofilm Agents I:
           Antibiotics versus Bacteriophages

    • Authors: Stephen Abedon
      Pages: 525 - 558
      Abstract: Bacteriophages, the viruses that infect bacteria, have for decades been successfully used to combat antibiotic-resistant, chronic bacterial infections, many of which are likely biofilm associated. Antibiotics as anti-biofilm agents can, by contrast, be inefficacious against even genetically sensitive targets. Such deficiencies in usefulness may result from antibiotics, as naturally occurring compounds, not serving their producers, in nature, as stand-alone disruptors of mature biofilms. Anti-biofilm effectiveness by phages, by contrast, may result from a combination of inherent abilities to concentrate lytic antibacterial activity intracellularly via bacterial infection and extracellularly via localized population growth. Considered here is the anti-biofilm activity of microorganisms, with a case presented for why, ecologically, bacteriophages can be more efficacious than traditional antibiotics as medically or environmentally applied biofilm-disrupting agents. Four criteria, it can be argued, generally must be met, in combination, for microorganisms to eradicate biofilms: (1) Furnishing of sufficiently effective antibacterial factors, (2) intimate interaction with biofilm bacteria over extended periods, (3) associated ability to concentrate antibacterial factors in or around targets, and, ultimately, (4) a means of physically disrupting or displacing target bacteria. In nature, lytic predators of bacteria likely can meet these criteria whereas antibiotic production, in and of itself, largely may not.
      PubDate: 2015-09-09
      DOI: 10.3390/ph8030525
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 559-589: Ecology of Anti-Biofilm Agents II:
           Bacteriophage Exploitation and Biocontrol of Biofilm Bacteria

    • Authors: Stephen Abedon
      Pages: 559 - 589
      Abstract: Bacteriophages are the viruses of bacteria. In the guise of phage therapy they have been used for decades to successfully treat what are probable biofilm-containing chronic bacterial infections. More recently, phage treatment or biocontrol of biofilm bacteria has been brought back to the laboratory for more rigorous assessment as well as towards the use of phages to combat environmental biofilms, ones other than those directly associated with bacterial infections. Considered in a companion article is the inherent ecological utility of bacteriophages versus antibiotics as anti-biofilm agents. Discussed here is a model for phage ecological interaction with bacteria as they may occur across biofilm-containing ecosystems. Specifically, to the extent that individual bacterial types are not highly abundant within biofilm-containing environments, then phage exploitation of those bacteria may represent a “Feast-or-famine” existence in which infection of highly localized concentrations of phage-sensitive bacteria alternate with treacherous searches by the resulting phage progeny virions for new concentrations of phage-sensitive bacteria to infect. An updated synopsis of the literature concerning laboratory testing of phage use to combat bacterial biofilms is then provided along with tips on how “Ecologically” such phage-mediated biofilm control can be modified to more reliably achieve anti-biofilm efficacy.
      PubDate: 2015-09-09
      DOI: 10.3390/ph8030559
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 590-606: Potential of Glutamate-Based Drug
           Discovery for Next Generation Antidepressants

    • Authors: Shigeyuki Chaki, Kenichi Fukumoto
      Pages: 590 - 606
      Abstract: Recently, ketamine has been demonstrated to exert rapid-acting antidepressant effects in patients with depression, including those with treatment-resistant depression, and this discovery has been regarded as the most significant advance in drug development for the treatment of depression in over 50 years. To overcome unwanted side effects of ketamine, numerous approaches targeting glutamatergic systems have been vigorously investigated. For example, among agents targeting the NMDA receptor, the efficacies of selective GluN2B receptor antagonists and a low-trapping antagonist, as well as glycine site modulators such as GLYX-13 and sarcosine have been demonstrated clinically. Moreover, agents acting on metabotropic glutamate receptors, such as mGlu2/3 and mGlu5 receptors, have been proposed as useful approaches to mimicking the antidepressant effects of ketamine. Neural and synaptic mechanisms mediated through the antidepressant effects of ketamine have been being delineated, most of which indicate that ketamine improves abnormalities in synaptic transmission and connectivity observed in depressive states via the AMPA receptor and brain-derived neurotrophic factor-dependent mechanisms. Interestingly, some of the above agents may share some neural and synaptic mechanisms with ketamine. These studies should provide important insights for the development of superior pharmacotherapies for depression with more potent and faster onsets of actions.
      PubDate: 2015-09-17
      DOI: 10.3390/ph8030590
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 607-636: Novel Targeted Agents in Hodgkin
           and Non-Hodgkin Lymphoma Therapy

    • Authors: Natalie Grover, Steven Park
      Pages: 607 - 636
      Abstract: There has been a recent emergence of novel targeted agents for treatment of Hodgkin and non-Hodgkin lymphoma. In particular, antibodies and antibody-drug conjugates directed against surface antigens, agents that block immune checkpoint pathways, and small molecule inhibitors directed against cell signaling pathways have shown significant promise in patients with relapsed and refractory disease and in the frontline setting. With the development of these new therapies, cytotoxic chemotherapy may be avoided entirely in some clinical settings. This review will present the latest information on these novel treatments in Hodgkin and non-Hodgkin lymphoma and will discuss both recently approved agents as well as drugs currently being studied in clinical trials.
      PubDate: 2015-09-17
      DOI: 10.3390/ph8030607
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 637-663: Pharmacogenomics Implications of

    • Authors: Nicholas Thomford, Kevin Dzobo, Denis Chopera, Ambroise Wonkam, Michelle Skelton, Dee Blackhurst, Shadreck Chirikure, Collet Dandara
      Pages: 637 - 663
      Abstract: The most accessible points of call for most African populations with respect to primary health care are traditional health systems that include spiritual, religious, and herbal medicine. This review focusses only on the use of herbal medicines. Most African people accept herbal medicines as generally safe with no serious adverse effects. However, the overlap between conventional medicine and herbal medicine is a reality among countries in health systems transition. Patients often simultaneously seek treatment from both conventional and traditional health systems for the same condition. Commonly encountered conditions/diseases include malaria, HIV/AIDS, hypertension, tuberculosis, and bleeding disorders. It is therefore imperative to understand the modes of interaction between different drugs from conventional and traditional health care systems when used in treatment combinations. Both conventional and traditional drug entities are metabolized by the same enzyme systems in the human body, resulting in both pharmacokinetics and pharmacodynamics interactions, whose properties remain unknown/unquantified. Thus, it is important that profiles of interaction between different herbal and conventional medicines be evaluated. This review evaluates herbal and conventional drugs in a few African countries and their potential interaction at the pharmacogenomics level.
      PubDate: 2015-09-21
      DOI: 10.3390/ph8030637
      Issue No: Vol. 8, No. 3 (2015)
  • Pharmaceuticals, Vol. 8, Pages 151-175: Reactive Oxygen Species,
           Apoptosis, Antimicrobial Peptides and Human Inflammatory Diseases

    • Authors: Babatunji Oyinloye, Abiola Adenowo, Abidemi Kappo
      Pages: 151 - 175
      Abstract: Excessive free radical generation, especially reactive oxygen species (ROS) leading to oxidative stress in the biological system, has been implicated in the pathogenesis and pathological conditions associated with diverse human inflammatory diseases (HIDs). Although inflammation which is considered advantageous is a defensive mechanism in response to xenobiotics and foreign pathogen; as a result of cellular damage arising from oxidative stress, if uncontrolled, it may degenerate to chronic inflammation when the ROS levels exceed the antioxidant capacity. Therefore, in the normal resolution of inflammatory reactions, apoptosis is acknowledged to play a crucial role, while on the other hand, dysregulation in the induction of apoptosis by enhanced ROS production could also result in excessive apoptosis identified in the pathogenesis of HIDs. Apparently, a careful balance must be maintained in this complex environment. Antimicrobial peptides (AMPs) have been proposed in this review as an excellent candidate capable of playing prominent roles in maintaining this balance. Consequently, in novel drug design for the treatment and management of HIDs, AMPs are promising candidates owing to their size and multidimensional properties as well as their wide spectrum of activities and indications of reduced rate of resistance.
      PubDate: 2015-04-02
      DOI: 10.3390/ph8020151
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 176-185: Edaravone Enhances Brain-Derived
           Neurotrophic Factor Production in the Ischemic Mouse Brain

    • Authors: Satoshi Okuyama, Mayu Morita, Atsushi Sawamoto, Tsukasa Terugo, Mitsunari Nakajima, Yoshiko Furukawa
      Pages: 176 - 185
      Abstract: Edaravone, a clinical drug used to treat strokes, protects against neuronal cell death and memory loss in the ischemic brains of animal models through its antioxidant activity. In the present study, we subcutaneously administrated edaravone to mice (3 mg/kg/day) for three days immediately after bilateral common carotid artery occlusion, and revealed through an immunohistochemical analysis that edaravone (1) accelerated increases in the production of brain-derived neurotrophic factor (BDNF) in the hippocampus; (2) increased the number of doublecortin-positive neuronal precursor cells in the dentate gyrus subgranular zone; and (3) suppressed the ischemia-induced inactivation of calcium-calmodulin-dependent protein kinase II in the hippocampus. We also revealed through a Western blotting analysis that edaravone (4) induced the phosphorylation of cAMP response element-binding (CREB), a transcription factor that regulates BDNF gene expression; and (5) induced the phosphorylation of extracellular signal-regulated kinases 1/2, an upstream signal factor of CREB. These results suggest that the neuroprotective effects of edaravone following brain ischemia were mediated not only by the elimination of oxidative stress, but also by the induction of BDNF production.
      PubDate: 2015-04-02
      DOI: 10.3390/ph8020176
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 186-195: Does Amifostine Reduce Metabolic
           Rate' Effect of the Drug on Gas Exchange and Acute Ventilatory Hypoxic
           Response in Humans

    • Authors: Jaideep Pandit, Caroline Allen, Evelyn Little, Federico Formenti, Adrian Harris, Peter Robbins
      Pages: 186 - 195
      Abstract: Amifostine is added to chemoradiation regimens in the treatment of many cancers on the basis that, by reducing the metabolic rate, it protects normal cells from toxic effects of therapy. We tested this hypothesis by measuring the metabolic rate (by gas exchange) over 255 min in 6 healthy subjects, at two doses (500 mg and 1000 mg) of amifostine infused over 15 min at the start of the protocol. We also assessed the ventilatory response to six 1 min exposures to isocapnic hypoxia mid-protocol. There was no change in metabolic rate with amifostine as measured by oxygen uptake (p = 0.113). However in carbon dioxide output and respiratory quotient, we detected a small decline over time in control and drug protocols, consistent with a gradual change from carbohydrate to fat metabolism over the course of the relatively long study protocol. A novel result was that amifostine (1000 mg) increased the mean ± SD acute hypoxic ventilatory response from 12.4 ± 5.1 L/min to 20.3 ± 11.9 L/min (p = 0.045). In conclusion, any cellular protective effects of amifostine are unlikely due to metabolic effects. The stimulatory effect on hypoxic ventilatory responses may be due to increased levels of hypoxia inducible factor, either peripherally in the carotid body, or centrally in the brain.
      PubDate: 2015-04-16
      DOI: 10.3390/ph8020186
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 196-220: Wharton’s Jelly-Derived
           Mesenchymal Stromal Cells as a Promising Cellular Therapeutic Strategy for
           the Management of Graft-versus-Host Disease

    • Authors: Joseph McGuirk, J. Smith, Clint Divine, Micheal Zuniga, Mark Weiss
      Pages: 196 - 220
      Abstract: Allogeneic hematopoietic cell transplantation (allo-HCT), a treatment option in hematologic malignancies and bone marrow failure syndromes, is frequently complicated by Graft-versus-host disease (GVHD). The primary treatment for GVHD involves immune suppression by glucocorticoids. However, patients are often refractory to the steroid therapy, and this results in a poor prognosis. Therefore alternative therapies are needed to treat GVHD. Here, we review data supporting the clinical investigation of a novel cellular therapy using Wharton’s jelly (WJ)-derived mesenchymal stromal cells (MSCs) as a potentially safe and effective therapeutic strategy in the management of GVHD. Adult-derived sources of MSCs have demonstrated signals of efficacy in the management of GVHD. However, there are limitations, including: limited proliferation capacity; heterogeneity of cell sources; lengthy expansion time to clinical dose; expansion failure in vitro; and a painful, invasive, isolation procedure for the donor. Therefore, alternative MSC sources for cellular therapy are sought. The reviewed data suggests MSCs derived from WJ may be a safe and effective cellular therapy for GVHD. Laboratories investigated and defined the immune properties of WJ-MSCs for potential use in cellular therapy. These cells represent a more uniform cell population than bone marrow-derived MSCs, displaying robust immunosuppressive properties and lacking significant immunogenicity. They can be collected safely and painlessly from individuals at birth, rapidly expanded and stored cryogenically for later clinical use. Additionally, data we reviewed suggested licensing MSCs (activating MSCs by exposure to cytokines) to enhance effectiveness in treating GVHD. Therefore, WJCs should be tested as a second generation, relatively homogeneous allogeneic cell therapy for the treatment of GVHD.
      PubDate: 2015-04-16
      DOI: 10.3390/ph8020196
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 221-229: Design and Synthesis of Novel
           N-Arylsulfonyl-3-(2-yl-ethanone)-6-methylindole Derivatives as Inhibitors
           of HIV-1 Replication

    • Authors: Zhiping Che, Shengming Liu, Yuee Tian, Zhenjie Hu, Yingwu Chen, Genqiang Chen
      Pages: 221 - 229
      Abstract: Seven novel N-arylsulfonyl-3-(2-yl-ethanone)-6-methylindole derivatives 4a–f and 6 were readily synthesized and have been identified as inhibitors of human immunodeficiency virus type-1 (HIV-1) replication. Initial biological studies indicated that among these derivatives, N-(p-ethyl)phenylsulfonyl-3-[2-morpholinoethanone]-6-methylindole (4f) and N-(p-ethyl)phenylsulfonyl-3-[2-(5-phenyl-1,3,4-oxadiazole-2-yl-thio)ethanone]-6-methylindole (6) showed the most promising activity against HIV-1 replication. The effective concentration (EC50) and therapeutic index (TI) values of 4f and 6 were 9.42/4.62 μM, and >49.77/66.95, respectively. The cytotoxicity of these compounds has also been assessed. No significant cytotoxicities were found for any of these compounds.
      PubDate: 2015-05-08
      DOI: 10.3390/ph8020221
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 230-249: Seatbelts in CAR therapy: How Safe
           Are CARS'

    • Authors: Kentaro Minagawa, Xiaoou Zhou, Shin Mineishi, Antonio Di Stasi
      Pages: 230 - 249
      Abstract: T-cells genetically redirected with a chimeric antigen receptor (CAR) to recognize tumor antigens and kill tumor cells have been infused in several phase 1 clinical trials with success. Due to safety concerns related to on-target/off-tumor effects or cytokine release syndrome, however, strategies to prevent or abate serious adverse events are required. Pharmacologic therapies; suicide genes; or novel strategies to limit the cytotoxic effect only to malignant cells are under active investigations. In this review, we summarize results and toxicities of investigations employing CAR redirected T-cells, with a focus on published strategies to grant safety of this promising cellular application.
      PubDate: 2015-05-08
      DOI: 10.3390/ph8020230
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 250-256: Immunotherapeutic Applications of
           NK Cells

    • Authors: Carter Davis, David Rizzieri
      Pages: 250 - 256
      Abstract: Natural Killer (NK) cells are lymphoid cells that exhibit an innate response against virus-infected cells. These cells are also capable of mounting an immune response against tumor cells after education through major histocompatibility complex (MHC) class I molecules. NK cell regulation is mediated through IFN-gamma and IL-15, important cytokines which can drive NK cell expansion in vivo. Previous studies have shown effective infusion of allogeneic NK cells after lymphodepleting regimens with induction of remission of poor prognosis acute myeloid leukemia (AML). Challenges remain in the expansion of these NK cells once infused and in their education to recognize tumor targets. A principal mechanism of tumor recognition is through KIR mismatch in cells lacking self MHC I molecules. Activating KIRs exist, though their ligands are unknown at this time. Impacting NK cell expansion and education in vivo has been challenging, and thus far clinical applications of NK cells have shown promise in helping to maintain remission in humans, though this remission has not been maintained. Future efforts to utilize NK cells clinically are focusing on developing more consistency in successful expansion of NK cell and educating them to recognize their tumor targets. Additional efforts to utilize novel antibody-based therapy to engage NK cells to their tumor targets are also in development.
      PubDate: 2015-05-25
      DOI: 10.3390/ph8020250
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 257-276: Microwave-Assisted Synthesis of a
           MK2 Inhibitor by Suzuki-Miyaura Coupling for Study in Werner Syndrome

    • Authors: Mark Bagley, Mohammed Baashen, Irina Chuckowree, Jessica Dwyer, David Kipling, Terence Davis
      Pages: 257 - 276
      Abstract: Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells.
      PubDate: 2015-06-03
      DOI: 10.3390/ph8020257
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 277-278: Pharmaceuticals Best Paper Award

    • Authors: Jean Eynde
      Pages: 277 - 278
      Abstract: It is always a difficult task for a jury to classify articles from a selection of outstanding manuscripts. [...]
      PubDate: 2015-06-05
      DOI: 10.3390/ph8020277
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 279-302: Synthesis, Biological Evaluation
           and Molecular Modeling of Substituted Indeno[1,2-b]indoles as Inhibitors
           of Human Protein Kinase CK2

    • Pages: 279 - 302
      Abstract: Due to their system of annulated 6-5-5-6-membered rings, indenoindoles have sparked great interest for the design of ATP-competitive inhibitors of human CK2. In the present study, we prepared twenty-one indeno[1,2-b]indole derivatives, all of which were tested in vitro on human CK2. The indenoindolones 5a and 5b inhibited human CK2 with an IC50 of 0.17 and 0.61 µM, respectively. The indeno[1,2-b]indoloquinone 7a also showed inhibitory activity on CK2 at a submicromolar range (IC50 = 0.43 µM). Additionally, a large number of indenoindole derivatives was evaluated for their cytotoxic activities against the cell lines 3T3, WI-38, HEK293T and MEF.
      PubDate: 2015-06-08
      DOI: 10.3390/ph8020279
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 303-320: X-Linked Dilated Cardiomyopathy: A
           Cardiospecific Phenotype of Dystrophinopathy

    • Authors: Akinori Nakamura
      Pages: 303 - 320
      Abstract: X-linked dilated cardiomyopathy (XLDCM) is a distinct phenotype of dystrophinopathy characterized by preferential cardiac involvement without any overt skeletal myopathy. XLDCM is caused by mutations of the Duchenne muscular dystrophy (DMD) gene and results in lethal heart failure in individuals between 10 and 20 years. Patients with Becker muscular dystrophy, an allelic disorder, have a milder phenotype of skeletal muscle involvement compared to Duchenne muscular dystrophy (DMD) and sometimes present with dilated cardiomyopathy. The precise relationship between mutations in the DMD gene and cardiomyopathy remain unclear. However, some hypothetical mechanisms are being considered to be associated with the presence of some several dystrophin isoforms, certain reported mutations, and an unknown dystrophin-related pathophysiological mechanism. Recent therapy for Duchenne muscular dystrophy, the severe dystrophinopathy phenotype, appears promising, but the presence of XLDCM highlights the importance of focusing on cardiomyopathy while elucidating the pathomechanism and developing treatment.
      PubDate: 2015-06-09
      DOI: 10.3390/ph8020303
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 321-336: A Critical Review of Alpha
           Radionuclide Therapy—How to Deal with Recoiling Daughters'

    • Authors: Robin de Kruijff, Hubert Wolterbeek, Antonia Denkova
      Pages: 321 - 336
      Abstract: This review presents an overview of the successes and challenges currently faced in alpha radionuclide therapy. Alpha particles have an advantage in killing tumour cells as compared to beta or gamma radiation due to their short penetration depth and high linear energy transfer (LET). Touching briefly on the clinical successes of radionuclides emitting only one alpha particle, the main focus of this article lies on those alpha-emitting radionuclides with multiple alpha-emitting daughters in their decay chain. While having the advantage of longer half-lives, the recoiled daughters of radionuclides like 224Ra (radium), 223Ra, and 225Ac (actinium) can do significant damage to healthy tissue when not retained at the tumour site. Three different approaches to deal with this problem are discussed: encapsulation in a nano-carrier, fast uptake of the alpha emitting radionuclides in tumour cells, and local administration. Each approach has been shown to have its advantages and disadvantages, but when larger activities need to be used clinically, nano-carriers appear to be the most promising solution for reducing toxic effects, provided there is no accumulation in healthy tissue.
      PubDate: 2015-06-10
      DOI: 10.3390/ph8020321
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 337-350: Tryptophan Breakdown in Patients
           with HCV Infection is Influenced by IL28B Polymorphism

    • Authors: Heinz Zoller, Annina Jenal, Albert Staettermayer, Sebastian Schroecksnadel, Peter Ferenci, Dietmar Fuchs
      Pages: 337 - 350
      Abstract: Until recently, the standard treatment of chronic hepatitis C virus (HCV) infection was a combination therapy with PEG-IFN-α plus ribavirin. Previous studies have proven that several markers predict the outcome of such therapy, e.g., pretreatment plasma levels of interferon inducible protein IP-10, HCV RNA and IL28B-related single nucleotide polymorphisms (SNP). Altered activity of tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) has been also shown in patients suffering from HCV infection. In this study, we investigated whether IL28B SNP in patients infected with HCV is related to the tryptophan breakdown rate. Before therapy, serum tryptophan and kynurenine concentrations were determined in 25 patients with established HCV infection and the kynurenine to tryptophan ratio (KYN/TRP) was calculated as an estimate of the tryptophan breakdown rate. In parallel, neopterin and nitrite concentrations were determined. A significant difference of serum KYN/TRP existed between the three IL28B polymorphism groups: C/C genotype had the highest and T/T genotype had the lowest KYN/TRP (p < 0.05). Likewise, C/C genotype was associated with higher KYN/TRP than non-C/C genotype (p = 0.01). There was a smaller difference between the three groups regarding the absolute kynurenine concentrations, the C/C genotype being associated with higher kynurenine concentrations. None of the other comparisons revealed any statistical significance. In conclusion, patients with C/C genotype presented with the highest tryptophan breakdown rate already before antiretroviral therapy with IFN-α/ribavirin. The differences in tryptophan metabolism might relate to HCV clearance and also to side effects of IFN-α therapy.
      PubDate: 2015-06-18
      DOI: 10.3390/ph8020337
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 351-365: Effects of a Formula Containing
           Two Types of Prebiotics, Bifidogenic Growth Stimulator and
           Galacto-oligosaccharide, and Fermented Milk Products on Intestinal
           Microbiota and Antibody Response to Influenza Vaccine in Elderly Patients:
           A Randomized Controlled Trial

    • Authors: Shinya Nagafuchi, Taketo Yamaji, Akihiro Kawashima, Yukiko Saito, Takeshi Takahashi, Takayuki Yamamoto, Mitsuo Maruyama, Hiroyasu Akatsu
      Pages: 351 - 365
      Abstract: We investigated the effect of a formula containing two different prebiotics (bifidogenic growth stimulator and galacto-oligosaccharide) and fermented milk products on intestinal microbiota and antibody responses to an influenza vaccine in enterally fed elderly in-patients. Patients were administered either formula containing prebiotics and fermented milk products (group F: n = 12, 79.9 ± 9.5 years old) or standard formula (group C: n = 12, 80.7 ± 10.1 years old) via percutaneous endoscopic gastrostomy during a 14-week intervention period. Subjects were immunized with an influenza vaccine (A/H1N1, A/H3N2, and B) at week 4 of the intervention. Blood biochemical indices, intestinal bacteria populations and antibody titers were analyzed. Bifidobacterium counts increased significantly in group F compared with group C. The enhanced antibody titers against A/H1N1 were maintained in group F for a longer period compared with group C. The titers against A/H3N2 were unchanged between both groups, and those against B were significantly lower in group F than in group C, although few subjects had seroprotective titers against A/H3N2 and B. These results suggest that administration of the formula containing prebiotics and fermented milk products may maintain antibody titers for longer periods through the improvement of intestinal microbiota.
      PubDate: 2015-06-18
      DOI: 10.3390/ph8020351
      Issue No: Vol. 8, No. 2 (2015)
  • Pharmaceuticals, Vol. 8, Pages 38-39: Acknowledgement to Reviewers of
           Pharmaceuticals in 2014

    • Authors: Pharmaceuticals Office
      Pages: 38 - 39
      Abstract: The editors of Pharmaceuticals would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2014:[...]
      PubDate: 2015-01-08
      DOI: 10.3390/ph8010038
      Issue No: Vol. 8, No. 1 (2015)
  • Pharmaceuticals, Vol. 8, Pages 40-61: γδ T Cell
           Immunotherapy—A Review

    • Authors: Hirohito Kobayashi, Yoshimasa Tanaka
      Pages: 40 - 61
      Abstract: Cancer immunotherapy utilizing Vγ9Vδ2 T cells has been developed over the past decade. A large number of clinical trials have been conducted on various types of solid tumors as well as hematological malignancies. Vγ9Vδ2 T cell-based immunotherapy can be classified into two categories based on the methods of activation and expansion of these cells. Although the in vivo expansion of Vγ9Vδ2 T cells by phosphoantigens or nitrogen-containing bisphosphonates (N-bis) has been translated to early-phase clinical trials, in which the safety of the treatment was confirmed, problems such as activation-induced Vγ9Vδ2 T cell anergy and a decrease in the number of peripheral blood Vγ9Vδ2 T cells after infusion of these stimulants have not yet been solved. In addition, it is difficult to ex vivo expand Vγ9Vδ2 T cells from advanced cancer patients with decreased initial numbers of peripheral blood Vγ9Vδ2 T cells. In this article, we review the clinical studies and reports targeting Vγ9Vδ2 T cells and discuss the development and improvement of Vγ9Vδ2 T cell-based cancer immunotherapy.
      PubDate: 2015-02-12
      DOI: 10.3390/ph8010040
      Issue No: Vol. 8, No. 1 (2015)
  • Pharmaceuticals, Vol. 8, Pages 62-106: Hitting the Bull’s-Eye in
           Metastatic Cancers—NSAIDs Elevate ROS in Mitochondria, Inducing
           Malignant Cell Death

    • Pages: 62 - 106
      Abstract: Tumor metastases that impede the function of vital organs are a major cause of cancer related mortality. Mitochondrial oxidative stress induced by hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary tumors to enhance their progression to metastasis. Emerging evidence now indicates that mitochondrial modifications and mutations resulting from oxidative stress, and leading to OxPhos stimulation and/or enhanced reactive oxygen species (ROS) production, are essential for promoting and sustaining the highly metastatic phenotype. Moreover, the modified mitochondria in emerging or existing metastatic cancer cells, by their irreversible differences, provide opportunities for selectively targeting their mitochondrial functions with a one-two punch. The first blow would block their anti-oxidative defense, followed by the knockout blow—promoting production of excess ROS, capitulating the terminal stage—activation of the mitochondrial permeability transition pore (mPTP), specifically killing metastatic cancer cells or their precursors. This review links a wide area of research relevant to cellular mechanisms that affect mitochondria activity as a major source of ROS production driving the pro-oxidative state in metastatic cancer cells. Each of the important aspects affecting mitochondrial function are discussed including: hypoxia, HIFs and PGC1 induced metabolic changes, increased ROS production to induce a more pro-oxidative state with reduced antioxidant defenses. It then focuses on how the mitochondria, as a major source of ROS in metastatic cancer cells driving the pro-oxidative state of malignancy enables targeting drugs affecting many of these altered processes and why the NSAIDs are an excellent example of mitochondria-targeted agents that provide a one-two knockout activating the mPTP and their efficacy as selective anticancer metastasis drugs.
      PubDate: 2015-02-13
      DOI: 10.3390/ph8010062
      Issue No: Vol. 8, No. 1 (2015)
  • Pharmaceuticals, Vol. 8, Pages 107-122: A Retrospective Study of the
           Impact of 21-Gene Recurrence Score Assay on Treatment Choice in Node
           Positive Micrometastatic Breast Cancer

    • Authors: Thomas Frazier, Kevin Fox, J. Smith, Christine Laronga, Anita McSwain, Devchand Paul, Michael Schultz, Joseph Stilwill, Christine Teal, Tracey Weisberg, Judith Vacchino, Amy Sing, Dasha Cherepanov, Wendy Hsiao, Eunice Chang, Michael Broder
      Pages: 107 - 122
      Abstract: To assess clinical utility of the 21-gene assay (Oncotype DX® Recurrence Score®), we determined whether women with HER2(−)/ER+ pN1mi breast cancer with low (<18) Recurrence Scores results are given adjuvant chemotherapy in a lower proportion than those with high scores (≥31). This was a multicenter chart review of ≥18 year old women with pN1mi breast cancer, HER2(−)/ER+ tumors, ductal/lobular/mixed histology, with the assay ordered on or after 1 January 2007. One hundred and eighty one patients had a mean age of 60.7 years; 82.9% had ECOG performance status 0; 33.7% had hypertension, 22.7% had osteoporosis, 18.8% had osteoarthritis, and 8.8% had type-2 diabetes. Mean Recurrence Score was 17.8 (range: 0–50). 48.6% had a mastectomy; 55.8% had a lumpectomy. 19.8% of low-risk group patients were recommended chemotherapy vs. 57.9% in the intermediate-risk group and 100% in the high-risk group (p < 0.001). A total of 80.2% of the low-risk group were recommended endocrine therapy alone, while 77.8% of the high-risk group were recommended both endocrine and chemotherapy (p < 0.001). The Oncotype DX Recurrence Score result provides actionable information that can be incorporated into treatment planning for women with HER2(−)/ER+ pN1mi breast cancer. The Recurrence Score result has clinical utility in treatment planning for HER2(−)/ER+ pN1mi breast cancer patients.
      PubDate: 2015-03-17
      DOI: 10.3390/ph8010107
      Issue No: Vol. 8, No. 1 (2015)
  • Pharmaceuticals, Vol. 8, Pages 123-150: Antimicrobial Peptides in 2014

    • Authors: Guangshun Wang, Biswajit Mishra, Kyle Lau, Tamara Lushnikova, Radha Golla, Xiuqing Wang
      Pages: 123 - 150
      Abstract: This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms.
      PubDate: 2015-03-23
      DOI: 10.3390/ph8010123
      Issue No: Vol. 8, No. 1 (2015)
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